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Melanoma Research: 2002-2006
     
Skinmed. 2006 Nov-Dec;5(6):271-6.
Phase 2 Trial of the Continuous IV Administration of Interferon-beta in Patients With Disseminated Malignant Melanoma.
Voelter-Mahlknecht S, Mahlknecht U, Letzel S, Fierlbeck G.
University of Mainz, Department of Occupational, Social and Environmental Medicine, Mainz, Germany; the University of Tubingen, Department of Dermatology, Tubingen, Germany voelterm@uni-mainz.de.

Background: Interferons have been reported to significantly contribute to tumor suppression via both induction of p53 gene expression and inhibition of angiogenesis. Objective: The assessment of treatment toxicity and antitumoral effectiveness of continuous IV administration of interferon-beta based on an overall evaluation of laboratory, radiographic, and clinical parameters observed during the trial. Methods: The authors treated patients with advanced malignant melanoma with continuous IV infusions of 1 x 106 IU interferon-beta daily ( approximately 0.6 x 106 IU interferon-beta/m2 daily). Results: Continuous IV administration of interferon-beta had no significant effect on overall patient outcome. Interferon side effects were not a reason for treatment discontinuation in any of the patients observed during this trial. Conclusions: Continuous IV interferon-beta had no significant effect on overall patient outcome in a group of patients with advanced malignant melanoma. To our knowledge, this is the first report on the continuous IV administration of interferon-beta in patients with advanced malignant melanoma.

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Lancet Oncol. 2006 Nov;7(11):919-24.
Complete metastasectomy in patients with stage IV metastatic melanoma.
Ollila DW.
Division of Surgical Oncology and Endocrine Surgery, University of North Carolina at Chapel Hill School of Medicine, 3010 Old Clinic Building, Chapel Hill, NC 27599, USA.

Patients with stage IV melanoma have traditionally been managed with various systemic treatments; however, overall survival with this approach has been disappointing. Findings of many retrospective, single-institution, and multicentre studies suggest that participants treated with complete metastasectomy for stage IV metastases have enhanced overall 5-year survival. Complete surgical resection of metastatic disease to stage IV sites-including skin, soft tissue, distant lymph nodes, lungs, or other non-CNS visceral regions-offers the best chance for prolonged survival. This Review will present data lending support to the idea that if complete surgical metastasectomy is technically feasible, then surgery should be the first option for properly selected patients with stage IV melanoma.

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J Clin Oncol. 2006 Nov 1;24(31):5060-9.
Phase I study of adoptive T-cell therapy using antigen-specific CD8+ T cells for the treatment of patients with metastatic melanoma.
Mackensen A, Meidenbauer N, Vogl S, Laumer M, Berger J, Andreesen R.
Department of Hematology/Oncology, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93042 Regensburg, Germany. andreas.mackensen@klinik.uni-regensburg.de

PURPOSE: The adoptive transfer of in vitro generated tumor antigen-specific cytotoxic T lymphocytes (CTL) provides a promising approach to the immunotherapy of cancer. A phase I study was conducted to test the feasibility, safety, and survival of adoptively transferred Melan-A-specific CTL lines in melanoma patients. PATIENTS AND METHODS: Eleven HLA-A2+ patients with metastatic melanoma received at least three intravenous infusions of Melan-A-specific CTL at 2-week intervals. CTL were generated by four rounds of in vitro stimulation of purified CD8+ peripheral blood lymphocytes with autologous dendritic cells pulsed with an HLA-A2 binding Melan-A peptide. Each T-cell infusion was accompanied by a 6-day course of low-dose interleukin-2. RESULTS: A total of 52 T-cell infusions were administered, averaging 2.1 x 10(8) Melan-A-specific CTL per infusion. Clinical adverse effects were mild and consisted of chills and low-grade fever in seven of 11 patients. Clinical and immunologic responses revealed an antitumor response in three of 11 patients (one complete regression, one partial regression, one mixed response), an elevated frequency of circulating Melan-A tetramer+ T cells up to 2 weeks in all the patients with a maximal frequency of 2% of total CD8+ T cells, an increase in eosinophils to up to 50% in seven of 11 patients, and a selective loss of Melan-A expression in lymph node metastases in two evaluated patients after T-cell transfer. CONCLUSION: Our data indicate that the adoptive transfer of antigen-specific T cells in melanoma patients can induce clinical tumor-specific immune responses without major adverse effects.

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Int J Radiat Oncol Biol Phys. 2006 Nov 15;66(4 Suppl):S20-5.
Stereotactic radiosurgery as therapy for melanoma, renal carcinoma, and sarcoma brain metastases: Impact of added surgical resection and whole-brain radiotherapy.
Rao G, Klimo P Jr, Thompson CJ, Samlowski W, Wang M, Watson G, Shrieve D, Jensen RL.
Department of Neurosurgery, University of Utah, Salt Lake City, Utah, UT.

Purpose: Brain metastases of melanoma, renal carcinoma, and sarcoma have traditionally responded poorly to conventional treatments, including surgery and whole-brain radiotherapy (WBRT). Several studies have suggested a beneficial effect of stereotactic radiosurgery (SRS). We evaluated our institutional experience with systematic SRS in patients harboring these "radioresistant" metastases. Methods and Materials: A total of 68 patients with brain metastases from melanoma, renal carcinoma, and sarcoma underwent SRS with or without WBRT or surgical resection. All patients had Karnofsky performance scores >70, and SRS was performed before the initiation of systemic therapy. The survival time was calculated from the diagnosis of brain metastases using the Kaplan-Meier product-limit method. Statistical significance was calculated using the log-rank test. Factors influencing survival, including surgical resection, WBRT, gender, number of SRS sessions, and histologic type, were evaluated retrospectively using Cox univariate models. Results: The overall median survival was 427 days (14.2 months), which appears superior to the results obtained with conventional WBRT. The addition of neither surgery nor WBRT to SRS provided a statistically significant increase in survival. Conclusion: Our results suggest that patients undergoing SRS for up to five cerebral metastases from "radioresistant" tumors (melanoma, renal cell carcinoma, and sarcoma) have survival rates comparable to those in other series of more selected patients. The addition of surgical resection or WBRT did not result in improved survival in our series.

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J Am Acad Dermatol. 2006 Nov;55(5):849-61. Epub 2006 Sep 18.
Melanoma chemoprevention.
Francis SO, Mahlberg MJ, Johnson KR, Ming ME, Dellavalle RP.
Department of Dermatology, University of Colorado Health Sciences Center, Aurora, Colorado, USA.

BACKGROUND: Despite efforts to promote sun protection behaviors, melanoma incidence continues to increase. The prognosis of advanced melanoma remains extremely poor in spite of treatment advances, emphasizing the importance of exploring additional preventive measures. OBJECTIVE: We sought to summarize the results of published research on candidate chemoprevention agents for melanoma. METHODS: We conducted a narrative review of the literature. RESULTS: Investigation into a possible role in melanoma chemoprevention continues for multiple agents, including sunscreen, lipid-lowering medications, nonsteroidal anti-inflammatory drugs, dietary nutrients, immunomodulators, and other drugs, including retinoids, difluoromethylornithine, and T4 endonuclease V. LIMITATIONS: Systematic review of the literature was not performed. CONCLUSION: Because no agent yet emerges as a clear choice for effective melanoma chemoprevention, sun avoidance and sun protection remain the mainstay of melanoma prevention for persons at high risk.

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Radiother Oncol. 2006 Oct 23; [Epub ahead of print]
A prospective phase II study of adjuvant postoperative radiation therapy following nodal surgery in malignant melanoma-Trans Tasman Radiation Oncology Group (TROG) Study 96.06.
Burmeister BH, Mark Smithers B, Burmeister E, Baumann K, Davis S, Krawitz H, Johnson C, Spry N.
University of Queensland, Melanoma Clinic, Princess Alexandra Hospital, Brisbane, Australia.

BACKGROUND: The role of adjuvant postoperative therapy after resection of localised malignant melanoma involving regional lymph nodes remains controversial. There are no randomised trials that confirm that postoperative radiation conveys a benefit in terms of regional control or survival. METHODS: Two hundred and thirty-four patients with melanoma involving lymph nodes were registered on a prospective study to evaluate the effect of postoperative radiation therapy. The regimen consisted of 48Gy in 20 fractions to the nodal basin using recommended treatment guidelines for each of the major node sites. The primary endpoints were regional in-field relapse and late toxicity. Secondary endpoints were adjacent relapse, distant relapse, overall survival, progression-free survival and time to in-field progression. RESULTS: Adjuvant radiation therapy was well tolerated by all of the patients. As the first site of relapse, regional in-field relapses occurred in 16/234 patients (6.8%). The overall survival was 36% at 5 years. The progression-free survival and regional control rates were 27% and 91%, respectively, at 5 years. Patients with more than 2 nodes involved had a significantly worse outcome in terms of distant relapse, overall and progression-free survival. CONCLUSION: We believe that adjuvant radiation therapy following nodal surgery could offer a possible benefit in terms of regional control. These results require confirmation in a randomised trial.

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Am Surg. 2006 Oct;72(10):917-20.
Factors affecting survival in patients with anal melanoma.
Podnos YD, Tsai NC, Smith D, Ellenhorn JD.
Department of General Oncologic Surgery, City of Hope National Medical Center, Duarte, California 91010, USA.

Anal melanoma is an aggressive tumor with a predilection for early infiltration and distant spread, resulting in poor overall survival. Because anal melanoma is rare, only small case series are reported in the literature, making it difficult to draw conclusions about optimal treatment and outcome. The Surveillance, Epidemiology, and End Results database was used to identify patients with anal melanomas from 1973 to 2001. In addition to demographics, disease extent at presentation, treatment administered, overall survival, and survival by decade of diagnosis were collected. A total of 126 patients with a mean age of 69.2 years was diagnosed with anal melanoma. Sixty-one per cent were female. Median follow-up was 22.5 months. Median survival was 10 months for those with distant disease, 13 months for patients with regional spread, and 34 months for patients with local disease (P = 0.0001). Five-year survival was 32 per cent, 17 per cent, and 0 per cent for patients presenting with local, regional, and distant disease, respectively (P = 0.0001). Neither age at diagnosis, operation performed, nor use of radiation significantly affected survival. Anal melanoma remains an uncommon but lethal disease. Extent of disease correlates with overall survival. Survival is improving, but the use and extent of operation are not associated with improved overall survival.

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Indian J Cancer. 2006 Jul-Sep;43(3):132-5.
Reducing the number of sentinel nodes removed in melanoma patients: A prospective study.
Danino AM, Kadlub N, Dalac S, Boichot C, Malka G.
Department of Plastic Surgery, Dijon University Hospital, Dijon University, France. alain.danino@chu-dijon.fr.

CONTEXT: Since 1992, sentinel lymph node (SLN) biopsy was generally applied to melanoma for tumor staging. As the literature points out, an increasing number of nodes are being removed for each procedure, driving up the cost for this procedure and wandering away from the defining concept of sentinel lymph node. AIMS: The objective of the current study was to show that the number of sentinel lymph node s removed can be minimized without influencing the reliability of tumor staging. MATERIALS AND METHODS: We conducted a single-arm prospective study in patients with stage I melanoma. For each patient, the sentinel lymph node was identified using the hand-held gamma probe technique. We removed only the hottest nodes as well as the nodes with radioactivity greater than 70% compared to the hottest. We analyzed the characteristics of each melanoma, the success rate of this procedure, how many nodes were removed and how many had micro metastases. STATISTICAL ANALYSIS: The results were compared to those of the literature, previously published Porter study using the chi-square test. RESULTS: We included 90 patients. The success rate of this technique was 100%. We dissected 1.3 sentinel lymph nodes for each patient, with 22% positive SLN. Statistical analyses point out a better selectivity of our study for a similar rate of pathological positivity and recurrence compared to the literature. CONCLUSIONS: Our technique for decreasing the number of sentinel lymph nodes removed is reliable. The removal of minimal number of nodes doesn't compromise the sensitivity of tumor staging, while it does reduce the cost of the procedure.

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Melanoma Res. 2006 Aug;16(4):365-370.
Phase II multicentre study of temozolomide in combination with interferon alpha-2b in metastatic malignant melanoma.
Garcia M, Del Muro XG, Tres A, Crespo C, Valladares M, Lopez JJ, Rifa J, Perez X, Filipovich E, Germa-Lluch JR.
Departments of aClinical Research Unit bClinical Oncology, Institut Catala d'Oncologia, Hospital Duran i Reynals IDIBELL cHospital Clinico de Zaragoza dHospital Ramon y Cajal de Madrid eHospital Juan Canalejo, A Coruna fHospital de Sant Pau, Barcelona gHospital Son Dureta, Palma de Mallorca, Spain.

OBJECTIVE: Temozolomide is a novel oral alkylating agent, active against metastatic melanoma. Combinations of chemotherapy and biological response modifiers have been associated with increased antitumour activity. A multicentre phase II study was performed to assess the activity and toxicity of temozolomide in combination with interferon alpha-2b. PATIENTS AND METHODS: Eligible patients had histologically confirmed metastatic melanoma. Previously untreated patients received temozolomide administered orally at a dose of 150 mg/m/day for 5 days every 4 weeks, in combination with interferon given continuously subcutaneously twice a week at a dose of 10 MU/m. Treatment continued until disease progression or for a maximum of 12 months. RESULTS: From June 1999 to August 2002, 27 eligible patients were included in the study at six centres. Median age was 59 (28-77) years; 17 male and 10 female patients were recruited; the median Karnofsky performance score was 90 (70-100); three patients had received prior adjuvant interferon; the majority of patients had fewer than three involved sites. A total of 96 cycles were administered; there were one complete response, four partial response and five stable disease (overall response rate: 18.5%, 95% confidence interval: 6.3-38.1). All responses were seen in patients with exclusively lymph node and pulmonary disease [M1a (one patient); M1b (four patients)]. The median response duration was 6.9 months. One patient remains in complete remission at 4 years. The median time to progression and the median survival were 1.87 and 9.5 months, respectively. Haematological toxicity was neutropenia G-IV: 1, G-III: 4, thrombocytopenia G-III: 2, and anaemia G-III: 2. Predominant non-haematological toxicity was hepatotoxicity G-III: 4. Other toxicities were mild or moderate. Dose reduction was required for nine cycles of interferon, one of temozolomide and two of both drugs. CONCLUSIONS: Temozolomide in combination with interferon is a well-tolerated palliative regimen that has moderate activity against metastatic melanoma. Further evaluation of this regimen in comparative studies or in combination with other drugs is warranted.

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Melanoma Res. 2006 Aug;16(4):357-63.
Alternating chemo-immunotherapy with temozolomide and low-dose interleukin-2 in patients with metastatic melanoma.
Masucci GV, Mansson-Brahme E, Ragnarsson-Olding B, Nilsson B, Wagenius G, Hansson J.
aDepartment of Oncology-Pathology, Karolinska Institute and Karolinska University Hospital, Stockholm bDepartment of Oncology, Uppsala University Hospital, Uppsala, Sweden.

Temozolomide is a rapidly absorbed chemotherapeutic agent, achieving significant central nervous system penetration. Previous clinical trials suggested that temozolomide in sequence with low-dose recombinant human interleukin-2 might be an efficacious and relatively non-toxic chemo-immunotherapeutic treatment, which may synergistically eliminate tumours. The primary objective was to determine the safety and tolerance of temozolomide administered orally 200 mg/m days 1-5, in sequential combination with subcutaneous injections of 4.5x10 IU recombinant human interleukin-2 on days 8-11, 15-18 and 22-25 in patients with measurable, progressive metastatic malignant melanoma without radiological signs of central nervous system metastases. The secondary objectives were to determine tumour response and time to progression. Twenty-seven patients were included, of which four were non-evaluable for response. Twenty-three patients tolerated the regimen with side effects below grade 3 according to the World Health Organization (WHO) scale. Three patients suspended the treatment because of WHO grade 3 side effects already during the first 3 days of the first course of temozolomide. Seven patients showed no tumour progression during the first four treatment cycles. Two patients had complete responses, three partial responses and two stable disease at the end of the four cycles defined by the protocol and they continued the treatment until signs of relapse or a maximum of 21 courses. Five of these patients are still alive. Thrombocytopenia was significantly more pronounced in patients with objective response and stable disease than in non-responders to therapy. The median time to progression for all patients was 3.1 months and for responding and stable disease patients was 15 months. Five of 23 treated patients (22%) developed brain metastases during follow-up. Temozolomide in combination with recombinant human interleukin-2 is a well-tolerated regimen for outpatient treatment and the bio-chemotherapy combination induced durable clinical responses. Thrombocytopenia might be a positive predictive factor for response to therapy.

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Melanoma Res. 2006 Aug;16(4):317-323.
Basal level and behaviour of cytokines in a randomized outpatient trial comparing chemotherapy and biochemotherapy in metastatic melanoma.
Guida M, Riccobon A, Biasco G, Ravaioli A, Casamassima A, Freschi A, Palma MD, Galligioni E, Nortilli R, Chiarion-Sileni V, Picozzo J, Romanini A, Nanni O, Ridolfi R; on behalf of Italian Melanoma Intergroup (IMI).
aOncology Division, Immunology Laboratory, Istituto Oncologico, Bari bImmunotherapy Unit, Oncology Department, Pierantoni Hospital, Forli cInstitute of Hematology and Medical Oncology L. and A. Seragnoli, Policlinico Sant'Orsola Malpighi, University of Bologna, Bologna dIstituto Oncologico Romagnolo, Forli eAviano Cancer Institute, Aviano fMedical Oncology Unit, S. Bortolo Hospital, Vicenza gOncology Center, S. Chiara Hospital, Trento hDepartment of Medical Oncology, Maggiore Hospital, Verona iDepartment of Medical Oncology, Busonera Hospital, Padova jMedical Oncology Unit, S. Chiara Hospital, Pisa kDepartment of Medical Oncology, Pierantoni Hospital, Forli

Cytokines play a crucial role in the host's immune response. In melanoma patients, cytokine profiles seems to be related to the clinical course and their imbalance could be associated to tumour progression. Thus, we studied a panel of baseline cytokines and their behaviour during treatment in order to verify their correlation with clinical outcomes. Interleukin-6, interleukin-8, interleukin-10, interleukin-12 and soluble receptor of interleukin-2 were evaluated in 90 out of 176 metastatic melanoma patients enrolled in a phase III study comparing chemotherapy and biochemotherapy. We divided patients into three different groups according to their own cytokine levels (low, intermediate and high) and then we correlated these groups with some clinical features. We also monitored the cytokines during the treatment in a subgroup of 37 patients. In univariate analysis, higher values of interleukin-6 (P = 0.005), soluble receptor of interleukin-2 (P = 0.001) and interleukin-12 (P = 0.010) were correlated with a worse survival. Conversely, interleukin-8 was unable to discriminate patients with different prognoses, and interleukin-10 was undetectable in the majority of patients. In multivariate analysis, only soluble receptor of interleukin-2 maintained its independent role in survival. The impact of baseline cytokines on response was insignificant. Regarding the behaviours of cytokines during treatment, the most remarkable aspect was a progressive increase of interleukin-12 and soluble receptor of interleukin-2 in patients with a better survival. In our metastatic melanoma patients, higher basal levels of interleukin-6, interleukin-12 and soluble receptor of interleukin-2 were associated with a worse survival. In contrast, a progressive increase of interleukin-12 and soluble receptor of interleukin-2 was observed during treatment in patients with a better survival.

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Eur J Surg Oncol. 2006 Jul 3; [Epub ahead of print]
The prognostic impact of the extent of lymph node dissection in patients with stage III melanoma.
Galliot-Repkat C, Cailliod R, Trost O, Danino A, Collet E, Lambert D, Vabres P, Dalac S.
Department of Dermatology, University Hospital, 2 Boulevard Marechal de Lattre de Tassigny, F-21033 Dijon, France.

AIMS: To analyse disease-free and overall survival in 67 melanoma patients who underwent dissection for clinically apparent regional lymph node metastases, taking into account the total number of excised lymph nodes. METHODS: After a median follow-up time of 16months, 47 recurrences were observed and 43 patients died. The median disease-free and overall survival intervals were 14 and 24months respectively. RESULTS: Multivariate analyses revealed that the number of excised lymph nodes had a significant impact on overall survival (P=0.036) but not on disease-free survival (P=0.97). Extranodal growth was the only statistically significant prognostic factor both for disease-free (P=0.005) and overall (P=0.038) survival. Age, nodal basin, primary tumor ulceration, tumor thickness and number of positive lymph nodes were not significant prognostic factors. CONCLUSIONS: Our results suggest that the total number of lymph nodes excised in the dissection has impact on overall survival of stage III melanoma patients and should be considered in clinical assays.

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Lancet Oncol. 2006 Jul;7(7):575-83.
Dispelling the myths surrounding radiotherapy for treatment of cutaneous melanoma.
Stevens G, McKay MJ.
Oncology Unit, Auckland Hospital, Grafton, Auckland, New Zealand. gstevens@adhb.govt.nz

The role of radiotherapy is well established in the management of most locally advanced and metastatic cancers; however, there has been reluctance to extend this role to melanoma. The reasons can be traced historically to in-vitro and in-vivo data suggesting that melanomas are resistant to radiation. Current findings indicate that these cancers have a wide range of sensitivity to radiation that overlaps extensively with those for common epithelial cancers: indeed, some melanomas show high sensitivity to radiation. Greater incorporation of radiotherapy into multidisciplinary management of melanoma is important because of the typical natural history of the disease (a propensity for both locoregional recurrence and distant metastases) and its poor response to systemic treatment. This review will discuss these issues and preview the strategies being developed for radiotherapy to further improve the care of patients with melanoma.

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Ugeskr Laeger. 2006 Jun 19;168(25):2457-62.
[Prognosis after sentinel node biopsy in cases of cutaneous malignant melanoma]
[Article in Danish]
Lock-Andersen J, Horn J, Sjostrand H.
Plastikkirurgisk Afdeling, Roskilde Amts Sygehus Roskilde, DK-4000 Roskilde. j.lock-andersen@dadlnet.dk

INTRODUCTION: Sentinel node biopsy (SNB) is used in patients with cutaneous malignant melanoma (MM) to detect subclinical spread to the regional lymph nodes, after which a radical lymph node dissection can be performed. Since 2001, the Department of Plastic Surgery, Roskilde Amts Sygehus, has used SNB routinely in patients with cutaneous MM who have a statistical risk of at least 10% of harbouring subclinical lymph node metastasis. MATERIALS AND METHODS: In the four-year period from 2001 to 2004, 248 consecutive patients with primary MM underwent SNB at the time of radical surgery for their MM. If metastatic spread was found in the removed sentinel node, a radical lymph node dissection was performed shortly afterward. All patients were followed up after their operation in the department's outpatient clinic. RESULTS: Regional lymph node metastatic spread was found by SNB in 32% of the patients. At radical lymph node dissection, further metastatic lymph nodes were found in 24% of the dissected cases. The median follow-up time was 21 months (range 1-51 months). 7% of SN-negative cases developed recurrence during follow-up, in contrast to 23% of the SN-positive cases. The median time to recurrence was 14 months. The two-year and four-year disease-free survival rates were 93% and 85% in the SN-negative group and 73% and 55% in the SN-positive group, respectively. Risk factors for recurrence were: extracapsular SN growth, more than one metastatic SN and further lymph node metastases being found by formal node dissection. 18% of the SN-positive patients died during the follow-up period, in contrast to 3% of the SN-negative cases. The MM-specific two-year and four-year survival rates were 84% and 64% in the SN-positive group and 99% and 97% in the SN-negative group, respectively. CONCLUSION: Sentinel node biopsy is a procedure that detects MM patients who have a very high risk of recurrence and death by MM within a few years after primary treatment. SNB status is a very strong prognostic factor, and SN-positive cases should be followed carefully.

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Skin Therapy Lett. 2006 Jun;11(5):1-7.
Immunological strategies to fight skin cancer.
Berman B, Perez OA, Zell D.
Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, USA.

Skin cancer is the most common human cancer, and is currently considered a global epidemic. Recently, there has been a growing interest in immunomodulators, or up-regulators of the immune response, for the treatment and cure of various forms of skin cancer, including melanoma and nonmelanoma skin cancers, cutaneous T-cell lymphoma, Kaposi's sarcoma, cutaneous extramammary Paget's disease, and vulvar intraepithelial carcinoma neoplasia. Strategies to augment the host's immune response against cancer cells and/or cancer cell antigenicity have been investigated, including recombinant cytokines, immunomodulators, dendritic cell immunization, tumor antigen vaccination, T-cell-based immunotherapy, and gene therapy. Although the current standard of care for most of these cancers includes Mohs micrographic surgery, curettage, and cryo-, laser-, or radiotherapy, immunomodulators are becoming essential in the treatment of patients who are poor surgical candidates and/or require noninvasive therapy.

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Surg Oncol. 2006 Jun 29; [Epub ahead of print]
The treatment of melanoma with an emphasis on immunotherapeutic strategies.
Jack A, Boyes C, Aydin N, Alam K, Wallack M.
Surgery Research Laboratory, Department of Surgery, Saint Vincent's Catholic Medical Centers/New York Medical College, 153 West 11th Street, Cronin Building, Room 667, New York, NY 10011, USA.

Melanoma continues to be one of the most difficult to treat of all solid tumors. Many new advances have been made in the surgical management of melanoma, including new guidelines for margins of excision, as well as sentinel node biopsy for the diagnosis of lymph node micrometastases. The search continues for an effective adjuvant melanoma treatment that can prevent local and distant recurrences. Melanoma is one of the most immunogenic of all tumors, and several clinical trials testing the immunotherapy of melanoma have been conducted, including trials in interferon, interleukin-2, and melanoma vaccines. Here we discuss many of the recent clinical trials in the surgical management of melanoma, in addition to the advances that have been made in the field of immunotherapy. A new second-generation melanoma vaccine, DC-MelVac (patent # 11221/5), has recently been granted FDA approval for Phase I clinical trials and will be introduced in this review.

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Exp Dermatol. 2006 Mar;15(3):175-86.
Antiangiogenic cancer therapies get their act together: current developments and future prospects of growth factor- and growth factor receptor-targeted approaches.
Gille J.
Department of Dermatology, Dermato-Oncology Unit, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.

Targeting the vascular endothelial growth factor (VEGF) in combination with standard chemotherapy has recently proved successful in the treatment of different types of advanced cancer. The achievements of combinatorial anti-VEGF monoclonal antibody bevacizumab (BEV) renewed the confidence in targeted antiangiogenic approaches to constitute a complementary therapeutic modality in addition to surgery, radiotherapy and chemotherapy. While several second-generation multitargeted tyrosine kinase inhibitors show promise in defined tumor entities, these novel antiangiogenic compounds have yet to meet or exceed the efficacy of combinatorial BEV therapy in ongoing clinical trials. Current developments of targeted antiangiogenic agents include their use in the adjuvant setting and the combination of different antiangiogenesis inhibitors to take a more comprehensive approach in blocking tumor angiogenesis. The identification of surrogate markers that can monitor the activity and efficacy of antiangiogenic drugs in patients belongs to the most critical challenges to exploit the full potential of antiangiogenic therapies. The opportunities and obstacles in further development of growth factor- and growth factor receptor-targeted antiangiogenic approaches for advanced cancer, including malignant melanoma, will be discussed herein with particular reference to selected ongoing clinical trials.

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Curr Opin Oncol. 2006 Mar;18(2):180-4.
What about chemoprevention for melanoma?
Demierre MF.
Skin Oncology Program, Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts, USA.

PURPOSE OF REVIEW: This paper aims to critically review the potential for a chemoprevention strategy in melanoma, and to discuss new data on candidate chemoprevention agents, as chemoprevention has been suggested as an unexplored approach in melanoma. RECENT FINDINGS: A strong scientific rationale, established long-term safety of candidate agents, and a systematic step-wise approach to chemoprevention agent development are all critical for melanoma chemoprevention research. Among potential agents, the lipid-lowering drugs, the statins, satisfy these prerequisites SUMMARY: Chemoprevention of cutaneous melanoma can become a valid strategy complementing current prevention approaches, as long as these important prerequisites are taken into consideration.

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Arch Ophthalmol. 2006 Feb;124(2):226-38.
Quality of life after iodine 125 brachytherapy vs enucleation for choroidal melanoma: 5-year results from the Collaborative Ocular Melanoma Study: COMS QOLS Report No. 3.
Melia M, Moy CS, Reynolds SM, Hayman JA, Murray TG, Hovland KR, Earle JD, Kurinij N, Dong LM, Miskala PH, Fountain C, Cella D, Mangione CM; Collaborative Ocular Melanoma Study-Quality of Life Study Group.
Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, MD, USA. mmelia@jaeb.org

OBJECTIVE: To describe health- and vision-targeted quality of life following treatment with iodine 125 brachytherapy vs enucleation for choroidal melanoma in a subgroup of patients who were treated and observed prospectively as part of a large randomized clinical trial. MAIN OUTCOME MEASURES: Difficulty with driving, near vision activities, and activities using stereopsis or binocularity; anxiety; and depression. PARTICIPANTS: Two hundred nine patients who enrolled in the Collaborative Ocular Melanoma Study trial for medium-sized tumors between March 1995 and July 1998 and gave informed consent prior to randomization to participation in an ancillary study of quality of life. METHODS: Patients were interviewed by telephone by a trained interviewer from the Collaborative Ocular Melanoma Study Coordinating Center at baseline (prior to randomization), at 6 months, and on annual anniversaries of enrollment. The questionnaire battery included the Medical Outcomes Study Short Form 36, the Activities of Daily Vision Scale, the National Eye Institute Visual Function Questionnaire, and the Hospital Anxiety and Depression Scale. Additional questions concerning satisfaction with posttreatment appearance and concerns about cancer recurrence also were included in posttreatment interviews. RESULTS: There was a significant increase in both treatment groups in levels of reported difficulty for most vision-oriented activities, and in bodily and ocular pain, 6 months following treatment. Differences in visual function between treatment groups reported during follow-up were relatively small, but significant differences favoring brachytherapy-treated patients were observed for driving during the first year of follow-up and for peripheral vision during the first 2 years of follow-up. Anxiety levels in both groups decreased significantly following treatment, but patients treated with brachytherapy with symptoms of anxiety were less likely to report later resolution of symptoms than patients with symptoms of anxiety who were treated with enucleation. This study was unable to assess impact of treatment on satisfaction with appearance and concern about cancer recurrence during the first year after treatment, but no treatment-related differences were found on these measures at 2 years and later follow-up times. CONCLUSIONS: Patients treated with brachytherapy reported significantly better visual function than patients treated with enucleation with respect to driving and peripheral vision for up to 2 years following treatment. Differences between treatments in visual function diminished by 3 to 5 years posttreatment, paralleling decline in visual acuity in brachytherapy-treated eyes. Patients treated with brachytherapy were more likely to have symptoms of anxiety during follow-up than patients treated with enucleation. APPLICATION TO CLINICAL PRACTICE: Given that no significant differences in survival between enucleation and brachytherapy have been found, the differences demonstrated here for driving and anxiety will allow the individual patient and physician to make informed choices regarding treatment based on personal preferences.

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Cancer. 2006 Feb 10; [Epub ahead of print]
Survival analysis after resection of metastatic disease followed by peptide vaccines in patients with Stage IV melanoma.
Tagawa ST, Cheung E, Banta W, Gee C, Weber JS.
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.

BACKGROUND: Metastatic melanoma carries a poor prognosis, with a median survival of 7-9 months. Surgical resection of metastatic disease has been advocated to improve survival. Immunotherapy after metastasectomy may further improve the outcome for high-risk resected disease. METHODS: Charts from patients treated on institutional vaccine trials were analyzed. Patients with American Joint Committee on Cancer (AJCC) Stage IV melanoma who underwent surgical resection of metastatic sites followed by treatment on a peptide vaccine trial were eligible for this study. Survival was calculated from the date of enrollment on the clinical trial. RESULTS: Forty-one patients met inclusion criteria. The median age was 56.5 years, with approximately equal numbers of men and women. The ECOG performance status was 0 in all patients. Approximately 46% of patients underwent resection of visceral metastases before vaccine. The median follow-up was 5.6 years. The median overall survival was 3.8 years. CONCLUSIONS: In selected patients with AJCC Stage IV melanoma, resection of metastatic disease followed by vaccine therapy can result in long-term survival. Cancer 2006. (c) 2006 American Cancer Society.

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Ann Oncol. 2006 Feb 9; [Epub ahead of print]
Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon-{alpha}2b in metastatic melanoma.
Bajetta E, Del Vecchio M, Nova P, Fusi A, Daponte A, Sertoli MR, Queirolo P, Taveggia P, Bernengo MG, Legha SS, Formisano B, Cascinelli N.
Medical Oncology Unit 2, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan.

BACKGROUND: The addition of cytokines to chemotherapy (CT) has obtained encouraging but contradictory results in metastatic melanoma. In this phase III trial, we compared the effects of CT [cisplatin, vindesine and dacarbazine (CVD)] with those of concurrent biochemotherapy (bioCT) consisting of CVD plus interleukin-2 and interferon-alpha2b. PATIENTS AND METHODS: A total of 151 untreated metastatic melanoma patients were randomized, 75 on arm A (cisplatin 30 mg/m(2) on days 1-3, vindesine 2.5 mg/m(2) on day 1 and dacarbazine 250 mg/m(2) on days 1-3), and 76 on arm B (same CVD scheme plus interferon-alpha2b on days 1-5 and interleukin-2 on days 1-5 and 8-15, both administered subcutaneously), either recycled every 3 weeks. Response was assessed every two cycles. RESULTS: Ten percent of the patients were alive at a median of 52 months from start of therapy. We observed a response rate (RR) of 21% on arm A versus 33% on arm B; three patients (4%) given bioCT had complete responses (CRs). Median time to progression (TTP) was identical; median overall survival (OS) time was 12 months on arm A and 11 months on arm B. CONCLUSIONS: BioCT is not better than CT alone; the trend in favor of the bioCT in terms of RR did not translate into better TTP or OS. Therefore, bioCT cannot be recommended as standard first-line therapy for metastatic melanoma.

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Ann Oncol. 2006 Feb 9; [Epub ahead of print]
Intra-arterial hepatic fotemustine for the treatment of liver metastases from uveal melanoma: experience in 101 patients.
Peters S, Voelter V, Zografos L, Pampallona S, Popescu R, Gillet M, Bosshard W, Fiorentini G, Lotem M, Weitzen R, Keilholz U, Humblet Y, Piperno-Neumann S, Stupp R, Leyvraz S.
Centre Pluridisciplinaire d'Oncologie and University of Lausanne Hospitals (CHUV), Lausanne, Switzerland.

BACKGROUND: Exclusive liver metastases occur in up to 40% of patients with uveal melanoma associated with a median survival of 2-7 months. Single agent response rates with commonly available chemotherapy are below 10%. We have investigated the use of fotemustine via direct intra-arterial hepatic (i.a.h.) administration in patients with uveal melanoma metastases. PATIENTS AND METHODS: A total of 101 patients from seven centers were treated with i.a.h. fotemustine, administered intra-arterially weekly for a 4-week induction period, and then as a maintenance treatment every 3 weeks until disease progression, unacceptable toxicity or patient refusal. RESULTS: A median of eight fotemustine infusions per patient were delivered (range 1-26). Catheter related complications occurred in 23% of patients; however, this required treatment discontinuation in only 10% of the patients. The overall response rate was 36% with a median overall survival of 15 months and a 2-year survival rate of 29%. LDH, time between diagnosis and treatment start and gender were significant predictors of survival. CONCLUSIONS: Locoregional treatment with fotemustine is well tolerated and seems to improve outcome of this poor prognosis patient population. Median survival rates are among the longest reported and one-third of the patients are still alive at 2 years.

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Photochem Photobiol Sci. 2006 Feb;5(2):243-53. Epub 2005 Aug 12.
Chemoprevention of photocarcinogenesis by selected dietary botanicals.
Baliga MS, Katiyar SK.
Department of Dermatology, University of Alabama at Birmingham, 1670 University Boulevard, Volker Hall 557, P.O. Box 202, Birmingham, AL, USA. skatiyar@uab.edu.

Epidemiological, clinical and laboratory studies have implicated solar ultraviolet (UV) radiation as a tumor initiator, tumor promoter and complete carcinogen, and their excessive exposure can lead to the development of various skin disorders including melanoma and nonmelanoma skin cancers. Sunscreens are useful, but their protection is not adequate to prevent the risk of UV-induced skin cancer. It may be because of inadequate use, incomplete spectral protection and toxicity. Therefore new chemopreventive methods are necessary to protect the skin from photodamaging effects of solar UV radiation. Chemoprevention refers to the use of agents that can inhibit, reverse or retard the process of skin carcinogenesis. In recent years, considerable interest has been focused on identifying naturally occurring botanicals, specifically dietary, for the prevention of photocarcinogenesis. A wide variety of botanicals, mostly dietary flavonoids or phenolic substances, have been reported to possess substantial anticarcinogenic and antimutagenic activities because of their antioxidant and antiinflammatory properties. This review summarizes chemopreventive effects of some selected botanicals, such as apigenin, curcumin, grape seed proanthocyanidins, resveratrol, silymarin, and green tea polyphenols, against photocarcinogenesis in in vitro and in vivo systems. Attention has also been focused on highlighting the mechanism of chemopreventive action of these dietary botanicals. We suggest that in addition to the use of these botanicals as dietary supplements for the protection of photocarcinogenesis, these botanicals may favorably supplement sunscreens protection and may provide additional antiphotocarcinogenic protection including the protection against other skin disorders caused by solar UV radiation.

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Med Sci (Paris). 2006 Feb;22(2):183-187.
[Melanoma immunotherapy.]
[Article in French]
Ghiringhelli F, Zitvogel L.
Inserm U.517, Faculte de Medecine et Centre Regional de Lutte contre le Cancer Georges-Francois Leclerc, 7, boulevard Jeanne d'Arc, 21079 Dijon Cedex, France. f.ghiringhelli@compaqnet.fr.

Melanoma incidence increases and conventional antitumor therapies are often ineffective, encouraging the design of novel therapies. Several lines of evidence support the notion of an immunological control of melanoma growth. Based on this information, active immunotherapy (vaccination) and adoptive immunotherapy trials (T cell therapy) were conducted in metastatic melanoma patients. The proof of principle of effective immunotherapy was brought up by pionnering trials using tumor infiltrated lymphocytes in lymphodepleted recipients or anti-CTLA4 Ab leading to tumor eradication but also autoimmune diseases. With the identification and characterization of tumor antigens recognized by cytotoxic T lymphocytes, the utilization of tumor rejection antigens along with adjuvants become available as tumor vaccines. The last five years have witnessed the emergence of dendritic cell based-vaccines that were efficient in priming and/or boosting T cell responses in normal volunteers and patients. This review highlights preclinical bases of cancer vaccines, their clinical development and discusses their limits. Correlations between immunomonitoring and tumor regressions await larger trials. double dagger.

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Melanoma Res. 2006 Feb;16(1):65-9.
A biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, temozolomide (Temodal), interferon-alfa and interleukin-2 for metastatic melanoma: a phase II study.
Ron IG, Sarid D, Ryvo L, Even Sapir E, Schneebaum S, Metser U, Asna N, Inbar MJ, Safra T.
Departments of aOncology bNuclear Medicine cSurgery A dDiagnostic Radiology, Tel Aviv-Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Our objective was to evaluate the toxicity and antitumor efficacy of concurrent biochemotherapy in metastatic melanoma patients and the effectiveness of adding temozolomide to protect the brain from metastases. Twenty-three patients with advanced inoperable melanoma were hospitalized for 5-6 days for the following treatment: cisplatin 20 mg/m daily for 4 days, vinblastine 1.6 mg/m daily for 4 days and oral temozolomide 250 mg/m daily for 5 days, with 18x10 IU/m intravenous interleukin-2 by continuous infusion for 4 days (the dose was cut daily by 50%) and 5x10 U/m interferon-alfa subcutaneously daily for 5 days, repeated at 28-day intervals for a maximum of nine courses. According to the standard World Health Organization response criterion, the objective response rate was 43.4% and the median survival was 18.6 months. All but one patient survived for more than 12 months, and no responding patient progressed first in the brain. Substituting dacarbazine by temozolomide in the MD Anderson melanoma section protocol appears to offer protection against dissemination of brain metastases, equal activity in the periphery and a possible lower incidence of toxicity due to the oral route.

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J Clin Oncol. 2005 Oct 31; [Epub ahead of print]
Prospective, Randomized, Multicenter, Double-Blind Placebo-Controlled Trial Comparing Adjuvant Interferon Alfa and Isotretinoin With Interferon Alfa Alone in Stage IIA and IIB Melanoma: European Cooperative Adjuvant Melanoma Treatment Study Group.
Richtig E, Soyer HP, Posch M, Mossbacher U, Bauer P, Teban L, Svolba G, Wolf IH, Fritsch P, Zelger B, Volc-Platzer B, Gebhart W, Mischer P, Steiner A, Pachinger W, Hintner H, Gschnait F, Rappersberger K, Pilarski P, Pehamberger H.
Department of Dermatology, Medical University of Graz; Section of Medical Statistics and Department of Dermatology, Medical University of Vienna; Department of Dermatology, Danube Hospital; Department of Dermatology, Wilhelminen Hospital; Roche Austria GmbH, Vienna; Department of Dermatology, Medical University of Innsbruck; Department of Dermatology, Hospital of St Polten; Department of Dermatology, Hospital of Wels; Department of Dermatology, Hospital of Klagenfurt; Department of Dermatology, Hospital of Salzburg; Department of Dermatology, Hospital of Lainz; and Department of Dermatology, Rudolfsstiftung, Wien, Austria.

PURPOSE: The combination of interferon alfa (IFNalpha) and isotretinoin has shown a direct antiproliferative effect on human melanoma cell lines, but it remained unclear whether this combination is more effective than IFNalpha alone in patients with metastatic melanoma. We evaluated safety and efficacy of IFNalpha and isotretinoin compared with IFNalpha alone as adjuvant treatment in patients with primary malignant melanoma stage IIA and IIB. PATIENTS AND METHODS: In a prospective, randomized, double-blind, placebo-controlled trial, 407 melanoma patients in stage IIA (301 patients) and IIB (106 patients) were randomly assigned to either IFNalpha and isotretinoin (isotretinoin group; 206 patients) or IFNalpha and placebo (placebo group; 201 patients) after excision of the primary tumor. IFNalpha was administered three times a week at a dose of 3 million units subcutaneously for 24 months. Isotretinoin at a dose of 20 mg for patients </= 73 kg, 30 mg for patients greater than 73 kg, or placebo daily for 24 months. RESULTS: A scheduled interim analysis revealed no significant differences in survival rates, with the isotretinoin group and the placebo group showing 5-year disease-free survival rates of 55% (95% CI, 46% to 65%) and 67% (95% CI, 59% to 75%), respectively, and overall 5-year survival rates of 76% (95% CI, 67% to 84%) and 81% (95% CI, 74% to 88%), respectively. The trial was stopped for futility. CONCLUSION: The addition of isotretinoin to an adjuvant treatment of low-dose IFNalpha in patients with stage IIA and IIB melanoma had no significant effect on disease-free or overall survival and is therefore not recommended.

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J Clin Oncol. 2005 Oct 31; [Epub ahead of print]
Temozolomide in Combination With Interferon-Alfa Versus Temozolomide Alone in Patients With Advanced Metastatic Melanoma: A Randomized, Phase III, Multicenter Study from the Dermatologic Cooperative Oncology Group.
Kaufmann R, Spieth K, Leiter U, Mauch C, von den Driesch P, Vogt T, Linse R, Tilgen W, Schadendorf D, Becker JC, Sebastian G, Krengel S, Kretschmer L, Garbe C, Dummer R.
Departments of Dermatology, J.W. Goethe-University, Frankfurt am Main; University of Tubingen, Tubingen; University of Koln, Cologne; University of Erlangen, Erlangen/Stuttgart; University of Regensburg, Regensburg; Helios Clinic Erfurt, Erfurt; Saarland University, Homburg; Skin Cancer Unit, German Cancer Research Center, Heidelberg; University of Wurzburg, Wurzburg; University of Dresden, Dresden; University of Schleswig-Holstein Campus Lubeck, Lubeck; University of Gottingen, Gottingen, Germany; and University of Zurich, Switzerland.

PURPOSE: Temozolomide (TMZ) has shown efficacy in metastatic melanoma equal to that of dacarbazine (DTIC), the standard chemotherapeutic agent for melanoma. As the combination with interferon-alfa (IFN-alpha) appears superior to single-agent DTIC regarding response rates, the purpose of this study was to compare TMZ alone and TMZ plus IFN-alpha in terms of objective response (OR), overall survival, and safety in a prospective, randomized, multicenter trial. PATIENTS AND METHODS: Two hundred ninety-four patients with untreated stage IV metastatic melanoma (American Joint Committee on Cancer staging system) were randomly assigned to receive either oral TMZ alone (200 mg/m(2)/day; days 1 through 5 every 28 days) or in combination with subcutaneous IFN-alpha (5 MU/m(2); days 1, 3, and 5 every week). RESULTS: Two hundred eighty-two patients were eligible for an intent-to-treat analysis, 271 patients were treated per protocol. In the TMZ + IFN-alpha arm, 33 (24.1%) of 137 patients responded to therapy (partial or complete remission) whereas in the monotherapy arm, in 18 (13.4%) of 134 patients, a response was evident. Thus, the response rate was significantly higher in the combination arm (P = .036). Median survival time was 8.4 months for patients treated with TMZ (95% CI, 7.07 to 9.27) and 9.7 months for those treated with the combination (95% CI, 8.26 to 11.18; P = .16). Dose modifications and interval prolongations due to hematologic toxicity were significantly more frequent in the TMZ + IFN-alpha arm (P < .001). CONCLUSION: In metastatic melanoma treatment with TMZ + IFN-alpha leads to a significantly superior OR rate compared to treatment with TMZ alone, which did not translate into prolonged survival in our study population.

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J Clin Oncol. 2005 Oct 31; [Epub ahead of print]
Low-Dose Outpatient Chemobiotherapy With Temozolomide, Granulocyte-Macrophage Colony Stimulating Factor, Interferon-{alpha}2b, and Recombinant Interleukin-2 for the Treatment of Metastatic Melanoma.
Weber RW, O'day S, Rose M, Deck R, Ames P, Good J, Meyer J, Allen R, Trautvetter S, Timmerman M, Cruickshank S, Cook M, Gonzalez R, Spitler LE.
Northern California Melanoma Center, St. Francis Memorial Hospital, San Francisco; Cancer Institute Medical Group affiliated with John Wayne Cancer Institute, Santa Monica, CA; and the University of Colorado Cancer Center, Denver, CO.

PURPOSE: The objective of this study was to further investigate the efficacy and safety of low-dose outpatient chemobiotherapy in patients with unresectable metastatic melanoma. PATIENTS AND METHODS: Thirty-one patients with histologically confirmed unresectable measurable metastatic melanoma were enrolled in an open-label, multicenter phase II study. The treatment regimen consisted of oral temozolomide followed by subcutaneous biotherapy with granulocyte macrophage colony-stimulating factor, interferon-alfa, and recombinant interleukin-2 (rIL-2). RESULTS: Twenty-eight patients (90%) had M1c disease, and 58% had three or more sites of metastasis. Four patients (13%), all with M1c disease, had a complete response, and four patients had a partial response. The median progression-free survival was 4.9 months and the median overall survival was 13.1 months. Two patients (6%) developed CNS metastasis as the first site of disease progression, and 7 (23%) of 30 experienced CNS progression after receiving chemobiotherapy. A total of 112 cycles of therapy were administered. Toxicity occurred in 78% of the cycles and was grade 1 or 2 in the majority of cases and easily managed. Grade 4 toxicity occurred in 3% of the cycles. CONCLUSION: This low-dose chemobiotherapy combination produces clinical responses in patients with metastatic melanoma, even in those with M1c disease, is well tolerated, and allows home dosing. It offers a reasonable alternative to high-dose regimens, such as high-dose biochemotherapy or rIL-2 requiring prolonged periods of hospitalization, or single agent outpatient regimens, such as dacarbazine, which is usually not effective in patients with M1c disease. Furthermore, it may protect against the development of brain metastases.

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Cancer Control. 2005 Oct;12(4):242-7.
Head and neck melanoma.
Kienstra MA, Padhya TA.
Head and Neck Oncology Division, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612 USA. kienstma@moffitt.usf.edu.

BACKGROUND: Melanoma of the head and neck and its treatment are complex issues. The behavior of head and neck melanoma is aggressive, and it has an overall poorer prognosis than that of other skin sites. METHODS: The authors review current data on the treatment of head and neck melanoma, including both cutaneous and mucosal melanoma. RESULTS: Current understanding of the behavior of head and neck melanoma is reviewed and treatment stratagems are presented. Controversies in treatment include lymphoscintigraphy with sentinel node biopsy, nodal dissection, margin size, role of radiation therapy, and reconstruction. The management goal is to treat melanoma aggressively while minimizing the effects of treatment on patient quality of life. CONCLUSIONS: Due to its aggressiveness, head and neck melanoma should be treated aggressively when morbidity is not significantly increased. Patient specific treatment is imperative.

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Cancer Control. 2005 Oct;12(4):236-41.
Choices in adjuvant therapy of melanoma.
Lawson DH.
Winship Cancer Institute, Atlanta, GA 30322 USA. David.Lawson@emoryhealthcare.org.

BACKGROUND: High-dose interferon (IFN) is the approved agent for adjuvant treatment of melanoma in the United States. This approval is for high-risk, predominantly stage III patients with cutaneous primaries. There are still decisions to be made in the care of these patients. Also, there are questions about whether the IFN data can be extrapolated to patients with other stages of melanoma and whether adjuvant treatment should be offered to these individuals. Clearly there is room for improvement in this area. METHODS: The literature on this topic and ongoing national trials in the United States were reviewed. RESULTS: The data are insufficient to recommend other agents in the adjuvant treatment of melanoma outside a clinical trial. Extrapolation of the IFN data to patient populations other than those studied is problematic at best. National trials are available for most patient populations. CONCLUSIONS: The adjuvant treatment of choice for melanoma patients is participation in a clinical trial.

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Br J Cancer. 2005 Oct 25; [Epub ahead of print]
Engineering T cells for cancer therapy.
Mansoor W, Gilham DE, Thistlethwaite FC, Hawkins RE.
1Cancer Research UK, Department of Medical Oncology, University of Manchester, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Withington, Manchester M20 4BX, UK.

It is generally accepted that the immune system plays an important role in controlling tumour development. However, the interplay between tumour and immune system is complex, as demonstrated by the fact that tumours can successfully establish and develop despite the presence of T cells in tumour. An improved understanding of how tumours evade T-cell surveillance, coupled with technical developments allowing the culture and manipulation of T cells, has driven the exploration of therapeutic strategies based on the adoptive transfer of tumour-specific T cells. The isolation, expansion and re-infusion of large numbers of tumour-specific T cells generated from tumour biopsies has been shown to be feasible. Indeed, impressive clinical responses have been documented in melanoma patients treated with these T cells. These studies and others demonstrate the potential of T cells for the adoptive therapy of cancer. However, the significant technical issues relating to the production of natural tumour-specific T cells suggest that the application of this approach is likely to be limited at the moment. With the advent of retroviral gene transfer technology, it has become possible to efficiently endow T cells with antigen-specific receptors. Using this strategy, it is potentially possible to generate large numbers of tumour reactive T cells rapidly. This review summarises the current gene therapy approaches in relation to the development of adoptive T-cell-based cancer treatments, as these methods now head towards testing in the clinical trial setting.British Journal of Cancer advance online publication, 25 October 2005; doi:10.1038/sj.bjc.6602839 www.bjcancer.com.

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J Fr Ophtalmol. 2005 Oct;28(8):833-9.
[Results of treating uveal melanoma with proton beam radiation: 10-year follow-up.]
[Article in French]
Hamrouni Z, Levy C, Lumbroso L, D'hermies F, Frau E, Mazal A, Delacroix S, Nauraye C, Dendale R, Schlienger P, Desjardins L.
Service d'Ophtalmologie, Institut Curie, Paris.

PURPOSE: We analyzed the long-term results of uveal melanoma treatment with proton beam irradiation in a series of patients with a follow-up of at least 10 years. PATIENTS AND METHODS: The patients were treated with proton beam radiation between September 1991and December 1992. They had an initial examination including visual acuity, funduscopy, A and B scan ultrasonography of the eye, fundus photographs and fluorescein angiography. General examination included chest radiography and B scan ultrasonography of the liver. All tumors received a total dose of 60 cobalt-Gray equivalents (applied in four daily fractions) at the Orsay proton therapy center. RESULTS: A total of 167 patients were treated with a median follow-up of 116 months. Their median age was 59 years. Thirteen tumors were anterior to the equator, 76 overlapped the equator and 78 were posterior to the equator. An initial retinal detachment was present in 41 cases. The optic disk was invaded in 10 cases. The median tumor diameter was 12 mm and the median tumor thickness was 5.8 mm. The mean initial acuity was 20/50. The survival rate was 62.93% at 10 years; 72.9% of deaths resulted from metastasis. Statistically significant risk factors for death identified in the multivariate analysis were tumor diameter greater than 12 mm (p=0.0004) and age over 60 years (p=0.0001). The metastasis rate at 10 years was 31%. The liver was affected in 97.8% of these patients. Risk factors for metastasis were the anterior site of the tumor, its volume greater than 0.4 cc and the presence of retinal detachment at diagnosis. The secondary enucleation rate at 10 years was 13.23%, mainly attributable to secondary neovascular glaucoma. The local recurrence rate was 6%. The visual acuity rate in 42.1% of patients was better than 20/100 at 10 years. Visual loss was mainly due to postradiation maculopathy and neuropathy. CONCLUSION: Our study confirms the long-term results found in the literature on proton beam radiation. This therapy allows good tumor control, an excellent eye retention rate, and good final visual acuity for approximately half of the patients.

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Curr Pharm Des. 2005;11(27):3461-73.
Melanoma immunotherapy: past, present, and future.
Saleh F, Renno W, Klepacek I, Ibrahim G, Asfar S, Dashti H, Romero P, Dashti A, Behbehani A.
Faculty of Medicine, Health Sciences Centre, Department of Anatomy, Kuwait University. Jabriya, P.O.Box: 24923, Safat, Kuwait, Postal Code 13110, Kuwait. Fred@hsc.edu.kw

The incidence of cancer and its related morbidity and mortality remain on the increase in both developing and developed countries. Cancer remains a huge burden on the health and social welfare sectors worldwide and its prevention and cure remain two golden goals that science strives to achieve. Among the treatment options for cancer that have emerged in the past 100 years, cancer vaccine immunotherapy seems to present a promising and relatively safer approach as compared to chemotherapy and radiotherapy. The identification of different tumour antigens in the last fifteen years using a variety of techniques, together with the molecular cloning of cytotoxic T lymphocytes (CTLs)- and tumour infiltrating lymphocytes (TILs)-defined tumour antigens allowed more refining of the cancer vaccines that are currently used in different clinical trials. In a proportion of treated patients, some of these vaccines have resulted in partial or complete tumour regression, while they have increased the disease-free survival rate in others. These outcomes are more evident now in patients suffering from melanoma. This review provides an update on melanoma vaccine immunotherapy. Different cancer antigens are reviewed with a detailed description of the melanoma antigens discovered so far. The review also summarises clinical trials and individual clinical cases in which some of the old and current methods to vaccinate against or treat melanoma were used. These include vaccines made of autologous or allogenic melanoma tumour cells, melanoma peptides, recombinant bacterial or viral vectors, or dendritic cells.

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Cancer Biother Radiopharm. 2005 Oct;20(5):479-86.
A retrospective study of biochemotherapy for metastatic melanoma: the importance of dose intensity.
Minor DR, Madland MT, Kashani-Sabet M, Denny SR, Harvey WB.
California Pacific Medical Center, San Francisco, CA.

Background: The utility of biochemotherapy for metastatic melanoma remains controversial. Dose intensity has been recognized as an important determinant of response and survival in the chemotherapy of several malignancies but has not been studied in biochemotherapy. In this retrospective study, we described the relationship between achieved dose intensity and the response rate of inpatient decrescendo biochemotherapy at our center. Methods: A study of 38 consecutive patients with metastatic melanoma was undertaken. The planned doses were dacarbazine 800 mg/m(2) on day 1 or temozolomide 150 mg/m(2) on days 1-4, cisplatin 20 mg/m(2) on days 1-4, vinblastine 1.5 mg/m(2) on days 1-4, interferon-alpha-2b (Schering) 5 million IU (MIU)/m(2) on days 1-5, and interleukin-2 36 MIU on day 1, 18 MIU on day 2, and 9 MIU on days 3 and 4. Results: Of 38 patients that received a total of 204 cycles of therapy, 8 (21%) complete responses and 14 (37%) partial responses were observed for an objective response rate of 58%. Median survival was 19.6 months. Achieved dose intensity was high with patients receiving 98.7% interleukin- 2, 87.1% interferon, 90.7% dacarbazine (DTIC), 94% temozolomide, 87.2% cisplatin, and 89.7% vinblastine. Conclusions: Six cycles of inpatient decrescendo biochemotherapy can be given with highdose intensity and acceptable toxicity. High response rates with biochemotherapy for melanoma may correlate with dose intensity, dose density, and the number of cycles given on time.

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Cochrane Database Syst Rev. 2005 Oct 19;(4):CD003697.
Statins and fibrates for preventing melanoma.
Dellavalle R, Drake A, Graber M, Heilig L, Hester E, Johnson K, McNealy K, Schilling L, Dellavalle R.

BACKGROUND: Effective treatment for advanced melanoma is lacking. While no drug therapy currently exists for prevention of melanoma, in vitro, case-control, and animal model evidence suggest that lipid-lowering medications, commonly taken for high cholesterol, might prevent melanoma. OBJECTIVES: To assess the effects of statin or fibrate lipid-lowering medications on melanoma outcomes. SEARCH STRATEGY: We searched the Cochrane Skin Group Specialised Register (February 2003), CENTRAL (The Cochrane Library Issue 1, 2005), MEDLINE (to March 2003), EMBASE (to September 2003), CANCERLIT (to October 2002), Web of Science (to May 2003), and reference lists of articles. We approached study investigators and pharmaceutical companies for additional information (published or unpublished studies). SELECTION CRITERIA: Trials involving random allocation of study participants, where experimental groups used statins or fibrates and participants were enrolled for at least four years of therapy. DATA COLLECTION AND ANALYSIS: Three authors screened 109 abstracts of articles with titles of possible relevance. We then thoroughly examined the full text of 72 potentially relevant articles. We requested unpublished melanoma outcomes data from the corresponding author of each qualifying trial. MAIN RESULTS: We identified 16 qualifying randomised controlled trials (RCTs) (seven statin, nine fibrate). Thirteen of these trials (involving 62,197 participants) provided data on incident melanomas (six statin, seven fibrate). A total of 66 melanomas were reported in groups receiving the experimental drug and 86 in groups receiving placebo or other control therapies. For statin trials this translated to an odds ratio of 0.90 (95% confidence interval 0.56 to 1.44) and for fibrate trials an odds ratio of 0.58 (95% confidence interval 0.19 to 1.82).Subgroup analyses failed to show statistically significant differences in melanoma outcomes by gender, melanoma occurrence after two years of participation in trial, stage or histology, or trial funding. Subgroup analysis by type of fibrate or statin also failed to show statistically significant differences, except for the statin subgroup analysis which showed reduced melanoma incidence for lovastatin, based on one trial only (odds ratio 0.52, 95% confidence interval 0.27 to 0.99). AUTHORS' CONCLUSIONS: The melanoma outcomes data collected in this review of RCTs of statins and fibrates does not exclude the possibility that these drugs prevent melanoma. There was a 10% and 42% reduction for participants on statins and fibrates, respectively, however these results were not statistically significant. Until further evidence is established, limiting exposure to ultraviolet radiation remains the most effective way to reduce the risk of melanoma.

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Radiother Oncol. 2005 Oct 7; [Epub ahead of print]
A phase II trial of low-dose total body irradiation and subcutaneous Interleukin-2 in metastatic melanoma.
Safwat A, Schmidt H, Bastholt L, Fode K, Larsen S, Aggerholm N, von der Maase H.
Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.

BACKGROUND AND PURPOSE: Our own experimental data suggests a therapeutic synergism between low-dose total body irradiation (LTBI) and interleukin-2 (IL-2). PATIENTS AND METHODS: Forty-five patients received a maximum of 2 cycles of high dose subcutaneous (s.c.) IL-2 and LTBI. One treatment cycle included 5 weeks treatment followed by 2 weeks break and composed of a single radiation fraction 0.1Gy on days 1, 8, 22 and 30 and IL-2: 18 MUx2 daily s.c. on days 2 to 5 and days 16-19 as well as 9MUx2 daily s.c. on days 9-12 and 31-34. In 17 patients, flow cytometric analyses of the various subpopulations of immune cells were done on blood samples before the first LTBI fraction and 24h after LTBI as well as after the first week of treatment. RESULTS: Two patients (4.4%) had a partial response (PR) and 13 patients (29%) had stable disease (SD). The duration of the partial remission and stable disease did not exceed 3 months. The median overall survival was 5.8 months (95% CI, 4-8 months). Thirty-four of the 58 treatment cycles (74%) were given in 100% of the intended dose without modification or delay. The dose was modified in 15 cycles (26%) because of progression (6), liver toxicity (3), CNS toxicity (2), thrombocytopenia (1), lung morbidity (1) and itching (1). There were no treatment-related deaths. Flowcytometry data showed a significant increase in the percentage of cells carrying the beta chain of IL-2 receptor (CD122+), a significant increase in the percentage of NK cells (CD56+ cells) as well as a significant reduction in the percentage of B cells (CD20+) and monocytes (CD14+). CONCLUSIONS: This LTBI and IL-2 regimen was well tolerated, however it cannot be recommended because of its low clinical efficacy. No indication of increased efficacy or altered toxicity was seen using LTBI.

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Ophthalmology. 2005 Aug 9; [Epub ahead of print]
Outcomes of Iodine 125 Plaque Radiotherapy after Initial Observation of Suspected Small Choroidal Melanomas A Pilot Study.
Sobrin L, Schiffman JC, Markoe AM, Murray TG.
Department of Ophthalmology, Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, Florida.

PURPOSE: To determine the visual and survival outcomes for patients undergoing plaque radiotherapy of suspected small choroidal melanomas after observation for growth in a pilot study. DESIGN: Noncomparative interventional case series. PARTICIPANTS: Forty-five patients with suspected small choroidal melanomas who were seen at the Bascom Palmer Eye Institute between 1974 and 2001 and had iodine 125 (I(125)) plaque radiotherapy between 1991 and 2002. METHODS: Patients with suspected small choroidal melanomas were monitored by clinical examination, photography, and echography. When the melanoma grew or developed orange pigment, patients were treated with I(125) plaque radiotherapy. Outcomes included visual acuity, ocular complications, tumor dimensions, metastasis, and death. MAIN OUTCOME MEASURE: Melanoma-specific mortality. RESULTS: In our pilot study, 1 patient died from metastatic melanoma. One patient developed metastatic disease and is still alive. One patient developed marginal tumor recurrence after treatment and after enucleation was performed. Globe conservation was achieved in 97.8% of patients. In patients with tumor margins >2 mm from the optic nerve, vision was preserved with less than a doubling of the visual angle (within approximately 2 Snellen lines of preoperative acuity) in 90.6% (29/32) of patients at 1 year postoperatively, 65.6% (21/32) at 2 years, and 52.2% (12/23) in the long term (4-11 years). CONCLUSIONS: Five-year melanoma-specific mortality after I(125) plaque radiotherapy of suspected small choroidal melanomas was 3.9% (95% confidence interval, 0%-11.2%). This information can be used to counsel patients with small suspected choroidal melanomas and to compare with other treatment modalities.

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Br J Dermatol. 2005 Aug;153(2):254-73.
Thalidomide: dermatological indications, mechanisms of action and side-effects.
Wu JJ, Huang DB, Pang KR, Hsu S, Tyring SK.
Department of Dermatology, University of California, Irvine, Irvine, CA, U.S.A.

Summary Thalidomide was first introduced in the 1950s as a sedative but was quickly removed from the market after it was linked to cases of severe birth defects. However, it has since made a remarkable comeback for the U.S. Food and Drug Administration-approved use in the treatment of erythema nodosum leprosum. Further, it has shown its effectiveness in unresponsive dermatological conditions such as actinic prurigo, adult Langerhans cell histiocytosis, aphthous stomatitis, Behcet's syndrome, graft-versus-host disease, cutaneous sarcoidosis, erythema multiforme, Jessner-Kanof lymphocytic infiltration of the skin, Kaposi sarcoma, lichen planus, lupus erythematosus, melanoma, prurigo nodularis, pyoderma gangrenosum and uraemic pruritus. This article reviews the history, pharmacology, mechanism of action, clinical uses and adverse effects of thalidomide.

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Cancer. 2005 Aug 3; [Epub ahead of print]
Wide excision without radiation for desmoplastic melanoma.
Arora A, Lowe L, Su L, Rees R, Bradford C, Cimmino VC, Chang AE, Johnson TM, Sabel MS.
Department of Surgery, University of Michigan, Ann Arbor, Michigan.

BACKGROUND: Adjuvant radiation has been proposed for the treatment of patients with desmoplastic melanoma, who reportedly have local recurrence rates as high as 40-60%. The authors investigated local recurrence rates at a tertiary referral center to determine the success of wide excision alone for patients with desmoplastic melanoma. METHODS: A review of a prospectively maintained melanoma clinical data base identified 65 patients between March 1997 and March 2004 with pure cutaneous desmoplastic melanoma. Complete surgical, histopathologic, and staging information was collected along with data on outcome, including local, regional, and distant recurrence and survival. RESULTS: Similar to previous reports, patients with desmoplastic melanoma had a male-to-female ratio of 2 to 1, a mean age of 65.0 years (range, 31-92 yrs), and the majority of their tumors (55%) were located on the head and neck. The mean Breslow depth at diagnosis was 4.21 mm, with 38% of tumors thicker than 4.0 mm. All patients in this series underwent wide excision without radiation therapy. Surgical margins </= 2 cm were obtained for all trunk and extremity lesions and for 63% of head and neck lesions that measured > 1 mm in depth (63%). Margins of 1-2 cm were obtained for the remaining patients. Among 49 patients who had a minimum of 2 years of follow-up (mean, 3.7 yrs), the local recurrence rate was 4% (2 of 49 patients). Seventy-eight percent of the patients studied remained alive with no evidence of disease. CONCLUSIONS: Local recurrence rates in the current series were considerably lower than the historically reported rates. This finding suggests that, for patients with desmoplastic melanoma, wide local excision with careful attention to appropriate margins produces excellent local control rates without the need for adjuvant radiation. Cancer 2005. (c) 2005 American Cancer Society.

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Int J Radiat Oncol Biol Phys. 2005 Aug 1;62(5):1405-1411.
Proton beam radiotherapy of choroidal melanoma: The Liverpool-Clatterbridge experience.
Damato B, Kacperek A, Chopra M, Campbell IR, Errington RD.
Ocular Oncology Service, St. Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, United Kingdom.

Purpose To report on outcomes after proton beam radiotherapy of choroidal melanoma using a 62-MeV cyclotron in patients considered unsuitable for other forms of conservative therapy. Methods and Materials A total of 349 patients with choroidal melanoma referred to the Liverpool Ocular Oncology Centre underwent proton beam radiotherapy at Clatterbridge Centre for Oncology (CCO) between January 1993 and December 2003. Four daily fractions of proton beam radiotherapy were delivered, with a total dose of 53.1 proton Gy, and with lateral and distal safety margins of 2.5 mm. Outcomes measured were local tumor recurrence; ocular conservation; vision; and metastatic death according to age, gender, eye, visual acuity, location of anterior and posterior tumor margins, quadrant, longest basal tumor dimension, tumor height, extraocular extension, and retinal invasion. Results The 5-year actuarial rates were 3.5% for local tumor recurrence, 9.4% for enucleation, 79.1% for conservation of vision of counting fingers or better, 61.1% for conservation of vision of 20/200 or better, 44.8% for conservation of vision of 20/40 or better, and 10.0% for death from metastasis. Conclusion Proton beam radiotherapy with a 62 MeV cyclotron achieves high rates of local tumor control and ocular conservation, with visual outcome depending on tumor size and location.

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J Neurooncol. 2005 Jul 30; [Epub ahead of print]
Combined Razoxane and Radiotherapy for Melanoma Brain Metastases. A Retrospective Analysis.
Rhomberg W, Eiter H, Boehler F, Saely C, Strohal R.
Department of Radiooncology, Federal Academic Hospital of Feldkirch, Austria.

We retrospectively compared the efficacy of razoxane and radiotherapy with radiotherapy alone or in combination with a non-razoxane based medication in patients with melanoma brain metastases. From 19 assessable patients receiving whole brain irradiation with or without a boost (mean total dose 40.5 Gy) for measurable brain metastases, 8 patients underwent an additional razoxane therapy with 125 mg per os twice daily started 5 days before radiotherapy and given throughout the whole radiation period. The median razoxane dose was 6.25 g (range 3.2-8.0 g). Endpoints included radiation response rates, median survival time and 1-year survival rates. To generate reliable prognostic parameters for this non-randomized study population, the Score Index for Stereotactic Radiosurgery and the Radiation Therapy Oncology Group Recursive Partitioning Analysis score were applied. Radiotherapy with razoxane led to higher response rates (62% vs. 27%) and a lower percentage of progressive disease (12.5% vs. 36%) if compared with radiotherapy alone or with a non-razoxane based medication. This combination was associated with a longer median survival (5 months vs. 2.2 months; P=0.052) and a 1-year survival rate of 37.5% vs. 0% (P=0.027). Both treatment groups belonged to similar prognosis subsets. The treatment was well tolerated. Taken together our data support the therapeutic concept of a combined razoxane radiation therapy in melanoma patients with brain metastases. The favorable treatment effects are probably due to the radiosensitizing and the cytorallentaric mode of action of razoxane. Since the patient numbers are low, confirmatory studies are certainly necessary.

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Am Fam Physician. 2005 Jul 15;72(2):269-76.
Cutaneous melanoma: update on prevention, screening, diagnosis, and treatment.
Rager EL, Bridgeford EP, Ollila DW.
Department of Surgery, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, USA. rager@email.unc.edu

Melanoma is an increasingly common malignancy, and it affects a younger population than most cancers. Risk factors for melanoma include white race, sun sensitivity, family history of melanoma, and melanocytic nevi. Sunburn and intermittent sun exposure appear to increase the risk of developing melanoma. The role of population-based screening for skin cancer remains unclear. Consistent screening results in the diagnosis of thinner melanomas, but there is no evidence that this leads to decreased mortality. The ABCDs--asymmetry, border, color, diameter--can be used as a guide to differentiate melanoma from benign lesions. Suspicious pigmented lesions should undergo full thickness biopsy. Treatment consists of surgical resection, lymph node evaluation, and systemic therapy for some patients. Prognosis depends on the stage at diagnosis. Patients with melanoma require dose follow-up because they are at risk for recurrence and diagnosis of a second primary tumor. Preventive strategies for melanoma should emphasize seeking shade when outdoors, wearing protective clothing, and avoiding exposure during the peak sunlight hours.

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Invest New Drugs. 2005 Jul 18; [Epub ahead of print]
Phase II Study of Perifosine in Previously Untreated Patients with Metastatic Melanoma.
Ernst DS, Eisenhauer E, Wainman N, Davis M, Lohmann R, Baetz T, Belanger K, Smylie M.
London Regional Cancer Centre, 790 Commissioners Rd East, London, ON, N6A 4L6, scott.ernst@lrcc.on.ca.

Purpose: To assess the response rate and toxicity of the alkylphosphocholine analogue, perifosine, in patients with metastatic or recurrent malignant melanoma.Patients and Methods: Patients had histologically proven, unidimensionally measurable disease which was incurable by standard therapy. Prior adjuvant immunotherapy was allowed but patients had not received prior chemotherapy. Perisfosine was given orally as a loading dose of 900 mg on day 1 followed by a maintenance dose of 150 mg po on days 2-21 in a 28 day cycle. The loading dose was 300 mg on day 1 of all subsequent cycles. Tumour response was assessed every 2 cycles.Results: 18 patients were accrued over 7 mos. No objective responses occurred in the 14 evaluable patients. Three patients (21%) achieved stable disease after 2 cycles and 11 had progression. Seventeen patients were evaluable for toxicity. Grade 3 or 4 non-hematologic toxicities included: diarrhea (12%), arthralgia (12%), nausea (6%), headache (6%), and fatigue (6%). No grade 3 or 4 hematological or biochemical toxicity were observed. Seventy-seven percent of patients received >/=90% of planned cycle 1 dose intensity and 58% received >/=90% of planned dose for cycle 2+. Four patients required dose reductions; treatment was delayed in 5 patients; and 5 patients missed doses because of toxicity.Conclusions: Perifosine can be safely administered when given as an initial loading dose followed by daily maintenance therapy over 28 days. Gastrointestinal toxicity is common but generally of low grade. Hematological toxicity is minimal. No objective responses were observed. No further development of single-agent perifosine is recommended in malignant melanoma.

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Expert Opin Investig Drugs. 2005 Jul;14(7):885-92.
Novel agents in development for the treatment of melanoma.
Tarhini AA, Agarwala SS.
Division of Medical Oncology and Hematology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.

In 2005, melanoma is estimated to affect 55,000 Americans. Of these, 7700 are estimated to die from the disease. Immunological approaches have yielded the only newly FDA-approved agents for melanoma in 30 years, which includes high-dose bolus IL-2, based on durable responses in some patients with metastatic melanoma. A survival advantage was shown in two of three randomised clinical trials with high-dose IFN-alpha2b in the high-risk adjuvant setting. However, both agents are associated with high cost and toxicity rates. A number of novel therapeutic agents are undergoing active clinical investigation. The more promising of these will be discussed in this review, including bcl-2 antisense therapy, v-raf murine sarcoma viral oncogene homologue B1 inhibition, heat-shock proteins, anti-alphavbeta3 integrin monoclonal antibody, thalidomide and newer immunomodulatory drugs, and anti-cytotoxic T lymphocyte-associated protein-4 monoclonal antibody.

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Melanoma Res. 2005 Jun;15(3):209-12.
Combined chemoimmunotherapy of metastatic melanoma: a single institution experience.
Di Lauro V, Scalone S, La Mura N, Zanetti M, Nigri P, Freschi A, Veronesi A.
Division of Medical Oncology C, Centro di Riferimento Oncologico, Aviano, Italy.

The addition of cytokines, such as interferon alpha-2b and interleukin-2, to chemotherapy in metastatic melanoma has produced conflicting results in phase II and III trials. We report our experience with a chemoimmunotherapeutic regimen using subcutaneous cytokines. Twenty-eight patients with advanced melanoma (median age, 45 years; male to female ratio, 19 : 9) were treated. Doses were as follows: cisplatin, 20 mg/m intravenously (iv) days 1-4; vinblastine, 1.6 mg/m iv days 1-4; dacarbazine, 800 mg/m iv day 1; interferon alpha-2b, 5 MIU/m subcutaneously (sc) days 1-5; interleukin-2, 9 MIU/m sc days 1-5 and 8-12. Treatment was repeated every 3 weeks for a maximum of six cycles. The response was assessed after two cycles and toxicity at every cycle, according to World Health Organization (WHO) and National Cancer Institute (NCI) criteria, respectively. At a median follow-up of 8 months, only four patients (14%) were still alive. The overall response rate was 33%, with three (11%) complete responses lasting for 17, 14 and >24 months. There were six (22%) partial responses and three stable disease. Amongst the responders, three patients progressed at the level of the central nervous system. The median time to progression and overall survival were 3.5 and 9 months, respectively. The most common grade 3-4 toxicity was neutropenia, reported in 25 of the 28 patients (92%). Only two patients (7%) experienced neutropenic fever. Thrombocytopenia grade 3-4 occurred in seven of the 28 patients (25%), with only one patient needing transfusional support. One toxic death due to neutropenic fever occurred. It can be concluded that the chemoimmunotherapy schedule evaluated is active and may be considered for patients with metastatic melanoma who have a good performance status and a limited disease burden.

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Int J Radiat Oncol Biol Phys. 2005 May 20; [Epub ahead of print]
Local tumor control after (106)Ru brachytherapy of choroidal melanoma.
Damato B, Patel I, Campbell IR, Mayles HM, Errington RD.
Ocular Oncology Service, St. Paul's Eye Unit, Royal Liverpool University Hospital, Liverpool, United Kingdom.

PURPOSE: To report on local tumor control after (106)Ru brachytherapy for choroidal melanoma. METHODS AND MATERIALS: A total of 458 patients with choroidal melanoma were treated at a single institution between January 1993 and December 2001. The tumors had a median longest basal dimension of 10.6 mm and a median height of 3.2 mm. The brachytherapy was administered using a 15- or 20-mm plaque. For posterior tumors, the plaque was positioned eccentrically with its posterior edge aligned with the posterior tumor margin to reduce the radiation dose to the optic disk and fovea. A minimal scleral dose sufficient to cause visible choroidal atrophy provided a permanent ophthalmoscopic record of the distribution of choroidal irradiation. If radiotherapy to the posterior tumor was uncertain, adjunctive transpupillary thermotherapy was administered 6 months postoperatively. RESULTS: The actuarial rates of tumor recurrence were 1%, 2%, and 3% at 2, 5, and 7 years, respectively. Local tumor recurrence correlated with the longest basal tumor dimension (Cox univariate analysis, p = 0.02, risk ratio 1.41, 95% confidence interval 1.06-1.88). Seven of the nine eyes with recurrent tumor were salvaged with additional conservative therapy. CONCLUSION: The low rate of local tumor recurrence suggests that ruthenium plaque radiotherapy is effective with good case selection and if special measures are taken to ensure that the plaque is positioned correctly.

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Cancer. 2005 May 10;103(12):2584-2589 [Epub ahead of print]
A phase II study of bortezomib in the treatment of metastatic malignant melanoma.
Markovic SN, Geyer SM, Dawkins F, Sharfman W, Albertini M, Maples W, Fracasso PM, Fitch T, Lorusso P, Adjei AA, Erlichman C.
Melanoma Study Group, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.

BACKGROUND: Bortezomib is a proteasome inhibitor with manageable clinical toxicity and laboratory evidence of anti-melanoma activity. Therefore, it was considered for clinical testing in patients with metastatic melanoma. METHODS: Patients with metastatic melanoma and adequate hematologic, renal, and hepatic function were treated with bortezomib (a 1.5-mg/m(2) intravenous bolus twice weekly for 2 of every 3 weeks). Eligible patients were age >/= 18 years with an Eastern Cooperative Oncology Group performance status of 0-1. The primary goal of the current study was to evaluate the 18-week disease progression-free survival rate and tolerability of bortezomib in these patients. RESULTS: The current study was intended to treat 45 patients. It was closed at the planned interim analysis due to early evidence of insufficient clinical efficacy. Twenty-seven patients with a median age of 56 years (range, 32-77 years)were accrued. There were no major clinical responses to treatment. Only 6 patients (22%) achieved stable disease. Of these 6 patients, 4 were still stable after 4 cycles of treatment, but were removed from the study due to toxicity. The median time to disease progression was 1.5 months (95% confidence interval [95% CI], 1.4-1.6) with a median overall survival of 14.5 months (95% CI, 9-22). Having failed bortezomib, most patients proceeded to other clinical trials. Twenty-six patients were evaluable for toxicity. One patient was removed from the study for other reasons and could not return for the cycle evaluation and thus was never evaluated. Of the 26 patients, no Grade 4/5 treatment-related toxicities (using the National Cancer Institute Common Toxicity Criteria [version 2.0]) were reported. Eleven patients (42%) had Grade 3 toxicities (believed to be at least possibly related to treatment), including sensory neuropathy, thrombocytopenia, constipation, fatigue, ileus, abdominal pain, and infection without neutropenia. The median number of treatment cycles patients received was two (range, one to six treatment cycles). Two patients (7%) had 1 dose delay and 6 patients (22%) had dose reductions during 1 treatment cycle due to adverse events. CONCLUSIONS: Single-agent bortezomib, administered twice weekly x 2 weeks, every 3 weeks at a dose of 1.5 mg/m(2), was not found to be effective in the treatment of patients with metastatic melanoma. Cancer 2005. (c) 2005 American Cancer Society.

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Curr Treat Options Oncol. 2005 May;6(3):185-93.
Treatment of metastatic malignant melanoma.
Atallah E, Flaherty L.
Karmanos Cancer Institute, Wayne State University, 4100 John R, Detroit, MI 48201, USA. flaherty@karmanos.org.

The rapid increase in incidence of malignant melanoma has not been associated with better therapeutic options over the years. Single-agent chemotherapy or immunotherapy remain the treatments of choice when systemic therapy is offered. Dacarbazine (DTIC) is the chemotherapy of choice with a response rate of 16%. Other chemotherapies, including cisplatinum, paclitaxel, docetaxel and the DTIC analogue temozolomide, have shown activity in this disease. Based on their single-agent activity, several combination chemotherapies have been investigated with preliminary results that appeared promising. However, in randomized phase III trials the two most active chemotherapy combination regimens, cisplatin, vinblastine, and DTIC (CVD) and the Dartmouth regimen (DTIC, cisplatin, bischloroethylnitrosourea , and tamoxifen), did not prove to be superior to single-agent DTIC for overall survival. Immunotherapy with either interleukin (IL)-2 or interferon (IFN) has demonstrated response rates of 10% to 15% in appropriately selected patients. In patients who achieve a complete response, responses can be of greater durability than those with chemotherapy. However, IL-2 and IFN administration are associated with multiple side effects, and only physicians experienced in the management of such therapies should administer them. The potential benefit of combining chemotherapy with immunotherapy has led to multiple phase II trials of biochemotherapy that appeared to be associated with higher response rates and longer median survivals. However, several phase III trials have been completed that have not consistently demonstrated an improvement in either response rates or overall survival, and these approaches to therapy cannot be routinely recommended outside the context of a clinical trial. The surgical resection of isolated metastatic disease has demonstrated an important palliative benefit in those patients who present with solitary single-organ disease with the exception of the liver. Radiation has an important role in the palliative management of brain metastasis and symptomatic bony metastasis. Both stereotactic radiosurgery and whole brain radiotherapy have been used alone and in combination to benefit patients in this troubling clinical circumstance. Isolated limb perfusion and a newer technique, isolated limb infusion have demonstrated high response rates for those uncommon patients who develop recurrent disease isolated to a limb. In our opinion, if complete metastasectomy is not feasible and in the absence of brain metastases, single-agent IL-2 is a good initial treatment choice in appropriately selected patients. Single-agent chemotherapy with DTIC is the treatment of choice for patients who are not candidates for IL-2. Adoptive immunotherapy combining nonmyeloablative chemotherapy with high-dose IL-2 is a potentially promising therapeutic strategy under investigation. Targeted therapy is also an area of promising development as single agents, in combination, and combined with chemotherapy. The latter will be the focus of at least one upcoming cooperative group phase III trial.

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Laryngoscope. 2005 May;115(5):817-22.
Conjunctival melanoma: the role of conservative surgery and radiotherapy in regional metastatic disease.
Tatla T, Hungerford J, Plowman N, Ghufoor K, Keene M.
Department of Otorhinolaryngology--Head and Neck Surgery, St. Bartholomew's Hospital, West Smithfield, London, UK.

OBJECTIVE: To evaluate prognostic factors and determine the role of conservative surgery and radiotherapy in managing metastatic conjunctival malignant melanoma (MM) involving preauricular/submandibular lymph nodes. METHOD: A retrospective analysis (1990-2003) of clinical and histopathologic data from 12 patients presenting with regional metastases after failed local treatment for conjunctival MM. Patients received a common, multispecialty, conservative management approach: wide local excision, topical cryotherapy or radiotherapy to conjunctival MM (orbital exenteration for more advanced local disease), lumpectomy, and adjuvant "ring" radiotherapy of regional metastases, with chemotherapy for distant metastases. RESULTS: Median age at primary diagnosis was 51 (range 28-86) years with equal sex predilection. Six of the 12 patients had primary tumors of the bulbar conjunctiva; the remainder arose in the palpebral conjunctiva, the caruncle, or the fornix. Of 11 originating in primary acquired melanosis (PAM), 2 were amelanotic. Epithelioid tumor cells were noted histologically in seven of eight specimens in which cell type could be determined. Eight tumors metastasised to preauricular nodes, three to submandibular and one to both, with a median interval of 23 (range 12-108) months after primary diagnosis. After conservative surgery and "ring irradiation," 7 of 12 patients remained free of regional nodal relapse at median interval of 16 (range 3-126) months. Five patients developed regional nodal recurrence at median interval of 11 (range 6-13) months, 3 of whom were within radiotherapy portals. Eight patients developed distant metastasis at median interval of 44 (range 22-138) months. Eleven patients had tumor-related death. The mean Kaplan-Meier adjusted survival time after primary diagnosis was 76 months with death ensuing postregional metastasis within a median 18 (range 4-127) months. The sole survivor's follow-up duration was 56 months. CONCLUSION: Locoregional metastasis after treatment for conjunctival MM is associated with a poor prognosis. Both epithelioid tumor cells and PAM are associated with disseminating disease and poorer outcome. Literature review has failed to demonstrate advantages of mutilating radical surgery over a conservative approach in this rare disease.

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Cancer. 2005 Apr 28;103(12):2590-2597 [Epub ahead of print]
Temozolomide plus thalidomide in patients with brain metastases from melanoma.
Hwu WJ, Lis E, Menell JH, Panageas KS, Lamb LA, Merrell J, Williams LJ, Krown SE, Chapman PB, Livingston PO, Wolchok JD, Houghton AN.
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.

BACKGROUND: Temozolomide plus thalidomide is a promising oral combination regimen for the treatment of metastatic melanoma. The current Phase II study examined the efficacy and safety of this combination in chemotherapy-naive patients with brain metastases. METHODS: Patients with histologically confirmed metastatic melanoma and measurable brain metastases received temozolomide (75 mg/m(2) per day for 6 weeks with a 2-week break between cycles) plus concomitant thalidomide (200 mg/day escalating to 400 mg/day for patients < 70 years or 100 mg/day escalating to 250 mg/day for patients >/= 70 years). The primary end point was tumor response in the brain assessed every 8 weeks. RESULTS: Twenty-six patients with a median age of 60 years were treated. All patients had progressive brain metastases: 16 were symptomatic and 25 had extensive extracranial metastases. Eight patients had received whole-brain radiotherapy, 4 had received stereotactic radiotherapy, and 8 had received craniotomy with resection of hemorrhagic lesions. Fifteen patients completed >/= 1 cycle (median, 1 cycle; range, 0-4 cycles), and 11 discontinued treatment before completing 1 cycle (7 for intracranial hemorrhage, 2 for pulmonary embolism, 1 for deep vein thrombosis, and 1 for Grade 3 rash). Of 15 patients assessable for response, 3 had a complete or partial response (12% intent to treat) and 7 had minor response or stable disease in the brain. However, 5 of these 10 patients had disease progression at extracranial sites. The median survival period was 5 months for all 26 patients and 6 months for the 15 assessable patients. CONCLUSIONS: Temozolomide plus thalidomide was an active oral regimen for patients with brain metastases from malignant melanoma. Cancer 2005. (c) 2005 American Cancer Society.

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Br J Dermatol. 2005 Apr;152(4):673-8.
Desmoplastic malignant melanoma: a systematic review.
Lens MB, Newton-Bishop JA, Boon AP.
Genetic Epidemiology Division, Cancer Research UK, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK. markolens@aol.com

BACKGROUND: Desmoplastic melanoma (DM) is an uncommonly encountered type of malignant melanoma. The clinical appearance of DM can be highly variable and thus, diagnosis of this tumour is difficult and very often may mislead the physician. OBJECTIVES: To make a critical review of the contemporary literature on DM, to pool the data from published studies and to evaluate the clinical and morphological characteristics of this neoplasm. METHODS: All studies or reports on DM including 10 or more participants with reported clinical and histological characteristics of the tumour were included. RESULTS: In the 17 studies that met the inclusion criteria a total of 856 patients with DM was reported. There was a male predilection, with a male/female ratio of almost 2 : 1 (63% of the lesions were diagnosed in males). The head and neck were the most common sites of DM for both sexes (53.2%). The data confirmed that DM usually has an advanced Breslow thickness at the time of presentation. Histopathological diagnosis of DM is sometimes difficult and the absence of pigmentation is probably the major cause for failure to recognize DM histologically. The pooled data from included studies showed that the incidence of nodal metastasis is lower in patients with DM than in patients with other forms of cutaneous melanoma. CONCLUSIONS: Prompt definitive surgical excision is the treatment of choice for DM. Improved knowledge of the clinical behaviour and histological features of DM is important for more effective management of patients with DM.

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Clin Cancer Res. 2005 Apr 15;11(8):3009-16.
Phase II trial of karenitecin in patients with malignant melanoma: clinical and translational study.
Daud A, Valkov N, Centeno B, Derderian J, Sullivan P, Munster P, Urbas P, Deconti RC, Berghorn E, Liu Z, Hausheer F, Sullivan D.
Cutaneous Oncology, Experimental Therapeutics, and Gastrointestinal Oncology Programs, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA. daudai@moffitt.usf.edu

PURPOSE: A phase II trial of the novel camptothecin karenitecin (BNP1350) was conducted to determine its efficacy and tolerability in patients with metastatic melanoma. Patients were biopsied to determine topoisomerase expression at baseline and response to therapy. PATIENTS AND METHODS: Eligible patients had metastatic melanoma with up to three prior chemotherapy and/or any number of immunotherapy regimens. Treatment consisted of an i.v. infusion of 1 mg/m(2) karenitecin daily for 5 days with cycles repeated every 3 weeks. Fine-needle aspiration biopsies were done before treatment and on day 3 to determine topoisomerase expression from patients' tumors. RESULTS: Forty-three patients were evaluable for response and toxicity. Most patients (72%) had stage M1C disease and were previously exposed to chemotherapy (56%). The investigational agent was well tolerated with limited gastrointestinal side effects or fatigue. The major toxicity seen was reversible noncumulative myelosuppression. One patient had a complete response after 11 months of therapy. No partial responses were seen, but 33% of the patients had disease stabilization lasting > or =3 months. Topoisomerase I, IIalpha, and IIbeta expression and localization were determined in a subset of patients. Topoisomerase I expression was highest, followed by topoisomerase IIbeta and topoisomerase IIalpha. CONCLUSION: Karenitecin was a well-tolerated investigational agent in this phase II study; side effects were generally mild and mostly hematologic. Karenitecin has significant activity in metastatic melanoma. Melanoma metastases express high levels of topoisomerase I. We did not observe any compensatory increase in topoisomerase II upon treatment with karenitecin.

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Anticancer Res. 2005 Mar-Apr;25(2B):1441-7.
Temozolomide and cisplatin in avdanced malignant melanoma.
Daponte A, Ascierto PA, Gravina A, Melucci M, Scala S, Ottaiano A, Simeone E, Palmieris G, Comella G.
National Tumor Institute Via M Semmola, 80131 Naples, Italy. antoniodaponte@libero.it

BACKGROUND: Temozolomide (TMZ) is an oral alkylating agent; it produces DNA methyl adducts, which are removed by the DNA repair enzyme AGAT. In vitro studies suggest that CDDP may enhance the antitumor activity of TMZ due to the ability of cisplatin (CDDP) to down-regulate AGAT activity. In a previous phase I study, the combination of TMZ and CDDP was tested, and the recommended dose for each drug was defined. On the basis of these results, we designed a phase II study to evaluate the activity and safety profile of the TMZ-CDDP association in patients with advanced melanoma. PATIENTS AND METHODS: From March 2001 to March 2002, 37 patients with metastatic melanoma, not amenable to surgery, were enrolled in this study. All eligible patients were treated with the combination of CDDP 75 mg/m2 i.v. d 1, TMZ 200 mg/m2 p.o. days 1-5 recycled every 4 weeks. Interferon alpha2b (IFN alpha2b) was administered at the end of chemotherapy to responsive patients at the dose of 5 M.I. U s.c. 3 times a week for 1 year. RESULTS: A total of 174 courses were administered, with a median number of 4 courses/patient (range 1-10). After chemotherapy, 9 CRs and 9 PRs were observed for an overall response rate of 48.6% (95% C.I., 31.9%-65.6%). One of 5 patients with initial brain metastases showed a complete response to the therapy. Five out of 9 CR patients were still with no evidence of recurrence, ranging from 28+ to 82+ weeks. The median survival time was 48 weeks. The schedule was well tolerated, with the most frequent adverse events reported being nausea and vomiting (59%), alopecia (14%) and fatigue (11%), all well controlled by supportive therapy. Haemotological toxicities were mild to moderate. Side-effects attributable to IFN alpha2b were also mild and manageable. CONCLUSION: The combination of TMZ and CDDP seems to be active in untreated patients with advanced melanoma. Absence of recurrence in the majority (5/9; 56%) of CR patients seems to indicate that IFN may act on the duration of the response to chemotherapy. The schedule was well tolerated, with nausea and vomiting as the most frequent adverse events.

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J Clin Oncol. 2005 Feb 1;23(4):889-98.
Phase I and pharmacokinetic study of oral irinotecan given once daily for 5 days every 3 weeks in combination with capecitabine in patients with solid tumors.
Soepenberg O, Dumez H, Verweij J, Semiond D, Dejonge MJ, Eskens FA, Steeg JT, Selleslach J, Assadourian S, Sanderink GJ, Sparreboom A, van Oosterom AT.
Department of Medical Oncology, Erasmus University Medical Center-Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, PO Box 5201, 3008 AE Rotterdam, the Netherlands; e-mail: o.soepenberg@erasmusmc.nl.

PURPOSE To assess the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary antitumor activity of oral irinotecan given in combination with capecitabine to patients with advanced, refractory solid tumors. PATIENTS AND METHODS Patients were treated from day 1 with irinotecan capsules given once daily for 5 consecutive days (50 to 60 mg/m(2)/d) concomitantly with capecitabine given twice daily for 14 consecutive days (800 to 1,000 mg/m(2)); cycles were repeated every 21 days. Results Twenty-eight patients were enrolled and received 155 cycles of therapy (median, five cycles; range, one to 18 cycles). With irinotecan 60 mg/m(2)/d and capecitabine 2 x 800 mg/m(2)/d, grade 3 delayed diarrhea in combination with grade 2 nausea (despite maximal antiemetic support) and grade 3 anorexia and colitis, were the first-cycle dose-limiting toxicities in two of six patients, respectively. At the recommended doses (irinotecan 50 mg/m(2)/d; capecitabine 2 x 1,000 mg/m(2)/d), side effects were mostly mild to moderate and uniformly reversible. Pharmacokinetic analysis showed that there was no interaction between oral irinotecan and capecitabine, and that body-surface area was not significantly contributing to the observed pharmacokinetic variability. Confirmed partial responses were observed in two patients with gallbladder carcinoma and in one patient with melanoma. Disease stabilization was noted in 16 patients. CONCLUSION The recommended phase II doses for oral irinotecan and capecitabine are 50 mg/m(2)/d for 5 consecutive days, and 2 x 1,000 mg/m(2)/d for 14 consecutive days repeated every 3 weeks, respectively.

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Cancer. 2005 Jan 19;103(4):780-787 [Epub ahead of print]
The feasibility of adjuvant interferon alpha-2b in children with high-risk melanoma.
Navid F, Furman WL, Fleming M, Rao BN, Kovach S, Billups CA, Cain AM, Amonette R, Jenkins JJ, Pappo AS.
Department of Hematology/Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

BACKGROUND: It has been shown that induction high-dose interferon alpha-2b (IFN-alpha-2b) followed by maintenance therapy improves recurrence-free survival in adults with high-risk, resected melanoma. In this study, the feasibility and toxicity of this regimen were evaluated in newly diagnosed pediatric patients with Stage III melanoma involving regional lymph nodes. METHODS: Fifteen patients age </= 18 years with newly diagnosed Stage III melanoma were enrolled on an institutional protocol. Patients were treated with wide local excision, sentinel lymph node biopsy, lymph node dissection, and adjuvant biotherapy, consisting of induction therapy with 20 million IU/m(2) per day IFN-alpha-2b intravenously 5 times per week for 4 weeks followed by maintenance therapy with IFN-alpha-2b 10 million IU/m(2) per day subcutaneously 3 times per week for 48 weeks. Patients were monitored for toxicity and tumor recurrence. RESULTS: All patients completed induction therapy, and nine patients completed maintenance therapy. Three patients currently are receiving maintenance, 2 patients developed recurrent disease on maintenance therapy, and 1 patient stopped maintenance therapy 5 weeks early. During induction therapy, Grade 3-4 toxicities included 14 episodes of neutropenia in 11 patients, 3 episodes of leukopenia in 2 patients, and 6 episodes of liver transaminase elevations in 5 patients. Dose modifications were required in four patients. During maintenance therapy, Grade 3-4 toxicities included 23 episodes of neutropenia in 10 patients and 2 episodes of liver transaminase elevations in 2 patients. Three patients required dose modifications. All toxicities were reversible with interruption or dose modification of therapy, and no patients were taken off study due to toxicity. CONCLUSIONS: High dose IFN-alpha-2b for 4 weeks followed by a lower dose maintenance phase for 48 weeks was feasible in children with Stage III melanoma and was associated with tolerable toxicity. Cancer 2005. (c) 2005 American Cancer Society.

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Int J Cancer. 2005 Jan 11; [Epub ahead of print]
Peptide vaccination after repeated resection of metastases can induce a prolonged relapse-free interval in melanoma patients.
Letsch A, Keilholz U, Fluck M, Nagorsen D, Asemissen AM, Schmittel A, Thiel E, Scheibenbogen C.
Hematology, Oncology and Transfusion Medicine, Medizinische Klinik III, Charite Campus Benjamin Franklin, Berlin, Germany.

This pilot study was carried out to gain a first insight into the effects of peptide vaccination in melanoma patients in the high-risk adjuvant disease setting. From the adjuvant peptide vaccination studies carried out in our institution since 1998, we identified all melanoma patients with a history of at least 3 completely resected metastases during the year preceding enrollment into the trial and describe the clinical and immunologic observations. Out of a total of 44 patients with resected cutaneous melanoma entered into adjuvant peptide vaccination trials, 9 patients were identified with more than 3 metastases in the year before vaccination. After initiation of vaccination, 2 patients remained relapse-free for 27 and 42+ months, 2 patients experienced single or several initial relapses and subsequent relapse-free intervals of 18 and 65+ months, whereas 5 patients progressed. In both patients with relapse after prolonged relapse-free intervals, the relapses were initially confined to the small intestine and could be resected. Induction or boosting of functional tyrosinase peptide-specific T cells was noted in 6 of 8 patients, including all 4 patients with prolonged relapse-free intervals. In conclusion, adjuvant peptide vaccination was associated with cessation of recurrences in 4 of 9 patients, of whom all 4 had an immunologic response to the vaccine. (c) 2004 Wiley-Liss, Inc.

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Radiother Oncol. 2005 Jan;74(1):71-3.
Treatment of medium-sized juxtapapillary melanoma with external Co-60 photon therapy.
Roberge D, Nordstrom S, Corriveau C, Gosselin M, Olivares M, Shenouda G.
Division of Radiation Oncology, McGill University, Montreal General Hospital, D5.400, 1650 Cedar Avenue, Montreal, Que., Canada H3G 1A4.

Twenty-six patients with medium-sized juxtapapillary choroidal melanomas were irradiated using D-shaped Co-60 beams. The overall 5-year actuarial survival was 86% with a trend towards better 5-year local control with 70 vs. 60Gy (100 vs. 75%). Of patients with pre-treatment >/=20/200 visual acuity, 37% had functional vision at 5 years.

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Cancer Biother Radiopharm. 2004 Dec;19(6):770-5.
High-dose continuous infusion plus pulse interleukin-2 and famotidine in melanoma.
Quan W, Ramirez M, Taylor WC, Vinogradov M, Khan N, Jackson S.
Division of Medical Oncology and Hematology, Medical College of Ohio, Toledo, OH.

High-dose, continuous infusion interleukin-2 (IL-2) regimens generate greater Lymphokine Activated Killer cell (LAK) cytotoxicity in vitro and a higher rebound lymphocytosis in vivo than do bolus IL-2 regimens. Lymphocytes initially activated by continuous infusion IL-2 then subsequently pulsed with IL-2 have increased cytotoxicity against cancer cells. Famotidine may enhance the lysis of tumors by cytotoxic lymphocytes. Fourteen patients with melanoma were treated with famotidine 20 mg intravenously twice per day and continuous infusion IL-2 (18 MIU/sq m/24 hours) for 72 hours, followed by a 24-hour rest, then IL-2 18 MIU/sq m over 15-30 minutes for 1 dose (12 patients) or daily for 3 doses (2 patients). Most common toxicities were fever, nausea/emesis, hypophosphatemia, hypomagnesemia, and rigors. Nine partial responses (64% response rate; 95% Confidence Interval: 39%-84%) have been seen. Median survival has not been reached at greater than 10 months. Two patients responding to therapy showed an increase in detectable CD 56+ cells in serial subcutaneous or lymph node biopsies, while 1 patient undergoing progression of disease had no such infiltrate. High-dose, 72-hour continuous infusion plus pulse interleukin-2 with famotidine has activity in melanoma. CD 56+ cells may play a role in responding patients.

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Cancer Biother Radiopharm. 2004 Dec;19(6):758-63.
Individualized Synthetic Peptide Vaccines with GM-CSF in Locally Advanced Melanoma Patients.
Atzpodien J, Fluck M, Reitz M.
Fachklinik Hornheide an der Universitat Munster, Munster, Germany, Europaisches Institut fur Tumor Immunologie und Pravention, Bonn, Germany.

We report on 10 patients with resected American Joint Committee on Cancer (AJCC)stage IIA-IIIC melanoma receiving individualized adjuvant peptide vaccinations derived from the melanosomal antigens MelanA/MART1, gp100 and tyrosinase, according to patient tumor associated HLA restricted antigen expression, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF). Except for 1 patient, all patients had received systemic pretreatment with immunotherapy (n = 8), chemoimmunotherapy (n = 1), chemotherapy (n = 1), or cefalectin therapy (n = 1). Upon prior therapy, 7 of 10 patients had progressed with subcutaneous/cutaneous (n = 2), lymph node (n = 3), or subcutaneous/cutaneous and lymph node (n = 2)metastases, which were subsequently resected prior to vaccination. After a mean of 6.5 vaccination cycles, progression-free survival was 6 months (median, range 2-10). Five patients were relapse-free for 1+ up to 21+ months, 3 patients developed a solitary cutaneous metastasis, and 2 patients developed multiple metastases during vaccination. Overall, vaccine treatment was well tolerated, with no severe side-effects. Eight of 10 patients developed local delayed type hypersensitivity (DTH)reactions to synthetic peptides after the first or second injection. In 2 patients, transient fever, nausea, diarrhea, and muscle pain of National Cancer Institute (NCI)Grade I occurred. In summary, individualized synthetic peptide vaccination, combined with GM-CSF, was feasible and warrants further clinical investigation.

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Cancer Biother Radiopharm. 2004 Dec;19(6):754-7.
Continuous infusion interleukin-2 and antihistamines in melanoma: a retrospective review showing activity of this combination.
Evangelista-Dean M, Khan N, Quan W.
Department of Medicine, East Carolina University School of Medicine, Greenville, NC.

A recent randomized trial suggests that there may be an advantage in terms of survival with the combination of histamine and subcutaneous interleukin-2 (IL-2), compared to IL-2 alone. It has been postulated, then, that antihistamines may actually be antagonistic to IL-2 and, therefore, interfere with its antitumor activity. Because antihistamines such as cimetidine and ranitidine are commonly used as prophylaxis against gastrointestinal toxicity commonly seen with IL-2, and, because antihistamines may increase natural killer cell activity, it is reasonable to examine the response rate for this combination. An OVID Medline(R) literature search between 1985 and 2003 was done. Continuous infusion (CIV) interleukin- 2 was used as the reference therapy because of the relatively constant IL-2 levels generated by this approach. Included studies were those in which either cimetidine, ranitidine, or famotidine were regularly scheduled and administered concurrently with IL-2, typically for gastrointestinal ulcer prophylaxis. Six (6) studies were identified. A total of 21 patients responded to therapy. Total response rate was 11%, with a 95% Confidence Interval: 7-17%. Four (4) complete responses were noted. Complete response rate was 2%, with a 95% Confidence Interval: 1-6%. These response rates are consistent with previously noted IL-2 response rates. In this retrospective review of CIV IL-2 and antihistamines, this combination appears to be active in melanoma. There appears to be no deleterious effect of routine antihistamine on the CIV IL-2 response rate.

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Cancer Biother Radiopharm. 2004 Dec;19(6):730-7.
Tumor-infiltrating lymphocytes and interleukin-2: dose and schedules of administration in the treatment of metastatic cancer.
Dillman R, Schiltz P, Priest CD, Barth N, Beutel L, Leon C, O'connor A, Nayak S.
Hoag Cancer Center, Newport Beach, CA.

Purpose: The potential for therapeutic use of tumor-infiltrating lymphocytes (TIL), as adoptive cellular therapy has been touted for many years with some encouraging reports in patients with metastatic melanoma. Materials and Methods: We previously described methodologies for TIL production and phenotypic characterization of TIL generated in our laboratory between 1991 and 1995 in semipermeable bags and between 1996 and 2000 in bioreactors. Patients treated in the earlier era were to have received a hybrid bolus and a 12-hour continuous infusion of interleukin (IL)-2 (total, 48 MIU), while in the latter era 4 days of interferon- alpha preceded the TIL and IL-2; which was given by a hybrid schedule that included bolus and 72- hour continuous IL-2 (total, 96 MIU). There were 55 patients, including 23 patients with melanoma, 9 patients with renal cell carcinoma, and 8 patients with colorectal cancer. There was only 1 objective tumor response, which was noted in a patient with renal cell carcinoma. The 55 patients who received these products were grouped in cohorts by treatment era, quantity of TIL received, amount of IL-2 intended, and different combinations of TIL and IL-2. Results: There was no difference in survival by production method (treatment era), or amount of IL-2 given with TIL, but 33 patients who received an intermediate or higher dose of TIL (mean = 54.4 x 10(9)) had a median survival of 11.8 months, compared to 6.4 months for 22 patients who received 1 low-dose TIL (mean = 6.48 x 10(9)) (p = 0.059, log rank test). The objective response rate in this heterogeneous group of patients was not encouraging. The data suggest there may be a dose/benefit relationship between the total number of TIL infused and survival.

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J Chemother. 2004 Nov;16 Suppl 4:77-82.
Platinums: extending their therapeutic spectrum.
Muggia FM, Fojo T.
New York University School of Medicine, NY, NY 10016, USA. franco.muggia@med.nyu.edu

Three decades since the introduction of cisplatin into clinical cancer treatment, this drug and its second generation analogues, carboplatin and oxaliplatin, form an integral part of recent evolving achievements in the treatment of solid tumors. For example, landmark studies have established a role for cisplatin after resection in lung cancer, and improved survival from platinum-based chemoradiation in cancer of the uterine cervix and combination chemotherapy in mesothelioma, small cell lung, ovarian, and endometrial cancers. Colon cancer survival has improved with the addition of oxaliplatin to its treatment. Here we summarize how insights into the mechanism of action of platinum compounds and studies of their structure-activity relationships may identify platinums with unusual selectivity towards tumors such as melanoma, renal cell, and breast cancer and other cancers not usually treated with existing platinums. Both new drug development and mechanistic studies with established drugs should lead to the next generation of clinical studies with platinum compounds, and their integration with emerging 'targeted therapies'.

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Eur J Surg Oncol. 2004 Dec;30(10):1107-12.
Isolated limb infusion with fotemustine after dacarbazine chemosensitisation for inoperable loco-regional melanoma recurrence.
Bonenkamp JJ, Thompson JF, de Wilt JH, Doubrovsky A, de Faria Lima R, Kam PC.
The Sydney Melanoma Unit, Royal Prince Alfred Hospital, Sydney, Australia.

BACKGROUND: Isolated limb infusion (ILI) is a simple yet effective alternative to conventional isolated limb perfusion for the treatment of advanced melanoma of the extremities. PATIENTS AND METHODS: The study group comprised 13 patients with very advanced limb disease who had failed to achieve a satisfactory response to one or more ILIs with melphalan, and in whom amputation was the only other realistic treatment option. The aim of this study was to evaluate the efficacy and toxicity of ILI with fotemustine after systemic chemosensitisation with dacarbazine (DTIC). RESULTS: Complete remission was achieved in four patients and partial remission in eight patients, with a median response duration of 3 months. Limb salvage was achieved in five of 12 assessable patients (42%). Limb toxicity peaked 9 days after ILI; two patients experienced Wieberdink grade IV (severe) toxicity and four patients had grade V toxicity (requiring early amputation). CONCLUSIONS: ILI with fotemustine after DTIC chemosensitisation can be successful when gross limb disease has not been controlled by one or more ILIs with melphalan. However, it cannot be recommended as a routine method of treatment for advanced melanoma of the extremities because of the high incidence of severe limb toxicity.

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J Gene Med. 2004 Nov 10 [Epub ahead of print]
DNA vaccination against tumors.
Prud'homme GJ.
Department of Laboratory Medicine and Pathobiology, St. Michael's Hospital and University of Toronto, Toronto, Ontario, Canada.

DNA vaccines have been used to generate protective immunity against tumors in a variety of experimental models. The favorite target antigens have been those that are frequently expressed by human tumors, such as carcinoembryonic antigen (CEA), ErbB2/neu, and melanoma-associated antigens. DNA vaccines have the advantage of being simple to construct, produce and deliver. They can activate all arms of the immune system, and allow substantial flexibility in modifying the type of immune response generated through codelivery of cytokine genes. DNA vaccines can be applied by intramuscular, dermal/epidermal, oral, respiratory and other routes, and pose relatively few safety concerns. Compared to other nucleic acid vectors, they are usually devoid of viral or bacterial antigens and can be designed to deliver only the target tumor antigen(s). This is likely to be important when priming a response against weak tumor antigens. DNA vaccines have been more effective in rodents than in larger mammals or humans. However, a large number of methods that might be applied clinically have been shown to ameliorate these vaccines. This includes in vivo electroporation, and/or inclusion of various immunostimulatory molecules, xenoantigens (or their epitopes), antigen-cytokine fusion genes, agents that improve antigen uptake or presentation, and molecules that activate innate immunity mechanisms. In addition, CpG motifs carried by plasmids can overcome the negative effects of regulatory T cells. There have been few studies in humans, but recent clinical trials suggest that plasmid/virus, or plasmid/antigen-adjuvant, prime-boost strategies generate strong immune responses, and confirm the usefulness of plasmid-based vaccination. Copyright (c) 2004 John Wiley & Sons, Ltd.

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J Immunother. 2004 Nov;27(6):442-451.
Active Specific Immunotherapy of Melanoma with a GM3 Ganglioside-Based Vaccine: A Report on Safety and Immunogenicity.
Guthmann MD, Bitton RJ, Carnero AJ, Gabri MR, Cinat G, Koliren L, Lewi D, Fernandez LE, Alonso DF, Gomez DE, Fainboim L.
From the *Immunogenetics Division, Hospital de Clinicas, University of Buenos Aires, Buenos Aires, Argentina; daggerLaboratory of Molecular Oncology, Department of Science and Technology, Quilmes National University, Bernal, Buenos Aires, Argentina; double daggerInstituto de Oncologia Angel Roffo, University of Buenos Aires, Buenos Aires, Argentina; section signHospital Carlos G. Durand, Buenos Aires, Argentina; Hospital Juan A. Fernandez, Buenos Aires, Argentina; and paragraph signVaccines Department, Center of Molecular Immunology, Havana, Cuba.

A novel cancer vaccine was obtained by combining GM3 ganglioside with Neisseria meningitidis outer membrane protein complex to obtain very-small-size proteoliposomes (GM3/VSSP). The authors report the results of a phase 1 study of intramuscular administration of GM3/VSSP/Montanide ISA 51 to patients with metastatic melanoma. Twenty-six patients were included in three dose-level cohorts of 120, 240, and 360 mug. The first five doses (induction phase) were given at 2-week intervals, and the remaining four doses were given monthly. Patients were evaluated for dose-related toxicities and antitumor effects. In addition, serum and peripheral blood mononuclear cells were obtained at baseline and throughout treatment to evaluate humoral and cellular immune responses. One episode of severe hypotension and fever was observed in a patient included at the highest dose level. Other toxicities consisted of local reactions at the site of injection and mild fever and chills. Five doses of GM3/VSSP induced an anti-GM3 IgM response in 44% of patients. Serum reactivity was also observed against melanoma cell lines and tumor biopsies. GM3/VSSP was shown to induce very strong in vitro IFNgamma secretion in all evaluated melanoma patients. Furthermore, in one patient IFNgamma secretion was shown to be GM3-specific. A 62% reduction of a mediastinal mass was documented in one patient (partial response), while a second patient benefited from initial disease stabilization followed by tumor reduction in nonmeasurable soft tissue lesions accompanied by vitiligo.

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Vaccine. 2004 Nov 15;23(1):97-113.
On the road to a tumor cell vaccine: 20 years of cellular immunotherapy.
Yannelli JR, Wroblewski JM.
Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky School of Medicine, Combs Building, Room 312, 800 Rose Street, Lexington, KY 40536, USA.

Cellular immunotherapy (CI), as we now know it, began in the early 1980s with the use of lymphokine-activated killer cells (LAK) and progressed to the use of the immunologically specific, tumor-infiltrating lymphocytes (TIL). TIL were shown to be particularly effective against melanoma and it was in these trials that we learned the importance of immunologic specificity for tumor. With the identification and characterization of tumor antigens recognized by TIL, we now see the use of these antigens in various forms constituting vaccines. Investigators are using tumor antigens alone or in combination with dendritic cells (DCs), the body's most efficient and powerful antigen-presenting cell. Therapies are being delivered to many patients with different types of cancer in order to combat bulky disease, eliminate micro-metastatic disease, and provide a memory mechanism to fight tumor recurrence. This review will detail the past 18 years and present the developments that have been made in this therapy. Many believe that with continued development, immunotherapy will provide a fourth modality of cancer therapy.

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Cancer. 2004 Nov 15;101(10):2247-56.
Pioglitazone and rofecoxib combined with angiostatically scheduled trofosfamide in the treatment of far-advanced melanoma and soft tissue sarcoma.
Reichle A, Bross K, Vogt T, Bataille F, Wild P, Berand A, Krause SW, Andreesen R.
Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany.

BACKGROUND: Combined treatment approaches targeting tumor cells as well as stromal cells may control chemorefractory malignancies. In the current study, the authors sought to test one such combined approach in the treatment of chemorefractory melanoma and soft tissue sarcoma. METHODS: A Phase II trial was initiated to analyze the activity of a continuously administered molecularly targeted treatment regimen (daily pioglitazone [45 mg administered orally] and rofecoxib [25 mg administered orally]) combined with sequentially added angiostatic chemotherapy for patients with previously treated metastatic melanoma (n = 19) or soft tissue sarcoma (n = 21). Angiostatic chemotherapy consisted of trofosfamide (50 mg) administered orally 3 times daily beginning on the 15th day after the start of molecularly targeted therapy. RESULTS: Forty patients were evaluable for response and toxicity. Major side effects (World Health Organization Grade 3 or 4) were not observed. Objective responses and disease stabilization lasting longer than 6 months were noted in 11% and 11%, respectively, of all patients with melanoma and in 19% and 14%, respectively, of all patients with soft tissue sarcoma. Complete remission was noted in one patient with melanoma and in three patients with sarcoma. Both normal C-reactive protein (CRP) levels and CRP levels that decreased by > 30% during the 14-day biomodulator pretreatment period were found to be predictive of prolonged progression-free survival. CONCLUSIONS: To our knowledge, the current study is the first to demonstrate that a novel, completely orally administered combined biomodulator/metronomic chemotherapy regimen may be active and well tolerated in patients with chemorefractory malignancies. Cancer 2004. (c) 2004 American Cancer Society.

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Expert Rev Anticancer Ther. 2004 Oct;4(5):823-35.
Adjuvant therapy for malignant melanoma.
Stoutenburg JP, Schrope B, Kaufman HL.

Malignant melanoma is increasing in incidence worldwide, and many patients remain at a significant risk of recurrence following surgical resection. Over the past 30 years, interferon-alpha has been the only agent approved for adjuvant therapy of melanoma. This review summarizes the rationale for adjuvant therapy, and discusses the roles of interferon, immunotherapy, chemotherapy and radiation therapy in the adjuvant setting. New approaches and novel combinations that appear promising for the adjuvant therapy of malignant melanoma are also outlined.

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Pediatr Blood Cancer. 2004 Oct 1 [Epub ahead of print]
High-risk surgically resected pediatric melanoma and adjuvant interferon therapy.
Chao MM, Schwartz JL, Wechsler DS, Thornburg CD, Griffith KA, Williams JA.
Department of Pediatric Hematology-Oncology, University of Michigan Health System, Ann Arbor, Michigan.

BACKGROUND: Pediatric patients with high-risk surgically resected melanoma are at risk for relapse, yet little is known about these young patients and how they tolerate high-dose interferon therapy. PROCEDURE: We reviewed medical records of patients (</=18 years) with high-risk melanoma referred to the University of Michigan Pediatric Hematology-Oncology service between January 1989 and July 2003. RESULTS: Fourteen patients were identified with high-risk resected melanoma. The median age at diagnosis was 8.5 years. The median time to establish diagnosis was 9 months. Primary lesions were diagnosed as unequivocal melanoma, atypical epithelioid melanocytic proliferations, or atypical Spitz tumor with indeterminate malignant potential. Twelve patients had a positive sentinel lymph node (SLN) biopsy or a palpable regional lymph node and underwent regional lymph node dissection (LND). Two patients with unequivocal melanoma with Breslow depth >4 mm had negative SLN biopsies. Twelve patients received adjuvant high-dose interferon. The following toxicities were observed: constitutional symptoms, gastrointestinal symptoms, depression or neuropsychiatric symptoms, myelosuppression, elevated AST or ALT, hypothyroidism, and hypertension. Grade 3 or 4 toxicities were uncommon with exception of neutropenia, resulting in modification of therapy in one patient. All patients are alive and free of disease at follow-up (median 24.5 months). CONCLUSIONS: Invasive melanoma can occur in very young children. Despite early signs of malignancy, there is often a delay in diagnosis. Histologically, diagnosis may be difficult because of overlap with Spitz nevi. Pediatric patients tolerated adjuvant high-dose interferon well and may be less likely than adults to require therapy modification secondary to toxicities. (c) 2004 Wiley-Liss, Inc.

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Melanoma Res. 2004 Oct;14(5):415-20.
The role of taxanes in the treatment of metastatic melanoma.
Gogas H, Bafaloukos D, Bedikian AY.
First Department of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital, Athens 11 527, Greece. hgogas@hol.gr

The management of patients with metastatic malignant melanoma remains difficult. Conventional chemotherapy has been disappointingly ineffective. Dacarbazine (DTIC) is considered to be one of the most active single agents with a response rate of approximately 15-20%. Many patients who initially respond to treatment subsequently relapse. Clearly, there is a need for improvement, and the evaluation of new agents is warranted. This article reviews current phase II studies of single-agent taxanes and their combinations in patients with metastatic melanoma, and examines the likely impact of taxanes on treatment strategies. Response rates from phase II trials with single-agent taxanes vary from 3.3% to 17%. Prolonged durations of disease control are observed. Combinations of taxanes with DTIC, temozolomide, cisplatin, carboplatin and tamoxifen have demonstrated response rates from 12% to 41%, suggesting that they are at least as effective as various other combination regimens. Encouraging results have been produced in the second-line metastatic setting. Taxanes, both as single agents and in combinations, may be a treatment option for some patients with metastatic melanoma, especially in the second-line setting.

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J Clin Oncol. 2004 Oct 13 [Epub ahead of print]
Phase I Clinical Trial of the Immunocytokine EMD 273063 in Melanoma Patients.
King DM, Albertini MR, Schalch H, Hank JA, Gan J, Surfus J, Mahvi D, Schiller JH, Warner T, Kim K, Eickhoff J, Kendra K, Reisfeld R, Gillies SD, Sondel P.
University of Wisconsin, Madison, WI; Departments of Medicine, Human Oncology, Surgery, Pathology, Biostatistics, Pediatrics, and Genetics, Ohio State University, Columbus, OH; The Scripps Research Institute, La Jolla CA; and EMD-Lexigen Research Center, Billerica, MA.

PURPOSE: To evaluate the safety, toxicity, in vivo immunologic activation, and maximum-tolerated dose (MTD) of EMD 273063 (hu14.18-IL-2) in patients with metastatic melanoma. PATIENTS AND METHODS: Thirty-three patients were treated with EMD 273063, a humanized anti-GD2 monoclonal antibody (mAb) linked to interleukin-2 (IL-2). EMD 273063 was given as a 4-hour intravenous infusion on days 1, 2, and 3 of week 1. Patients with stabilization or regression of disease could receive a second course of treatment at week 5. Dose levels evaluated were 0.8, 1.6, 3.2, 4.8, 6.0, and 7.5 mg/m(2)/d. RESULTS: Nineteen of 33 patients completed course 1 with stable disease and went on to receive course 2. Eight patients had stable disease on completion of course 2. Grade 3 adverse events included hypophosphatemia (11 patients), hyperglycemia (three patients), hypotension (two patients), thrombocytopenia (one patient), hypoxia (three patients), elevated hepatic transaminases (two patients), and hyperbilirubinemia (one patient). Opioids were required for treatment-associated arthralgias and/or myalgias during 17 of 52 treatment courses. No grade 4 adverse events were observed. Dose-limiting toxicities at the MTD included hypoxia, hypotension, and elevations in AST/ALT. Grade 3 toxicities were anticipated based on prior studies of IL-2 or anti-GD2 mAbs, and all resolved. Immune activation was induced, as measured by lymphocytosis, increased peripheral-blood natural killer activity, and cell numbers, and increased serum levels of the soluble alpha chain of the IL-2 receptor complex. CONCLUSION: Treatment with the immunocytokine EMD 273063 induced immune activation and was associated with reversible clinical toxicities at the MTD of 7.5 mg/m(2)/d in melanoma patients.

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Laryngoscope. 2004 Sep;114(9):1660-7.
High-dose Cisplatin with amifostine: ototoxicity and pharmacokinetics.
Ekborn A, Hansson J, Ehrsson H, Eksborg S, Wallin I, Wagenius G, Laurell G.
Department of Otolaryngology-Head and Neck Surgery, Karolinska Institute, Stockholm, Sweden. Andreas.Ekborn@ks.se

OBJECTIVES/HYPOTHESIS: Ototoxicity is a common side effect of high-dose cisplatin treatment. Thiol-containing chemoprotectors ameliorate cisplatin ototoxicity under experimental conditions. The trial was initiated to test the efficacy of amifostine protection in high-dose cisplatin treatment (125-150 mg/m) for metastatic malignant melanoma, to correlate the ototoxic outcome with cisplatin pharmacokinetics, and to evaluate the importance of using a selective analytical method for the quantification of cisplatin. STUDY DESIGN: Prospective study of 15 patients with stage IV malignant melanoma. METHODS: Clinical follow-up of therapeutic response, pure-tone audiometry, and analysis of cisplatin and its monohydrated complex in blood ultrafiltrate by liquid chromatography with postcolumn derivatization were performed. Ultrafiltered blood platinum was analyzed by inductively coupled plasma mass spectrometry. RESULTS: Ototoxicity and gastrointestinal toxicity were the most prominent side effects. Three patients ultimately required hearing aids. All patients had audiometric changes at one or more frequencies after the second treatment course, and all but one patient reported auditory symptoms. No correlation was found between hearing loss and blood cisplatin pharmacokinetics. Platinum levels determined by inductively coupled plasma mass spectrometry were higher than total platinum levels calculated from cisplatin and monohydrated complex concentrations obtained by liquid chromatography analysis. CONCLUSION: Ototoxicity was unacceptable despite amifostine treatment. Cisplatin pharmacokinetics during the first treatment course were not predictive of hearing loss. Amifostine caused a lowering of dose-normalized area under the concentration-time curve for cisplatin and monohydrated complex. Use of the unselective inductively coupled plasma mass spectrometry analysis leads to an overestimation of active drug. Selective analysis of cisplatin is especially important when evaluating cisplatin pharmacokinetics during chemoprotector treatment.

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Cancer. 2004 Aug 15;101(4):825-33.
Initial treatment of melanoma brain metastases using gamma knife radiosurgery: an evaluation of efficacy and toxicity.
Radbill AE, Fiveash JF, Falkenberg ET, Guthrie BL, Young PE, Meleth S, Markert JM.
Department of Medicine, Children's Hospital, Boston, Massachusetts, USA.

BACKGROUND: Melanoma is the primary malignancy that is most likely to metastasize to the brain. Because such an event carries an almost uniformly poor prognosis, the current study reviewed outcomes and identified associated prognostic indicators for 51 consecutive patients receiving gamma knife (GK) radiosurgery in the initial treatment of 188 intracranial melanoma metastases. METHODS: Data were collected retrospectively from a single-center GK radiosurgery database and from primary patient medical records and radiographs. RESULTS: At presentation, 71% of patients had multiple intracranial metastases, and extracranial metastases were present in 66% of patients. Thirty-two patients (63%) were initially treated with GK radiosurgery alone, whereas the remainder received GK radiosurgery in combination with surgery and/or whole-brain radiotherapy (WBRT). Overall median survival from time of GK radiosurgery was 26 weeks. Subgroup analysis revealed a median survival of 77 weeks for patients presenting with a single lesion, compared with 20 weeks for patients presenting with multiple lesions (P = 0.003). Patients in recursive partitioning analysis (RPA) Class I survived a median of 57 weeks, compared with a median survival of 20 weeks for patients in RPA Class II or III (P = 0.002). Although long-term imaging follow-up revealed that a majority of patients experienced distant brain metastases, multivariate analysis showed that distant metastases occurred significantly sooner in patients with extracranial metastases (P = 0.0004). Addition of initial WBRT had no significant effect on the time to development of new brain metastases (P = 0.13). Local control (crude) was observed in 81% of lesions initially treated with GK. Patients experienced improved or stable symptoms for a median of 37 weeks post-GK radiosurgery. CONCLUSIONS: Survival analyses supported the use of GK radiosurgery in the initial treatment of patients with melanoma brain metastases, with best results occurring in patients presenting with a single lesion. Copyright 2004 American Cancer Society.

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Eur J Surg Oncol. 2004 Aug;30(6):686-91.
Selective lymphadenectomy in sentinel node-positive patients may increase the risk of local/in-transit recurrence in malignant melanoma.
Thomas JM, Clark MA.
Melanoma and Sarcoma Unit, Department of Surgery, The Royal Marsden Hospital, 203 Fulham Road, London SW3 6JJ, UK. josephmeirion.thomas@rmh.nthames.nhs.uk

AIM: To determine whether sentinel lymph node biopsy (SLNB) for cutaneous malignant melanoma, particularly when followed by selective lymphadenectomy (SL) if involved nodes are found, alters the incidence of local/in-transit recurrence. METHODS: A literature overview of SLNB with or without SL has been performed, concentrating on the reported site(s) of first recurrence, and with specific reference to the incidence of local/in-transit recurrence. This is compared to the incidence after wide local excision (WLE) alone. RESULTS: The incidence of local/in-transit recurrence after WLE alone is 2.5-6.3% over a given range of tumour thickness, and is 9.0% after SLNB (with or without SL). In the latter group, the local/in-transit recurrence rate is 5.7% following SLNB alone in SN-negative patients, and is 20.9% after SLNB plus SL in SN-positive patients. CONCLUSIONS: The incidence of local/in-transit recurrence following selective lymphadenectomy in sentinel node-positive patients may be greater than four times the incidence expected. This possible iatrogenic risk should be confirmed or refuted by randomised controlled trial. Until then the SLNB procedure should be regarded as experimental and not performed outside validation trials.

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Melanoma Res. 2004 Aug;14(4):289-294.
The effect of temozolomide-based chemotherapy in patients with cerebral metastases from melanoma.
Bafaloukos D, Tsoutsos D, Fountzilas G, Linardou H, Christodoulou C, Kalofonos HP, Briassoulis E, Panagiotou P, Hatzichristou H, Gogas H.
Department of Oncology, Metropolitan Hospital, N. Faliro; Department of Plastic Surgery and Microsurgery, General Hospital of Athens 'G. Gennimatas', Athens; AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki; Henry Dunan Hospital, Athens; 'Rio' Hospital, University of Patras, Patras; University of Ioannina, Ioannina; First Department of Medicine, University of Athens, Athens, Greece.

Cerebral metastases from melanoma are correlated with a poor prognosis. Temozolomide is an oral alkylating agent that can cross the blood-brain barrier and in phase II and III trials, patients with advanced metastatic melanoma achieved overall response rates of 13 to 21%. The present study evaluated the efficacy and toxicity of temozolomide-based chemotherapy in patients with cerebral metastases from melanoma. Twenty-five patients (median age 48 years) with histologically confirmed stage IV melanoma and cerebral metastases treated with temozolomide-based chemotherapy. 10 patients received temozolomide plus docetaxel, nine patients temozolomide plus cisplatin and six patients temozolomide as single agent. Six patients achieved an objective response (24%). All responses were partial. The disease was stable in five patients (20%) and 13 patients progressed (52%). The median response duration was 6.9 months (range 1.8 to 16 months). The median time to progression (TTP) for all patients was 2 months, compared with a median TTP of 3.9 months, among responders and a median TTP of 1.8 months, for patients who remained stable or progressed (P<0.0001). The median survival time for the entire patient population was 4.7 months. The median survival for responders was 5.5 months and for non-responders was 3.6 months. The difference was statistically significant (P<0.05). The toxicity was mild. The most frequently reported adverse event were myelotoxicity and nausea and vomiting. Four patients developed grade 3/4 leukopenia, two grade 4 neutropenia, and one patient developed grade 3 thrombocytopenia. There was no treatment discontinuation caused by toxicity. Temozolomide-based chemotherapy may have a role in patients with cerebral metastases from melanoma. Further exploration is required. Toxicity was manageable.

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Eur J Cancer. 2004 Aug;40(12):1825-36.
Re-evaluating the role of dacarbazine in metastatic melanoma: what have we learned in 30 years?
Eggermont AM, Kirkwood JM.
Department of Surgical Oncology, Erasmus University Medical Center, Groene Hilledijk 301, Daniel Den Hoed Cancer Center, Rotterdam, The Netherlands.

Since dacarbazine was approved for treating metastatic melanoma in the 1970s, numerous studies have evaluated whether different schedules and dacarbazine-based combinations improve clinical outcomes. This evidence-based review shows that combining dacarbazine with other drugs having single-agent activity and/or hormonal or immunotherapeutic compounds fails to provide clinically meaningful improvements in survival, and may increase toxicity. In patients with metastatic melanoma, dacarbazine was previously administered in cycles of multiple consecutive daily infusions per cycle. The introduction of potent antiemetics, together with concerns relating to patient comfort and clinic utilisation time, has enabled regimens involving single-dose dacarbazine, administered at the same total dose per cycle. These appear to be as effective as multiple-dose schedules, are well tolerated, and are more straightforward to administer. Single-administration dacarbazine (850-1000 mg/m(2)), once every 3 weeks, is currently the standard reference therapy in patients with advanced melanoma. New effective therapies are urgently needed for this treatment-refractory disease.

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Lancet Oncol. 2004 Aug;5(8):497-508.
The present and future role of photodynamic therapy in cancer treatment.
Brown SB, Brown EA, Walker I.
Centre for Photobiology and Photodynamic Therapy, School of Biochemistry and Microbiology, University of Leeds, UK. s.b.brown@leeds.ac.uk

It is more than 25 years since photodynamic therapy (PDT) was proposed as a useful tool in oncology, but the approach is only now being used more widely in the clinic. The understanding of the biology of PDT has advanced, and efficient, convenient, and inexpensive systems of light delivery are now available. Results from well-controlled, randomised phase III trials are also becoming available, especially for treatment of non-melanoma skin cancer and Barrett's oesophagus, and improved photosensitising drugs are in development. PDT has several potential advantages over surgery and radiotherapy: it is comparatively non-invasive, it can be targeted accurately, repeated doses can be given without the total-dose limitations associated with radiotherapy, and the healing process results in little or no scarring. PDT can usually be done in an outpatient or day-case setting, is convenient for the patient, and has no side-effects. Two photosensitising drugs, porfirmer sodium and temoporfin, have now been approved for systemic administration, and aminolevulinic acid and methyl aminolevulinate have been approved for topical use. Here, we review current use of PDT in oncology and look at its future potential as more selective photosensitising drugs become available.

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Ann Oncol. 2004 Aug;15(8):1151-60.
Thalidomide in cancer medicine.
Eleutherakis-Papaiakovou V, Bamias A, Dimopoulos MA.
Department of Clinical Therapeutics, University of Athens, School of Medicine, Athens, Greece.

Thalidomide, an oral agent with antiangiogenic and immunomodulatory properties, is being investigated extensively in the management of advanced cancer. Multiple studies with large numbers of patients have confirmed that this drug has significant activity in multiple myeloma. Some patients with myelofibrosis or myeodysplatic syndromes may reduce their need for transfusions after thalidomide treatment. The activity of thalidomide in solid tumors is less prominent. Studies in Kaposi's sarcoma, malignant melanoma, renal cell carcinoma and prostate cancer appear more promising especially when thalidomide is combined with biological agents or with chemotherapy. Limited activity was demonstrated in patients with glioma, while thalidomide appears to be inactive in patients with head and neck cancer, breast or ovarian cancer.

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Expert Rev Vaccines. 2004 Aug;3(4):403-11.
Heat shock protein-based cancer vaccines.
Oki Y, Younes A.
Department of Lymphoma and Myeloma, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. ayounes@mdanderson.org

Heat shock proteins (HSPs) exist ubiquitously across all species and function as chaperones stabilizing and delivering peptides. Tumor-derived HSP-peptide complex has been known to induce immunity against the original tumor in preclinical studies. HSP-based vaccines work across tumor types and bypass the need for identifying the responsible peptide(s) for inducing immunity. These vaccines are tumor- and patient-specific in that they capture the tumor cells' fingerprints. HSP-based vaccines have been studied in early phase clinical trials, mostly using HSP glycoprotein 96, for various types of malignancies including melanoma, renal cell carcinoma, gastric cancer, pancreatic cancer, low-grade lymphoma, colorectal cancer and chronic myelogenous leukemia. All showed minimal toxicity and potential efficacy. Phase III studies for melanoma and renal cell carcinoma are ongoing. HSP-based vaccines are a novel vaccine preparation with a promising role in cancer management. Further studies to determine the administering strategy and specific indication are warranted.

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Br J Dermatol. 2004 Jul;151(1):91-8.
Temozolomide and interferon alpha 2b in metastatic melanoma stage IV.
Richtig E, Hofmann-Wellenhof R, Pehamberger H, Forstinger Ch, Wolff K, Mischer P, Raml J, Fritsch P, Zelger B, Ratzinger G, Koller J, Lang A, Konrad K, Kindermann-Glebowski E, Seeber A, Steiner A, Fialla R, Pachinger W, Kos C, Klein G, Kehrer H, Kerl H, Ulmer H, Smolle J.
Department of Dermatology, University of Graz, Austria. erika.richtig@uni-graz.at

BACKGROUND: A multicentre, centrally randomized, open-labelled study with temozolomide and interferon (IFN)-alpha 2b was carried out to study the therapeutic effect in patients with metastatic melanoma stage IV. OBJECTIVES: The response rate, efficacy, side-effects, reasons for discontinuation of therapy and survival rate of 47 patients treated with temozolomide in combination with two different dosing regimens of IFN-alpha 2b were documented. PATIENTS/METHODS: Twenty-nine male and 18 female patients (mean age 57.6 years, range 34-74) were centrally randomized to two different arms: 20 patients received a treatment schedule with temozolomide 150 mg m(-2) on days 1-5 orally every 28 days in combination with IFN-alpha 2b 10 MIU m(-2) every other day and 27 patients received temozolomide 150 mg m(-2) on days 1-5 every 28 days in combination with IFN-alpha 2b in a fixed dose of 10 MIU every other day. RESULTS: We observed an overall response rate of 27.6% comprising five complete remissions (10.6%: one patient group A, four patients group B), in two of these five patients at the last follow-up in the study (4.3%, both in group B); and eight partial remissions (17%: six patients in group A, two patients in group B), in three of these eight patients at the last follow-up in the study (6.4%, two patients in group A, one patient in group B). Three patients showed stable disease (6.4%: one patient in group A, two patients in group B). Mean survival was 14.5 months [95% confidence interval (CI) 10-19] with no significant differences between treatment groups. However, there was a significant correlation with response after three cycles (log rank test, P < 0.03). Within the 32 patients who completed at least three cycles of therapy, seven patients (three in group A and four in group B) with a partial or complete response showed a significantly better mean survival of 30.6 months (95% CI 19.1-42) compared with 25 patients who did not respond (13.7 months 95% CI 9.2-18.3). In total, patients with at least one complete remission showed the longest survival (37.1 months 95% CI 26.3-47.9), followed by patients with at least one partial response (17.4 95% CI 10.9-23.9). Major side-effects of the treatment were nausea, vomiting, headache, leucopenia, thrombopenia, elevation of liver function parameters and neurological symptoms. In five patients, the side-effects led to a discontinuation of treatment: neurological symptoms (two patients), sepsis (one patient), brain haemorrhage (one patient) and exanthema (one patient). There were no treatment-related deaths. CONCLUSIONS: The combination of temozolomide and IFN-alpha 2b can easily be administered and shows tolerable toxicity. When an objective response occurs after three cycles, it indicates a significant survival advantage.

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Anticancer Res. 2004 May-Jun;24(3b):1837-42.
Combined treatment with histamine dihydrochloride, interleukin-2 and interferon-alpha in patients with metastatic melanoma.
Lindner P, Rizell M, Mattsson J, Hellstrand K, Naredi P.
Department of Surgery, Sahlgrenska University Hospital, SE-413 45 Goteborg, Sweden.

BACKGROUND: Histamine inhibits phagocyte-derived production of reactive oxygen species and improves the anti-tumour efficiency of interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) in vitro and in tumour-bearing animals. PATIENTS AND METHODS: In a phase-II study, twenty-seven patients with stage IV melanoma received subcutanous injections of histamine dihydrochloride (histamine) 1.0 mg and IL-2 2.4 MIU/m2 twice daily (BID) days 1-5 and 8-12. IFN-alpha 3 MIU once daily was administered throughout a cycle (days 1-28; n=14). Alternatively, bolus doses of IL-2 10 MIU/m2 BID days 1 and 2 and histamine days 1-28 (n=13) were administered. The aim was to study efficiency (survival and tumour response), toxicity and histamine pharmacokinetics. RESULTS: The median survival time was 11.3 (2.5-45) months. One patient achieved a complete response and 3 patients had partial responses. The compounds were safely self-administered with low toxicity. Plasma histamine concentrations significantly increased after an injection of histamine over 10 minutes (3 +/- 1 vs. 63 +/- 27 nmol/l). CONCLUSION: Histamine, IL-2 and IFN-alpha treatment is safe, well-tolerated and tumour responses were observed. The putative efficiency of histamine as an adjunct to cytokine therapy in metastatic melanoma needs to be confirmed in later randomized trials.

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Clin Dermatol. 2004 May-Jun;22(3):251-65.
Immunotherapy for melanoma.
Komenaka I, Hoerig H, Kaufman HL.
Section of Surgical Oncology and Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York, USA.

The immunogenicity of melanoma and the identification of melanoma-associated antigens is the basis for immunotherapy. This review will discuss the current status of melanoma immunotherapy with a focus on non-specific cytokines and highly specific vaccines, including peptides, viruses, dendritic cells, and whole cell vaccines. The passive transfer of melanoma-specific monoclonal antibodies and T-cells will also be reviewed. The problem of tumor escape and the association of immunotherapy to autoimmunity will be discussed. The use of immunotherapy in combination with other therapeutic agents and genetic profiling to predict responses suggests that immunotherapy will continue to play a role in the treatment of melanoma.

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Clin Dermatol. 2004 May-Jun;22(3):240-50.
Surgical treatment of stage IV melanoma.
Spanknebel K, Kaufman HL.
Department of General Surgery, Columbia University College of Physicians and Surgeons, New York, New York, USA.

Surgical therapy plays an important role in the management of selected patients with metastatic melanoma. Patients are frequently symptomatic from metastatic lesions, have few effective therapeutic options, and are faced with dismal outcomes. Surgical resection may provide successful palliation of symptomatic lesions with low morbidity and operative mortality. In carefully selected patients, resections performed with curative intent may result in improved survival if a pattern of disease recurrence suggestive of favorable tumor biology is present, and if complete resection of tumor is achieved. Because the majority of post-surgical metastatic patients eventually relapse and succumb to distant disease, adjuvant immunotherapeutic strategies are currently being evaluated.

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Cancer. 2004 Apr 15;100(8):1699-704.
A Phase II trial of vinorelbine tartrate in patients with disseminated malignant melanoma and one prior systemic therapy: a Southwest Oncology Group study.
Whitehead RP, Moon J, McCachren SS, Hersh EM, Samlowski WE, Beck JT, Tchekmedyian NS, Sondak VK; Southwest Oncology Group.
University of Texas Medical Branch, Galveston, Texas, USA.

BACKGROUND: Single-agent chemotherapy with dacarbazine continues to be the standard of care for the treatment of metastatic melanoma. However, there is a large population of patients who have failed first-line therapy and might benefit from additional treatment. In the current study, the authors evaluated the antitumor effects and toxicity of vinorelbine therapy in patients who had failed one prior systemic therapy. METHODS: Patients were required to have a histologic diagnosis of melanoma and be of Stage IV with measurable disease, a Southwest Oncology Group (SWOG) performance status (PS) of 0-2, no evidence of brain metastases, and adequate bone marrow and liver function. Treatment was comprised of vinorelbine given at a dose of 30 mg/m(2)/week by intravenous bolus. RESULTS: Twenty-four patients were registered to the study, 3 of whom were determined to be ineligible. The 21 eligible patients had a median age of 58 years with a SWOG PS of 0 in 7 patients, 1 in 13 patients, and 2 in 1 patient. There were no complete or partial responses observed, for a response rate of 0 of the 21 patients studied (95% confidence interval [95% CI], 0-16%); the study closed after the first stage of accrual. The estimated median progression-free survival was 2 months (95% CI, 1.5-3.3 months) and the estimated median overall survival was 6 months (95% CI, 3.7-8.3 months). There was one death due to febrile neutropenia reported, with six patients experiencing one or more Grade 4 toxicities, including neutropenia/granulocytopenia, leukopenia, dyspnea, and fatigue. CONCLUSIONS: Despite impressive preclinical activity against melanoma, vinorelbine does not appear to have enough clinical activity to be of interest in previously treated patients with disseminated melanoma. The progression-free and overall survival results noted in previously treated patients in the current study were similar to results reported in prior SWOG Phase II trials in untreated patients. The group of previously treated patients may be used to evaluate new agents for the treatment of disseminated melanoma. Copyright 2004 American Cancer Society.

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Ann Surg Oncol. 2004 Apr 12 [Epub ahead of print]
Isolated Limb Perfusion Prolongs the Limb Recurrence-Free Interval After Several Episodes of Excisional Surgery for Locoregional Recurrent Melanoma.
Noorda EM, Takkenberg B, Vrouenraets BC, Nieweg OE, Van Geel BN, Eggermont AM, Hart GA, Kroon BB.
Department of Surgery, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Rotterdam, The Netherlands.

BACKGROUND: The influence of isolated limb perfusion (ILP) on the limb recurrence-free interval (LRFI) and the number of lesions per recurrence was studied for patients with frequently recurring regional in-transit metastases previously managed by excisional surgery. METHODS: All 43 patients who had their first ILP for a third or further limb recurrence were selected from our computer database of 451 patients who underwent therapeutic ILP for recurrent extremity melanoma in our centers. Eighteen patients had resectable and 25 had locally unresectable lesions at the time of ILP. The patients had a total of 269 intervals between treatment of their primary melanoma and last recurrence or last follow-up. Median follow-up was 35 months (interquartile range, 14-64 months). RESULTS: The median LRFI decreases over time from primary melanoma to the third or further recurrence for which ILP was performed (P < 0.001). The median LRFI is 4.7 times longer (95% confidence interval [CI], 2.8-7.9; P < 0.001) after ILP in comparison with the last interval before ILP. Patients with resectable lesions have a median LRFI that is 5.9 times longer (95% CI, 2.7-13; P < 0.001). In all patients, the number of lesions increases by 22% per recurrence number (95% CI, 10%-35%; P = 0.02). At the same recurrence number, patients before ILP have a 2.6-fold higher (95% CI, 1.6-4.5) mean number of lesions than do patients after ILP (P < 0.001). CONCLUSIONS: ILP lengthens the LRFI and decreases the number of lesions per recurrence significantly in patients with repeatedly recurrent limb melanoma. Therefore, ILP could be a valuable adjunct to excisional surgery for in-transit metastases in these patients whose LRFIs tend to shorten over time.

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Curr Opin Oncol. 2004 Mar;16(2):155-60.
Role of surgery in patients with stage IV melanoma.
Wong SL, Coit DG.
Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. coitd@mskcc.org

PURPOSE OF REVIEW: The purpose of this brief review is to highlight recent advances in the surgical treatment of metastatic melanoma; to review factors important in the decision-making process of selecting the most appropriate patients for resection; and to discuss the current literature in the context of site of recurrence. RECENT FINDINGS: While there are relatively few new findings on the surgical treatment of metastatic melanoma, recent reports do support prior observations in the field. The recently revised staging system for melanoma groups metastatic disease according to prognostic features. There is currently a great deal of interest in the use of 18-fluorodeoxyglucose positron emission tomography (FDG-PET) to more accurately evaluate metastatic disease. The use stereotactic radiosurgery for brain metastases has expanded recently and adds to local treatment options. When procedures are performed with palliative intent, treatment goals must be clearly defined and communicated among the patient, family and surgeon. Improved understanding of the goals of palliative surgery may be facilitated by the concept of a palliative triangle, which helps define the decision making process among the patient, family members, and surgeon. SUMMARY: Metastatic melanoma is usually associated with a dismal prognosis. When a procedure is performed with palliative intent, appropriately selected patients usually experience reliable relief of symptoms and improved quality of life. Improved survival after a complete resection with curative intent is often predicted by good performance status, longer disease-free interval, limited extent of metastatic disease, and less aggressive tumor biology.

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Curr Opin Oncol. 2004 Mar;16(2):161-6.
Management of brain metastases in patients with melanoma.
Tarhini AA, Agarwala SS.
Department of Medicine and Division of Hematology/Oncology, Melanoma Center, University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Pittsburgh, PA 15232, USA.

PURPOSE OF REVIEW: Melanoma is the third most common metastatic brain tumor in the United States and is a major cause of morbidity and mortality. The development of more effective therapies for melanoma brain metastases is a major unmet clinical need and is summarized in this review. RECENT FINDINGS: Management strategies include symptomatic treatment with corticosteroids and anticonvulsants, and definitive therapy in the form of whole-brain radiation therapy, surgical resection, stereotactic radiosurgery, and systemic therapy. The data on whole-brain radiation therapy show little impact on survival, but there is evidence that it may improve neurologic deficits. Surgery may provide a survival advantage in combination with whole-brain radiation therapy in the management of a single brain melanoma metastasis, compared with whole-brain radiation therapy alone. Stereotactic radiosurgery may offer a survival advantage (in a select group of patients with limited disease) when used alone or in combination with whole-brain radiation therapy, compared with whole-brain radiation therapy alone. Fotemustine, temozolomide, and thalidomide are three agents with high central nervous system penetration that are being actively investigated as part of systemic therapy. SUMMARY: The currently available therapeutic options offer palliative relief of symptoms in most patients and a survival advantage in selected patients with melanoma and brain metastases. An urgent need exists to further define these treatments in the context of randomized trials, several of which are under way in the United States and abroad.

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Oncol Rep. 2004 Mar;11(3):559-95.
Recent clinical trials using cisplatin, carboplatin and their combination chemotherapy drugs (review).
Boulikas T, Vougiouka M.
Regulon, Inc, Mountain View, CA 94043, USA. teni@regulon.org

Cisplatin continues to play a central role in cancer chemotherapy in spite of its toxicity. It is used as first-line chemotherapy against epithelial malignancies of lung, ovarian, bladder, testicular, head and neck, esophageal, gastric, colon and pancreatic but also as second- and third-line treatment against a number of metastatic malignancies including cancers of the breast, melanoma, prostate, mesothelioma, leiomyosarcomas, malignant gliomas and others. Cisplatin has become the gold standard treatment against cervical cancer in combination with radiotherapy. This review summarizes the state of the art on clinical trials published mainly in 2002 using cisplatin and carboplatin in their combinations with other anticancer drugs. For most advanced cancers the response rate to chemotherapy is about 50% in first-line treatments and about 15% in second- or third-line treatments; for example response rates of 25-50% have been observed for chemonaive patients with advanced non-small cell lung cancer treated with cisplatin or carboplatin in combination with gemcitabine or taxanes and in exceptional cases these rates are up to 80% with addition of radiotherapy. Response rates are very discouraging in second- or third-line chemotherapy treatments (7-25%). Despite an increase in response rate from the use of modern-day chemotherapy drugs, no major difference in long-term survival has been achieved. It is a high priority to invent novel approaches for cancer treatment. It is hoped that a fraction of the numerous experimental drugs will show virtues in the anticancer arena especially combined with existing treatment regimens. Efforts should focus on diminution of side effects improving the quality of life of the patient. A preferential tumor targeting of chemotherapy treatments would bring a revolution in molecular medicine and would greatly advance cancer therapy in the upcoming years.

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N Engl J Med. 2004 Feb 19;350(8):757-66.
Excision margins in high-risk malignant melanoma.
Thomas JM, Newton-Bishop J, A'Hern R, Coombes G, Timmons M, Evans J, Cook M, Theaker J, Fallowfield M, O'Neill T, Ruka W, Bliss JM; United Kingdom Melanoma Study Group; British Association of Plastic Surgeons; Scottish Cancer Therapy Network.
Royal Marsden Hospital National Health Service Trust, London, United Kingdom.

BACKGROUND: Controversy exists concerning the necessary margin of excision for cutaneous melanoma 2 mm or greater in thickness. METHODS: We conducted a randomized clinical trial comparing 1-cm and 3-cm margins. RESULTS: Of the 900 patients who were enrolled, 453 were randomly assigned to undergo surgery with a 1-cm margin of excision and 447 with a 3-cm margin of excision; the median follow-up was 60 months. A 1-cm margin of excision was associated with a significantly increased risk of locoregional recurrence. There were 168 locoregional recurrences (as first events) in the group with 1-cm margins of excision, as compared with 142 in the group with 3-cm margins (hazard ratio, 1.26; 95 percent confidence interval, 1.00 to 1.59; P=0.05). There were 128 deaths attributable to melanoma in the group with 1-cm margins, as compared with 105 in the group with 3-cm margins (hazard ratio, 1.24; 95 percent confidence interval, 0.96 to 1.61; P=0.1); overall survival was similar in the two groups (hazard ratio for death, 1.07; 95 percent confidence interval, 0.85 to 1.36; P=0.6). CONCLUSIONS: A 1-cm margin of excision for melanoma with a poor prognosis (as defined by a tumor thickness of at least 2 mm) is associated with a significantly greater risk of regional recurrence than is a 3-cm margin, but with a similar overall survival rate. Copyright 2004 Massachusetts Medical Society

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Oncology (Huntingt). 2004 Jan;18(1):99-107; discussion 107-10, 113-4.
Radiotherapy for cutaneous malignant melanoma: rationale and indications.
Ballo MT, Ang KK.
Department of Radiation Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, Texas, USA. mballo@mdanderson.org

The use of radiation as adjuvant therapy for patients with cutaneous malignant melanoma has been hindered by the unsubstantiated belief that melanoma cells are radioresistant. An abundance of literature has now demonstrated that locoregional relapse of melanoma is common after surgery alone when certain clinicopathologic features are present. Features associated with a high risk of primary tumor recurrence include desmoplastic subtype, positive microscopic margins, recurrent disease, and thick primary lesions with ulceration or statellitosis. Features associated with a high risk of nodal relapse include extracapsular extension, involvement of four or more lymph nodes, lymph nodes measuring at least 3 cm, cervical lymph node location, and recurrent disease. Numerous studies support the efficacy of adjuvant irradiation in these clinical situations. Although data in the literature remain sparse, evidence also indicates that elective irradiation is effective in eradicating subclinical nodal metastases after removal of the primary melanoma. Consequently, there may be an opportunity to integrate radiotherapy into the multimodality treatment of patients at high risk of subclinical nodal disease, particularly those with an involved sentinel lymph node. Such patients are known to have a low rate of additional lymph node involvement, and thus in this group, a short course of radiotherapy may be an adequate substitute for regional lymph node dissection. This will be the topic of future research.

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Int J Radiat Oncol Biol Phys. 2004 Jan 1;58(1):284-91.
A modified relocatable stereotactic frame for irradiation of eye melanoma: design and evaluation of treatment accuracy.
Muller K, Nowak PJ, Luyten GP, Marijnissen JP, de Pan C, Levendag P.
Department of Radiation Oncology, Erasmus Medical Center, Rotterdam, The Netherlands.

PURPOSE: To describe a reliable, patient-friendly relocatable stereotactic frame for irradiation of eye melanoma and to evaluate the repositioning accuracy of the stereotactic treatment. METHODS AND MATERIALS: An extra construction with a blinking light and a camera is attached to a noninvasive relocatable Gill-Thomas-Cosman stereotactic frame. The position of the blinking light is in front of the unaffected eye and can be adjusted to achieve an optimal position for irradiation. The position of the diseased eye is monitored with a small camera. A planning CT scan is performed with the affected eye in treatment position and is matched with an MR scan to improve the accuracy of the delineation of the tumor. Both the translation and rotation of the affected eye are calculated by comparing the planning CT scan with a control CT scan, performed after the radiation therapy is completed. RESULTS: Nineteen irradiated eye melanoma patients were analyzed. All patients received 5 fractions of 10 Gy within 5 days. The depth-confirmation helmet measurements of the day-to-day treatment position of the skull within the Gill-Thomas-Cosman frame were analyzed in the anteroposterior, lateral, and vertical directions and were 0.1 +/- 0.3, 0.0 +/- 0.2, and 0.2 +/- 0.2 mm (mean +/- SD), respectively. The average translations of the eye on the planning and control CT scan were 0.1 +/- 0.3 mm, 0.1 +/- 0.4, and 0.1 +/- 0.5 mm, respectively. The median rotation of the diseased eye was 8.3 degrees. CONCLUSIONS: The described Rotterdam eye fixation system turned out to be a feasible, reliable, and patient-friendly system.

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Cancer. 2004 Jan 1;100(1):122-9.
Prolonged survival after complete resection of metastases from intraocular melanoma.
Hsueh EC, Essner R, Foshag LJ, Ye X, Wang HJ, Morton DL.
John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, California 90404, USA.

BACKGROUND: The median survival time is only 2-6 months after a diagnosis of metastases from intraocular melanoma. Because complete resection of metastatic melanoma from a cutaneous primary tumor can prolong survival, the authors hypothesized that resection also might benefit patients with metastases from an intraocular site. METHODS: From 1971 to 1999, 112 patients with metastatic melanoma from an intraocular site were enrolled in various treatment protocols after informed consent was obtained. Prospectively recorded clinical variables and follow-up information were retrieved from the patient database. Survival curves were estimated using the Kaplan-Meier method. Univariate analysis was performed with the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model. Propensity score analysis was used to reduce the imbalance between subgroups and to assess treatment effect. RESULTS: Seventy-eight patients (70%) presented with liver involvement. Twenty-four patients (21%) underwent resection of metastatic lesions. At a median follow-up time of 11 months (range, 1-97 months; > 36 months for survivors), the median survival period was 11 months and the 5-year survival rate was 7%. Univariate analysis showed that surgical resection, site of metastases, number of metastatic lesions, and disease-free interval were correlated significantly with survival (P < 0.001, P < 0.001, P < 0.001, and P = 0.031, respectively). Multivariate analysis showed that surgical resection was significant (P = 0.008) but that the site of metastases was not (P = 0.146). The median survival and the 5-year survival rate were 38 months and 39%, respectively, for surgical patients, versus 9 months and 0%, respectively, for nonsurgical patients. After adjusting for covariate imbalance by propensity score analysis, surgery remained significant (P = 0.021) on multivariate analysis. CONCLUSIONS: Complete resection may prolong survival in certain patients with distant metastases from intraocular primary melanoma. However, the overall unfavorable prognosis indicates an urgent need for more effective nonsurgical interventions. Copyright 2003 American Cancer Society.

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Cancer. 2004 Jan 15;100(2):383-9.
Elective radiotherapy provides regional control for patients with cutaneous melanoma of
the head and neck.
Bonnen MD, Ballo MT, Myers JN, Garden AS, Diaz EM Jr, Gershenwald JE, Morrison WH, Lee JE, Oswald MJ, Ross MI, Ang KK.
Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

BACKGROUND: In the current study, the authors assessed the efficacy of elective radiotherapy in providing regional (lymph node) control in patients with cutaneous melanoma of the head and neck who were at high risk for lymph node involvement. Toxicity was also assessed. METHODS: From 1983 to 1998, 157 patients with Stage I or II cutaneous melanoma of the head and neck received elective regional radiotherapy after wide local excision of the primary lesion. None of the patients had received sentinel lymph node biopsy or dissection of the lymph nodes. Their medical records were reviewed retrospectively and analyzed for outcome. RESULTS: The median follow-up for the current review was 68 months (range, 7-185 months). The disease recurred locally in 9 patients, in the neck lymph nodes in 15 patients, and distantly in 57 patients. The actuarial regional control rate was 89% at both 5 years and 10 years. The actuarial disease-specific survival and distant metastasis-free survival rates were 68% and 63%, respectively, at 5 years and 58% and 49%, respectively, at 10 years. Breslow thickness was a significant determinant of disease-specific survival and distant metastasis-free survival rates. At 10 years, 6% of patients had developed a symptomatic treatment-related complication. There were no treatment-related deaths. CONCLUSIONS: The results of the current study confirmed the efficacy and safety of elective regional radiotherapy for patients with cutaneous head and neck melanoma predicted to have a high rate of lymph node involvement. Elective irradiation was a viable alternative to elective lymph node dissection. It may also serve as an alternative to sentinel lymph node biopsy, particularly for patients for whom dissection and systemic therapy are not therapeutic options. Copyright 2003 American Cancer Society.

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Drugs Today (Barc). 2003;39 Suppl C:17-38.
Metastatic malignant melanoma.
Meric JB, Rixe O, Khayat D.
SOMPS, Salpetriere Hospital, Paris, France.

Malignant melanoma is one of the most worrisome tumors in terms of epidemiology, and incidence is increasing. The estimated lifetime risk in the United States is 1 in 75 people. As soon as the first distant metastasis appears, the disease becomes one of the most aggressive and chemoresistant tumors: 90-95% of patients do not survive more than 3 years. Results with chemotherapy are disappointing as few drugs have demonstrated an impact on survival. Drug combinations provide only a slightly higher response rate and do not overcome the natural chemoresistance of this tumor. Tamoxifen, which was widely investigated in the late 1980s and 1990s, has not added any benefit in terms of response rate or survival. Since their description as immunomodulating molecules, the cytokines interferon-alpha and interleukin-2 (IL-2) have been extensively tested in malignant melanoma. They seem to achieve higher response rates and survival rates than chemotherapy but undoubtedly lead to more long-term unmaintained remissions. Their combination with chemotherapeutic drugs, "chemoimmunotherapy", has been tested using various doses and schedules (one or two cytokines, single drug or combination chemotherapy). The combination of cisplatin and IL-2 plays a key role in this strategy. However, because of its higher toxicity, the real benefit of chemoimmunotherapy on patient survival still needs to be proven.

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Cancer Invest. 2003;21(6):821-9.
Health-related quality of life in patients with advanced metastatic melanoma: results of a randomized phase III study comparing temozolomide with dacarbazine.
Kiebert GM, Jonas DL, Middleton MR.
MEDTAP International, Inc., London, UK.

Health-related quality of life (HRQL) is a crucial endpoint in the evaluation of treatments that have limited survival benefits. The HRQL evaluations help ensure that patients are not sacrificing life quality for quantity. Current treatments for metastatic melanoma are primarily palliative, because cure is unattainable. The purpose of this article is to report detailed HRQL results of a phase III clinical trial comparing temozolomide to dacarbazine (DTIC) in patients with metastatic melanoma. Patients were randomized to receive either oral temozolomide for 5 days every 4 weeks or intravenous DTIC for 5 days every 3 weeks. The HRQL was evaluated on day 1 cycle 1 and after each subsequent treatment cycle using the EORTC QLQ-C-30. The HRQL was compared between groups at weeks 12 and 24. Patients treated with temozolomide reported significantly better physical functioning and less fatigue and sleep disturbances than patients treated with DTIC at week 12. For all but two function and symptom subscales, EORTC QLQ-C30 subscale scores were numerically better for patients treated with temozolomide at week 12. All subscales except diarrhea were better for temozolomide at week 24. Analyses of change scores revealed that patients treated with temozolomide reported statistically significant improvements in emotional well-being and sleep disturbance. Patients also reported near significant change in cognitive functioning (3.9, p = 0.06). Patients treated with DTIC deteriorated on most function subscales and many symptom subscales at week 12. Deterioration in physical functioning approached significance (-6.8, p = 0.06). At week 24, patients treated with DTIC improved on the emotional functioning subscale and deteriorated on the physical, role, and global HRQL subscales, although many of the symptom scores improved. The results of this study suggest that treatment with temozolomide leads to important functional improvements and decreased symptoms compared to treatment with DTIC in patients being treated for metastatic melanoma.

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Gan To Kagaku Ryoho. 2003 Dec;30(13):2030-5.
[Heavy charged particle radiotherapy—proton beam]
[Article in Japanese]
Ogino T.
Division of Radiation Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa 277-8577, Japan.

Proton beam therapy (PBT) makes it possible to deliver a higher concentration of radiation to the tumor by its Bragg-peak, and is easy to utilize due to its identical biological characteristics with X-rays. PBT has a half-century history, and more than 35,000 patients have been reported as having had treatments with proton beams worldwide. The historic change to this therapy occurred in the 1990s, when the Loma Linda University Medical Center began clinical activity as the first hospital in the world to utilize a medically dedicated proton therapy facility. Since then, similar hospital-based medically dedicated facilities have been constructed. Results from around the world have shown the therapeutic superiority of PBT over alternative treatment options for ocular melanoma, skull base sarcoma, head and neck cancer, lung cancer, esophageal cancer, hepatocellular carcinoma, and prostate cancer. PBT is expected to achieve further advancement both clinically and technologically.

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Tumori. 2003 Sep-Oct;89(5):502-9.
Clinical application of proton beams in the treatment of uveal melanoma: the first therapies carried out in Italy and preliminary results (CATANA Project).
Spatola C, Privitera G, Raffaele L, Salamone V, Cuttone G, Cirrone P, Sabini MG, Lo Nigro S.
Servizio di Radioterapia, Policlinico Universitario Catania, Catania, Italy. cor_spatola@hotmail.com

BACKGROUND: The first Italian proton therapy facility was realized in Catania, at the INFN-LNS. With its energy (62 MeV proton beam), it is ideal for the treatment of shallow tumors like those of the ocular region: uveal melanoma, first of all (the most common primary intraocular malignancy of adults) and other less frequent lesions like choroidal hemangioma, conjunctiva melanoma, and eyelid tumors. MATERIAL AND METHODS: The first patient was enrolled in February 2002, and to date 30 patients have been treated. All patients had a localized uveal melanoma, with no systemic metastases, and had specific indications for proton beam radiation therapy: lesions between 5-25 mm basal diameter, not exceeding 15 mm thickness, absence of total retinal detachment or glaucoma. According to the tumor dimensions, 2 patients had a small lesion or T1 (6%), 3 had a medium-sized lesion or T2 (10%), 14 had a large lesion or T3 (47%), and 11 had an extra-large lesion or T3 (37%); no patient had extrascleral invasion or T4 of the TNM-AJCC Staging System. In most cases, the tumor infiltrated only the choroid (14 patients, 47%) or the choroid plus the ciliary body (14 patients, 47%). We also treated a primitive iris melanoma, without diffusion to the ciliary body. The target volume was defined as the tumor plus a safety margin of 2.5 mm, laterally and antero-posteriorly; this margin was increased to 3 mm if ciliary body involvement was present. The treatment was carried out in 4 fractions on 4 consecutive days to a total dose of 54.5 Gy (single fraction 13.6 Gy), which corresponds to 60 CGE (Cobalt Gray Equivalent; single fraction 15 CGE), because the relative biological effectiveness is 1.1. RESULTS: The first follow-up is planned at 6-8 months after the end of the treatment, and our clinical end points are local control (defined as cessation of growth or tumor shrinkage), eye retention, and maintenance of a good visual function. At the time of this writing, we had preliminary results from 13 patients. Nine patients showed tumor shrinkage (69%), 3 a substantially stable dimension (23%), but almost all patients presented an increased ultrasound reflectivity (a surrogate for tumor control). DISCUSSION AND CONCLUSIONS: The literature data show that charged particle therapy has allowed an optimal local control in the treatment of uveal melanomas (about 96% in the different series, superior to that obtained with plaquetherapy [between 83% and 92%]), a metastatic rate slightly better than enucleation reports, and a survival rate of almost 90% at 5 years. Our preliminary results show a tumor response in almost all cases, with no major acute or subacute side effects. We thus plan to continue with our treatment procedures and our dose prescription.

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J Clin Oncol. 2003 Oct 15;21(20):3826-35.
Intranodal administration of peptide-pulsed mature dendritic cell vaccines results in superior CD8+ T-cell function in melanoma patients.
Bedrosian I, Mick R, Xu S, Nisenbaum H, Faries M, Zhang P, Cohen PA, Koski G, Czerniecki BJ.
Harrison Department of Surgical Research, University of Pennsylvania, Philadelphia, PA 19104, USA.

PURPOSE: We evaluated the feasibility, safety, and immunogenicity of mature, peptide-pulsed dendritic cell (DC) vaccines administered by different routes. PATIENTS AND METHODS: We performed a randomized, phase I, dose-escalation study in 27 patients with metastatic melanoma receiving four autologous peptide-pulsed DC vaccinations. Patients were randomly assigned to an intravenous (IV), intranodal (IN), or intradermal (ID) route of administration (ROA). For each route, primary end points were dose-limiting toxicity, maximum-tolerated dose, and T-cell sensitization. Sensitization was evaluated through tetramer staining, in vitro peptide recognition assays, and delayed-type hypersensitivity (DTH) responses. RESULTS: Twenty-two (81.5%) of 27 patients completed all four vaccinations. Vaccinations were well tolerated; a few patients exhibited grade 1 to 2 toxicities including rash, fever, and injection site reaction. All routes of administration induced comparable increases in tetramer-staining CD8+ T cells (five of seven IV, four of seven IN, and four of six ID patients). However, the IN route induced significantly higher rates for de novo development of CD8+ T cells that respond by cytokine secretion to peptide-pulsed targets (six [85.7%] of seven IN patients v two [33%] of six ID patients v none [0%] of six IV patients; P =.005) and de novo DTH (seven [87.5%] of eight IN patients v two [33.3%] of six ID patients v one [14.3%] of seven IV patients; P =.01) compared with other routes. CONCLUSION: Administration of this peptide-pulsed mature DC vaccine by IN, IV, or ID routes is feasible and safe. IN administration seems to result in superior T-cell sensitization as measured by de novo target-cell recognition and DTH priming, indicating that IN may be the preferred ROA for mature DC vaccines.

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Cancer. 2003 Oct 1;98(7):1355-61.
Use of tamoxifen in the treatment of malignant melanoma.
Lens MB, Reiman T, Husain AF.
University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. markolens@aol.com

BACKGROUND: Tamoxifen has been used in the treatment of patients with metastatic malignant melanoma either as a single agent or, more commonly, in combination with other chemotherapeutic agents. The aim of the current study was to summarize the available clinical evidence on the role of the tamoxifen in different combination chemotherapy regimens because clinical studies including tamoxifen have produced inconclusive results. METHODS: The authors designed a systematic review and metaanalysis of published randomized controlled trials to assess the benefit of tamoxifen added to various single-agent or multiagent chemotherapy or biochemotherapy regimens. RESULTS: Six randomized trials met the inclusion criteria and were analyzed. These 6 trials involved a combined total of 912 patients. Of this number, 455 patients were randomized to receive tamoxifen added to chemotherapy or biochemotherapy regimens and 457 were randomized to receive chemotherapy or biochemotherapy without tamoxifen. The overall response rate was not improved significantly by the addition of tamoxifen to the chemotherapy regimen (odds ratio [OR], 1.16; 95% confidence interval [CI], 0.75-1.82; test for overall effect: P = 0.14). The results were not statistically significant for complete response (OR, 0.64; 95% CI, 0.33-1.25; test for overall effect: P = 0.19). CONCLUSIONS: The current metaanalysis demonstrated that tamoxifen does not improve the overall response rate, complete response rate, or survival rate when administered along with combined chemotherapy regimens. Currently, the strength of evidence does not support the use of tamoxifen in combination with other systemic chemotherapy for the treatment of metastatic melanoma. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11644

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Nat Rev Cancer. 2003 Sep;3(9):666-75.
Adoptive-cell-transfer therapy for the treatment of patients with cancer.
Dudley ME, Rosenberg SA.
Surgery Branch, National Cancer Institute, Building 10, Room 2B-34, 10 Center Drive, Bethesda, Maryland 20892-1502, USA. Mark_Dudley@nih.gov

Adoptive immunotherapy--the isolation of antigen-specific cells, their ex vivo expansion and activation, and subsequent autologous administration--is a promising approach to inducing antitumour immune responses. The molecular identification of tumour antigens and the ability to monitor the persistence and transport of transferred cells has provided new insights into the mechanisms of tumour immunotherapy. Recent studies have shown the effectiveness of cell-transfer therapies for the treatment of patients with selected metastatic cancers. These studies provide a blueprint for the wider application of adoptive-cell-transfer therapy, and emphasize the requirement for in vivo persistence of the cells for therapeutic efficacy.

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Int J Cancer. 2003 Sep 10;106(4):626-31.
Treatment of patients with progressive unresectable metastatic melanoma with a heterologous polyvalent melanoma whole cell vaccine.
Vilella R, Benitez D, Mila J, Vilalta A, Rull R, Cuellar F, Conill C, Vidal-Sicart S, Costa J, Yachi E, Palou J, Malvehy J, Puig S, Marti R, Mellado B, Castel T.
Department of Immunology, Hospital Clinic and IDIBAPS, Barcelona, Spain. rvilella@medicina.ub.es

Unresectable metastatic melanoma has no elective treatment. Neither chemotherapy, intravenous IL-2 nor biochemotherapy clearly improves the overall survival. Recent assays with therapeutic vaccines have been recently yielded promising results. Here, we describe the application, clinical tolerance and antitumoural activity of a heterologous polyvalent melanoma whole cell vaccine in patients with metastatic melanoma. Twenty-eight AJCC stage III/IV melanoma patients with progressive unresectable metastatic disease were treated with our heterologous polyvalent melanoma whole cell vaccine between July 1, 1998 and July 1, 2002. All patients had already been unsuccessfully treated with high doses of IFN-alpha2 and/or polychemotherapy and/or biochemotherapy and/or perfusion of extremities, or could not receive other treatments due to their age or underlying illness. Twenty-three were assessable. The vaccine was constituted by 10 melanoma cell lines, derived from primary, lymph node and metastatic melanomas. Prior to intradermal inoculation, the cells were irradiated and mixed with BCG, and 50% were treated with DNFB. After a median follow-up of 19 months, 26% of patients responded: 3 CR (18, 16+, and 26+ months), 2 PR (8 and 22 months) and 1 MR (36+ months). The median survival of the whole group was 20.2 months. None of the 28 patients initially included in the study presented significant toxicity. This vaccination program had specific antitumoural activity in advanced metastatic melanoma patients and was well tolerated. The clinical responses and the median survival of our group of patients, together with the low toxicity of our polyvalent vaccine, suggest that this approach could be applied to earlier metastatic melanoma patients. Copyright 2003 Wiley-Liss, Inc.

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J Clin Oncol. 2003 Sep 1;21(17):3351-6.
Phase II study of temozolomide plus thalidomide for the treatment of metastatic melanoma.
Hwu WJ, Krown SE, Menell JH, Panageas KS, Merrell J, Lamb LA, Williams LJ, Quinn CJ, Foster T, Chapman PB, Livingston PO, Wolchok JD, Houghton AN.
Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA. hwuw@mskcc.org.

PURPOSE: To further investigate the efficacy and safety of temozolomide plus thalidomide in patients with metastatic melanoma without brain metastases. PATIENTS AND METHODS: Patients with histologically confirmed advanced-stage metastatic melanoma were enrolled in an open-label, phase II study. The primary end point was response rate. Patients received temozolomide (75 mg/m2/d x 6 weeks with a 2-week rest between cycles) plus concomitant thalidomide (200 mg/d with dose escalation to 400 mg/d for patients < 70 years old, or 100 mg/d with dose escalation to 250 mg/d for patients >/= 70 years old). Treatment was continued until unacceptable toxicity or disease progression occurred. RESULTS: Thirty-eight patients (median age, 62 years) with stage IV (three patients with M1a, eight with M1b, and 26 with M1c) or stage IIIc (one patient) melanoma and a median of four metastatic sites were enrolled, and received a median of two cycles of therapy. Twelve patients (32%) had an objective tumor response, including one with an ongoing complete response of 25+ months' duration and 11 with partial responses. Five patients achieving partial response with a more than 90% reduction of disease were converted to a complete response with surgery. Treatment was generally well tolerated. Median survival was 9.5 months (95% confidence interval, 6.05 to 19.38 months), with a median follow-up among survivors of 24.3 months. CONCLUSION: The combination of temozolomide plus thalidomide seems to be a promising and well-tolerated oral regimen for metastatic melanoma that merits further study.

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Cancer Treat Rev. 2003 Aug;29(4):241-52.
Does adjuvant interferon-alpha for high-risk melanoma provide a worthwhile benefit? A meta-analysis of the randomised trials.
Wheatley K, Ives N, Hancock B, Gore M, Eggermont A, Suciu S.
University of Birmingham Clinical Trials Unit, Park Grange, 1 Somerset Road, Edgbaston, Birmingham, B15 2RR, UK. k.wheathley@bham.ac.uk

BACKGROUND: Several randomised trials have compared interferon-alpha with control as adjuvant therapy for high-risk malignant melanoma. The results of the individual trials have been either inconclusive or even apparently conflicting. To assess all the available evidence we performed a meta-analysis of these trials. METHODS: Standard methods for quantitative meta-analysis based on published data were used. Endpoints evaluated were recurrence-free survival and overall survival. A subgroup analysis by dose of interferon-alpha was performed. FINDINGS: Twelve trials, comprising 14 comparisons of interferon-alpha with control, with results available were identified. Recurrence-free survival was improved with interferon-alpha: hazard ratio 0.83, 95% confidence interval 0.77 to 0.90, p=0.000003. The benefit on overall survival was less clear (0.93, 0.85 to 1.02, p=0.1) and the confidence interval is compatible both with no benefit and with a moderate, but clinically worthwhile, benefit. There was some evidence of a dose response relationship with a significant trend for the benefit of interferon-alpha to increase with increasing dose for recurrence-free survival (test for trend: p=0.02) but not for overall survival (trend: p=0.8). INTERPRETATION: This meta-analysis provides the most reliable synthesis of the data currently available. Adjuvant interferon-alpha produces clear reductions in recurrence of high-risk melanoma, with some evidence of an effect of dose of interferon-alpha, but it is unclear whether this translates into a worthwhile survival benefit or not. Additional and more mature data are needed to resolve these issues and an individual patient data meta-analysis should be performed.

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Vopr Onkol. 2003;49(3):312-5.
[Chemotherapy in combination with laser coagulation or interstitial hyperthermia--effective combined therapy for disseminated skin melanoma]
[Article in Russian]
Akimov MA, Gel'fond ML, Gershanovich ML, Barchuk AS.
N.N. Petrov Research Institute of Oncology, Ministry of Health of the RF, St. Petersburg.

Thirty-eight patients with disseminated skin melanoma received chemotherapy in conjunction with laser coagulation or interstitial hyperthermia of intra- or subcutaneous metastases. Use of combination therapy was followed by a rise to 37% in total response and 16%--complete regression, respectively. Most effectiveness was attained when the dacarbazine + cisplatin + BCNU + tamoxifen regime was employed. In this group of 16 patients (46%), total response was 56% and, what is most significant, 31% in complete regression. In all cases of apparent response, polychemotherapy was administered both before and after laser coagulation or interstitial hyperthermia.

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Arch Otolaryngol Head Neck Surg. 2003 Aug;129(8):864-8.
The role of postoperative adjuvant radiation therapy in the treatment of mucosal melanomas of the head and neck region.
Owens JM, Roberts DB, Myers JN.
Department of Otolaryngology-Head and Neck Surgery, University of Colorado Health Sciences Center, Denver 80262, USA. jonathan.owens@uchsc.edu

BACKGROUND: Mucosal melanoma of the head and neck is uncommon, and has a poor prognosis due to locoregional and distant failure. The optimal treatment paradigm for patients with this disease has yet to be determined. OBJECTIVE: To compare the outcomes of patients treated with various commonly used protocols for mucosal melanoma of the head and neck. DESIGN: Retrospective study. SETTING: Academic tertiary referral center. PATIENTS: The medical records of 48 consecutive patients treated at a single institution from January 1, 1985, to December 31, 1998, were reviewed. INTERVENTIONS: Patients were treated with surgery alone, surgery and adjuvant radiotherapy, or surgery and biochemotherapy, with or without adjuvant radiotherapy. MAIN OUTCOME MEASURES: The outcomes of disease recurrence and survival were correlated with the treatment received. RESULTS: Twenty patients received surgical treatment alone; in 9 patients (45%), this treatment failed locoregionally, and 10 (50%) of the patients developed distant metastases. The 5-year survival rate was 45% (9 of 20 patients). Twenty-four patients received postoperative adjuvant radiotherapy; in 4 patients (17%), this treatment failed locally, and 11 (46%) of the patients developed distant metastases. The 5-year survival rate was 29% (7 of 24 patients). CONCLUSION: The addition of radiotherapy tended to decrease the rate of local failure (P =.13), but did not significantly improve survival (P =.73), because of the high rate of distant metastatic disease.

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Urology. 2003 Aug;62(2):351.
Management of metastatic malignant melanoma of the bladder.
Lee CS, Komenaka IK, Hurst-Wicker KS, Deraffele G, Mitcham J, Kaufman HL.
Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, Maryland, USA.

Recombinant interleukin-2 (IL-2) has demonstrated antitumor activity and durable clinical responses in patients with metastatic melanoma. Careful screening and selection of appropriate patients has improved the safety profile of IL-2 administration. Gross hematuria would ordinarily preclude the safe delivery of IL-2. We report a case of metastatic melanoma to the bladder presenting with hematuria. A complete resection was performed and subsequently allowed the administration of high-dose, bolus IL-2. The combination of resection and IL-2 therapy resulted in a partial response maintained for more than 18 months. Symptomatic bladder melanoma should be aggressively treated to allow for systemic immunotherapy, which can provide durable responses.

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J Clin Oncol. 2003 Aug 1;21(15):2883-8.
Prospective randomized trial of interferon alfa-2b and interleukin-2 as adjuvant treatment for resected intermediate- and high-risk primary melanoma without clinically detectable node metastasis.
Hauschild A, Weichenthal M, Balda BR, Becker JC, Wolff HH, Tilgen W, Schulte KW, Ring J, Schadendorf D, Lischner S, Burg G, Dummer R.
Department of Dermatology, University of Kiel, St Georg Hospital,Hamburg, Germany. ahauschild@dermatology.uni-kiel.de.

PURPOSE: Low-dose interferon alfa (IFNalpha) has been shown to have limited effects in the adjuvant treatment of patients with intermediate- and high-risk primary melanoma. We hypothesized that a combination regimen with low-dose interleukin-2 (IL-2) may improve survival prospects in these patients. PATIENTS AND METHODS: After wide excision of primary melanoma without clinically detectable lymph node metastasis (pT3 to 4, cN0, M0), 225 patients from 10 participating centers were randomly assigned to receive either subcutaneous low-dose IFNalpha2b (3 million international units [MU]/m2/d, days 1 to 7, week 1; three times weekly, weeks 3 to 6, repeated all 6 weeks) plus IL-2 (9 MU/m2/d, days 1 to 4, week 2 of each cycle) for 48 weeks, or observation alone. The primary end point was prolongation of a relapse-free interval. RESULTS: Of the 225 enrolled patients, 223 were found to be eligible. Median follow-up time was 79 months. All evaluated prognostic factors were well balanced between the two arms of the study. Relapses were noticed in 36 of 113 patients treated with IFNalpha2b plus IL-2 and in 34 of 110 patients with observation alone. Five-year disease-free survival of those who had routine surgery supplemented by IFNalpha2b and IL-2 treatment was 70.1% (95% confidence interval [CI], 61.3% to 78.9%), compared with 69.9% in those receiving surgery and observation alone (95% CI, 60.7% to 79.1%) in the intention-to-treat analysis. Evaluation of the overall survival did not show any difference between treated and untreated melanoma patients (P =.93). CONCLUSION: Adjuvant treatment of intermediate- and high-risk melanoma patients with low-dose IFNalpha2b and IL-2 is safe and well tolerated by most patients, but it does not improve disease-free or overall survival.

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Tumori. 2003 Jul-Aug;89(4 Suppl):241-3.
[Anti-blastic hyperthermic perfusion in the treatment of melanoma of the extremities in the loco-regional diffusion phase]
[Article in Italian]
Di Filippo F, Garinei R, Anza M, Cavaliere F, Botti C, Perri P, Di Filippo S.
Polo Oncologico, Istituto Regina Elena, Roma.

Primary limb melanoma may recur in terms of satellitosis, in transit metastases and/or regional node involvement. Hyperthermic antiblastic perfusion (HAP) permits the isolation of involved extremity from the systemic circulation and to deliver high doses of antineoplastic drugs. The association of cytostatic drugs to hyperthermia (> or = 41.5 degrees C) results in a synergistic effect with an increased therapeutic effectiveness. The overall 5 and 10-year survival rates in relation to the disease stages are st. II 75% and 67%; st. IIIA 59% and 42%; st. IIIAB 36% and 30% respectively. The results confirm that HAP is considered the treatment of choice of loco-regional spreading limb melanoma. Recently, the tumor necrosis factor (TNF) has been combined with Melphalan and hyperthermia. This trimodality association seems to be superior to Melphalan and hyperthermia alone only in patient with bulky tumors (i.e., multiple nodules), as a matter of fact the complete tumor response rates observed in these patients have been 67% and 20% respectively. The greater effectiveness of trimodality association has to be confirmed by multicentric randomized trials.

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Vojnosanit Pregl. 2003 Jul-Aug;60(4):427-33.
[Plastic surgery in the treatment of primary cutaneous melanoma]
[Article in Serbian]
Panajotovic L, Kozarski J, Krtinic S, Stanojevic B.
Vojnomedicinska akademija, Klinika za plasticnu hirurgiju i opekotine, Beograd.

Surgery is still the most effective treatment modality of skin melanoma. The margins of excision are determined by the thickness of primary tumor. From January 1999 to December 2001, 99 patients (57 male and 42 female, of the average age 55), were surgically treated at the Clinic for Plastic Surgery and Burns of the Military Medical Academy. The most usual localization of the primary tumor was the back (23.23%), followed by the forearm, and the lower leg. Regarding the clinical type of the melanoma, nodular melanoma dominated (62.62%). Microscopic staging of the melanoma (classification according to Clark and Breslow), showed that the majority of patients already suffered from the advanced primary disease, which called for radical excision and the choice of reconstructive methods in the closure of post-excision defects. The reconstructive plastic surgical methods enabled the closure of post-excision tissue defects, regardless of their size, structure, and localization. During the closure of post-excision defects, direct wound closure or split skin draft was performed in 76.76% of patients. Flaps were applied in 19.19% of patients with the primary melanoma of the head, face, foot, and hand. The sufficiency of the available reconstructive procedures makes plastic surgery irreplaceable in the surgical treatment of the primary melanoma of the skin.

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Ann Surg Oncol. 2003 Jul;10(6):689-96.
Changing surgical therapy for melanoma of the external ear.
Pockaj BA, Jaroszewski DE, DiCaudo DJ, Hentz JG, Buchel EW, Gray RJ, Markovic SN, Bite U.
Department of Surgery, Mayo Clinic, Scottsdale, Arizona 85259, USA. pockaj.barbara@mayo.edu

BACKGROUND: The purpose of this study was to evaluate the prognostic variables and clinical ramifications of melanoma of the ear. METHODS: A retrospective chart review of patients treated since 1985 at the Mayo Clinic in Scottsdale, AZ, and Rochester, MN, identified 78 patients with complete follow-up. RESULTS: Of these 78 patients, 68 (87%) were men; the mean age was 64 years (range, 23-87 years). Melanoma thickness averaged 1.7 mm (range,.2-7.0 mm). Treatment of the primary melanoma included wedge resection (59%), Mohs resection (14%), partial amputation (11%), skin and subcutaneous resection with perichondrium preservation (9%), and total amputation (7%). Nineteen patients underwent an elective lymph node dissection, and lymph node metastases were found in seven (37%). Two patients presented with clinically positive lymph nodes. Sentinel lymph node biopsy was performed in 10 patients. After a mean follow-up of 55.7 months, 10 patients (13%) had local recurrence, 9 patients (12%) had regional recurrence, and systemic metastases had developed in 17 patients (22%). Tumor thickness, lymph node metastases, and local recurrence significantly affected systemic recurrence. CONCLUSIONS: The treatment of malignant melanoma of the external ear should follow current standard guidelines, which require wide local excision with negative margins. Sentinel lymph node biopsy can be used to identify patients with lymph node metastases who are at high risk of recurrence.

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Am J Ophthalmol. 2003 Jul;136(1):161-70.
Changing concepts in the management of choroidal melanoma.
Robertson DM.
Department of Ophtalmology, Mayo Clinic, Rochester, Minnesota 55905, USA. robertson.dennis@mayo.edu

PURPOSE: To review emerging information related to changing concepts in the management of choroidal melanoma. DESIGN AND METHODS: This perspective reviews and discusses selected studies from the past two decades that have influenced management strategies for large, medium, and small-size choroidal melanomas. RESULTS: Large choroidal tumors continue to be managed primarily by enucleation. The large tumor trial of the Collaborative Ocular Melanoma Study (COMS) demonstrated neither a positive nor negative effect on 5- and 8-year mortality rates among more than 1000 patients whose eyes containing large choroidal melanomas were randomized to treatment between enucleation alone or enucleation preceded by external radiation. The medium-size tumor trial of the COMS randomized more than 1300 patients between iodine-125 brachytherapy and enucleation. Mortality rates following brachytherapy did not differ from mortality rates following enucleation for up to 12 years after treatment. Iodine-125 has become the most commonly used isotope for brachytherapy in North America. Ten-year follow-up of eyes treated with helium ion and 20 years of experience with proton beam confirm the relative safety and efficacy of these modalities for treatment of choroidal melanoma. Although there is a trend toward earlier treatment of small melanomas, controversy exists regarding the indications for treatment as well as the choice of specific therapy. Recurrences of melanoma after eye-sparing treatment appear to be associated with an increased rate of metastatic disease. Effective adjunctive therapy to prevent or treat melanoma metastasis is lacking. CONCLUSIONS: Choroidal melanoma is a lethal tumor. Although evidence suggests that patients with untreated choroidal melanomas have a poorer prognosis than patients who receive treatment, our current treatments are unable to prevent tumor-related deaths for many patients. The use of preoperative external radiation as an adjunct to enucleation for large choroidal melanomas is unsupported by data from the COMS trial. The use of radiation with either brachytherapy or charged particles for the management of medium-size choroidal melanomas is well supported on the basis of long-term follow-up studies. There is a trend toward treatment of smaller choroidal melanomas. Treatment of melanomas should be directed toward minimizing the potential for recurrences as recurrent melanomas are associated with an increased rate of metastatic disease. Gains in our ability to manage choroidal melanoma will likely be modest at best until effective systemic therapies can be identified.

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Am J Ophthalmol. 2003 Jul;136(1):47-54.
Mortality after deferral of treatment or no treatment for choroidal melanoma.
Straatsma BR, Diener-West M, Caldwell R, Engstrom RE; Collaborative Ocular Melanoma Study Group.
Department of Ophthalmology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California 90095-7000, USA. straatsma@jsei.ucla.edu

PURPOSE: To report mortality of patients who were eligible for enrollment in the Collaborative Ocular Melanoma Study (COMS) clinical trials of medium-sized choroidal melanoma or large-sized choroidal melanoma but chose to defer treatment or receive no melanoma treatment. DESIGN: Prospective nonrandomized multicenter cohort study as an adjunct to the COMS randomized clinical trials. METHODS: Patient follow-up procedures included examinations, correspondence, telephone contacts, and National Death Index searches. Primary outcome was patient death measured by all-cause mortality. Secondary outcomes were melanoma treatment and melanoma metastasis. RESULTS: Of 77 patients eligible for the COMS clinical trials who chose to defer or receive no melanoma treatment, 61 were appropriate candidates and 45 (74%) enrolled in the natural history study. Forty-two patients (42 eyes) had medium melanoma, and median follow-up was 5.3 years (range, 4-10.7 years). Twenty-two patients (52%) had subsequent melanoma treatment, and 20 (48%) had no melanoma treatment. For the 42 patients, the Kaplan-Meier estimate of 5-year mortality was approximately 30% (95% confidence interval [CI], 18%-47%). For the COMS medium melanoma trial, 5-year mortality was 18% (95% CI, 16% -20%), not statistically significantly different from the natural history study patients. After adjusting for differences in age and longest basal diameter, the 5-year risk of death for natural history study patients vs COMS trial patients was 1.54 (95% CI, 0.93-2.56). Three patients had large melanoma. Melanoma metastasis was confirmed or suspected in eight (42%) of 19 deaths. CONCLUSION: Greater mortality and higher risk of death for natural history study patients are probative but not conclusive evidence of a beneficial, life-extending effect of medium melanoma treatment.

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Ophthal Plast Reconstr Surg. 2003 Jul;19(4):270-4.
Immunotherapy for melanoma metastatic to the orbit.
Baroody M, Hartstein ME, Holds JB.
Pennsylvannia State University, Department of Surgery, USA.

PURPOSE: To present 3 cases of melanoma metastatic to the orbit treated with various traditional modalities including surgery and chemotherapy and being treated with melanoma vaccines and to present background information on immunotherapy. METHODS: Retrospective review of 3 patients with melanoma metastatic to the orbit who were treated with melanoma vaccines along with conventional treatments. One patient had known orbital involvement before vaccine treatment; 2 patients had orbital metastases subsequent to vaccine administration. RESULTS: Patients survived at least 13 months after the diagnosis of metastatic melanoma, with 1 patient surviving 51 months after the onset of metastases and administration of melanoma vaccine. CONCLUSIONS: Although still unproven, immunotherapy with melanoma vaccines is a promising new treatment modality for metastatic melanoma with few side effects.

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Eur J Cancer. 2003 Jul;39(11):1577-85.
Quality of life evaluation in a randomised trial of chemotherapy versus bio-chemotherapy in advanced melanoma patients.
Chiarion-Sileni V, Del Bianco P, De Salvo GL, Lo Re G, Romanini A, Labianca R, Nortilli R, Corgna E, Dalla Palma M, Lo Presti G, Ridolfi R; Italian Melanoma Intergroup (IMI).
Department of Medical Oncology, Padova University Hospital, Via Gattamelata 64, 35128 Padova, Italy. mgaliz@tiscalinet.it

This study analyses the health related quality of life (HRQOL) of advanced melanoma patients, in a randomised trial comparing bio-chemotherapy (bio-CT) versus chemotherapy (CT). The trial enrolled 178 patients and the median survival was not statistically different between the two arms. HRQOL was assessed at baseline and before each cycle of therapy, using the Rotterdam Symptom Checklist (RSCL) questionnaire completed with 140 patients. At baseline, overall quality of life and psychological distress scores were the most impaired, compared with the normal population. During treatment, the difference between the two arms in the changes from baseline was statistically significant (P=0.03) only in the overall quality of life score, with a decrease of 6.28 points in the bio-CT arm. The mean values decreased significantly in all domains in bio-CT arm, but only in activity level and physical symptom distress scores in the CT arm. Testing HRQOL variables and prognostic clinical factors in a Cox model, only the serum level of lactic dehydrogenase, baseline overall quality of life and the physical symptom distress scores remained significant independent prognostic factors for survival. A score of less than 75 points in the overall quality of life and in the physical symptom distress domains was associated with a Hazard Ratio (HR) of 2.31 (95% Confidence Interval (CI): 1.09-4.90) and 1.92 (95% CI: 1.10-3.36), respectively.

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Bull Mem Acad R Med Belg. 2003;158(1-2):103-11; discussion 111-2.
[Treatment of intraocular melanoma: new concepts]
[Article in French]
De Potter P.
Unite d'Oncologie oculaire, Cliniques Universitaires Saint-Luc-U.C.L.

The management of posterior uveal melanoma has evolved tremendously for the past decades and, more recently, there is a trend toward more focal conservative treatment. Transpupillary thermotherapy (TTT) with infrared diode laser (810 nm.) is the newest modality used as primary treatment or as complementary method to radiotherapy or surgical resection in very selected cases of choroidal melanoma. Plaque radiotherapy or charged-particle irradiation is particularly recommended for medium- or small-sized uveal melanoma not suitable to TTT or resection. Special custom-designed plaque radiotherapy (iodine-125) can be used for iris, ciliary body or juxta-paillary choroidal melanoma. The tumor control rate after plaque or charged-particle radiotherapy appears to be similar, but charged-particle irradiation may produce worse anterior segment complications than plaque radiotherapy. Stereotatic radiation therapy for choroidal melanomas may be effective in controlling tumor growth but the number of patients treated with the approach is too small to draw strong conclusions. Local tumor resection using trans-scleral resection is mainly suitable for selected iris, ciliary body, or anterior choroidal melanoma, particularly with smaller basal dimensions and greater thickness. Combined therapies (radiotherapy plus TTT, tumor resection plus TTT) appears to be more effective in decreasing the incidence of intraocular tumor recurrence. Enucleation is still performed for large uveal melanoma when there is no hope for useful vision. Based on the published ophthalmic literature, it seems that enucleation carries the same survival prognosis as each of the conservative treatment modalities.

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Bull Cancer. 2003 Jul;90(7):583-6.
[Passive immunotherapy of melanoma]
[Article in French]
Jotereau F, Labarriere N, Gervois N, Pandolfino MC, Dreno B.
Inserm U463, Institut de Biologie, CHR, 9, quai Moncousu, 44093 Nantes, France. jotereau@nantes.inserm.fr

The protocols of tumor immunotherapy have been largely developed in the past ten years due to the identification of many tumor antigens recognized specifically by CD8 and CD4 T lymphocytes. Among the various immunotherapies currently tested, passive immunotherapy (i.e injection of T lymphocytes generated and selected ex-vivo from blood or from the tumor), seems to be particularly promising. Indeed, three recent studies evidence the efficacy of such therapy in melanoma treatment. For the first time, a precise immunological follow-up was carried out, thus showing the correlation between the therapeutic benefit and the injection of tumor antigen specific T lymphocytes, and the survival and the preferential migration of these lymphocytes to the tumor sites. Although all the questions about optimal methods for this mode of therapy are not solved, these recent results constitute a major breakthrough in the field of the tumor immunotherapy. Copyright John Libbey Eurotext 2003.

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Expert Rev Vaccines. 2003 Jun;2(3):353-68.
Melacine: an allogeneic melanoma tumor cell lysate vaccine.
Sosman JA, Sondak VK.
Melanoma Program, Vanderbilt Ingram Cancer Center, Division of Hematology/Oncology, Nashville, TN 37027, USA. jeff.sosman@vanderbilt.edu

Cancer vaccines have represented the holy grail of tumor immunology to many. In 2003, there are innumerable approaches to active specific immunotherapy for cancer. The identification of tumor antigens recognized by and able to activate human T-lymphocytes has heightened the enthusiasm for this approach. Melanoma is one of the diseases that has been primarily targeted by vaccine approaches. The identification of peptides and proteins associated with cancer has provided strategies to target specific components of the cancer cell. However, older vaccines utilizing products from whole cells may have a number of advantages. Melacine (Corixa Corp.) is an allogeneic melanoma tumor cell lysate combined with the adjuvant DETOX. Pioneered by Malcolm Mitchell, it has rare but confirmed antitumor activity in metastatic melanoma (5-10%). However, previous analysis of responses in advanced disease and a recent analysis in early-stage adjuvant trials suggest that Melacine may have its greatest benefit in a large subset of melanoma patients who express either the human leukocyte antigen (HLA) class I antigens A2 and/or HLA-C3. This finding must now be confirmed in a large perspective observation-controlled clinical trial to solidify the role of Melacine as an effective cancer vaccine in melanoma

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J Fam Pract. 2003 Jun;52(6):456-64.
Treatment of skin malignancies.
Reynolds PL, Strayer SM.
470th Air Base, USAF Clinic, Geilenkirchen, Germany.

Malignant melanomas in situ can usually be treated in consultation with a specialist (C). Larger lesions may require referral. Based on best available evidence, surgical excision is the first-line treatment for most nonmelanoma skin cancers, with cure rates as high as 98% with proper margins. Consider Mohs surgery for larger lesions, sclerosing lesions with morpheaform histology, or for cosmetically sensitive areas. With properly selected lesions, curettage/electrodesiccation and cryosurgery have cure rates comparable to that of surgical excision.

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Head Neck. 2003 Jun;25(6):423-8.
Efficacy of radiation therapy in the local control of desmoplastic malignant melanoma.
Vongtama R, Safa A, Gallardo D, Calcaterra T, Juillard G.
Department of Radiation Oncology, University of California, 200 UCLA Medical Plaza, Suite B265, Los Angeles, California 90024, USA. vongtama@radonc.ucla.edu

BACKGROUND: Desmoplastic malignant melanoma (DMM) is a rare variant of malignant melanoma with high local recurrence rate after surgical excision. We performed a retrospective review to address the role of radiation therapy in local control of this tumor. METHODS: Between 1976 and 1997, 44 patients with the pathologic diagnosis of DMM were registered at our tumor registry. Fourteen patients received postoperative RT, and one patient received preoperative RT. Three of the irradiated lesions had gross residual or positive surgical margins. Doses ranged from 44 to 66 Gy. RESULTS: Sixty-eight percent of DMM lesions occurred in the head and neck region. Forty-eight percent (21 of 44) of patients experienced a local recurrence after initial excision (mean time to recurrence, 12 months). Local failure in head and neck was 46% (14 of 30). Clark level, primary site, and neurotropism did not predict local recurrence; the Clark level predicted distant metastasis. No viable tumor was found in the surgical specimen of the patient who received preoperative RT. None of 15 patients who received adjuvant irradiation had any additional recurrences (mean follow-up, 64.7 months). By contrast, four of seven patients with history of recurrence who did not receive RT had local relapse (p =.005). The incidence of distant metastasis did not reach statistical significance between the irradiated and nonirradiated groups. CONCLUSIONS: The high rate of local recurrence of DMM after surgical resection is dramatically reduced by adjuvant radiation therapy. We recommend adjuvant postoperative radiation therapy as a part of treatment of DMM. Copyright 2003 Wiley Periodicals, Inc.

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Clin Oncol (R Coll Radiol). 2003 May;15(3):132-5.
Combination chemotherapy with docetaxel and irinotecan in metastatic malignant melanoma.
Tas F, Camlica H, Kurul S, Aydiner A, Topuz E.
Institute of Oncology, University of Istanbul, Istanbul, Turkey.

AIM: The aim of the current trial was to assess the efficacy and toxicity of 3-weekly intravenous docetaxel and irinotecan in the treatment of patients with metastatic malignant melanoma. MATERIALS AND METHODS: Sixteen patients with no history of previous cytotoxic agents or immunological treatment for advanced disease were treated with docetaxel 50 mg/m2 and irinotecan 150 mg/m2 intravenously over 60 min every 21 days. Prior immunotherapy with interferon and chemotherapy for adjuvant therapies were accepted provided there was a minimum 4-week treatment-free interval. Response evaluation was performed after two cycles. RESULTS: None of the patients had chemotherapy-induced tumour response. Eight patients achieved stable disease and others had progression of disease. The median survival time was 136 days (95% CI: 30.2-241.8), and the 3-month survival rate was 62.5%. Patients with stable disease (n = 8) had a longer survival than non-responders (P = 0.023, Breslow test). Generally side effects were mild and tolerable. Grade III-IV haematological toxicity occurred in approximately 10%. Severe emesis, stomatitis and diarrhoea was seen in less than 20% of the patients. Alopecia was observed in all patients. CONCLUSION: A 3-weekly intravenous docetaxel and irinotecan combination appears to be inactive in the treatment of patients with malignant melanoma and has not been recommended.

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J Chemother. 2003 Apr;15(2):198-202.
Chemotherapy and bio-chemotherapy in patients with advanced melanoma: combination therapy
with a nitrosourea.
Ridolfi R, Tanganelli L, Scelzi E, Manente P, Palmeri S, Ravaioli A, Fiammenghi L, Romanini A; Italian Melaoma Intergroup.
Oncologia Medica, Ospedale Pierantoni, Forli, Italy. r.ridolfi@ausl.fo.it

The treatment of advanced melanoma is still disappointing. In a multicenter randomized clinical trial to compare a chemotherapy (CT) with or without low doses of IL-2 and IFN (Bio-CT), the participating centers chose whether or not to add a nitrosourea, carmustine (BCNU) to the therapy. The aim of the present paper is to report the clinical results of the patients (pts) treated in both arms with BCNU. One hundred and seventy-six pts with advanced melanoma were enrolled in the study from 27 centers and a total of 18 pts also received BCNU in 3 centers. No further changes to the protocol criteria were allowed. One patient refused the treatment. No complete responses were observed. Irrespectively of the treatment arm, 9/17 pts showed a partial response to therapy (53%) (5/9 in the CT and 4/8 in the BioCT arm). The most important adverse events observed were hematological: 12 pts presented grade 3 (6 pts) or grade 4 (6 pts) leukocytopenia and 9 pts had grade 4 thrombocytopenia, all of which resolved spontaneously. The addition of a nitrosourea to CT or Bio-CT appears to improve response rates compared to the same regimens without nitrosourea. Patient tolerability is acceptable. Further studies using this combination are warranted.

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Surg Clin North Am. 2003 Apr;83(2):417-30.
Coping with melanoma--ten strategies that promote psychological adjustment.
Kneier AW.
Department of Dermatology, Comprehensive Cancer Center, University of California at San Francisco, 1600 Divisadero Street, Box 1706, San Francisco, CA 944115, USA. awkneier@orca.ucsf.edu

The coping strategies discussed above are not right for everyone, but there is good evidence that they are generally helpful to patients who are dealing with cancer, including melanoma. The bottom line is that these strategies help patients feel better and stronger. They feel better because they are facing the illness squarely and working through its emotional impacts, and yet also keeping a perspective on it so that it does not define them or take over their lives. Through all the trials and challenges that cancer can bring, they are keeping their wits about them and able to carry on. They feel stronger because they have support, from other people and from within themselves. They have taken stock of their most cherished reasons for living, which strengthens and sustains them in their fight against cancer. And yet they also feel that their survival is not the only important objective; the quality of their lives and relationships, the values they live by, and their spirituality also deserve attention and effort. They have the peace of knowing that their death from cancer, if it comes to that, will not obliterate the meaning, value, and joy that their life has given to them and their loved ones.

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Surg Clin North Am. 2003 Apr;83(2):343-70.
Immunotherapy of malignant melanoma.
Kadison AS, Morton DL.
John Wayne Cancer Institute, 2200 Santa Monica Boulevard, Santa Monica, CA 90404, USA.

Several areas of immunotherapeutic research may ultimately improve the effectiveness of active specific immunotherapy for melanoma and other malignancies. Identification of the most relevant tumor antigens will continue to be a vital component of vaccine design. Optimizing delivery of these antigens by use of adjuvants, dendritic cells, or heat shock proteins will enhance the immunogenicity of vaccines. The use of DNA vaccines to deliver nucleotides that encode relevant antigens and immunologic molecules, such as costimulatory molecules, and the use of targeted therapy with immunocytokines have yielded promising results in animal studies. Finally, cutting-edge techniques such as quantitative polymerase chain reaction and gene/protein microarrays will be used to monitor the response to a vaccine and thereby guide management decisions. Although IFN-alpha 2b is the only FDA-approved adjuvant treatment for AJCC stage IIB/III melanoma, recent data failed to show a benefit in overall survival. For patients with AJCC stage IV melanoma, chemotherapy with dacarbazine is currently the standard of care, with modest response rates of 15% to 20%. The encouraging response rates and low toxicities that were reported in phase I/III trials suggest that active immunotherapy may prove to be the most effective adjuvant therapy. At present, there are no FDA-approved cancer vaccines for malignant melanoma, and the results of ongoing randomized phase III clinical trials are greatly anticipated.

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Surg Clin North Am. 2003 Feb;83(1):109-56.
Surgical treatment of malignant melanoma.
Essner R.
John Wayne Cancer Institute, 2200 Santa Monica Boulevard, Santa Monica, CA 90404, USA. essnerr@jwci.org

The surgical management of melanoma has evolved over the last 100 years. when early concepts of lymphatic permeation of the tumors and metastases led surgeons to perform radical operative procedures. Wide excision of primary melanoma is now performed with 1- to 2-cm radial margins, significantly reducing the need for complex plastic closures, skin grafts. and hospital admissions. Although elective lymph node dissection remains controversial as a therapeutic procedure, the development of SL has improved the staging of the regional lymph nodes and diminished the morbidity of lymph node dissection. The role of SL for routine care of melanoma patients remains unknown. Metastasectomy, which is the surgical resection of distant metastases with tumor-free surgical margins, has not been popular for AJCC stage IV patients with multiple metastases, because surgery is considered a local therapy and therefore of little value for management of disseminated disease. Nevertheless, the many reports of long-term survival after resection of distant melanoma metastases to diverse soft tissue and organ sites clearly indicate that this form of cytoreductive surgery can be extremely successful in carefully selected patients. Unlike chemotherapy, complete surgical metastasectomy can rapidly render a patient disease-free with only a short period of postoperative morbidity. Most patients fully recover from the surgical procedure within 6 weeks, returning to most or all activities. The ability to select patients for surgery is based on the development of more sophisticated imaging techniques, which allow better preoperative differentiation of patients with single versus multiple metastases and improve the surgeon's ability to identify and resect multiple metastatic sites. The overall data suggest that patients whose metastases can be completely resected will experience improved overall survival and occasional long-term cure regardless of the metastatic organ site and number of metastases. We believe that increased understanding of the biology of the primary and metastases, dramatic improvement in the accuracy of staging metastatic disease, and better techniques of surgical resection provide the best chance for long-term palliation or cure of melanoma. Cytoreductive surgery should be considered a form of immunotherapy. The long-term clinical benefit of this therapy depends on the patient's immune response to, the surgical reduction in tumor burden: an immune response that controls subclinical micrometastases should optimize postoperative survival.

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Surg Clin North Am. 2003 Apr;83(2):323-42.
Radiation therapy for malignant melanoma.
Ballo MT, Ang KK.
Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA. mballo@mdanderson.org

Although surgery remains the primary treatment for patients with localized melanoma, available data indicate that there is a need for improved local-regional control in situations where complete surgical resection may be difficult or when high-risk features are noted pathologically. Retrospective and phase II prospective studies have revealed that elective/adjuvant radiotherapy can significantly improve the local-regional control rate in these clinical settings. The impact of elective/adjuvant radiotherapy on the incidence of distant metastasis and overall survival has yet to be determined, however. Additionally, there remains a role for radiotherapy as a primary treatment alternative for elderly patients with large facial lentigo maligna melanoma. The optimal radiation fractionation schedule remains controversial. The hypofractionated regimen is well tolerated, has resulted in improved local-regional control as compared with historical surgical results, and is convenient for a group of patients in whom survival expectations are low. Significant improvements in outcome will require commensurate improvements in systemic disease control. The importance of local control to reduce local morbidity, however, should not be underestimated, and future research goals should include randomized clinical trials to further define the role of adjuvant irradiation alone or in combination with systemic therapy.

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Dermatol Surg. 2002 Dec;28(12):1143-52.
Dietary factors in the prevention and treatment of nonmelanoma skin cancer and melanoma.
Bialy TL, Rothe MJ, Grant-Kels JM.
Department of Dermatology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.

BACKGROUND: The endogenous antioxidant system of the skin scavenges reactive oxygen species and combats ultraviolet induced oxidative skin damage. Supporting this cutaneous defense system with topical or oral antioxidants may provide a successful strategy for the treatment and prevention of skin cancer. OBJECTIVE: Review evidence regarding treatment and prevention of melanoma and nonmelanoma skin cancers through dietary and topical antioxidants, vitamins, and herbal supplements. METHODS: Literature review. RESULTS: Review of the literature demonstrates that the administration of synthetic retinoids has not proved beneficial for otherwise healthy patients with nonmelanoma skin cancer. Selenium supplementation has reduced the incidence of several internal malignancies but not of nonmelanoma skin cancer. Synergistic use of beta-carotene with vitamins C and E has demonstrated prophylaxis against reactive oxygen radicals involved in nonmelanoma skin cancer and reduced sunburn reactions significantly. 1,25-dihydroxyvitamin D3 analog CB1093 has demonstrated promise as a therapeutic agent in the regression of the early stages of melanoma in specific cell lines. CONCLUSION: Delivery of exogenous antioxidants in combination appears to be a more successful strategy for enhancing the cutaneous antioxidant system than the administration of isolated antioxidants alone. Vitamin D analogs may have a role in the medical therapy of melanoma. However, avoiding exposure to ultraviolet light appears to be the only true panacea against the development of melanoma and NMSC.

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Am J Clin Dermatol. 2002;3(9):609-16.
Tumor vaccines: a role in preventing recurrence in melanoma?
Sabel MS, Sondak VK.
University of Michigan Comprehensive Cancer Center, Ann Arbor 48109, USA. msabel@umich.edu

Patients presenting with thick primary melanomas or those with regional nodal metastases have a high risk of recurrence after surgery alone. Chemotherapy has limited efficacy in the adjuvant setting, and while the use of high-dose interferon in the adjuvant setting has been reported to improve survival, treatment with interferon is not without significant cost and toxicity. Mounting evidence suggests a prominent role for the immune system in the natural history of melanoma, and the clinical success of interferon highlights the potential for immunotherapy to prevent recurrence. Many researchers hope to use melanoma vaccines to reduce recurrence without significant toxicity, and many different vaccine strategies are under investigation. Peptide vaccines attempt to induce immunity to melanoma MHC-restricted peptide antigens by delivering the peptide to the patient along with an immune adjuvant meant to induce inflammation and stimulate immunity. While peptide vaccines have advantages with regard to cost and feasibility, it is still unclear whether highly purified peptides will stimulate an adequate immune response. An alternative approach is the use of cellular vaccines. Autologous cellular vaccines present all biologically relevant antigens to the immune system, but this is limited to individuals with sufficient tumor to prepare a vaccine. Allogeneic cellular vaccines are based on the fact that melanoma-associated antigens are shared among a large number of patients, so a vaccine prepared from a cultured cell line could stimulate an anti-tumor immune response in many patients. Allogeneic vaccines are available for all patients, and can be standardized, preserved and distributed in a manner akin to any other therapeutic agent. Because of this, they are more readily available for evaluation in large trials, and there are two major allogeneic vaccines presently being evaluated as an adjuvant therapy for melanoma. Several additional approaches to vaccine therapies are being investigated including among others ganglioside vaccines, viral oncolysates, cytokine gene-modified tumor cell vaccines, dendritic cell vaccines, anti-idiotype antibodies and DNA vaccines. While there appears to be tremendous potential for vaccines, it must be remembered that there has been significant interest in immunotherapy for melanoma for over 50 years and, to date, no large prospective, randomized trial has shown a survival benefit.

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Semin Oncol. 2002 Oct;29(5):503-12.
Gene-based therapy of malignant melanoma.
Schadendorf D.
Skin Cancer Unit of the German Cancer Research Center at the Department of Dermatology, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany.

Melanoma continues to present a major therapeutic challenge to oncologists, oncologic surgeons, and dermatologists. Recent advances in molecular genetics and improvement in our understanding of immune responses to tumors have generated an interest in using gene-based treatment strategies to fight melanoma. Several basic strategies have emerged: (1) strengthening of the immune response against tumors by genetic modification of some target cell populations of the host using immunostimulatory genes such as cytokines and by genetic immunization with the genes coding for melanoma-associated antigens recognized by cytotoxic T cells; (2) interference with signaling cascades; and (3) suicide gene strategies. This article reviews these novel strategies and summarizes the most recent data generated by European groups either in experimental studies or in clinical trials. Copyright 2002, Elsevier Science (USA). All rights reserved.

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Oncology. 2003;64(4):328-35.
Biochemotherapy for metastatic melanoma with limited central nervous system involvement.
Boasberg PD, O'Day SJ, Kristedja TS, Martin M, Wang H, Deck R, Shinn K, Ames P, Tamar B, Petrovich Z.
Division of Medical Oncology, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, CA 90404, USA. boasbergp@jwci.org

OBJECTIVES: Biochemotherapy outcomes were examined in stage IV melanoma patients with previously treated or active central nervous system (CNS) metastases prior to systemic therapy. PATIENTS AND METHODS: Patients who received biochemotherapy for metastatic melanoma with active or pretreated CNS metastases were compared to patients without evidence of CNS metastases in terms of response, time to progression (TTP), overall survival (OS), and treatment toxicity. RESULTS: Twenty-six (16%) of 159 total patients began biochemotherapy with previously treated or active CNS metastases (group I), compared to 133 (84%) who were radiographically free of CNS involvement (group II). A partial or complete response to biochemotherapy was seen in 13 (50%) group I patients, compared to 56 (42%) group II patients (p = 0.243). The median TTP and median survival were 5.5 and 7.0 months, respectively, for group I patients and 6.0 and 9.9 months, respectively, for group II patients (p = 0.222 and 0.434 for TTP and OS, respectively). Five (19%) group I patients survived longer than 24 months. Gamma Knife radiosurgery or surgical resection of CNS disease prior to biochemotherapy improved survival versus delayed treatment (p = 0.017 and 0.005, respectively). CONCLUSION: Patients with limited CNS metastases and widespread systemic disease can achieve prolonged survival with targeted treatment of CNS lesions and aggressive systemic therapy. Copyright 2003 S. Karger AG, Basel

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Surg Clin North Am. 2003 Apr;83(2):453-6, x.
Future perspectives on malignant melanoma.
Leong SP.
Department of Surgery, University of California at San Francisco Comprehensive Cancer Center, 1600 Divisadero Street, San Francisco, CA 94143-1674, USA. leongs@surgery.ucsf.edu

Emphasis for the treatment of melanoma should be shifted more to prevention and early diagnosis, because early melanoma may potentially be cured in most cases. Clinical trials are important to establish more effective adjuvant modalities against melanoma. Multifaceted aspects of micrometastasis, including differentiation of different clones with respect to the primary tumor, acquisition of adhesion molecules, and host interaction with the microscopic tumor, will shed new light on the biology and mechanism of early metastasis. New molecular and genetic tools may be used to dissect the mechanisms of lymphatic and hematogenous routes of metastasis. If such mechanisms can be understood, potential therapeutic maneuvers can be developed to prevent the process of micrometastasis.

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Surg Clin North Am. 2003 Apr;83(2):371-84, ix
The role of isolated limb perfusion for melanoma confined to the extremities.
Eggermont AM, van Geel AN, de Wilt JH, ten Hagen TL.
Department of Surgical Oncology, Erasmus University Medical Center, Rotterdam-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. eggermont@chih.azr.nl

Isolated limb perfusion with Melphalan is the best treatment option to control symptomatic multiple small in-transit metastases. When lesions are bulky, Isolated Limb Perfusion (ILP) with Tumor Necrosis Factor (TNF) + Melphalan is superior as in soft tissue sarcoma. TNF changes the pathophysiology, greatly enhances the uptake of Melphalan and destructs selectively the vasculature of large tumors. To date, ILP is not indicated in an adjuvant setting.

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Am J Ophthalmol. 2003 May;135(5):648-56.
Custom-designed plaque radiotherapy for nonresectable iris melanoma in 38 patients: tumor control and ocular complications.
Shields CL, Naseripour M, Shields JA, Freire J, Cater J.
Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

PURPOSE: To evaluate plaque radiotherapy for iris melanoma. DESIGN: Prospective noncomparative interventional case series. METHODS: For 38 patients, custom-designed plaque radiotherapy using iodine 125 isotope was applied overlying the cornea with a tumor apex dose of 80 Gy. The main outcome measures were tumor control and ocular complications using Kaplan-Meier estimates and Cox proportional hazards regression analysis. RESULTS: In all cases, the melanoma was nonresectable owing to large or discohesive tumor. The tumor configuration was nodular in 24 cases (63%) and flat (diffuse) in 14 (37%). The mean tumor basal diameter was 9 mm (range 4 to 13 mm). Solid tumor extended into the anterior chamber angle in 36 eyes (95%). Tumor seeds were noted on the iris stroma for a mean of 7 clock hours and in the anterior chamber angle for a mean of 4 clock hours. Five-year follow up revealed tumor metastasis in 0% and tumor recurrence in 8% of patients. Visual acuity of 20/200 or worse was found in 16% at 5 years. Radiation-related complications at 5 years included corneal epitheliopathy (9%), cataract (70%), and neovascular glaucoma (8%). No patients developed corneal necrosis, scleral necrosis, retinopathy, or papillopathy. After treatment, the combined incidence of tumor-related and radiation-related elevated intraocular pressure at 5 years was 33%. Enucleation was necessary in 13% at 5 years, for tumor recurrence (n = 3) and patient preference (n = 1). CONCLUSIONS: Plaque radiotherapy is a useful alternative to enucleation for eyes with nonresectable iris melanoma. Tumor control is 92% at 5 years, but related complications, especially cataract and elevated intraocular pressure, should be anticipated.

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Am J Clin Oncol. 2003 Apr;26(2):141-5.
Does continuous-infusion interleukin-2 increase survival in metastatic melanoma?
Dillman RO, O'Connor AA, Simpson L, Barth NM, VanderMolen LA, Vanderplas P.
Hoag Cancer Center, One Hoag Drive, Building 41, Newport Beach, CA 92658, U.S.A. rdillman@hoaghospital.org

Pharmacy logbooks and clinical trial records were used to identify all 60 patients with metastatic melanoma who were treated as inpatients with intermediate-dose, continuous-infusion interleukin-2 (IL-2) in Hoag Hospital during 1987 to 1998. The hospital tumor registry was used to identify contemporary controls who had not received inpatient IL-2, matched for having distant metastatic melanoma, and by year and stage at original diagnosis, gender, and age. The mean time from original diagnosis to the documentation of distant metastatic disease was similar in both groups, 24 to 26 months. From the date of starting IL-2 therapy, patients had a median survival of 8.8 months, 38% 1-year survival, and 20% 5-year survival, with 8 patients alive beyond 5 years. However, there was no difference in survival from the first date of distant metastatic disease (median 25.8 months for IL-2 versus 31.5 months for controls, with survival rates 5 years after metastatic disease of 26% versus 31%). There was also no difference in overall survival from the date of original diagnosis (60.1 months for the IL-2 group versus 86.3 months for controls, with 5-year survival rates of 51% versus 64%, and 10-year survival rates of 29% versus 33%). This single-institution study failed to establish a survival advantage for patients with metastatic melanoma who received intermediate-dose, continuous-infusion IL-2 administered in the inpatient setting, compared to contemporary, matched-control patients who never received inpatient IL-2 therapy. However, the 5-year survival rates after a diagnosis of distant metastatic disease were a surprisingly high 26% to 31% in both groups. In the absence of a control group, the survival impact of IL-2 has probably been overestimated from single-arm phase II and III trials.

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Indian J Ophthalmol. 2003 Mar;51(1):17-23.
Golden Jubilee Lecture. Randomised clinical trials of choroidal melanoma treatment.
Straatsma BR.
Jules Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095-7000, USA. straatsma@jsei.ucla.edu

PURPOSE: To illustrate an approach to evidence-based medical practice by reporting the Collaborative Ocular Melanoma Study (COMS) randomised clinical trials and cohort studies of choroidal melanoma. METHODS: COMS randomised clinical trials of Iodine-125 (I-125) brachytherapy, adjunctive cohort study of visual acuity in eyes treated with brachytherapy and adjunctive natural history study. COMS randomised clinical trial of pre-enucleation radiation. RESULTS: The COMS I-125 brachytherapy trial (N = 1,317 patients) of medium-sized choroidal melanoma showed 5-year all-cause mortality of 18% [95% Confidence Interval (CI), 16-20%] and no statistically significant difference in mortality following I-125 brachytherapy or enucleation. Adjunctive cohort natural history study (N-42 patients) of patients eligible for the I-125 brachytherapy trial who deferred treatment or had no melanoma treatment had a 5-year all-cause mortality of 30% (95% CI, 18-47%). The COMS pre-enucleation radiation trial (N = 1,003 patients) of large-sized choroidal melanoma showed 5-year all-cause mortality of 40% (95% CI, 37-44%). CONCLUSIONS: Evidence derived from randomised clinical trials and cohort studies shows the need for longterm (> or = 5 years) follow-up to determine the efficacy of treatment for choroidal melanoma by any modality. The rather similar 5-year mortality for treated and untreated medium melanoma patients suggests that metastatic dissemination may occur at an early stage of choroidal melanoma. To increase longterm survival, ocular treatment of choroidal melanoma must strive for diagnosis and treatment of melanoma at an early stage when metastasis is less likely and be combined with measures to detect and treat micrometastasis.

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Surg Clin North Am. 2003 Feb;83(1):157-85, vii.
Selective sentinel lymphadenectomy for malignant melanoma.
Leong SP.
Department of Surgery, University of California at San Francisco, University of California at San Francisco Comprehensive Cancer Center at Mount Zion, 1600 Divisadero Street, San Francisco, CA 94143-1674, USA. leongs@surgery.ucsf.edu

To date, selective sentinel lymphadenectomy (SSL) should be considered a standard approach for staging patients with primary invasive melanoma greater than or equal to 1 mm. It is imperative that the multidisciplinary team master the techniques of preoperative lymphoscintigraphy, intraoperative lymphatic mapping, and postoperative pathologic evaluation of the sentinel lymph nodes (SLNs). A SLN is defined as a blue, "hot", or any subsequent lymph node greater than 10% of the in vivo count of the hottest lymph node and as an enlarged or indurated lymph node. Frozen sections are not recommended. For extremity melanoma, delayed SSL may be performed. Preoperative lymphoscintigraphy for extremity melanoma may be done the night before so that surgery can be scheduled as the first case of the following day. Every surgeon who uses blue dye should be cognizant of the potential adverse reaction to isosulfan blue and treatment for such a potential fatal reaction. A complete lymph node dissection is done if the SLN is found to be positive. Elective lymph node dissection should not be done if SSL can be done as a staging procedure. It is important for investigators involved with SSL to follow the clinical outcome of their patients so that the role of SSL can be further defined.

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Dermatol Surg. 2003 Apr;29(4):366-74.
"Functional" surgery in subungual melanoma.
Moehrle M, Metzger S, Schippert W, Garbe C, Rassner G, Breuninger H.
Department of Dermatology, University of Tuebingen, Tuebingen, Germany. matthias.moehrle@med.uni-tuebingen.de

BACKGROUND: Subungual melanomas represent approximately 2% to 3% of cutaneous melanomas in White populations. Complete or partial amputation proximal to the distal interphalangeal joint of the digits has been suggested. Recently, we introduced for acral melanomas, similar to lentigo maligna melanoma, limited excision and complete histology of excisional margins (three-dimensional histology). OBJECTIVE: To evaluate the prognostic relevance of clinical parameters and different surgical management in patients with subungual melanoma. STUDY DESIGN: From 1980 to 1999, subungual melanoma was diagnosed in 62 of 3,960 stage I and II melanoma patients (1.6%) of the melanoma registry of the Department of Dermatology (University of Tuebingen). A retrospective comparative analysis of two treatment groups was performed: Thirty-one patients had an amputation in or proximal to the distal interphalangeal joint (median follow-up of 55 months), and 31 patients had "functional" surgery with local excision of the tumor and only partial resection of the distal phalanx (median follow-up of 54 months). RESULTS: In the univariate analysis, the level of invasion (P=0.0059), ulceration (P=0.0024), and tumor thickness (P=0.0004) were significant prognostic factors for recurrence-free survival but not for survival. In a multivariate analysis, only lower tumor thickness and a reduced level of amputation were independent significant prognostic parameters for recurrence-free survival (P=0.035 and P=0.0069). Patients with an amputation in or proximal to the distal interphalangeal joint did not fare better than patients with less radical "functional" surgery. CONCLUSION: Limited excision with partial resection of the distal phalanx only and three-dimensional histology to assure tumor-free resection margins give better cosmetic and functional results and do not negatively affect the prognosis of patients with subungual melanoma.

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Cancer. 2003 Apr 1;97(7):1789-96.
Adjuvant irradiation for cervical lymph node metastases from melanoma.
Ballo MT, Bonnen MD, Garden AS, Myers JN, Gershenwald JE, Zagars GK, Schechter NR, Morrison WH, Ross MI, Kian Ang K.
Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas77030, USA. mballo@mdanderson.org

BACKGROUND: The risk of regional disease recurrence after surgery alone for lymph node metastases from melanoma is well documented. The role of adjuvant irradiation remains controversial. METHODS: The medical records of 160 patients with cervical lymph node metastases from melanoma were reviewed retrospectively. Of these, 148 (93%) presented with clinically palpable lymph node metastases. All patients underwent surgery and radiation to a median dose of 30 grays (Gy) at 6 Gy per fraction delivered twice weekly. Surgical resection was either a selective neck dissection in 90 patients or local excision of the lymph node metastasis in 35 patients. Only 35 patients underwent a radical, modified radical, or functional neck dissection. RESULTS: At a median follow-up of 78 months, the actuarial local, regional, and locoregional control rates at 10 years were 94%, 94%, and 91%, respectively. Univariate analysis of patient, tumor, and treatment characteristics failed to reveal any association with the subsequent rate of local or regional control. The actuarial disease-specific (DSS), disease-free, and distant metastasis-free survival (DMFS) rates at 10 years were 48%, 42%, and 43%, respectively. Univariate and multivariate analyses revealed that patients with four or more involved lymph nodes had a significantly worse DSS and DMFS. Nine patients developed a treatment-related complication requiring medical management, resulting in a 5-year actuarial complication-free survival rate of 90%. CONCLUSIONS: Adjuvant radiotherapy resulted in a 10-year regional control rate of 94%. Complications for all patients were rare and manageable when they did occur. The authors recommend adjuvant irradiation for patients with extracapsular extension, lymph nodes measuring 3 cm in size or larger, the involvement of multiple lymph nodes, recurrent disease, or any patient having undergone a selective therapeutic neck dissection. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11243

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Cancer Radiother. 2003 Feb;7(1):1-8.
[Randomised phase III trial of fotemustine versus fotemustine plus whole brain irradiation in cerebral metastases of melanoma]
[Article in French]
Mornex F, Thomas L, Mohr P, Hauschild A, Delaunay MM, Lesimple T, Tilgen W, Nguyen BB, Guillot B, Ulrich J, Bourdin S, Mousseau M, Cupissol D, Bonneterre J, de Gislain C, Bensadoun JR, Clavel M.
Centre hospitalier Lyon-Sud, service de radiotherapie-oncologie, EA 643, 69495 cedex, Pierre-Benite, France. mornex@radiotherapie.univ-lyon.fr

PURPOSE: The main objective of this prospective multicenter randomised phase III study was to compare a combined regimen of fotemustine plus whole brain irradiation versus fotemustine alone in terms of cerebral response and time to cerebral progression in patients with melanoma brain metastases. PATIENTS AND METHODS: Seventy-six patients (instead of the 106 planned patients; study was stopped after the interim analysis) were randomised receiving either fotemustine (arm A, n = 39) or fotemustine and whole brain irradiation (arm B, n = 37). Fotemustine was administered intravenously at 100 mg m(-2) on day 1, 8 and 15, followed by a 5-week rest period, then every 3 weeks in non-progressive patients. In arm B, a concomitant whole brain irradiation was performed at the total dose of 37.5 Gy (2.5 Gy/d(-1), days 1-5, 3 consecutive weeks). RESULTS: Although patients who received fotemustine alone had worse prognostic factors, there was no significant difference in brain response (arm A: 7.4%, B: 10.0%) or control rates (objective response plus stable disease) after seven weeks (arm A: 30%, B: 47%) and overall survival (arm A: 86d, B: 105d). However, there was a significant difference in favour of arm B for the time to brain progression (p = 0.028, Wilcoxon test). CONCLUSION: Fotemustine plus whole brain irradiation delayed the time to brain progression of melanoma cerebral metastases compared to fotemustine alone but without a significant improvement in terms of objective control or overall survival.

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Am Surg. 2003 Feb;69(2):127-30.
Low-dose adjuvant interferon for stage III malignant melanoma.
Inman JL, Russell GB, Savage P, Levine EA.
Surgical Oncology Service and Section of Medical Oncology, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina 27157, USA.

The role of interferon as adjuvant therapy in stage III melanoma has recently been questioned. Prospective randomized studies have shown conflicting results regarding the efficacy of adjuvant treatment. The purpose of this study was to examine the use of low-dose adjuvant interferon alpha2-b (IFN) in stage III melanoma patients treated at a single institution. This study was a retrospective analysis of 60 stage III melanoma cases from Wake Forest University treated between 1983 and 1998. Cases were identified via the tumor registry. All patients underwent standard lymphadenectomy after diagnosis. After recovery from surgery patients were offered low-dose IFN (3 million units subcutaneous TIW for 1 month and then 6 million units subcutaneous TIW for 11 months) as adjuvant therapy for stage III melanoma. The patients were followed up jointly by medical and surgical oncology. There were 39 male and 21 female patients with mean age of 60.0 (range 37-89) years. The average number of positive nodes was 3.6 (median = 1) for the treated group and 1.8 (median = 1) for those untreated (P = 0.71). The average tumor thickness was similar between groups: 4.71 versus 4.88 mm for the IFN and observation groups respectively. The IFN group (N = 25) that received low-dose treatment had a median survival of 7.9 years with a 5-year survival rate of 69 per cent. The 35 cases that did not receive interferon had a median survival of 6.5 years and a 5-year survival rate of 52 per cent. These survival rates were not significantly different (P = 0.91). The median disease-free survival for patients who did not receive IFN treatment was 2.4 years and 1.4 years for the treated group (P = 0.19). The data show that there was similar survival for those who did and did not receive the low-dose IFN treatment. Although only large prospective trials can conclusively exclude a small survival time this experience suggests that there is no significant survival advantage to low-dose adjuvant IFN therapy for stage III melanoma patients. Hopefully upcoming cooperative group trials will clarify the potential value of adjuvant IFN in this setting. However, although the toxicity of this regimen was mild we suggest that low-dose adjuvant IFN for stage III melanoma should not be utilized outside the setting of a clinical trial.

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J Surg Oncol. 2003 Mar;82(3):209-16.
Current management of melanoma: benefits of surgical staging and adjuvant therapy.
McMasters KM, Swetter SM.
Division of Surgical Oncology, University of Louisville, J. Graham Brown Cancer Center, Louisville, Kentucky 40202, USA. kelly.mcmasters@nortonhealthcare.org

Issues regarding appropriate management of stage I to III melanoma are addressed. Accurate surgical staging is critical to identifying patients who can benefit from therapeutic lymph node dissection and adjuvant therapy. Patients with primary tumors > or = 1 mm thick are appropriate candidates for sentinel lymph node biopsy, and node-positive patients benefit from therapeutic lymphadenectomy. Although the overall survival benefit of high-dose interferon has been questioned, the weight of evidence supports the use of adjuvant therapy in patients with stage IIB and III disease. Copyright 2003 Wiley-Liss, Inc.

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Br J Cancer. 2003 Jan 27;88(2):175-80.
Temozolomide followed by combined immunotherapy with GM-CSF, low-dose IL2 and IFN alpha in patients with metastatic melanoma.
de Gast GC, Batchelor D, Kersten MJ, Vyth-Dreese FA, Sein J, van de Kasteele WF, Nooijen WJ, Nieweg OE, de Waal MA, Boogerd W.
Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. g.d.gast@nki.nl

The purpose of this study is to determine the toxicity and efficacy of temozolomide (TMZ) p.o. followed by subcutaneous (s.c.) low-dose interleukin-2 (IL2), granulocyte-monocyte colony stimulating factor (GM-CSF) and interferon-alpha 2b (IFN alpha) in patients with metastatic melanoma. A total of 74 evaluable patients received, in four separate cohorts, escalating doses of TMZ (150-250 mg m(-2)) for 5 days followed by s.c. IL2 (4 MIU m(-2)), GM-CSF (2.5 microg kg(-1)) and IFN alpha (5 MIU flat) for 12 days. A second identical treatment was scheduled on day 22 and cycles were repeated in stable or responding patients following evaluation. Data were analysed after a median follow-up of 20 months (12-30 months). The overall objective response rate was 31% (23 out of 74; confidence limits 20.8-42.9%) with 5% CR. Responses occurred in all disease sites including the central nervous system (CNS). Of the 36 patients with responding or stable disease, none developed CNS metastasis as the first or concurrent site of progressive disease. Median survival was 252 days (8.3 months), 1 year survival 41%. Thrombocytopenia was the primary toxicity of TMZ and was dose- and patient-dependent. Lymphocytopenia (grade 3-4 CTC) occurred in 48.5% (34 out of 70) fully monitored patients following TMZ and was present after immunotherapy in two patients. The main toxicity of combined immunotherapy was the flu-like syndrome (grade 3) and transient liver function disturbances (grade 2 in 20, grade 3 in 15 patients). TMZ p.o. followed by s.c. combined immunotherapy demonstrates efficacy in patients with stage IV melanoma and is associated with toxicity that is manageable on an outpatient basis.

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J Fr Ophtalmol. 2003 Jan;26(1):31-7.
[Iris melanomas. A retrospective study of 11 patients treated by surgical excision]
[Article in French]
Cardine S, Labetoulle M, Kirsch O, Di Nolfo M, Offret H, Frau E.
CHU de Kremlin-Bicetre, Service d'Ophtalmologie, Le Kremlin-Bicetre.

INTRODUCTION: Iris melanoma, even when a malignant tumor, has a slow progressive course. Surgical treatment is easy because of localization of the tumor but can be accompanied by a range of complications, from photophobia to cosmetic problems. MATERIALS AND METHODS: We reviewed the records of 11 patients with iris melanoma treated by surgical excision with posterior limbus incision. Conventional iridectomy was performed in nine cases and iridocyclectomy in two cases. RESULTS: There were seven females and four males ranging in age from 27 to 76 years. Histologically, 10 tumors were composed of B spindle cells and one was mixed. For all patients, followed up for 1-5 years, final visual acuity was more than 6/10. One patient complained of photophobia and cataract developed in one 76-year-old woman at the end of follow-up. CONCLUSION: Because of the good prognosis of iris melanoma, conservative treatment can be given in most of cases (without local complications). Surgical resection confirms diagnosis after histopathological examination, with good final functional result thanks to scleral tunnel incision, which induces less astigmatism than corneal incisions. In the future, these findings will have to be confirmed by a corneal topography study before and after surgery.

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Int J Radiat Oncol Biol Phys. 2003 Mar 15;55(4):867-80.
Eye retention after proton beam radiotherapy for uveal melanoma.
Egger E, Zografos L, Schalenbourg A, Beati D, Bohringer T, Chamot L, Goitein G.
Division of Radiation Medicine, Paul Scherrer Institute, Villigen, Switzerland. EmmanuelEgger@psi.ch

PURPOSE: To analyze the long-term results of eye retention after conservative treatment of uveal melanoma with proton beam radiotherapy, and to analyze the causes leading to enucleation after this conservative treatment approach. MATERIALS AND METHODS: This was a prospective, noncomparative, interventional, consecutive case series. A total of 2645 patients (2648 eyes) with uveal melanoma were treated between 1984 and 1999 with proton beam radiotherapy. Data were analyzed as of February 2001. Patients' age ranged from 9 to 90 years, 1284 were men, and 1361 were women. Largest tumor diameter ranged from 4 to 27.5 mm, and tumor height from 0.9 to 15.6 mm. Median follow-up time was 44 months. RESULTS: The overall eye retention rate at 5, 10, and 15 years after treatment was 88.9%, 86.2%, and 83.7%, respectively. In total, 218 eyes had to be enucleated. Enucleation was related to larger tumor size, mainly tumor height, proximity of posterior tumor margin to optic disc, male gender, high intraocular pressure, and large degree of retinal detachment at treatment time. After optimization of the treatment technique, the eye retention rate at 5 years was increased from 97.1% to 100% for small tumors, from 86.7% to 99.7% for medium, and from 71.1% to 89.5% for large tumors. CONCLUSIONS: The treatment technique as used today results in excellent eye retention rates, even in less favorable cases such as large tumors and tumors located close to the optic disc. The experience and a continuous quality control program allowed us to improve the 5-year eye retention rate for all tumor sizes. These findings demonstrate the positive impact of experience and quality control-based efforts for treatment technique optimization.

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J Am Coll Surg. 2003 Feb;196(2):206-11.
Surgical therapy for anorectal melanoma.
Bullard KM, Tuttle TM, Rothenberger DA, Madoff RD, Baxter NN, Finne CO, Spencer MP.
Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.

BACKGROUND: Anorectal melanoma is a rare but highly lethal malignancy. Historically, radical resection was considered the "gold standard" for treatment of potentially curable anorectal melanoma. The dismal prognosis of this disease has prompted us to recommend wide local excision as the initial therapeutic approach. The purpose of this study was to review our results in patients who underwent wide local excision or radical surgery (abdominoperineal resection [APR]) for localized anorectal melanoma. STUDY DESIGN: We reviewed the charts of all patients referred for resection of anorectal melanoma between 1988 and 2002. Endpoints included overall survival, disease-free survival, and local, regional, or systemic recurrence. RESULTS: Fifteen patients underwent curative-intent surgery; four underwent APR and 11 underwent wide local excision. Eight patients (53%) are alive; 7 (47%) are disease-free (followup 6 months to 13 years). Of 12 patients who have been followed for more than 2 years, 4 are alive (33%) and 3 are disease-free (25%). Seven patients have been followed for more than 5 years and two are alive and disease-free (29%). All of the longterm survivors underwent local excision as the initial operation. There were no differences in local recurrence, systemic recurrence, disease-free survival, or overall survival between the APR group and the local excision group. Local recurrence occurred in 50% of the APR group and 18% of the local excision group; regional recurrence occurred in 25% versus 27%. Distant metastases were common (75% versus 36%). CONCLUSION: In patients who have undergone resection with curative intent for anorectal melanoma, most recurrences occur systemically regardless of the initial surgical procedure. Local resection does not increase the risk of local or regional recurrence. APR offers no survival advantage over local excision. We advocate wide local excision as primary therapy for anorectal melanoma when technically feasible.

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Ophthalmologe. 2003 Feb;100(2):122-8.
[Stereotactic radiosurgery using the Gamma Knife for large uveal melanomas]
[Article in German]
Mueller AJ, Schaller U, Talies S, Horstmann GA, Wowra B, Kampik A.
Augenklinik der LMU, Munich. amueller@ak-i.med.uni-muenchen.de

BACKGROUND: We report the results over 3 years with stereotactic radiosurgery using the Gamma Knife for large and unsuitably located uveal melanomas. PATIENTS AND METHODS: A total of 100 patients (51 male, 49 female) have been treated since 1997 following a standardised treatment protocol (outpatient single-shot treatment, maximum dose 50 Gy, tumour margin dose min.25 Gy, retrobulbar anaesthesia alone for globe fixation). The localisation and/or dimension of the tumours did not allow radiation brachytherapy with Ru106 plaques. Of the tumours 18 were located in the ciliary body, 61 were located at the posterior pole, and 21 were located in the mid-periphery. All patients were followed and tested ophthalmologically and neuroradiologically at regular intervals. The 1-year follow-up data were available for 73 patients, 2-year follow-up data for 33 patients and 3-year follow-up-data for 17 patients. RESULTS: Before therapy the maximum apical tumour height (MAH) was median 7.8 mm (95% CI 2.9-12.5 mm): 1 year after treatment (73 patients) the MAH was median 5.7 mm (95% KI 2.4-10.2 mm),2 years after treatment (33 patients) the MAH was median 4.3 mm (95% KI 2.2-8.8 mm),and 3 years after treatment (17 patients) the MAH was median 4.6 mm (95% KI 2.4-8.5 mm). All differences to the MAH of the corresponding patients before treatment were statistically significant (paired t-test). Within the first year after treatment seven patients were enucleated due to a painful secondary glaucoma,within the second year after radiation two patients (one tumour recurrence, and one secondary glaucoma) and within the third year one more patient (tumour recurrence) was enucleated. CONCLUSIONS: Our 3-year results demonstrate that radiosurgery using the Gamma Knife is beneficial in achieving a local tumour control in 98% of eyes with large and unsuitably located uveal melanomas. The risk for a secondary enucleation is highest in the first year after treatment with a favourable overall rate of 10%. Due to the excellent local tumour control rate we decreased the maximum dose to 40 Gy (min.tumour margin dose 20 Gy) in the subsequently treated patients.

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Clin Experiment Ophthalmol. 2003 Feb;31(1):8-13.
Current trends in the treatment of ocular melanoma by radiotherapy.
Hungerford JL.
Ocular Oncology Services, Saint Bartholomew's and Moorfields Eye Hospitals, London, UK. hungerford.england@btopenworld.com

The Collaborative Ocular Melanoma Study (COMS) has recently confirmed once and for all that it is safe to attempt to preserve an eye with a posterior uveal melanoma by demonstrating no survival advantage of enucleation over plaque radiotherapy. While COMS has been under way, we have set out in London to define the selection criteria for conservative therapy versus enucleation for the various categories of melanoma in terms of size, location within the eye, and presence or absence of retinal detachment. The evolution of this approach has culminated in an overall ocular survival rate of 94% in 597 patients following radiation therapy combined with a mean loss of visual acuity of only 2.4 Snellen lines in the eyes preserved.

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Cancer. 2003 Jan 1;97(1):121-7.
Temozolomide in combination with interferon alpha-2b in patients with metastatic melanoma: a phase I dose-escalation study.
Agarwala SS, Kirkwood JM.
Melanoma Center, Cancer Institute, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15213, USA. agarwalass@msx.upmc.edu

BACKGROUND: Metastatic melanoma (MM) is associated with a high risk of central nervous system (CNS) metastases, and current chemotherapy does not adequately treat or protect patients with MM against CNS metastases. Therefore, the authors initiated a Phase I study to determine the pharmacokinetics and safety profile of temozolomide (TMZ), a novel oral alkylating agent known to cross the blood-brain barrier, in combination with interferon alpha-2b (IFN-alpha2b). METHODS: Twenty-three patients with MM were enrolled in this single-center, open-label study. Patients with CNS metastasis were excluded. One cohort (n = 6 patients) received oral TMZ (200 mg/m(2) per day) for 5 days every 28-day cycle plus subcutaneous IFN-alpha2b (5 million International Units [MIU]/m(2) per day, 3 times per week). A second cohort (n = 17 patients) received TMZ 150 mg/m(2) per day on the same schedule plus escalating doses of IFN-alpha2b (5.0 MIU/m(2) per day, 7.5 MIU/m(2) per day, and 10 MIU/m(2) per day 3 times per week). RESULTS: The most common adverse events were fatigue, fever, nausea/emesis, anxiety, and diarrhea. Most toxicity was mild to moderate in severity. The primary dose-limiting toxicity was thrombocytopenia. The maximum tolerated dose was either TMZ 150 mg/m(2) plus IFN-alpha2b 7.5 MIU/m(2) or TMZ 200 mg/m(2) plus IFN-alpha2b 5.0 MIU/m(2). Four patients (17%) had objective responses (one complete response and three partial responses), and four patients had stable disease. The median survival was 9 months. The pharmacokinetics of TMZ were not affected by coadministration of IFN-alpha2b. CONCLUSIONS: TMZ can be combined safely with IFN-alpha2b. This regimen demonstrated clinical activity in patients with MM and merits further investigation to define its effect on the incidence of brain metastases. Copyright 2003 American Cancer Society.

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Presse Med. 2003 Jan 11;32(1):39-43.
[Treatment of melanoma]
[Article in French]
Dreno B, Wallon-Dumont G.
Unite de cancero-dermatologie, Clinique dermatologique, CHU Hotel-Dieu, Nantes. bdreno@wanadoo.fr

At the stage of primary tumour and lymph node extension, the treatment of melanoma is mainly surgical. Interferon alpha has obtained marketing authorisation to be used as adjuvant therapy at different doses in the treatment of these two stages of the disease and must therefore be discussed with the patient. At the metastatic stage, no real progress in chemotherapy has been noted for more than 20 years. Combined therapy with chemotherapy and cytokines (interferon alpha or interleukine 2) increases the percentage of response but without increasing the overall survival. THREE IMMUNOTHERAPY TECHNIQUES: Cellular immunotherapy represents the main hope of these future years in the treatment of melanoma, with the injection of in vitro expanded cytotoxic T cells, vaccination and dendritic cells. Although clinical results are starting to be published, cellular immunotherapy remains in the field of clinical research, within the framework of clinical trials.

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Wiad Lek. 2002;55(9-10):608-16.
[Present view on malignant melanoma treatment]
[Article in Polish]
Trzmiel DA, Wygledowska-Kania ME, Lis AD, Pierzchala EK, Brzezinska-Wcislo LA.
Katedry i Kliniki Dermatologii, Slaskiej Akademii Medycznej w Katowicach.

Malignant melanoma is a tumor arising from melanocytes. Epidemiological data indicate rapid and progressive increase of malignant melanoma cases in Poland and other countries. Early diagnosis in malignant melanoma is the most important for the prognosis. Therefore the best treatment is ultraviolet prevention--sunscreen prophylactic, educational campaigns. Early diagnosis of malignant melanoma is based on ABCDE rules, seven point check Glasgow scale, dermatoscopy (a modern method in the differential diagnostics) and the knowledge of predisposing factors. There are several methods of treatment of malignant melanoma (chemotherapy, radiotherapy, immunotherapy etc.) among them surgical procedure is still a treatment of choice.

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Curr Med Chem Anti-Canc Agents. 2002 May;2(3):371-85.
Perspectives in melanoma treatment with signal transduction.
La Porta CA.
Department of General Physiology and Biochemistry, Section of General Pathology, Celoria 26, University of Milan, Italy. Caterina.LaPorta@unimi.it

Data from all parts of the world show a rising incidence of cutaneous malignant melanoma. The latter is one of the most difficult malignancies to treat. Early stage melanoma is curable but once metastatic it is almost uniformly fatal. Systemic therapy for advanced melanoma includes chemotherapy, either with dacarbazine alone or a multiagent combination chemotherapy, and biological therapy with recombinant interferon-alpha and/or interleukine-2. However none of these treatments options has produced long-term control of the disease except on rare occasion. In the present review, new strategies in the treatment of malignant melanoma that are now under investigations are discussed. Such new strategies might could be open new perspectives avoiding the toxicity of the conventional treatments too. In particular, possible agents acting on signal transduction pathways, such as Protein Kinase C modulators, and on the cell cycle are reviewed. Melanoma is the most immunogenic tumor among all tumor neoplasia. The feature has led to test several immunological strategies for manipulating immune responses in order to induce tumor growth control in vivo. Thus, the most interesting and recent strategies in this field and in particular the possibility to use specific vaccines are also considered.

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J Neurosurg. 2002 Dec;97(5 Suppl):640-3.
High-compared with low-dose radiosurgery for uveal melanomas.
Langmann G, Pendl G, Mullner K, Feichtinger KH, Papaefthymiouaf G.
Department of Ophthalmology, Karl-Franzens University, Graz, Austria. gerald.langmann@uni-graz.at

OBJECT: The authors compared the results of gamma knife radiosurgery in patients with uveal melanoma who underwent high-dose (treated from 1992-1995) and low-dose irradiation (treated from 1996-2002). METHODS: Thirty-one patients with uveal melanomas were treated with a mean margin dose of 52.1 Gy (high dose) and 33 with a mean dose of 41.5 Gy (low dose), and results were compared between groups. The technical procedure was the same in each group except for radiation dose. In the low-dose group, complete tumor regression (scar formation) occurred in 12% and in the high-dose group in 26%. Partial regression (reduction of the tumor prominence between 50 and 80%) occurred in 81% of the low-dose group and in 58% of the high-dose group. Neovascular glaucoma as a severe complication developed in 9% of the low-dose group and in 48% of the high-dose group. CONCLUSIONS: Reduction of the margin dose from 52.1 to 41.5 Gy appears to achieve the same rate of tumor regression but is associated with a lower rate of severe side effects such as neovascular glaucoma. The follow-up period in the low-dose group, however, was much shorter.

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J Neurosurg. 2002 Dec;97(5 Suppl):635-9.
Leksell gamma knife treatment of uveal melanoma.
Simonova G, Novotny J Jr, Liscak R, Pilbauer J.
Department of Stereotactic and Radiation Neurosurgery, Na Homolce Hospital, Prague, Czech Republic. gabriela.simonova@homolka.cz

OBJECT: The purpose of this study was to analyze treatment results, radiation-induced side effects, and prognostic survival factors for patients with uveal melanoma. METHODS: Eighty-one patients with uveal melanoma were treated using the Leksell gamma knife during a period of 6 years (1996-2001). There were 45 men and 36 women with a median age of 59 years (range 22-85 years). Seventy-five of these patients underwent minimal follow up 10 months after treatment. After patient eye immobilization, magnetic resonance (MR) imaging was performed to enable stereotactic localization. A scoring system was used to measure radiation side effects. The median target volume was 640 mm3, and the median applied minimal dose was 31.4 Gy. All patients were examined by an ophthalmologist and with MR imaging at regular intervals. Factors influencing posttreatment survival and side effects were statistically analyzed. CONCLUSIONS: Local tumor control in the 75 patients who underwent minimal follow up after 10 months was achieved in 63 patients (84%), whereas progression was observed in 12 patients (16%). The most frequent side effect was secondary glaucoma, which was detected in 18 patients (25%). The incidence of this side effect was significantly higher when the total volume of peripheral isodose was greater than 1000 mm3 (p = 0.015). Toxicity in the optic nerve here was also significantly higher when the maximum dose to this structure was higher than 9 Gy (p = 0.011), in the cornea when the maximum dose was higher than 15 Gy (p = 0.010), and in the lens when the maximum dose was higher than 10 Gy (p = 0.035). Altogether three pretreatment variables (patient age, tumor location, and dissemination of the disease) and one treatment variable (the minimum dose applied) were identified as having a significant influence on a patient's survival.

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Rev Med Interne. 2002 Nov;23 Suppl 4:489s-493s.
[Interferons and malignant melanoma]
[Article in French]
Dreno B.
Service de dermatologie, Hotel Dieu, place Alexis-Ricordeau, 44093 Nantes, France. bdreno@wanadoo.fr

BACKGROUND: Alpha interferon is currently used in the treatment of malignant melanoma mainly as adjuvant therapy at the first stage of the illness (primary tumor) and at the second stage (lymph node invasion). CURRENT POSITION AND MAIN POINTS: At metastatic stage, interferon alpha has no adverse indication when used alone. However, studies are on going to assess its potential synergistic effect combined with chemotherapy and its interest for maintaining clinical response. Beta and gamma interferon have no adverse indication in the treaTment of malignant melanoma. PERSPECTIVE: Although its action has been mainly demonstrated on relapse free survival, and the impact on quality of life remains important, additional new studies will be required to confirm its interest as adjuvant therapy for melanoma. In addition, the future use of pegylated interferon which would permit a reduction in the number of injections is of a significant interest.

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Am J Clin Oncol. 2002 Dec;25(6):552-6.
Randomized, placebo-controlled, phase III surgical adjuvant clinical trial of megestrol acetate (Megace) in selected patients with malignant melanoma.
Markovic S, Suman VJ, Dalton RJ, Woods JE, Fitzgibbons RJ Jr, Wold LE, Buckner JC, Kugler JW, Mailliard JA, Rowland KM, Krook JE, Brown DW, Tirona MT, Creagan ET.
Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, USA.

A randomized, double-blind, placebo-controlled phase III clinical trial was performed to assess megestrol acetate (Megace) as a postsurgical adjuvant therapy for patients with locally advanced malignant melanoma. Patients whose tumors were greater than 1.7 mm thick and had no regional lymph node involvement and patients with regional lymph node involvement were randomized to receive either 160 mg twice per day oral suspension of megestrol acetate or placebo. Treatment was administered for a maximum of 2 years or until disease progression. The study accrued 262 eligible patients. All but two patients were followed until death or a minimum of 4.5 years. Disease progression was documented in 156 patients. Neither progression-free survival (PFS) nor overall survival (OS) was found to differ between the treatments. The median PFS was 2.4 years in the megestrol acetate arm and 2.3 years in the placebo arm. Multivariate analysis revealed a significantly decreased PFS for patients with four or more positive regional lymph nodes and metachronous nodal disease. Median OS was 5.3 years in the megestrol acetate arm and 3.9 years in the placebo arm. Multivariate analysis revealed that OS was significantly decreased for patients 70 years of age or older with four or more positive lymph nodes. Adjuvant therapy with megestrol acetate oral suspension administered at a dose of 160 mg twice a day for 2 years was not found to be effective in prolonging PFS or OS in patients with surgically resected, locally advanced melanoma.

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Clin Cancer Res. 2002 Dec;8(12):3696-701.
Active immunotherapy of metastatic melanoma with allogeneic melanoma lysates and interferon alpha.
Vaishampayan U, Abrams J, Darrah D, Jones V, Mitchell MS.
Karmanos Cancer Institute, Department of Medicine, Wayne State University, Detroit, Michigan 48201, USA.

PURPOSE: A therapeutic lyophilized melanoma vaccine consisting of two mechanically disrupted allogeneic melanoma cell lines and the immunological adjuvant Detox-PC (Melacine) has demonstrated encouraging activity in metastatic malignant melanoma, often in regimens containing pretreatment with low-dose cyclophosphamide. In addition, IFN-alpha2b (INTRON A; Schering-Plough Corporation, Kenilworth, NJ) has shown efficacy in melanoma refractory to Melacine. In this Phase II trial, the combination of cyclophosphamide, Melacine, and IFNalpha was tested in metastatic malignant melanoma. EXPERIMENTAL DESIGN: Eligibility criteria included measurable disease, no prior systemic therapy for a minimum of 4 weeks, and adequate marrow, renal, and hepatic function. Cyclophosphamide was administered once at a dose of 300 mg/m(2) i.v. on day -3 before the first dose of Melacine. Melacine was administered at a dose of 2 x 10(7) tumor cell equivalents per dose admixed with 0.25 ml of Detox-PC s.c. once a week on weeks 1-4 and week 6. Melacine maintenance was then given monthly from the 8th week, until progression or intolerable toxicity. IFN was started in the evening after the fourth dose of Melacine at a dose of 5,000,000 units/m(2) 3 times a week, and continued until progression. RESULTS: Forty-seven patients were enrolled, of whom 39 completed the full course and were considered evaluable. The toxicity of the regimen was minimal and consisted mainly of pain at injection sites and granulomas caused by Detox-PC, and constitutional symptoms attributable to IFN. In 39 evaluable patients, the overall objective response rate was 10.2%, but 64% of patients had stabilization of their disease for at least 16 weeks. The median time to disease progression in evaluable patients was 8 months [95% confidence interval (CI), 6-13 months]. Median survival time for all of the 47 patients enrolled was 12.5 months (95% CI, 8-15 months) with a median time to disease progression of 4 months (95% CI, 3-7 months). CONCLUSION: Despite a low objective response rate, this combination holds great promise because of its tolerability and the high proportion of prolonged durations of remission or disease stabilization that it elicited.

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Arch Ophthalmol. 2002 Dec;120(12):1665-71.
Evidence-based estimates of outcome in patients irradiated for intraocular melanoma.
Gragoudas E, Li W, Goitein M, Lane AM, Munzenrider JE, Egan KM.
Retina Service, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114, USA. evangelos_gragoudas@meei.harvard.edu

BACKGROUND: Melanoma of the eye is the only potentially fatal ocular malignancy in adults. Until radiation therapy gained wide acceptance in the 1980s, enucleation was the standard treatment for the tumor. Long-term results after proton beam irradiation are now available. METHODS: We developed risk score equations to estimate probabilities of the 4 principal treatment outcomes-local tumor recurrence, death from metastasis, retention of the treated eye, and vision loss-based on an analysis of 2069 patients treated with proton beam radiation for intraocular melanoma between July 10, 1975, and December 31, 1997. Median follow-up in surviving patients was 9.4 years. RESULTS: Tumor regrowth occurred in 60 patients, and 95% of tumors (95% confidence interval, 93%-96%) were controlled locally at 15 years. Risk scores were developed for the other 3 outcomes studied. Overall, the treated eye was retained by 84% of patients (95% confidence interval, 80%-87%) at 15 years. The probabilities for vision loss (visual acuity worse than 20/200) ranged from 100% to 20% at 10 years and for death from tumor metastases from 95% to 35% at 15 years, depending on the risk group. CONCLUSIONS: High-dose radiation treatment was highly effective in achieving local control of intraocular melanomas. In most cases, the eye was salvaged, and functional vision was retained in many patients. The mortality rate was high in an identifiable subset of patients who may benefit from adjuvant therapies directed at microscopic liver metastases.

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Oncology (Huntingt). 2002 Nov;16(11 Suppl 13):4-10.
Current status of interleukin-2 therapy for metastatic renal cell carcinoma and metastatic melanoma.
Dutcher J.
New York Medical College, Bronx, USA. Jpd4401@aol.com

Interleukin-2 (IL-2, Proleukin) is one of the most effective agents in the treatment of metastatic renal cell carcinoma and metastatic melanoma. High-dose IL-2 therapy produces overall response rates of 15% to 20%; however, it is associated with significant toxicities that affect essentially every organ system. Although IL-2-related toxicities are usually reversible with therapy discontinuation, alternative IL-2 regimens have been evaluated. Several phase II studies have demonstrated that administering lower doses of IL-2 by IV bolus or continuous IV infusion or subcutaneously produces overall response rates similar to those with high-dose IL-2 therapy; however, randomized clinical trials have not yet been completed. In renal cell carcinoma, combining IL-2 with interferon alfa (Intron A, Roferon-A) or chemotherapy agents produces similar or increased overall response rates compared with the response rates of IL-2 alone, with no survival advantage. Combination IL-2 regimens in metastatic melanoma patients have produced variable results. The most promising regimens have included various IL-2-based biochemotherapy regimens in other patients. Randomized studies confirming the superiority of these regimens over high-dose IL-2 therapy are needed.

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Ann Surg Oncol. 2002 Dec;9(10):968-74.
Safety and efficacy of isolated limb perfusion in elderly melanoma patients.
Noorda EM, Vrouenraets BC, Nieweg OE, van Geel AN, Eggermont AM, Kroon BB.
Department of Surgery, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. e.noorda@nki.nl

BACKGROUND: Older patients are assumed to have a higher risk of complications from isolated limb perfusion (ILP). A study was performed evaluating the safety and efficacy of ILP in patients older than 75 years with advanced melanoma of the limbs. METHODS: A total of 218 therapeutic ILPs with melphalan with or without tumor necrosis factor alpha were performed in 202 patients with advanced measurable melanoma and were analyzed retrospectively. Fifty-three patients (28%) were 75 years or older. RESULTS: Complete response rates were 56% for those older than 75 years and 58% for the younger group (P =.79). Locoregional relapse occurred in 56% of the older group versus 51% in the younger group (P =.61). Limb toxicity, systemic toxicity, local complications, and long-term morbidity were similar in both age groups. Perioperative mortality was low, with one procedure-related death in the older group. Older patients stayed in the hospital for a median of 23 days (younger patients, 19 days; P <.01). CONCLUSIONS: ILP results in similar response rates in the elderly with recurrent melanoma, without increased toxicity, complications, or long-term morbidity compared with younger patients. Older age in itself is not a contraindication for ILP.

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Clin Exp Dermatol. 2002 Oct;27(7):597-601.
Vaccines and melanoma.
Nestle FO.
Department of Dermatology, University of Zurich Hospital, Germany. nestle@derm.unizh.ch

Melanoma is one of the prototypic immunogenic tumors. Various immunotherapeutic approaches for melanoma have been developed in the past decades. Recent scientific progress includes the discovery of defined melanoma antigens, new tools for monitoring of an anti-cancer immune response and application of novel adjuvants for amplification of the immune response such as dendritic cells. These and other advances in the field of melanoma vaccines will be discussed.

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Int J Radiat Oncol Biol Phys. 2002 Dec 1;54(5):1438-45.
Palladium-103 plaque radiotherapy for choroidal melanoma: an 11-year study.
Finger PT, Berson A, Ng T, Szechter A.
The New York Eye Cancer Center, St. Vincent's Comprehensive Cancer Center, New York, NY 10021, USA. pfinger@eyecancer.com

PURPOSE: To describe 11 years of experience with 103Pd ophthalmic plaque brachytherapy for intraocular melanoma. METHODS AND MATERIALS: Since 1990, 152 patients have been diagnosed with uveal melanoma, found to be negative for metastatic disease, and treated with 103Pd radioactive plaque radiotherapy. This study presents the first 100 patients treated with 103Pd and followed for > or = 2 years. Plaques were sewn to the episclera to cover the base of the intraocular tumor. Treatment involved delivery of a mean apical radiation dose of 80.5 Gy during 5-7 days' continuous treatment. Patients were evaluated for local tumor control, visual acuity, radiation damage (retinopathy, optic neuropathy, cataract), and metastatic disease. RESULTS: Patients in this series were followed for a mean of 4.6 years (55.4 months). 103Pd seeds were found to be equivalent to 125I with respect to plaque manufacture and ease of dosimetric calculations. We noted a local control rate of 96% and six secondary enucleations. Including the enucleated patients, the visual acuity evaluations revealed that 35% lost six or more lines of vision and 73% had vision of 20/200 or better. CONCLUSION: Long-term results now exist describing the use of 103Pd plaque radiotherapy for uveal (iris, ciliary body, and choroidal) melanoma. Compared with the results from centers using 125I, patients in this series experienced equivalent local control rates and better visual function.

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Ann Oncol. 2002 Dec;13(12):1919-24
A phase II study of outpatient subcutaneous histamine dihydrochloride, interleukin-2 and interferon-alpha in patients with metastatic melanoma.
Schmidt H, Larsen S, Bastholt L, Fode K, Rytter C, Von Der Maase H.
Department of Oncology, Aarhus University Hospital, Denmark. hs@oncology.dk

BACKGROUND: Experimental data had suggested a synergistic effect of histamine with interleukin-2 (IL-2) and interferon-alpha (IFN-alpha). PATIENTS AND METHODS: Forty-one patients with metastatic melanoma received IL-2 9 MU subcutaneously (s.c.) twice daily on days 4-8 and 25-29, and once daily on days 11-15 and 32-36. IFN-alpha-2b was given as 5 MU s.c. on days 1-3 and then daily to day 43. Histamine 1 mg s.c. was administered twice daily, following IL-2 and IFN injections starting on day 4. Efficacy and toxicity were compared with those of 42 patients included on exactly the same criteria and receiving the same regimen but without histamine. RESULTS: Two patients achieved a partial response (PR) for an objective response rate of 5% [95% confidence interval (CI) 1% to 17%]. Median overall survival was 7.8 months (95% CI 6.4-9.1). In the control group, two complete responses and one PR were achieved. Median overall survival was 7.1 months (95% CI 5.4-8.9). CONCLUSIONS: This IL-2 and IFN regimen was well tolerated on an outpatient basis. However, the applied regimen cannot be recommended because of the low clinical efficacy. Histamine did not add efficacy or toxicity in combination with this moderate-dose schedule of IL-2 and IFN.

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J Clin Oncol. 2002 Dec 1;20(23):4549-54.
Prolonged survival after complete resection of disseminated melanoma and active immunotherapy with a therapeutic cancer vaccine.
Hsueh EC, Essner R, Foshag LJ, Ollila DW, Gammon G, O'Day SJ, Boasberg PD, Stern SL, Ye X, Morton DL.
Sonya Valley Ghidossi Vaccine Laboratory, John Wayne Cancer Institute, Santa Monica, CA 90404, USA.

PURPOSE: The curative effect of surgery in certain patients with metastatic melanoma suggests the presence of endogenous antitumor responses. Because melanoma is immunogenic, we investigated whether a therapeutic cancer vaccine called Canvaxin (CancerVax Corporation, Carlsbad, CA) could enhance antitumor immune responses and thereby prolong survival. PATIENTS AND METHODS: Of 263 patients who underwent complete resection of American Joint Committee on Cancer stage IV melanoma, 150 received postoperative adjuvant vaccine therapy and 113 did not. The overall survival (OS) for the two groups was compared by Cox regression. Further survival analysis was performed by matched-pair analysis according to three prognostic variables: sex, metastatic site, and number of tumor-involved organ sites. RESULTS: Five-year OS rates were 39% for vaccine and 19% for nonvaccine patients. On multivariate analysis, vaccine therapy was the most significant prognostic variable in this cohort (P =.0001). Analysis of 107 matched pairs of vaccine and nonvaccine patients revealed a significant OS advantage for vaccine therapy (P =.0009): 5-year OS was 39% for vaccine patients versus 20% for nonvaccine patients. There was a significant delayed-type hypersensitivity (DTH) response to adjuvant vaccine therapy (P =.0001), and OS was significantly correlated with DTH to vaccine (P =.0001) but not with DTH to purified protein derivative (PPD), a control antigen. CONCLUSION: Prolonged survival was observed in patients who received postoperative active immunotherapy with Canvaxin therapeutic cancer vaccine. The correlation of survival with vaccine-DTH responses but not PPD-DTH indicates a treatment-specific effect. These findings suggest that adjuvant active specific immunotherapy should be considered after cytoreductive surgery for advanced melanoma.

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Invest New Drugs. 2002 Nov;20(4):431-7.
Phase II study of marimastat (BB-2516) in malignant melanoma: a clinical and tumor biopsy study of the National Cancer Institute of Canada Clinical Trials Group.
Quirt I, Bodurth A, Lohmann R, Rusthoven J, Belanger K, Young V, Wainman N, Stewar W, Eisenhauer E; National Cancer Institute of Canada Clinical Trials Group.
Department of Medical Oncology & Hematology, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Canada. ian.quirt@uhn.on.ca

OBJECTIVES: To determine the tolerability and efficacy of daily oral marimastat (BB-2516 in patients with metastatic melanoma and to determine the matrix metalloproteinase (MMP) activity, tumour necrosis, peri- and intra-tumoral fibrosis and tumor inflammation in pre- and post-treatment tumor biopsies. PATIENTS AND METHODS: Patients with measurable metastatic melanoma who had received no more than one prior chemotherapy regimen and lesions accessible for biopsy were eligible. The first 18 were treated with 100 mg p.o. twice daily and the next 11 received a reduced dose of 10 mg p.o. twice daily because of musculoskeletal toxicity. Response was assessed according to standard criteria. RESULTS: Twenty-nine patients were entered and 28 were eligible. Five had early progression (< 4 weeks of therapy), 2 experienced a partial responses persisting for 3.2 months and 3.6 months, 5 had stable disease and 16 progressive disease. Eleven patients had both pre- and post-treatment biopsies. In 3, no tumor tissue was present in one or the other biopsy. Two patients showed a clear increase in peri-tumoral fibrosis and two others showed an increase in tumor necrosis, but no consistent pattern in histologic changes was seen. In one patient, who later developed a PR, apoptosis was increased. CONCLUSION: Marimastat has only limited activity in patients with metastatic malignant melanoma. However, the observation of two partial responses was interesting given that this agent might have been expected to cause tumor stasis rather than regression. Additional studies will be required to determine if the development of peri-tumoral fibrosis or tumor necrosis antedates a clinical response to marimastat.

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Klin Monatsbl Augenheilkd. 2002 Oct;219(10):710-21.
[Malignant conjunctival melanoma. Clinical review with recommendations for diagnosis, therapy and follow-up]
[Article in German]
Lommatzsch PK, Werschnik C.
Augenarztliche Gemeinschaftspraxis Leipzig, Germany.

BACKGROUND: Malignant conjunctival melanoma is a rare disease with an incidence of 0.03 - 0.08. This tumour is potentially lethal, even after prompt and proper treatment, especially after delayed onset of therapy. Conjunctival melanoma arises from primary acquired melanosis (PAM), from a preexisting nevus or "de novo" without any precursor at all. In contrast to uveal melanomas, conjunctival melanoma metastasizes via the ipsilateral lymph nodes and in rare cases through the lacrimal duct into the nasal cavities. RESULTS: Removing the local tumour with preservation of visual functions and avoidance of metastases is the therapy of choice. Excision alone is followed by a high rate of recurrence. To minimize local recurrence rate surgical excision should be combined with an additional procedure such as cryotherapy, irradiation, or local chemotherapy with MMC. Surgical technique is characterized by a so-called "no-touch" method avoiding any direct manipulation of the tumour to prevent tumour cell seeding into a new area. The behaviour of conjunctival melanomas is individually unpredictable. Prognostic factors are tumour size and tumour location. Tumours growing extralimbal especially at the fornix, plica and caruncle have a significantly poorer prognosis than limbal tumours. In our own patients the 5-year, 10-year, and 15-year cumulative melanoma-specific survival rate was 84.4 %, 77.7 %, and 75.0 %, respectively. Up to now there is no effective treatment of the metastatic disease. CONCLUSION: In all cases with pigmented lesions of the conjunctiva exclusion of a malignant melanoma has to be the first aim. A patient suffering from a conjunctival melanoma should be referred to an ophthalmo-oncological center for proper treatment. An indefinite follow-up including photodocumentation is necessary since the rate of recurrence is high. An international prospective study would be worthwhile to answer open questions and to develop new kinds of treatment of this potentially fatal tumour.

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Cancer Immunol Immunother. 2002 Dec;51(11-12):630-6. Epub 2002 Oct 15.
Phase I/II study of sequential chemoimmunotherapy (SCIT) for metastatic melanoma: outpatient treatment with dacarbazine, granulocyte-macrophage colony-stimulating factor, low-dose interleukin-2, and interferon-alpha.
Groenewegen G, Bloem A, De Gast GC.
Department of Oncology, University Medical Centre Utrecht, P.O. Box 85500, 3508GA Utrecht, the Netherlands. g.groenewegen@azu.nl

A regimen of sequential chemoimmunotherapy (SCIT) was studied in a phase I/II study to analyze toxicity, anti-tumor and immunomodulatory effects in patients with previously untreated metastatic cutaneous melanoma. Treatment consisted of dacarbazine (DTIC) 800 mg/m2 administered intravenously (i.v.) on day 1, followed by subcutaneous (s.c.) molgramostim (GM-CSF), 10 times 2.5 micro g/kg on days 2 to 12, s.c. low-dose interleukin-2 (IL-2), 10 times 1.8 MU on days 8 to 18, and s.c. interferon-alpha-2b (IFN-alpha), 5 times 6 MU on days 15 to 20. Dosages were not escalated. Therapy was given in the form of outpatient treatment. Changes in T-lymphocyte phenotype and in soluble mediators were monitored during treatment. A total of 32 patients with stage IV melanoma were enrolled in the study. Treatment was well tolerated, without serious toxicity. In all cases, it could be given as outpatient treatment. Ten subjects out of the 31 patients evaluated showed an objective response, with 4 complete responses (CR) and 6 partial responses (PR); the response rate amounted to 32% (95% CI: 16-49%). Median survival of all patients was 8 months, with those patients who responded to treatment living longer than the non-responding group. Survival rate at 1 year was 22%. Monitoring of the effects of treatment revealed increased numbers of activated T-lymphocytes, both in the CD4 and in the CD8 subsets. The levels of soluble mediators such as sIL-2R and sCD8 were also increased. Changes were noted as early as the GM-CSF treatment period, and were observed to a further extent during IL-2 treatment. In the present study, it was found that this sequential chemoimmunotherapy regimen consisting of 4 agents (DTIC, GM-CSF, IL-2, IFN-alpha) has acceptable toxicity, can be administered on an outpatient basis, results in increased numbers of activated T-lymphocytes, and induces activity against metastatic melanoma that warrants further investigation.

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Cancer. 2002 Dec 1;95(11):2366-72.
Chemoimmunotherapy with bleomycin, vincristine, lomustine, dacarbazine (BOLD), and human leukocyte interferon for metastatic uveal melanoma.
Pyrhonen S, Hahka-Kemppinen M, Muhonen T, Nikkanen V, Eskelin S, Summanen P, Tarkkanen A, Kivela T.
Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.

BACKGROUND: A Phase II trial comprising patients with metastatic uveal melanoma (Stage IVB) was undertaken to determine the activity of bleomycin, vincristine, lomustine, and dacarbazine (BOLD) chemotherapy with human leukocyte interferon, as well as the progression-free and overall survival of the patients according to the substage before treatment. METHODS: Twenty-two patients with histologically proven metastatic uveal melanoma received 15 mg of bleomycin (Days 2 and 5), 1 mg/m(2) vincristine (Days 1 and 4), 200 mg/m(2) dacarbazine (Days 1 to 5), and 80 mg lomustine (Day 1) every 4 weeks together with a leukocyte interferon preparation (3 x 10(6) IU daily for 6 weeks followed by 6 x 10(6) IU three times per week). RESULTS: Of 20 evaluable patients, 3 (15%; 95% confidence interval [CI] 0-38) obtained a partial objective response in hepatic and extrahepatic sites and 11 (55%; 95% CI 32-77) showed stable disease after receiving more than two cycles. The median progression-free survival was 4 months (95% CI 2-10) and the median overall survival was 12 months (95% CI 8-22). Eleven patients who had favorable pretreatment characteristics (Stage IVBa) survived a median of 17 months (95% CI 4-37) whereas 10 patients with less favorable characteristics (Stage IVBb) survived a median of 11 months (95% CI 1-23). Moderate toxicity occurred with this outpatient regimen. CONCLUSIONS: The BOLD/human leukocyte interferon regimen had modest activity against metastatic uveal melanoma in hepatic and extrahepatic sites. The median overall survival approached that reported for more aggressive intrahepatic therapy regimens. Substage differences can significantly impact study outcomes. Therefore, substage information should be reported to facilitate comparisons between studies. Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10996

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Semin Oncol. 2002 Oct;29(5):462-70.
Antibody-based vaccines for the treatment of melanoma.
Lutzky J, Gonzalez-Angulo AM, Orzano JA.
Melanoma Multidisciplinary Program, Mount Sinai Comprehensive Cancer Center, Miami Beach, FL, USA.

Malignant melanoma remains a difficult clinical problem. Chemotherapy is not effective and immunotherapy has long been contemplated as the preferred approach to this disease. Extensive passive and active immunotherapy trials have been conducted. Active vaccination with whole cells or defined antigens, administered with a panoply of techniques to increase immunogenicity, has yielded inconsistent results. The development of antibody-based vaccines has allowed vaccination without the need for tumor tissue material or purified antigens. The idiotype network theory originally proposed by Lindemann and by Jerne provided the basis for the development of anti-idiotype (anti-Id) antibody vaccines, which mimic the internal image of the epitope targeted for immunization. Preclinical and phase I clinical data are available for various malignancies. In melanoma, some of the anti-Id vaccines have targeted gangliosides. One of these vaccines, TriGem, has been successful in generating a robust and specific humoral immunity in melanoma patients. Phase II data suggest this anti-Id vaccine has clinical activity. Copyright 2002, Elsevier Science (USA). All rights reserved.

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Semin Oncol. 2002 Oct;29(5):456-61.
Biochemotherapy for advanced melanoma.
Keilholz U, Gore ME.
Department of Medicine III (Hematology, Oncology, and Transfusion Medicine), University Hospital Benjamin Franklin, Free University of Berlin, Berlin, Germany.

The outcome of chemotherapy for patients with stage IV melanoma is unsatisfactory, since durable responses are rarely achieved. More experimental treatments, such as vaccine approaches, antibody treatments, and gene therapy are being developed and are of high scientific interest; however, their efficacy in advanced melanoma patients has so far been very limited. Based on the observation of a small proportion of long-term responses, the use of biotherapy or biochemotherapy is currently preferred in many institutions as first-line treatment in stage IV melanoma. Various interleukin-2 (IL-2) dosing schedules and combinations with interferon alpha (IFN-alpha) have been tested in patients with advanced melanoma during the past decade. The response rates reported with IL-2 as a single agent or in combination with IFN-alpha varies from 10% to 41%, with a small, but remarkable proportion of durable responses. Subsequently, biochemotherapy regimens combining IL-2, IFN-alpha, and chemotherapy have been evaluated in phase II trials, which have suggested improved response rates. Recent randomized trials have investigated the role of biochemotherapy as compared to biotherapy alone or as compared to chemotherapy for the treatment of advanced melanoma. So far, none of the approaches has been proven to confer a survival benefit and thus the uniform desire is to include as many patients as possible in controlled clinical trials. Copyright 2002, Elsevier Science (USA). All rights reserved.

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Semin Oncol. 2002 Oct;29(5):427-45.
Metastatic melanoma: chemotherapy.
Bajetta E, Del Vecchio M, Bernard-Marty C, Vitali M, Buzzoni R, Rixe O, Nova P, Aglione S, Taillibert S, Khayat D.
Medical Oncology Unit B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.

The incidence of cutaneous melanoma has been rapidly increasing, with an estimate of 47,700 new cases diagnosed in 2000 in the United States. In the early phase of its natural history, melanoma is cured in most cases by surgery, but once the metastatic phase develops, it is almost always fatal. The treatment of metastatic melanoma remains unsatisfactory. Systemic therapy has not been successful up to now, with very low response rates to single-agent chemotherapy. Polychemotherapy has increased the response rate (RR), without a significant improvement in overall survival. Immunotherapy alone is able to induce only a few durable complete responses (CRs). New chemotherapeutic and biologic agents are now available and promising combined approaches targeting the tumor by several different mechanisms are desirable and will probably represent the future modality of treatment. Copyright 2002, Elsevier Science (USA). All rights reserved.

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