Renal Cell Carcinoma Research: 2002-2006
  
Cancer. 2006 Oct 6; [Epub ahead of print]
Improved tolerability and quality of life with maintained efficacy using twice-daily low-dose interferon-alpha-2b: results of a randomized phase II trial of low-dose versus intermediate-dose interferon-alpha-2b in patients with metastatic renal cell carcinoma.
Tannir NM, Cohen L, Wang X, Thall P, Mathew PF, Jonasch E, Siefker-Radtke A, Pagliaro LC, Ng CS, Logothetis C.
Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

BACKGROUND.: In vivo data have shown a more potent antiangiogenic effect and a higher antitumor activity of low-dose interferon (IFN) given twice daily. In a randomized Phase II trial, the authors tested the hypothesis that twice-daily low-dose IFN is more effective than daily intermediate-dose IFN in patients with metastatic renal cell cancer (MRCC). METHODS.: A total of 118 patients (59 per arm) were randomly assigned to receive IFN at a dose of 0.5 million units (MU) given subcutaneously twice daily (IFN1) or IFN at a dose of 5 MU given subcutaneously daily (IFN5). The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate (RR), overall survival (OS), toxicity, and quality of life (QOL). RESULTS.: There were no significant differences in either PFS or OS between IFN1 and IFN5 (median of 3.7 months and median of 3.4 months PFS, respectively; median of 25.5 months and median of 17.5 months OS, respectively). The RRs were identical in the 2 arms (6.7%; 95% confidence interval [95% CI], 1.8-16.5%). Two patients, 1 in each arm, remained in complete remission at the time of last follow-up, at 45+ and 38+ months from treatment. Thirty-two patients receiving IFN5 and 19 patients receiving IFN1 experienced Grade 3 or higher adverse events (graded using the National Cancer Institute Common Toxicity Criteria [version 2.0]) (P = .025). Eighteen patients receiving IFN5 and 4 patients receiving IFN1 had dose reductions (P = .002). There was a significant deterioration in QOL and an increase in depression associated with IFN5 but no change was noted with IFN1. CONCLUSIONS.: Compared with IFN5, IFN1 is neither more nor less effective but is less toxic, with a better reported QOL. These results may have implications for the design of combination regimens incorporating IFN with targeted agents. Cancer 2006. (c) 2006 American Cancer Society.

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Clin Genitourin Cancer. 2006 Sep;5(2):120-130.
Adjuvant therapy of renal cell carcinoma.
Yap TA, Eisen TG.
Department of Medicine, Royal Marsden Hospital, London, UK.

Metastatic renal cell carcinoma (RCC) has a highly variable natural history and carries a dismal prognosis. Unlike many other tumors, RCC is generally unresponsive to cytotoxic, hormonal, and radiation adjuvant therapies after cytoreductive surgery. Different modalities of treatment have been tried and tested with modest success. Until recently, only immunotherapies such as interleukin-2 and interferon-alpha have been shown to provide a response, albeit in a minority of patients and often with severe treatment-associated toxicities. Other adjuvant therapies, such as active specific immunotherapy with Bacillus Calmette-Guerin and autologous renal tumor cell vaccines, have not provided alternative solutions. Recent approaches include heat-shock protein peptide complex 96 vaccine and cG250 monoclonal antibody therapy. Novel targeted therapies have been developed using our knowledge of the molecular genetics that belie RCC. This culminated in sorafenib and sunitinib, the first Food and Drug Administration-approved drugs for RCC in more than a decade in the United States. The future will see further trials being carried out in the development of targeted therapies with emphasis placed on patient selection. Staging systems will need to be updated to integrate molecular biomarkers, which could potentially act not just as diagnostic and prognostic predictors, but also as tools for appropriate patient selection for treatment. In the future, this could potentially lead us to our ultimate goal of personalized medicine.

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Clin Genitourin Cancer. 2006 Sep;5(2):114-119.
Interleukin-2 Therapy of Metastatic Renal Cell Carcinoma: Update of Phase III Trials.
McDermott DF, Regan MM, Atkins MB.
Beth Israel Deaconess Medical Center and the Dana-Farber/Harvard Cancer Center Renal Cancer Program, Boston, MA; E-mail: dmcdermo@bidmc.harvard.edu.

High-dose bolus interleukin-2 (IL-2) was granted Food and Drug Administration approval for the treatment of metastatic renal cell carcinoma based on its ability to produce durable responses in a small number of patients. Results from randomized phase III trials suggest that regimens involving lower doses of IL-2 alone or in combination with interferon produce fewer tumor regressions of decreased overall quality. Because of the toxicity and limited efficacy of this treatment, recent studies have focused on identifying predictors of response (or resistance) to IL-2 therapy. This year, investigators will launch a clinical trial designed to prospectively determine whether patients who are more likely to respond to high-dose IL-2 can be identified before therapy is initiated.

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Cancer Chemother Pharmacol. 2006 Sep 29; [Epub ahead of print]
A phase II trial of continuous low-dose oral cyclophosphamide and celecoxib in patients with renal cell carcinoma.
Krzyzanowska MK, Tannock IF, Lockwood G, Knox J, Moore M, Bjarnason GA.
Department of Medical Oncology and Hematology, Princess Margaret Hospital, 610 University Avenue, 5-227, M5G 2M9, Toronto, ON, Canada, monika.krzyzanowska@uhn.on.ca.

PURPOSE: The lack of effective systemic therapies for patients with advanced renal cell carcinoma (RCC) has stimulated interest in evaluating novel treatment strategies for this disease. METHODS: This was a two-institution, two-stage, phase II trial of continuous low-dose oral cyclophosphamide (50 mg daily) in combination with celecoxib (400 mg twice daily) in patients with progressive, locally advanced or metastatic RCC. The primary endpoint was disease control rate (DCR) defined as the number of patients with complete (CR) or partial response (PR) or prolonged (>/=6 months) stable disease (SD). Secondary endpoints included time to progression and toxicity. RESULTS: Between May 2001 and January 2003, 36 patients were enrolled onto the trial of which 32 were evaluable for response. One patient had a PR and three others had SD for longer than 6 months (DCR 12.5%, 95% CI 3.5-29.0%). The median progression free survival was 3.5 months (95% CI, 1.9-4.1 months) and the median overall survival was 14.5 months (95% CI, 8.4-20.8 months). One patient experienced grade five gastrointestinal bleeding. Otherwise, the treatment was well tolerated. CONCLUSIONS: Although generally well tolerated, continuous therapy with low-dose cyclophosphamide and celecoxib had limited activity in RCC.

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Acta Oncol. 2006;45(7):870-5.
A prospective Phase II trial of using extracranial stereotactic radiotherapy in primary and metastatic renal cell carcinoma.
Svedman C, Sandstrom P, Pisa P, Blomgren H, Lax I, Kalkner KM, Nilsson S, Wersall P.
Department of General Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden.

A retrospective study has indicated that stereotactic radiotherapy (SRT) has a value in treating both primary tumors and singular metastatic lesions that cause local symptoms. Here we present the results of a prospective study evaluating the safety and local efficacy of SRT in metastatic or inoperable primary renal cancer. Thirty patients with metastatic renal cell carcinoma (RCC) or inoperable primary RCC received high-dose fraction SRT. In total, 82 lesions were treated. Dose/fractionation schedules varied depending on target location and size. The most frequently used fractionations were 8 Gyx4, 10 Gyx4, 15 Gyx2 or 15 Gyx3 prescribed to the periphery of the PTV. Local control, defined as radiologically stable disease (SD) or partial/complete response (PR/CR) was obtained in 98% of treated lesions but 19% of lesions were in patients with a follow time of less than 6 months. CR was observed in 21% of the patients and 58% of the patients had a partial volume reduction or local stable disease after a median follow-up of 52 months (range 11-66) for patients alive and 18 months (range 4-57) for deceased patients. Local progression was seen in two lesions. Side effects were grade I-II in 90% of cases. The overall survival was 32 months. SRT for patients with primary and metastatic RCC resulted in high local control rate with generally low toxicity. The method can thus be considered a therapeutic option to surgery in patients with a limited number of metastases, as local treatment in RCC with an indolent presentation or as a method of reducing tumor burden prior to medical treatment.

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Urology. 2006 Sep;68(3):528-32. Epub 2006 Sep 18.
Laparoscopic cytoreductive nephrectomy: the M. D. Anderson Cancer Center experience.
Matin SF, Madsen LT, Wood CG.
Department of Urology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

OBJECTIVES: Cytoreductive nephrectomy (CN) is an integral component in treating patients with metastatic renal cell carcinoma. Critics of CN argue that perioperative morbidity or postoperative disease progression may preclude patients from receiving systemic therapy. Laparoscopic cytoreductive nephrectomy (LCN) may allow for reduced morbidity and may increase the likelihood of patients receiving systemic therapy. METHODS: From April 2001 to March 2005, 38 patients underwent LCN at our institution. We evaluated perioperative parameters such as demographics, blood loss, operative time, complications, follow-up time, interval to systemic therapy, and survival. A contemporary open cytoreductive surgery group was evaluated for comparison. RESULTS: The median patient age was 62 years (range 41 to 82). Most patients had a performance status of 1 or less. The median operative time was 188 minutes, and the median blood loss was 175 mL. All specimens were removed intact. The median tumor size was 8 cm (range 3.5 to 14). The median hospitalization was 3 days. Two major (5.7%) and four minor (11.4%) complications occurred, but no perioperative mortality. Postoperatively, 97.4% of patients were eligible for, or received, systemic therapy at a median of 41 days. The overall median survival was 18.1 months. In contrast to open CN, LCN resulted in decreased blood loss and hospital stay, with no differences in complications, operative time, or interval to systemic therapy. CONCLUSIONS: LCN is a safe and effective surgical approach for select patients with metastatic renal cell carcinoma. Our results have indicated that with proper patient selection, LCN is feasible, morbidity is minimized, and systemic therapy is delivered in a timely fashion.

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Onkologie. 2006 Sep;29(8-9):394-402. Epub 2006 Sep 6.
Targeted approaches for treating advanced clear cell renal carcinoma.
Van Spronsen DJ, De Mulder PH.
Department of Medical Oncology, Raboud University Nijmegen Medical Centre, The Netherlands.

The mainstay of any curative treatment in renal cell carcinoma (RCC) is surgery. In the case of metastatic disease at presentation, a radical nephrectomy is recommended to good performance status patients prior to the start of cytokine treatment. Interferon (IFN)-a offers in a small but significant percentage of patients advantage in overall survival. Interleukin (IL)-2-based therapy gives similar survival rates. To date, hormonal therapy and chemotherapy do not have a proven impact on survival. Recent insights demonstrate that the majority of clear cell RCC harbor abnormalities of the von Hippel-Lindau (VHL) gene. This gene plays a key role in the stimulation of angiogenesis by vascular endothelial growth factor (VEGF) in this highly vascularized tumor. This opens interesting new treatment strategies including blockade of VEGF with the monoclonal antibody bevacizumab (Avastin) and inhibition of VEGF receptor tyrosine kinases with small oral molecules such as sunitinib (SU11248, Sutent) or PTK787. Likewise, inhibition of the Raf kinase pathway with oral sorafenib (Bay 43-9006, Nexavar) or inhibition of the mTOR pathway with intravenous CCI-779 are under investigation. Preliminary clinical results with all these compounds are promising, and the results of ongoing first-line phase III studies will become available in the next years.

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BJU Int. 2006 May;97(5):939-45.
Comparison of outcomes in elective partial vs radical nephrectomy for clear cell renal cell carcinoma of 4-7 cm.
Dash A, Vickers AJ, Schachter LR, Bach AM, Snyder ME, Russo P.
Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

OBJECTIVE To compare the outcomes of patients who had a elective partial nephrectomy (PN) or radical nephrectomy (RN) for clear cell renal cell carcinoma (RCC) of 4-7 cm. PATIENTS AND METHODS From March 1998 to July 2004, 45 and 151 patients underwent PN and RN, respectively, for clear cell RCC. A multivariate Cox model was constructed for disease-free survival with adjustment for markers of disease severity, and a propensity-score approach used as a confirmatory analysis. RESULTS In the PN and RN cohorts the treatment failed in one and 20 patients, respectively; the median follow-up was 21 months. The hazard ratio (95% confidence interval) for PN after adjusting for disease severity was 0.36 (0.05-2.82; P = 0.3). Using planned PN as a predictor (intent-to-treat analysis) the hazard ratio was 1.06 (0.32-3.53; P = 0.9). In the propensity-score model, planned PN was associated with a hazard ratio of 1.75 (0.50-6.14; P = 0.4). The serum creatinine level 3 months after surgery was significantly lower in patients who had PN, with a difference between the means of 0.36 (0.23-0.48; P < 0.001). CONCLUSIONS Renal function was preserved after PN for 4-7 cm clear cell RCC tumours. When comparing the outcomes of PN and RN it is important to consider the intended operation as an independent variable. There was no clear evidence that PN was associated with worse cancer control, although a continued follow-up of this and other cohorts is warranted.

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BJU Int. 2006 May;97(5):933-8.
Renal cell carcinoma local recurrences: impact of surgical treatment and concomitant metastasis on survival.
Bruno JJ 2nd, Snyder ME, Motzer RJ, Russo P.
Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

The local recurrence of renal cancer is an uncommon event, but it is often tempting to remove such recurrences surgically. Authors from the USA analysed the survival benefit of such a strategy in the presence and the absence of concomitant metastatic disease. They found that, in the absence of metastases, complete surgical resection of local recurrences is associated with improved survival. Authors from the same institution compared outcomes in elective partial vs radical nephrectomy for renal cancers of 4.7 cm. They found no clear evidence that partial nephrectomy was associated with worse cancer control, but suggest that continued follow-up of this cohort is required. OBJECTIVE To analyse the survival benefit of resecting local recurrence (LR) of renal cell carcinoma (RCC) in the presence and absence of concomitant metastasis. PATIENTS AND METHODS From 1989 to 2004 we identified 34 patients with LRs (2.9%) of the 1165 radical nephrectomies performed for T1-4N0M0 disease. Of these, 18 (53%) had no evidence of metastasis (isolated LR incidence, 1.5%) and 16 (47%) had synchronous metastasis. Of the 18 patients with no metastasis, 11 had complete surgical resection (group I) and seven had nonsurgical therapy (group II). Of the 16 patients with synchronous metastasis, five had surgery (group III) and 11 did not (group IV). Survival was projected using the Kaplan-Meier method and log-rank test for each group. RESULTS Eight of the 34 patients (24%) were symptomatic. The T stage of the initial nephrectomy was T1a in two cases, T1b in six, T2 in five, T3a in six, T3b in eight, T4 in six and unknown in one; 22 patients (65%) had clear cell histology. There were no significant differences in median time to LR or the LR size among the groups. The median (range) follow-up was 16.9 (0.5-103.6) months. Of the 11 patients in group I, three remain with no evidence of disease, three are alive with metastatic disease, and five died from disease. By contrast, 21 of the 23 patients (91%) in groups II, III and IV died from disease. The overall estimated 1-, 3- and 5-year survivals were 63%, 31% and 18%. The median survival time was 71.4 months for group I, 9.9 for II, 16.3 for III, and 11.8 for IV (P < 0.01) with a 5-year survival of 62% for group I and 0% for groups II, III, and IV. CONCLUSIONS LR after radical nephrectomy is rare (2.9%) and has a poor prognosis. The presence of synchronous metastasis and nonoperative therapy are related to these low survival rates. However, if there is no metastatic disease, complete surgical resection of LRs is associated with improved survival.

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J Clin Oncol. 2006 Apr 24; [Epub ahead of print]
Phase II Placebo-Controlled Randomized Discontinuation Trial of Sorafenib in Patients With Metastatic Renal Cell Carcinoma.
Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Kaye SB, Rosner GL, Gore M, Desai AA, Patnaik A, Xiong HQ, Rowinsky E, Abbruzzese JL, Xia C, Simantov R, Schwartz B, O'dwyer PJ.
University of Chicago, Chicago, IL; Royal Marsden Hospital, Surrey, United Kingdom; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; The University of Texas M.D. Anderson Cancer Center, Houston; Cancer Therapy and Research Center, San Antonio, TX; Bayer Pharmaceuticals Corporation, West Haven, CT.

PURPOSE: This phase II randomized discontinuation trial evaluated the effects of sorafenib (BAY 43-9006), an oral multikinase inhibitor targeting the tumor and vasculature, on tumor growth in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Patients initially received oral sorafenib 400 mg twice daily during the initial run-in period. After 12 weeks, patients with changes in bidimensional tumor measurements that were less than 25% from baseline were randomly assigned to sorafenib or placebo for an additional 12 weeks; patients with >/= 25% tumor shrinkage continued open-label sorafenib; patients with >/= 25% tumor growth discontinued treatment. The primary end point was the percentage of randomly assigned patients remaining progression free at 24 weeks after the initiation of sorafenib. RESULTS: Of 202 patients treated during the run-in period, 73 patients had tumor shrinkage of >/= 25%. Sixty-five patients with stable disease at 12 weeks were randomly assigned to sorafenib (n = 32) or placebo (n = 33). At 24 weeks, 50% of the sorafenib-treated patients were progression free versus 18% of the placebo-treated patients (P = .0077). Median progression-free survival (PFS) from randomization was significantly longer with sorafenib (24 weeks) than placebo (6 weeks; P = .0087). Median overall PFS was 29 weeks for the entire renal cell carcinoma population (n = 202). Sorafenib was readministered in 28 patients whose disease progressed on placebo; these patients continued on sorafenib until further progression, for a median of 24 weeks. Common adverse events were skin rash/desquamation, hand-foot skin reaction, and fatigue; 9% of patients discontinued therapy, and no patients died from toxicity. CONCLUSION: Sorafenib has significant disease-stabilizing activity in metastatic renal cell carcinoma and is tolerable with chronic daily therapy.

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Urologe A. 2006 Apr 19; [Epub ahead of print]
[Systemic therapy of metastatic renal cell carcinoma.]
[Article in German]
Autenrieth M, Heidenreich A, Gschwend JE.
Klinik fur Urologie und Kinderurologie, Urologische Universitatsklinik, Prittwitz-Strasse 43, 89075, Ulm, juergen.gschwend@medizin.uni-ulm.de.

Cytokine-based immunotherapy was the only viable option in metastatic, nonresectable renal cell carcinoma (RCC) for many years. Systemic immunotherapy has become increasingly established as a standard therapy during the last 15 years. In this context, interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) turned out to be the most effective single agents in RCC. Subsequently, the approved subcutaneous application of these compounds was the preferred administration route in Germany. Response rates with cytokine combination therapy were almost similar to those of more aggressive concepts using additional chemotherapeutic agents.Currently, new compounds targeting specific signaling pathways are readily available and have passed clinical testing. Such small molecules like tyrosine kinase inhibitors, monoclonal antibodies, or the mTOR inhibitor CCI-779 may dramatically change the established concepts of systemic RCC treatment. This paper gives an overview of established, current, and evolving concepts of systemic therapy in RCC.

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Rofo. 2006 Apr;178(4):391-9.
[Preoperative and palliative embolization of renal cell carcinomas: follow-up of 49 patients]
[Article in German]
Hallscheidt P, Besharati S, Noeldge G, Haferkamp A, Lopez R, Kauffmann GW.
Abteilung Radiodiagnostik, Universitatsklinikum Heidelberg. hallscheidt@yahoo.de

PURPOSE: To evaluate the influence of preoperative and palliative embolization of renal cell carcinomas on survival, intra- and post-operative procedures, and symptom control for palliative and preoperative indications. MATERIALS AND METHODS: 56 patients who underwent renal cell carcinoma embolization from 1981 to 1999 were included in this retrospective study. RESULTS: 24 women and 32 men were included (mean age 59.4 years). Complete follow-up data was available for 49 patients. 42 patients underwent preoperative embolization at different tumor stages (pT1: 1 patient, pT2: 6, pT3 a: 4, pT3 b: 19, pT3 c: 2, pT4: 5). 14 patients underwent palliative embolization (T1: 0 patients, T2: 5, T3: 4, T4: 4). Indications for preoperative embolization were bleeding of the renal tumor in 6 cases -- non-recurrent bleeding reported, flank pain in 4 patients -- 3 of 4 patients had no further symptoms, recurrent tumor embolization in 1 patient, and 2 patients who wanted to be treated without symptoms. The mean survival time of preoperative embolized patients was 3.1 +/- 5.11 years with a 5-year survival rate of 50 %. The mean survival time of palliative embolized patients was 0.67 +/- 0.76 years with initial metastases (n = 7) and 2.33 +/- 2.40 without metastases (n = 6). CONCLUSION: Palliative embolization of renal cell carcinomas is a safe therapeutic method to treat advanced renal cell carcinomas allowing control of symptoms such as hematuria and flank pain in more than 90 % of our cases. Preoperative embolization yields a patient survival time comparable to that of patients at earlier tumor stages and is dependent on the metastases.

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Eur Urol. 2006 Mar 23; [Epub ahead of print]
Excellent Long-Term Cancer Control with Elective Nephron-Sparing Surgery for Selected Renal Cell Carcinomas Measuring More Than 4cm.
Becker F, Siemer S, Hack M, Humke U, Ziegler M, Stockle M.
Department of Urology and Paediatric Urology, Homburg, University of the Saarland, Germany.

OBJECTIVES: Elective nephron-sparing surgery (NSS) for renal cell carcinoma (RCC)<4cm has been accepted as alternative to radical nephrectomy (RN). However, NSS for tumours >4cm is controversial. We present our experiences and long-term oncologic outcome of RCC>4cm treated with NSS in a retrospective single-institutional analysis of 69 patients. METHODS: Between 1975 and 2004, elective NSS was performed in 368 patients at our institution, including 69 patients with sporadic, nonmetastatic RCC>4cm. Overall and cancer-specific survivals were estimated using the Kaplan-Meier method. RESULTS: Complications were seen in nine patients (13.0%). After a mean follow-up of 6.2 yr (median, 5.8 yr) seven patients (10.1%) had died, none of them of tumour-related causes. Tumour recurrence was detected in four patients (5.8%). The 5-yr overall survival probability was 94.9%. The 10-yr and 15-yr overall survival rates were both 86.7%. Cancer-specific survival was 100% after 5, 10, and 15 yr. CONCLUSIONS: Selected patients with localized RCC even >4cm can be treated with elective NSS providing optimal long-term outcome. The surgeon's decision for organ-preserving surgery should depend on tumour localisation and technical feasibility rather than on tumour size.

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J Vasc Interv Radiol. 2006 Mar;17(3):513-9.
Radiofrequency ablation of small renal cell carcinomas using multitined expandable electrodes: preliminary experience.
Clark TW, Malkowicz B, Stavropoulos SW, Sanchez R, Soulen MC, Itkin M, Patel A, Mondschein JI, Wein AJ.
Section of Interventional Radiology, Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, USA. timothy.clark@med.nyu.edu

PURPOSE: Radiofrequency ablation is a minimally invasive, nephron-sparing option for renal cell carcinoma (RCC) in poor surgical candidates. We report our contemporary experience with RCC radiofrequency ablation using multitined expandable electrodes along with an aggressive treatment strategy to displace adjacent viscera away from probe tines. Involution of the treatment zone was assessed over time. MATERIALS AND METHODS: Over a 36-month period, a quality-assurance database identified 22 patients with 26 sporadic RCC who underwent 43 ablations during 27 radiofrequency ablation sessions. The mean age of the cohort was 71 years (range, 47-89 y). Mean RCC diameter was 2.2 cm (range, 1-4 cm). Twenty-six of radiofrequency ablation sessions were performed using multitined expandable electrodes. All ablations used CT guidance with moderate sedation. Adjunctive techniques used during ablation were recorded, as were instances in which ablation mandated penetration of tines beyond the kidney margin. Post-treatment ablation zones were measured from CT/MR images to evaluate serial involution and treatment response. RESULTS: Technical success in targeting and ablation was 100%. Follow-up periods ranged from 1 to 31 months (mean, 11.2). During this period, one patient presented with marginal local recurrence and underwent repeat radiofrequency ablation. Adjunctive techniques in four patients included water injection for displacement of the tail of the pancreas (n = 1) or descending colon (n = 3). Deliberate penetration of tines beyond the margins of the kidney was performed in 41% of cases; no hemorrhage occurred in these cases. No major complications occurred. Minor complications occurred in 17% of patients, including asymptomatic pneumothorax, perirenal hematomas, subcutaneous hematoma, and subcutaneous abscess. After 6 months, mean involution of the ablation zone was 15% from baseline volume per year. CONCLUSION: Multitined expandable radiofrequency electrodes produce a high rate of local control for small RCCs with a low complication rate, even when tine penetration of the kidney is required for an adequate tumor treatment margin. Adjacent organs can be protected with adjunctive percutaneous maneuvers.

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Urology. 2006 Mar;67(3):502-6; discussion 506-7.
Evolution of surgical technique and patient outcomes for laparoscopic partial nephrectomy.
Weld KJ, Venkatesh R, Huang J, Landman J.
Division of Urology, Washington University School of Medicine, St. Louis, Missouri, USA.

OBJECTIVES: To review the operative technique, complication rates, and short-term oncologic efficacy of the first 60 laparoscopic partial nephrectomies performed by a single surgeon and to report changes in our technique and the associated outcomes. METHODS: Between January 2002 and December 2004, data regarding patient characteristics, intraoperative technique, and outcome of 60 consecutive patients undergoing laparoscopic partial nephrectomy were prospectively collected. RESULTS: All 60 procedures were successfully completed laparoscopically without conversion to an open or hand-assisted approach. Histopathologic examination revealed renal cell carcinoma in 60% of patients with no positive margins or recurrences at a mean follow-up of 25.3 months. The overall complication rate was 30.0%, with 8 urologic (13.3%) and 10 nonurologic (16.7%) complications. CONCLUSIONS: With experience, laparoscopic partial nephrectomy is a viable alternative to open partial nephrectomy for small renal masses. At present, energy technologies and surgical pharmaceuticals are helpful adjuncts, but are not reliable for primary hemostasis and collecting system closure. Adaptation of traditional open techniques, including vascular control, excision of the tumor with cold scissors, and suture reconstruction of the collecting system and parenchyma, remain necessary to consistently perform laparoscopic partial nephrectomy successfully.

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J Cancer Res Clin Oncol. 2006 Mar;132(3):137-49. Epub 2005 Nov 25.
Second-line strategies for metastatic renal cell carcinoma: classics and novel approaches.
Schrader AJ, Varga Z, Hegele A, Pfoertner S, Olbert P, Hofmann R.
Department of Urology, Philipps-University Medical School, Baldingerstrasse, 35043, Marburg, Germany.

Objectives: Renal cell carcinoma is an aggressive malignancy with a high propensity for both early and metachronous regional and distant metastasis. While surgical resection is the mainstay of therapy for patients with localized disease, the prognosis for patients with distant metastasis is poor with a 5-year survival rate of less than 10%. Response rates to first-line immunotherapy or immunochemotherapy range from 10-35%; responses achieved are predominantly partial remissions of short duration. Until today, there is no standard therapeutic procedure for the growing number of patients who relapse following first-line therapy and desire further active treatment. Materials and Methods: This article reviews classic and recent publications about second- and third-line approaches, their potential efficacy and toxicity. Results: Several novel approaches have raised well-founded hope. Especially the application of monoclonal antibodies targeting VEGF signalling as well as different receptor tyrosine kinase inhibitors have the potential to change the face of second-line treatment of patients with metastatic RCC. Both groups of agents are focused in current phase III trials, either as mono- and/or combination therapy. Conclusions: Until today, second-line treatment of patients with metastatic RCC progressing under therapy with biological response modifiers remains an unresolved issue. The results of ongoing clinical trials evaluating novel targeted approaches can be expected with suspense.

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Expert Rev Anticancer Ther. 2006 Jan;6(1):141-52.
Maintenance biotherapy with interleukin-2 and interferon for metastatic renal cell cancer.
Porta C.
Medical Oncology and Laboratory of Preclinical Oncology and Developmental Therapeutics, IRCCS San Matteo University Hospital, Piazzale Camillo Golgi, 2I-27100 Pavia, Italy. c.porta@smatteo.pv.it

The term maintenance immunotherapy comprises at least two different therapeutic approaches: the continuation of immunotherapy beyond disease progression and the use of chronic immunotherapy after the achievement of an initial response (or disease stabilization) with more intensive treatment modalities, such as chemotherapy. The former therapeutic approach was proposed in renal cell carcinoma some years ago relying on several immunological considerations. Some years later, we have learned that it is feasible and endowed with a favorable therapeutic index; furthermore, its immunologic effects are well described and reproducible, and it has antitumor activity. However, due to the lack of adequate randomized Phase III studies, the actual impact of this treatment strategy on patient survival has not yet been proved. The rationale of this treatment, its immunological and clinical results, as well as its pitfalls and perspectives, will be presented and discussed in this review.

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J Clin Oncol. 2006 Jan 1;24(1):25-35. Epub 2005 Nov 28.
Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer.
Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, Bello C, Deprimo S, Brega N, Massimini G, Armand JP, Scigalla P, Raymond E.
Department of Medicine, Gustave-Roussy Institute, Villejuif, France.

PURPOSE: To establish the safety, pharmacokinetics, and recommended dose of sunitinib, a novel oral multitargeting tyrosine kinase inhibitor with antiangiogenic and antitumor properties, in patients with advanced malignancies. PATIENTS AND METHODS: Sunitinib was given orally for 4 weeks every 6 weeks. RESULTS: Twenty-eight patients received doses ranging from 15 to 59 mg/m2 (ranging from 50 mg every other day to 150 mg/d). Dose-limiting toxicities reported at the maximum-tolerated doses > or = 75 mg/d were reversible grade 3 fatigue, grade 3 hypertension, and grade 2 bullous skin toxicity. Therefore, the recommended dose was 50 mg/d. At this dose, the main adverse effects were sore mouth, edema, and thrombocytopenia. Hair discoloration and yellow coloration of the skin were observed at doses > or = 50 mg/d. Pharmacokinetic data indicate that potentially active target plasma concentrations > or = 50 ng/mL can be achieved with moderate interpatient variability and a long half-life compatible with a single daily dosing. Six objective responses were observed in three renal cell carcinomas, one neuroendocrine tumor, one stromal tumor, and one unknown primary adenocarcinoma patient. At higher doses (> or = 75 mg/d), tumor responses were often associated with reduced intratumoral vascularization and central tumor necrosis, eventually resulting in organ perforation or fistula. CONCLUSION: At the dose of 50 mg/d (4 weeks on, 2 weeks off), sunitinib displays manageable toxicity. Antitumor activity supports further studies in patients with renal cell carcinoma, gastrointestinal, neuroendocrine, and stromal tumors. Future studies may consider including prospective imaging techniques such as high frequency ultrasound to monitor tumor density.

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Urologe A. 2005 Dec 22; [Epub ahead of print]
[Therapy strategies for advanced renal cell carcinoma.]
[Article in German]
Staehler M, Haseke N, Schoppler G, Stadler T, Adam C, Stief CG.
Urologische Universitatsklinik, Klinikum Grosshadern der Ludwig-Maximilians-Universitat Munchen, .

The therapeutic regimen for metastatic renal cell cancer has changed substantially in the last years. Formerly, metastatic disease was regarded as being inoperable and had a disastrous prognosis. Nowadays, radical nephrectomy is the accepted urologic-oncologic standard therapy in metastatic primaries, if technically feasible. A complete resection of metastases may be curative, or can achieve a substantial palliative benefit. A better understanding of prognostic parameters helps in the selection of patients with a chance of benefiting from systemic immunochemotherapy. For patients with rapidly progressing tumors or sarcomatoid dedifferentiation, new effective chemotherapy regimens are available. New angiogenesis inhibitors such as sutent, avastin or sorafenib can potentially be effectively used in future therapeutic regimens.

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Eur Urol. 2005 Dec 9; [Epub ahead of print]
Elective Nephron Sparing Surgery Should Become Standard Treatment for Small Unilateral Renal Cell Carcinoma: Long-term Survival Data of 216 Patients.
Becker F, Siemer S, Humke U, Hack M, Ziegler M, Stockle M.
Department of Urology and Paediatric Urology, University of Saarland, Germany.

OBJECTIVES: Our experiences with elective nephron-sparing surgery (NSS) for renal cell carcinoma (RCC) in a consecutive series of 216 patients are presented. Clinicopathological features and long-term oncological outcome is compared to patients treated with radical nephrectomy (RN). METHODS: Between 1975 and 2002, NSS was performed in 488 patients; 311 of these patients had elective indications. Renal cell carcinoma was found in 241/311 patients (77.5%). Long-term follow up data could be obtained in 216/311 patients. Cancer-specific survival was estimated using the Kaplan-Meier method. Cox's regression analysis and log-rank tests were used to evaluate independent predictive values of different clinicopathological features. Survival data of the 216 patients after NSS surgery were compared to 369 patients with small RCC treated with RN. RESULTS: After a mean follow up of 66 months (median 64 months) 29 (13.4%) of 216 patients treated with NSS had died, 4 of them (1.8%) tumour-related. Tumour recurrence was detected in 12 patients (5.6%). 204 patients (94.4%) were free of tumour at last follow-up. Cancer specific survival rates at 5 and 10 years for patients treated with NSS (RN) were 97.8% (95.5%) and 95.8% (84.4%). CONCLUSIONS: Elective NSS surgery provides optimal long-term outcome in patients with small localized RCC. Compared to RN, renal parenchyma is preserved without any disadvantage in survival rates. Consequently elective NSS should be accepted as gold standard for small renal tumours.

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Expert Rev Anticancer Ther. 2005 Dec;5(6):1053-9.
High-intensity focused ultrasound as a treatment option in renal cell carcinoma.
Hacker A, Dinter D, Michel MS, Alken P.
Department of Urology, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany. axel.haecker@chir.ma.uni-heidelberg.de

Due to the widespread use of modern imaging modalities, small renal masses are discovered incidentally at increasing rates. Advances in minimally invasive technologies have changed the treatment options for renal cell carcinoma. High-intensity focused ultrasound aims to completely ablate renal tumors in a noninvasive manner. Experimental studies have demonstrated principle feasibility and safety of the technology. However, clinical studies on renal cell carcinoma are very limited and no substantial oncologic results are available to date. Major technical improvements are mandatory to enable high-intensity focused ultrasound as an effective treatment option for patients with small renal masses.

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Expert Rev Anticancer Ther. 2005 Dec;5(6):1041-51.
Lymphocyte therapy of renal cell carcinoma.
Dillman RO.
Hoag Comprehensive Cancer Center, Newport Beach, CA 92658, USA. rdillman@hoaghospital.org

During the past 20 years, there has been considerable interest in lymphocyte therapy as a treatment for renal cell carcinoma. There is no therapeutic role for B-lymphocyte therapy, but their products, monoclonal antibodies, now have widespread clinical applications. The major types of autologous lymphocyte therapy that have been explored in clinical trials are cytotoxic lymphokine-activated killer cells, which are natural killer cells and T-cells that have been stimulated in vitro by interleukin-2 or other similar cytokines; cytotoxic and noncytotoxic tumor infiltrating lymphocytes, which are T-cells derived from tumor tissue; other tumor antigen-stimulated T-lymphocytes derived from regional lymph nodes or peripheral blood; and noncytotoxic lymphocytes of the memory/helper phenotype. More recently, allogeneic immune therapy using nonmyeloablative hematopoietic stem cell transplant and/or donor lymphocyte therapy has also shown promise.

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Expert Rev Anticancer Ther. 2005 Dec;5(6):973-86.
Peripheral gammadelta T-lymphocytes as an innovative tool in immunotherapy for metastatic renal cell carcinoma.
Viey E, Laplace C, Escudier B.
Institut National de la Sante et de la Recherche Medicale U487IFR 54, Institut Gustave Roussy, 94805 Villejuif, France. viey@igr.fr

Renal cell carcinoma represents 3% of solid malignancies in adults and nephrectomy remains the main treatment. Failure of conventional approaches for patients presenting with advanced disease has prompted the exploration of new strategies. This review describes the potential use of peripheral gammadelta (Vgamma9Vdelta2) T-cells in metastatic renal cell carcinoma. This peripheral lymphocyte population from the innate immune system has demonstrated an in vitro antitumor cytotoxicity against primary or established renal cell lines. Moreover, these Vgamma9Vdelta2 lymphocytes undergo a rapid and extensive expansion in vitro as well as in vivo upon stimulation with a synthetic potent agonist, the bromohydrin pyrophosphate molecule. Preclinical results obtained on specific in vitro amplification of Vgamma9Vdelta2 T-cells by bromohydrin pyrophosphate in renal cell carcinoma patients are presented in this review, while Phase I clinical trials are currently running. As there is growing evidence for the low efficiency of monotherapy in cancer patients, innovative approaches combining immunomodulatory gammadelta agonists with classic chemotherapies or administration of antiangiogenic agents are discussed.

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J Vasc Interv Radiol. 2005 Nov;16(11):1551-5.
Radiofrequency ablation of a central renal tumor: protection of the collecting system with a retrograde cold dextrose pyeloperfusion technique.
Wah TM, Koenig P, Irving HC, Gervais DA, Mueller PR.
Department of Radiology, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, United Kingdom. tze.wah@leedsth.nhs.uk

Renal radiofrequency (RF) ablation therapy is a safe and effective therapy for small renal cell carcinoma. Although the risk of complications is low, the potential for ureteral or calyceal injury does increase in the case of a centrally located lesion. A retrograde cold dextrose pyeloperfusion technique was designed to protect the collecting system in a patient who underwent percutaneous RF ablation of a central tumor of the left kidney.

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Oncology. 2005;69 Suppl 3:46-56. Epub 2005 Nov 21.
Investigating the potential of bevacizumab in other indications: metastatic renal cell, non-small cell lung, pancreatic and breast cancer.
de Gramont A, Van Cutsem E.
Hopital Saint-Antoine, Paris, France. aimery.de-gramont@sat.ap-hop-paris.fr

Bevacizumab (Avastin) has unprecedented survival benefit in patients with metastatic colorectal cancer. Trials are already in progress to investigate the potential of bevacizumab in indications including metastatic renal cell cancer (RCC), non-small cell lung cancer (NSCLC), pancreatic cancer, breast and ovarian cancer. Bevacizumab offers the potential to increase survival without substantially altering the toxicity profile in these tumor types. Bevacizumab has shown activity in patients with refractory metastatic RCC, where progression-free survival (PFS) was significantly longer in patients treated with bevacizumab (10 mg/kg every 2 weeks) than those treated with placebo (hazard ratio=2.55, p<0.001). In addition, combining bevacizumab with erlotinib (Tarceva) has shown a median time to progression of more than 11 months. In NSCLC, a phase II trial revealed that adding bevacizumab to chemotherapy increased therapeutic benefit compared with chemotherapy alone. Adverse events were mild and easily managed, but six patients receiving bevacizumab developed severe hemoptysis. Entry criteria for NSCLC trials have been adjusted to exclude patients with squamous cell histology to try to avoid this issue. Adding bevacizumab (10 mg/kg) to the current standard of care, gemcitabine, in stage IV pancreatic cancer has also shown promising efficacy. Partial responses were seen in 19% of patients, with a further 48% having stable disease. Several ongoing clinical trials are also studying bevacizumab with various chemotherapy and radiotherapy regimens. Bevacizumab combined with carboplatin (Paraplatin)/paclitaxel (Taxol) was further examined in a phase III randomized trial that accrued 878 patients with advanced non-squamous cell NSCLC. Patients given chemotherapy (paclitaxel and carboplatin) plus bevacizumab had a higher response rate, longer PFS and an increase in survival compared with patients on chemotherapy alone. Both regimens were generally well tolerated. Bevacizumab has also shown activity in patients with metastatic breast cancer. In 715 patients, a significant, 2-fold increase in response rate was observed in patients receiving bevacizumab plus paclitaxel compared with paclitaxel alone. Median PFS was also significantly increased (p<0.001). Bevacizumab has the potential to provide significant efficacy benefits for patients with metastatic RCC, NSCLC, pancreatic cancer, and other tumor types when used first line in combination with standard therapy. Copyright (c) 2005 S. Karger AG, Basel.

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Urology. 2005 Nov;66(5 Suppl):36-42.
Lessons learned in the surgical management of renal cell carcinoma.
Sengupta S, Zincke H.
Department of Urology, Mayo Clinic, Rochester, Minnesota 55905, USA.

Surgical excision, the mainstay of management of renal cell carcinoma (RCC), has evolved significantly over the last 4 decades. Radiological imaging is crucial to the diagnosis and staging of RCC, and technological advances have facilitated more precise preoperative assessment. Additionally, wider use of cross-sectional imaging modalities has led to increasing incidental diagnosis of small, early-stage RCC. Nephron-sparing surgery (NSS), originally developed to treat RCC arising in a solitary functioning kidney, has been demonstrated to be a safe and effective alternative to radical nephrectomy. NSS is now also applicable to tumors of suitable size and anatomy in patients with a normal contralateral kidney, thus facilitating preservation of renal function and management of metachronous contralateral pathology. Laparoscopic and percutaneous approaches have developed over the last decade, thus providing minimally invasive modalities, with shortened convalescence and improved cosmesis. Advanced RCC, involving venous extension or nodal spread, is increasingly amenable to surgical management, although appropriate patient selection is crucial. Furthermore, surgical excision of the primary lesion appears to be an integral part of systemic therapy for metastatic RCC.

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J Clin Oncol. 2005 Oct 3; [Epub ahead of print]
Treatment of Metastatic Renal Cell Carcinoma With a Combination of Bevacizumab and Erlotinib.
Hainsworth JD, Sosman JA, Spigel DR, Edwards DL, Baughman C, Greco A.
Sarah Cannon Research Institute; and Vanderbilt-Ingram Cancer Center, Nashville, TN.

PURPOSE: To evaluate the efficacy and toxicity of combined treatment with two targeted agents, an antibody against vascular endothelial growth factor (bevacizumab) and an epidermal growth factor receptor tyrosine kinase inhibitor (erlotinib), in the treatment of patients with metastatic clear-cell renal carcinoma. PATIENTS AND METHODS: Sixty-three patients with metastatic clear-cell renal carcinoma were treated with bevacizumab 10 mg/kg intravenously every 2 weeks and erlotinib 150 mg orally daily. Patients were reevaluated after 8 weeks of treatment; patients who responded continued treatment until they experienced tumor progression. RESULTS: Fifteen (25%) of 59 assessable patients (95% CI, 16% to 37%) had objective responses to treatment, and an additional 36 patients (61%) had stable disease after 8 weeks of treatment. Only eight patients' (14%) disease had progressed at this time point. The median and 1-year progression-free survivals were 11 months and 43%, respectively. After a median follow-up of 15 months, median survival has not been reached; survival at 18 months was 60%. Treatment was generally well tolerated; only two patients discontinued treatment because of toxicity (skin rash). Grade 1/2 skin rash and diarrhea were the most frequent treatment-related toxicities. CONCLUSION: The combination of bevacizumab and erlotinib is an effective and well-tolerated treatment for patients with advanced renal cell carcinoma. The efficacy of these two drugs in combination suggests that targeting of separate pathways critical to tumor growth and dissemination may achieve results superior to either drug as a single agent. Additional development of this and other combinations of targeted agents is warranted.

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Br J Cancer. 2005 Oct 3;93(7):757-62.
Two randomised phase II trials of subcutaneous interleukin-2 and histamine dihydrochloride in patients with metastatic renal cell carcinoma.
Donskov F, Middleton M, Fode K, Meldgaard P, Mansoor W, Lawrance J, Thatcher N, Nellemann H, von der Maase H.
1Department of Oncology, Aarhus University Hospital, Norrebrogade 44, 8000 Aarhus C, Denmark.

Histamine inhibits formation and release of phagocyte-derived reactive oxygen species, and thereby protects natural killer and T cells against oxidative damage. Thus, the addition of histamine may potentially improve the efficacy of interleukin-2 (IL-2). Two randomised phase II trials of IL-2 with or without histamine dihydrochloride (HDC) in patients with metastatic renal cell carcinoma (mRCC) were run in parallel. A total of 41 patients were included in Manchester, UK and 63 in Aarhus, Denmark. The self-administered, outpatient regimen included IL-2 as a fixed dose, 18 MIU s.c. once daily, 5 days per week for 3 weeks followed by 2 weeks rest. Histamine dihydrochloride was added twice daily, 1.0 mg s.c., concomitantly with IL-2. A maximum of four cycles were given. The Danish study showed a statistically significant 1-year survival benefit (76 vs 47%, P=0.03), a trend towards benefit in both median survival (18.3 vs 11.4 months, P=0.07), time to PD (4.5 vs 2.2 months, P=0.13) and clinical benefit (CR+PR+SD) (58 vs 37%, P=0.10) in favour of IL-2/HDC, whereas the UK study was negative for all end points. Only three patients had grade 4 toxicity; however, two were fatal. A randomised phase III trial is warranted to clarify the potential role of adding histamine to IL-2 in mRCC.British Journal of Cancer (2005) 93, 757-762. doi:10.1038/sj.bjc.6602768 www.bjcancer.com Published online 30 August 2005.

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J Urol. 2005 Oct;174(4 Pt 1):1222-5.
Long-term survival analysis after laparoscopic radical nephrectomy.
Permpongkosol S, Chan DY, Link RE, Sroka M, Allaf M, Varkarakis I, Lima G, Jarrett TW, Kavoussi LR.
Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore 21287, USA.

PURPOSE: This report assesses the long-term oncological efficacy of laparoscopic radical nephrectomy compared with open radical nephrectomy in patients with clinically localized renal cell carcinoma. MATERIALS AND METHODS: We analyzed the data from 121 patients who underwent radical nephrectomy between 1991 and 1999 for clinical tumor stage T1/2 N0M0. The medical records of all patients were retrospectively reviewed with emphasis on tumor recurrence and survival. Statistical comparison was performed using Kaplan-Meier analysis. RESULTS: The median followup was 73 months for the laparoscopic group and 80 months for the open group. Of the 67 patients who underwent laparoscopic surgery, 53 survived without any recurrence of disease, 2 are currently alive with metastasis, 2 died of metastatic disease in months 12 and 17, and 10 patients died without any disease recurrence. Laparoscopic port site metastasis did not develop in any patients. Of the 54 who underwent open surgery, 34 survived without any recurrence of disease, 1 currently has metastasis, 6 died of metastasis within 17 to 74 months, and 13 died without any disease recurrence. A comparison of the 5 and 10-year disease-free survival rates of the laparoscopic and open groups revealed no significant differences. In addition, the 5 and 10-year cancer specific and actuarial survival rates were not significantly different. CONCLUSIONS: Based on long-term followup, our evaluation confirmed for clinical tumor stage T1/2 N0M0 that laparoscopic radical nephrectomy is oncologically equivalent to open radical nephrectomy.

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Urol Oncol. 2005 Sep-Oct;23(5):381.
Adjuvant treatment with interleukin-2- and interferon-alpha2a-based chemoimmunotherapy in renal cell carcinoma post tumour nephrectomy: Results of a prospectively randomised trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN)
Atzpodien J, Schmitt E, Gertenbach U, Fornara P, Heynemann H, Maskow A, Ecke M, Woltjen HH, Jentsch H, Wieland W, Wandert T, Reitz M, German Cooperative Renal Carcinoma Chemo-Immunotherapy Trials Group (DGCIN), Fachklinik Hornheide an der Universitat Munster, Internistische Onkologie, Munster, Germany. Trump DL.

We conducted a prospectively randomised clinical trial to investigate the role of adjuvant outpatient immunochemotherapy administered postoperatively in high-risk patients with renal cell carcinoma. In total, 203 renal carcinoma patients' status post radical tumour nephrectomy were stratified into three risk groups: patients with tumour extending into renal vein/vena cava or invading beyond Gerota's fascia (pT3b/c pN0 or pT4pN0), patients with locoregional lymph node infiltration (pN+), and patients after complete resection of tumour relapse or solitary metastasis (R0). Patients were randomised to undergo either (A) 8 weeks of outpatient subcutaneous interleukin-2 (sc-rIL-2), subcutaneous interferon-alpha2a (sc-rIFN-alpha2a), and intravenous 5-fluorouracil (iv-5-FU) according to the standard Atzpodien regimen (Atzpodien et al, 2004) or (B) observation. Two-, 5-, and 8-year survival rates were 81, 58, and 58% in the treatment arm, and 91, 76, and 66% in the observation arm (log rank P = 0.0278), with a median follow-up of 4.3 years. Two, 5-, and 8-year relapse-free survival rates were calculated at 54, 42, and 39% in the treatment arm, and at 62, 49, and 49% in the observation arm (log rank P = 0.2398). Stage-adapted subanalyses revealed no survival advantages of treatment over observation, as well. Our results established that there was no relapse-free survival benefit and the overall survival was inferior with an adjuvant 8-week-outpatient sc-rIL-2/sc-rIFN-alpha2a/iv-5-FU-based immunochemotherapy compared to observation in high-risk renal cell carcinoma patients following radical tumour nephrectomy.

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Transplantation. 2005 Sep 27;80(6):865-7.
Nephron-sparing surgery for de novo renal cell carcinoma in allograft kidneys.
Moudouni SM, Tligui M, Doublet JD, Haab F, Gattegno B, Thibault P.
Department of Urology, Tenon Hospital, Paris, France.

Renal cell carcinomas account for 4.6% of post-transplant cancers, 10% of which occur in allograft kidneys. We report three such cases among kidney grafts that were performed or followed from 1970 to 2004. In all patients, we performed a partial allograft nephrectomy after consideration of the tumor size, location, and absence of metastases and local extension. Renal function has remained stable, and there has been no sign of graft rejection, tumor recurrence or metastases. The surgery was technically feasible without exposing the patients to increased postoperative risks. The lateral, peripherally located tumor allowed excision without renal hilar dissection or entry into the collecting system. In agreement with data emerging from the literature, the present cases confirm that even in the setting of long-standing immunosuppression, de novo RCC of the kidney graft warrants a minimally invasive approach to spare patients graft loss and return to hemodialysis.

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Invest New Drugs. 2005 Sep 20; [Epub ahead of print]
Phase II study of interferon-alpha and doxycycline for advanced renal cell carcinoma.
Huie M, Oettel K, Van Ummersen L, Kim KM, Zhang Y, Staab MJ, Horvath D, Marnocha R, Douglas J, Drezen A, Alberti D, Wilding G.
University of Wisconsin Comprehensive Cancer Center, 600 Highland Avenue, K6/550 CSC, Madison, WI, 53792.

Objective: To assess the efficacy and toxicity of the combination of interferon-alpha and doxycycline in patients with metastatic renal cell carcinoma and to assess the effect of this treatment on serum vascular endothelial growth factor (VEGF) levels. Patients and Methods: Seventeen patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and life expectancy greater than 4 months with radiologically evident advanced renal cell carcinoma were enrolled. Eight patients had prior nephrectomy and 10 patients were treated within 4 months of their diagnosis. Treatment consisted of interferon-alpha up to 9 million units subcutaneously three times per week and doxycycline 300 mg orally twice per day for weeks one and three of each four-week cycle. Toxicity was evaluated on a biweekly basis and response on a bimonthly basis. VEGF plasma levels were assessed monthly as a measure of potential antiangiogenic effect. Results: No objective responses were seen. The mean duration of study was 2.6 cycles (range: 0.8-6.0 cycles). Three patients (17%) tolerated therapy and displayed stable disease for greater than four months. Five patients withdrew from study before the first response evaluation. Ten patients experienced grade 2 gastrointestinal toxicity requiring dose reduction of doxycycline. Eight patients experienced grade 2 fatigue requiring dose reduction of interferon. VEGF plasma levels were initially suppressed in patients who demonstrated progressive disease but not in patients with stable disease. Conclusion: This regimen of doxycycline and interferon-alpha was not efficacious as treatment for renal cell carcinoma. Plasma VEGF levels were significantly decreased during the first two cycles of treatment, but this does not correlate with clinical outcome.

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Cancer. 2005 Sep 21; [Epub ahead of print]
A phase II trial of palliative radiotherapy for metastatic renal cell carcinoma.
Lee J, Hodgson D, Chow E, Bezjak A, Catton P, Tsuji D, O'brien M, Danjoux C, Hayter C, Warde P, Gospodarowicz MK.
Department of Radiation Oncology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada.

BACKGROUND: Renal cell carcinoma (RCC) has previously been described as being less responsive to radiotherapy (RT) than other tumor types. The authors conducted a prospective study to assess the effect of RT on symptoms and quality of life (QOL) in patients with metastatic RCC. METHODS: Between 1996 and 2002, patients with symptomatic metastatic RCC were entered into a prospective study in two cancer centers. Symptomatic sites of disease were treated with 30 grays (Gy) in 10 fractions. Patients reported pain, analgesic use, symptoms, and QOL using validated questionnaires before RT, 1 month and 3 months after treatment, and every 3 months to 1 year thereafter. RESULTS: Thirty-one patients (19 males and 12 females) were entered into the trial. The median age of the patients was 61 years (range, 35-81 yrs). The most common indication for RT was bone pain (n = 24). The median duration of follow-up was 4.3 months (range, 1-15 mos). Of 23 evaluable patients treated for pain, 83% (n = 19) experienced site-specific pain relief after RT, and 48% (n = 11) did not have an associated increase in analgesic medication use. The median duration of site-specific pain response was 3 months (range, 1-15 mos). The global pain response rate was only 15% (n = 3) because many patients developed other painful metastases. Global QOL was found to improve in 33% (n = 8) of the evaluable patients. CONCLUSIONS: A palliative radiotherapy dose of 30Gy in 10 fractions can result in a significant response rate and the relief of local symptoms in patients with bone metastases from RCC. Improvements in global pain and QOL appear to be limited by the effects of progressive systemic disease. Cancer 2005. (c) 2005 American Cancer Society.

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J Clin Oncol. 2005 Sep 20;23(27):6540-8.
Lack of efficacy of two consecutive treatments of radioimmunotherapy with 131I-cG250 in patients with metastasized clear cell renal cell carcinoma.
Brouwers AH, Mulders PF, de Mulder PH, van den Broek WJ, Buijs WC, Mala C, Joosten FB, Oosterwijk E, Boerman OC, Corstens FH, Oyen WJ.
Department of Nuclear Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. a.h.brouwers@nucl.umcg.nl

PURPOSE: A previous activity dose-escalation study using 131I-labeled chimeric monoclonal antibody cG250 in patients with progressive metastatic renal cell carcinoma (RCC) resulted in occasional therapeutic responses. The present study was designed to determine the safety and therapeutic efficacy of two sequential high-dose treatments with 131I-cG250. PATIENTS AND METHODS: Patients (n = 29) with progressive metastatic RCC received a low dose of (131)I-cG250 for assessment of preferential targeting of metastatic lesions, followed by the first radioimmunotherapy (RIT) with 2220 MBq/m2 131I-cG250 (n = 27) 1 week later. If no grade 4 hematologic toxicity was observed, a second low-dose 131I-cG250 (n = 20) was given 3 months later. When blood clearance was not accelerated, a second RIT of 131I-cG250 was administered at an activity-dose of 1110 MBq/m2 (n = 3) or 1665 MBq/m2 (n = 16). Patients were monitored weekly for toxicity, and tumor size was evaluated by computed tomography once every 3 months intervals. RESULTS: The maximum-tolerated dose (MTD) of the second RIT was 1,665 MBq/m2 because of dose-limiting hematological toxicity. Based on an intention-to-treat analysis, after two RIT treatments, the disease stabilized in five of 29 patients, whereas it remained progressive in 14 of 29 patients. Two patients received no RIT, and eight of 29 received only one 131I-cG250 RIT because of grade 4 hematologic toxicity, formation of human antichimeric antibodies, or disease progression. CONCLUSION: In patients with progressive end-stage RCC, the MTD of the second treatment was 75% of the MTD of the first RIT. In the majority of patients, two cycles of 131I-cG250 could be safely administered without severe toxicity. No objective responses were observed, but occasionally two RIT doses resulted in stabilization of previously progressive disease.

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Crit Rev Oncol Hematol. 2005 Sep;55(3):193-9.
Age does not impair the efficacy of immunochemotherapy in patients with metastatic renal carcinoma.
Atzpodien J, Wandert T, Reitz M.
Fachklinik Hornheide an der Universitat Munster, Dorbaumstr. 300, 48157 Munster, Germany. sekrprofatzpodien@yahoo.de

PURPOSE: Based on the increasing proportion of elderly cancer patients, we compared the efficacy of subcutaneous cytokine based home therapy in older (age > or = 60 years) and younger (age < 60 years) patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: As a rule, patients at an age of 60 years or older received a 20% dose reduction of s.c. IL-2. Treatment consisted of (A) s.c. interferon-alpha2a (s.c. INF-alpha2a), s.c. interleukin-2 (s.c. IL-2), (B) s.c. IFN-alpha2a, s.c. IL-2 and i.v. 5-fluorouracil (5-FU) or (C) s.c. IFN-alpha2a, s.c. IL-2 and i.v. 5-FU combined with p.o. 13-cis-retinoic acid (p.o. 13cRA). RESULTS: Patient age groups > or = 60 years (n=174) and < 60 years (n=251) showed no significant difference in objective response (27% versus 31%), in median overall survival (22 months versus 19 months), and in progression-free survival (6 months versus 5 months). Within the elderly patients group, median overall survival was 20 months (pts. 60-64 years) versus 23 months (pts. > or = 65 years) and median progression-free survival was 4 months (pts. 60-64 years) versus 8 months (pts. > or = 65 years). CONCLUSION: Our results demonstrated that patient age and related IL-2 dose reduction do not impair the efficacy of s.c.-IL-2 plus s.c.-INF-2a based outpatient immunochemotherapy in metastatic renal carcinoma.

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Cancer Biother Radiopharm. 2005 Aug;20(4):410-6.
Metastatic renal carcinoma long-term survivors treated with s.c. interferon-alpha and s.c. interleukin-2.
Atzpodien J, Reitz M.
Fachklinik Hornheide an der Universitat Munster, Munster, Germany. SekrProfAtzpodien@yahoo.de

AIM: The aim of this retrospective analysis was to identify common features of long-term survivors among 218 advanced renal cell carcinoma patients sequentially entered on subcutaneous-recombinant-cytokine- based therapies between 1988 and 1993. PATIENTS AND METHODS: All patients were treated with subcutaneous (s.c.) interferon-alpha2a (IFN-alpha2a) and s.c. interleukin-2 (IL-2) alone (n = 98 pts) or in combination with intravenous (i.v.) 5-fluorouracil (5-FU) (Atzpodien regimen; n = 120 pts); those patients who survived more than 10 years were classified as long-term survivors. RESULTS: Thirteen patients (6.3%) were identified as long-term survivors with a median follow-up of 141 months (range, 122-174 months). According to a validated model of known clinical predictors, the long-term survivor group consisted of 6 low-risk, 5 intermediate-risk, and 2 high-risk patients, respectively. Within their clinical course, 9 longterm survivors achieved a complete response with a median duration of 141 months (range, 91-161 months), 1 patient yielded a partial remission, and 3 patients achieved stable disease. Maximum response was observed between 2 and 40 months after treatment initiation (median, 4 months), while treatment time to maximum response ranged from 2 to 14 months (median, 4 months). There was no correlation between treatment time and maximum response. Overall, long-term survivors underwent treatment for 4 and up to 80 months (median, 8 months). CONCLUSION: Our data suggest that long-term survival of metastatic renal carcinoma patients beyond 10 years is independent of known clinical risk factors and treatment time. However, long-term survival of cytokine-treated, advanced renal cell carcinoma (RCC) patients remains a rare event and, thus, emphasizes the need for further investigations toward more effective therapies.

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Anticancer Drugs. 2005 Aug;16(7):709-17.
Novel treatment strategies in clear-cell metastatic renal cell carcinoma.
van Spronsen DJ, de Weijer KJ, Mulders PF, De Mulder PH.
Departments of aMedical Oncology bUrology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

Metastatic renal-cell carcinoma (mRCC) is highly resistant to cytotoxic agents or hormones and is currently mainly treated with cytokine-based therapy. Transient responses and moderate survival advantages have been achieved in a subset of patients with these aspecific biological response modifiers. Side-effects are considerable, especially with high-dose interleukin (IL)-2. Efforts made in the field of specific immunotherapy have focused on optimization of dendritic cell vaccination and on administration of monoclonal antibodies, either cold (unconjugated) or hot (radioactively labeled). Furthermore, allogeneic bone marrow transplantation is able to induce remissions but, regrettably, is related to substantial morbidity and mortality. Neutralization of the biological activity of some immunosuppressive cytokines produced by RCC (IL-6 and tumor necrosis factor-alpha) with monoclonal antibodies is currently under investigation. Insights gained into the processes and pathways underlying carcinogenesis have led to the development of new treatment strategies. These treatments can be used for clear cell RCC, since they focus on blocking gene products that are upregulated by mutations in the von Hippel-Lindau gene. Specific strategies include anti-vascular endothelial growth factor monoclonal antibody (bevacizumab) or inhibition of its receptor kinases (oral SU11248 or PTK787), or targeting the Raf kinase pathway (by BAY 43-9006) or the mammalian target of rapamycin (mTOR) pathway (by CCI-779). Early clinical results are promising, but their place in the treatment of RCC has to be determined.

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Invest New Drugs. 2005 Jul 18; [Epub ahead of print]
Phase II study of the efficacy and safety of oral GD0039 in patients with locally advanced or metastatic renal cell carcinoma.
Shaheen PE, Stadler W, Elson P, Knox J, Winquist E, Bukowski RM.
Experimental Therapeutics Program, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH, United States.

Seventeen patients with locally advanced or metastatic renal cell carcinoma (RCC) were enrolled in this phase II trial. The purpose of the trial was to assess the efficacy of the administration of oral GD0039, and to further assess the pharmacokinetics and pharmacodynamics of this drug. Patients were given an initial dose of 37.5 mu g/kg b.i.d for 3 weeks followed by one week off in each cycle, with the treatment continuing until disease progression or adverse effects. All 17 patients discontinued treatment due to disease progression or toxicity. Adverse events such as fatigue, nausea and diarrhea were common but generally mild. No evidence of anti-tumor activity of GD0039 was seen in this study.

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World J Surg Oncol. 2005 Jul 20;3(1):48 [Epub ahead of print]
Management of Renal Cell Carcinoma with Solitary Metastasis: Results from a Single Institute Series.
Thyavihally YB, Mahanthshetty UM, Chamarajanagara RS, Raibhattanavar SG, Tongaonkar HB.

BACKGROUND: Metastatic renal cell carcinoma comprises a poor prognosis disease and survival is poor. However, excision of solitary metastasis with radical nephrectomy seems to be justified in selected patients. The aim of the study was to review our data on management of solitary metastasis from renal cell carcinoma. We describe survival after surgical excision or radiotherapy of solitary metastatic lesion from renal cell carcinoma and reviewed the literature. Materials and Methods: Between 1988-2001, 43 patients with solitary metastasis to different sites from renal cell carcinoma who underwent either surgical excision or radiotherapy were analyzed. The solitary nature of the lesions was confirmed by appropriate investigations. All patients had radical nephrectomy for the primary lesion. RESULTS: All solitary metastatic lesions were treated with intent of cure either by excision or radiotherapy. 13 patients had solitary metastasis at the time of presentation in whom 3 year overall median survival was 26 months. The survival of those who had solitary metastases during follow up after nephrectomy (n=30) for primary had survival of 45 months. The patients with long metastatic free interval, low stage and grade of the primary tumor had better prognosis. CONCLUSION: Complete resection of either synchronous or metachronous solitary metastases from renal cell carcinoma is justified based on our results and review of literature. For metastases that are resected with a curative intent, the best long-term results can be achieved after complete or radical resection.

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Expert Rev Vaccines. 2005 Jun;4(3):259-74.
Vaccines in cancer: GVAX, a GM-CSF gene vaccine.
Nemunaitis J.
jnemunaitis@mcmrc.com

GVAX is a granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transfected tumor cell vaccine. Original work with GM-CSF as a recombinant DNA protein (Leukine) involved proliferative stimulation of macrophages and neutrophils for the purpose of reducing hematopoietic toxicity related to dose-intensive chemotherapy. Following US Food and Drug Administration approval of Leukine several years ago, extensive preclinical results have demonstrated an immunostimulatory effect related to GM-CSF gene when transfected into tumor cells and used as a vaccine (GVAX). Tumor regression and prolonged survival was demonstrated in animal models. Toxicology with GVAX indicated no adverse effects, which enabled further testing in cancer patients. A small number of responses were demonstrated in Phase I trials in immunosensitive cancer patients (renal cell carcinoma and melanoma). However, a series of dramatic complete and durable responses in advanced non-small cell lung cancer patients, demonstrated in recent clinical trials, have generated interest in further development of this vaccine in nontraditional cancer disease types. The rationale of GVAX development and a summary of clinical results are reviewed.

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World J Urol. 2005 Jun 30; [Epub ahead of print]
Surgery for metastatic renal cell cancer.
Sengupta S, Leibovich BC, Blute ML, Zincke H.
Department of Urology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA, Zincke.horst@mayo.edu.

Renal cell carcinoma (RCC) often presents in its metastatic form, or progresses after curative treatment. While the management of metastatic RCC has historically been mainly surgical, contemporary approaches often incorporate systemic immunotherapy. This review examines the current indications and scope of surgical treatment of patients with metastatic RCC. Surgery is sometimes indicated for symptom palliation at either the primary or secondary sites. However, other less invasive therapies may be equally effective, and should be considered carefully. Cytoreductive surgery prior to immunotherapy appears to confer a survival advantage, but only selected patients are suitable for this treatment regimen. Primary immunotherapy followed by surgical removal of the tumour in partial responders is an alternative treatment strategy, which has not yet been evaluated as in randomized trials. As immunotherapy develops further, the precise timing and role of surgery in multimodality treatment will need to be carefully evaluated. Occasionally, the complete surgical excision of metastases, and the primary tumour, if present, is feasible and this may prolong survival. Empirically, it would seem that such patients should also be treated with adjuvant immunotherapy, as eventual relapse is frequent. Surgery with the aim of inducing spontaneous tumour regression is not justifiable, given the rarity of this phenomenon.

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Crit Rev Oncol Hematol. 2005 Jun 23; [Epub ahead of print]
Novel treatments for metastatic renal cell carcinoma.
van Spronsen DJ, Mulders PF, De Mulder PH.
Department of Medical Oncology 550, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

The mainstay of any curative treatment in renal cell carcinoma (RCC) is surgery. In case of metastatic disease at presentation a radical nephrectomy is recommended to good performance status patients prior to start of interferon-alfa treatment. Interferon-alpha (IFN-alpha) offers in a small but significant percentage of patients advantage in overall survival; interleukin-2 (IL-2) based therapy gives similar survival rates. To date hormonal and chemotherapy do not have a proven impact on survival. The recent new insights in the molecular biology of clear RCC has revealed a key-role for vascular endothelial growth factor (VEGF) in the stimulation of angiogenesis in this highly vascularized tumour. This opens interesting new treatment strategies including: blockage of VEGF with the monoclonal antibody bevacizumab and inhibition of VEGF receptor tyrosine kinases (with small oral molecules such as SU11248 or PTK787). Likewise, inhibition of the Raf kinase pathway (with oral Bay 43-9006) or inhibition of the mTOR pathway (with i.v. CCI-779) are under investigation. Preliminary clinical results with all these compounds are interesting and the results of ongoing phase III studies will become available in the next years.

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Curr Opin Oncol. 2005 May;17(3):261-7.
Renal cell carcinoma.
Rathmell WK, Godley PA, Rini BI.
aLineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina and bUCSF Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.

PURPOSE OF REVIEW: This review focuses on recent developments in the biology and clinical therapeutics of renal cell carcinoma. Given historically limited advances in this disease, a more thorough understanding and testing of rationally targeted agents is needed. RECENT FINDINGS: Von Hippel-Lindau gene inactivation is observed in most clear cell renal carcinoma, driving the malignant phenotype. The resulting vascular endothelial growth factor overexpression has been targeted though various approaches, with a clear signal of anti-tumor activity. In addition, immunotherapy remains a therapeutic standard in renal cell carcinoma and an area of ongoing investigation. Observation of small renal masses may represent a viable clinical option. SUMMARY: Renal cell carcinoma has become a model disease for rationally targeted therapeutics based on significant understanding of the underlying biology. Recent advances have increased the potential for meaningful improvements in clinical outcomes for renal cell carcinoma patients.

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World J Urol. 2005 Apr 5; [Epub ahead of print]
Novel approaches in the therapy of metastatic renal cell carcinoma.
Lam JS, Leppert JT, Belldegrun AS, Figlin RA.
Department of Urology, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 66-118 CHS, Los Angeles, California 90095-1738, Box 951738, USA.

Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, with approximately 40% of patients eventually dying of cancer progression. Approximately one third of patients present with metastatic disease, and up to 40% treated for localized disease have a recurrence. Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of RCC have paved the way for developments that may enhance early diagnosis, better predict tumor prognosis, and improve survival for RCC patients. The recent discovery of molecular tumor markers is expected to revolutionize the staging of RCC in the future and lead to the development of new therapies based on molecular targeting. Cytokine-based immunotherapy can be considered standard therapy in the treatment of metastatic RCC today. However, new therapies such as tumor vaccines, anti-angiogenesis agents, and small molecule inhibitors are being developed to improve efficacy and treat those patients who are unable to tolerate or are resistant to systemic immunotherapy. The aim of this review is to provide an update on current therapeutic approaches and targeted molecular therapy for metastatic RCC.

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World J Urol. 2005 Apr 2; [Epub ahead of print]
Immunotherapy in metastatic renal cell carcinoma.
Rohrmann K, Staehler M, Haseke N, Bachmann A, Stief CG, Siebels M.
Department of Urology, Ludwig Maximilian University of Munich-Grosshadern, Grosshadern Medical Center, Marchioninistrasse 15, 81377 Munich, Germany, Karl.Rohrmann@med.uni-muenchen.de.

Metastatic renal cell carcinoma has a poor prognosis. Conventional therapies such as chemotherapy, radiation or hormonal treatment have hardly any effect on the progression of this disease. As renal cell carcinoma seems to be an immunogenic tumor, several immunotherapeutic approaches with different response rates have been developed since the early 1990s. We present an overview of various immunotherapeutic approaches such as cytokine-based regimes, with and without different cytotoxic chemotherapy, of metastatic renal cell carcinoma. In addition, local therapies (e.g. inhalation of interleukin-2) are reviewed.

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World J Urol. 2005 Mar 25; [Epub ahead of print]
Combination of surgery and immunotherapy in metastatic renal cell carcinoma.
Mickisch GH, Mattes RH.
Center of Operative Urology, c/o Academic Hospital Bremen "Links der Weser", Robert Koch Strasse 34a, 28277 Bremen, Germany, gerald.mickisch@coub.de.

The treatment of choice for non-disseminated renal cell cancer (RCC) is surgery. However, the 5-year survival rates for all stages do not exceed 60%, even in contemporary series. Further improvement will most likely have to await the development of a more effective systemic therapy and the application of combined treatment modalities to counter the relatively high number of patients presenting with advanced stages. Whereas textbook belief up to the 1990s suggested refraining from surgical antitumor-therapy in the case of metastatic RCC, current strategies clearly advocate debulking tumor nephrectomy in the context of modern immunotherapies. This dramatic change of attitude stemmed from two randomized phase III trials conducted by EORTC and SWOG, including a combined analysis of both studies, in which cytoreductive tumor nephrectomy conveyed a significant survival benefit over immunotherapy alone. Concepts and progress in this field appear to be of major interest for modern oncologic urologists following the advent of immunotherapeutic strategies that require surgical intervention at some stage of the treatment cascade.

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Cancer Chemother Pharmacol. 2005 Mar 25; [Epub ahead of print]
A phase II study of flavopiridol in patients with advanced renal cell carcinoma: results of Southwest Oncology Group Trial 0109.
Van Veldhuizen PJ, Faulkner JR, Lara PN Jr, Gumerlock PH, Goodwin JW, Dakhil SR, Gross HM, Flanigan RC, Crawford ED.
University of Kansas Medical Center, Kansas City, KS, USA.

PURPOSE: Flavopiridol is a cyclin-dependent kinase inhibitor that prevents cell cycle progression and tumor growth. In initial phase I studies, encouraging responses were seen in advanced renal cell cancer (RCC). In a phase II study of flavopiridol given as a 72-h continuous infusion every 2 weeks in RCC, a response rate of 6% was seen but with considerable grade 3 or 4 asthenia, diarrhea, and thrombosis. Subsequently, an alternative 1-h bolus schedule was reported to have enhanced tolerability in a phase I trial. We therefore conducted a phase II study of this bolus regimen.METHODS: A total of 38 patients with advanced RCC were entered into this multi-institutional phase II study. Flavopiridol (50 mg/m(2) per day) was administered by bolus intravenous injection daily for three consecutive days, repeated every 3 weeks.RESULTS: Out of 34 eligible patients, one complete response and three partial responses were observed, for an overall response rate of 12% (95% CI 3-27%). Of the 34 patients, 14 (41%) had stable disease (SD). The probability of not failing treatment by 6 months was 21% (95% CI 9-35%). Median overall survival time was 9 months (95% CI 8-18 months). The most common grade 3 or 4 toxicities were diarrhea (35%) and tumor pain (12%) along with anemia, dyspnea, and fatigue (9% each).CONCLUSIONS: Flavopiridol at this dose and schedule is feasible with an acceptable toxicity profile. Flavopiridol has some modest biologic activity against advanced RCC, as evidenced by its single-agent objective response and SD rates.

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Eur Radiol. 2005 Mar 9; [Epub ahead of print]
Percutaneous radiofrequency ablation of renal cell carcinoma.
Gervais DA, Arellano RS, Mueller PR.
Department of Radiology, Division of Abdominal Imaging and Intervention, Massachusetts General Hospital, White 270, 34 Fruit Street, Boston, MA, 02114, USA, dgervais@partners.org.

Conventional curative therapy for renal cell carcinoma has been open nephrectomy. However, several less invasive and/or nephron-sparing procedures have been developed as alternatives in selected patients. The newest of these therapeutic modalities involves percutaneous image-guided ablation with straight or expandable needle applicators that deposit energy. Radiofrequency ablation is the modality for which there is the largest reported experience with percutaneous application, and involves the use of electrical current to generate frictional heating of tissue. Animal studies confirm the ability of radiofrequency ablation to cause regions of necrosis within normal kidney and in VX2 tumors. Clinically, radiofrequency ablation of small renal cell carcinoma is increasingly being performed in selected patients who are not ideal surgical candidates. Results are excellent for small exophytic tumors, but successful treatment is less likely as tumor size increases or the location becomes more central. Complete treatment of most tumors requires one or more overlapping ablations with the needle electrodes positioned so as to cause necrosis in the entire volume of tumor. The number of overlapping ablations and the position of the needle electrodes vary based on tumor size and geometry. For very large tumors, pre-ablation catheter embolization may enhance the results of ablation by decreasing blood flow and perfusion mediated cooling. Following ablation, imaging with CT or MR is performed to assess the result and to diagnose any residual tumor so that it can be treated. Because the tumor remains in situ, imaging follow-up continues indefinitely. The complication rate of radiofrequency ablation is favorable when compared to surgical techniques. Long-term survival data are not yet available.

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Can J Urol. 2005 Feb;12 Suppl 1:66-70; discussion 105.
New treatments for metastatic kidney cancer.
Mancuso A, Sternberg CN.
Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome, Italy.

Renal cell carcinoma accounts for approximately 3% of adult malignancies and 90%-95% of neoplasms arising from the kidney. It is characterized by a lack of early warning signs, diverse clinical manifestations, resistance to radiation and chemotherapy, and infrequent but reproducible responses to immunotherapy with agents such as interferon alpha (IFNa) and interleukin 2 (IL-2). International studies have shown objective response rates of < 15% in patients with advanced and metastatic disease, with 5-year disease-specific survival ranging between 0-20%. Considering these poor outcomes, renal cancers' very vascular nature and overexpression of receptors for vascular endothelial growth factor (VEGF), various biologic and angio-suppressive therapies are being evaluated in clinical trials. Promising results in terms of overall response rate and median time to progression have been reported especially as second-line therapy following cytokine failure, a setting where no effective systemic therapy has been recognized (SU011248, Bay 43-9006, Bevacizumab and Erlotinib). While confirmatory studies are ongoing, other novel treatments in first line trials (CCI-779, Infliximab, PTK-787, and Thalidomide) have drawn international attention. This review, analyzing basic translational research principles, will summarize the available data on the use of these new therapeutic approaches in RCC.

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Hinyokika Kiyo. 2005 Feb;51(2):81-4.
[Comparison of endoscopic versus open radical nephrectomy for stage T1 and T2 renal cancer]
[Article in Japanese]
Mita K, Shigeta M, Mutaguchi K, Kajiwara M, Usui T.
Department of Urology, Graduate School of Biomedical Sciences, Hiroshima University.

The aim of this study was to compare the efficacy, efficiency and patient well-being of endoscopic radical nephrectomy (ERN) with those of open radical nephrectomy (ORN) in patients with stage T1 and stage T2 renal cell carcinoma during the period from 1995 to 2003. Eighty-four patients including 53 patients receiving ERN and 31 patients receiving ORN were evaluated. The two groups were analyzed for sex, side of tumor, clinical stage, age, tumor diameter, operative time, operative blood loss, postoperative time to oral intake and ambulation. There was no difference in patient background between the ERN and ORN groups. Although the mean operative times between the ORN and ERN group were not different (mean 240 versus 267 min. in ERN group, P N .S.), ERN patients had significantly less operative blood loss (mean 123 versus 469 ml. in ERN group, P < 0.01), significantly shorter time to start the oral intake of rice gruel (mean 1.4 versus 4.6 days. in ERN group, P < 0.01) and significantly shorter time to ambulation (mean 1.2 versus 3.1 days. in ERN group, P < 0.01). These findings revealed that endoscopic radical nephrectomy for the patients with stage T1 and T2 renal cell carcinoma appears to be associated with less morbidity and faster recovery rather than open radical nephrectomy.

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World J Urol. 2005 Feb 22; [Epub ahead of print]
Chemotherapy in metastatic renal cell cancer.
Lilleby W, Fossa SD.
Department of Medical Oncology and Radiotherapy, The Norwegian Radium University Hospital, Oslo, Norway, wolfgang.lilleby@klinmed.uio.no.

Currently, there is no standard treatment for patients with advanced renal cell carcinoma (RCC) who do not respond to or progress after transient remission to first-line immunotherapy. At the end of the 1990s, no single chemotherapeutic drug, alone or in combination with interleukin-2 (IL-2) or interferon-alfa (IFN), had shown activity beyond the one expected by immunotherapy alone. New drugs on the market such as the pyrimidine analog gemcitabine or taxane-based chemotherapeutics may show promising tumor activity in combination with targeted therapy, but this has to be substantiated in upcoming trials. There is a great need to develop effective systemic therapy for advanced MRCC and to evaluate the efficacy of new drugs in clinical trials.

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Cochrane Database Syst Rev. 2005 Jan 25;(1):CD001425.
Immunotherapy for advanced renal cell cancer.
Coppin C, Porzsolt F, Awa A, Kumpf J, Coldman A, Wilt T.
Division of Medical Oncology, Fraser Valley Cancer Centre, 13750-96th Avenue, Surrey, BC, CANADA, V3V 1Z2.

BACKGROUND: The course of advanced renal cell carcinoma is extremely variable, ranging from spontaneous remission to disease progression refractory to chemotherapy. Immunotherapy has held promise of improved outcomes based on uncontrolled studies and randomized controlled trials generally limited by small size and low power. OBJECTIVES: To evaluate immunotherapy for advanced renal cell carcinoma by comparing: (1) high dose interleukin-2 to other options and (2) interferon-alfa to other options. The primary outcome of interest was overall survival at one year, with remission as the main secondary outcome of interest. SEARCH STRATEGY: A systematic search of the CENTRAL, MEDLINE, and EMBASE databases was conducted for the period 1966 through end of December 2003. Handsearches were made of the proceedings of the periodic meetings of the American Urologic Association, the American Society of Clinical Oncology, ECCO - the European Cancer Conference, and the European Society of Medical Oncology for the period 1995 to June 2004. SELECTION CRITERIA: Randomized controlled trials that selected (or stratified) patients with advanced renal cell carcinoma, utilized an immunotherapeutic agent in at least one study arm, and reported remission or survival by allocation. Fifty-three identified studies involving 6117 patients were eligible and all but one reported remission; 32 of these studies reported the one-year survival outcome. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted each article by following a prospectively designed protocol. Dichotomous outcomes for treatment remission (partial plus complete) and for deaths at one year were used for the main comparisons. Survival hazard ratios were also used for studies of interferon-alfa versus controls, and for two randomized studies of the value of initial nephrectomy prior to interferon-alfa in fit patients with mestases detected at the time of diagnosis. MAIN RESULTS: Combined data for a variety of immunotherapies gave an overall chance of partial or complete remission of only 12.9% (99 study arms), compared to 2.5% in 10 non-immunotherapy control arms, and 4.3% in two placebo arms. Twenty-eight percent of these remissions were designated as complete (data from 45 studies). Median survival averaged 13.3 months (range by arm, 6 to 27+ months). The difference in remission rate between arms was poorly correlated with the difference in median survival so that remission rate is not a good surrogate or intermediate outcome for survival for advanced renal cancer. We were unable to identify any published randomized study of high-dose interleukin-2 versus a non-immunotherapy control, or of high-dose interleukin-2 versus interferon-alfa reporting survival. It has been established that reduced dose interleukin-2 given by intravenous bolus or by subcutaneous injection provides equivalent survival to high dose interleukin-2 with less toxicity. Results from four studies (644 patients) indicate that interferon-alfa is superior to controls (OR for death at one year = 0.56, 95% confidence interval 0.40 to 0.77). Using the method of Parmar 1998, the pooled overall hazard ratio for death was 0.74 (95% confidence interval 0.63 to 0.88). The weighted average median improvement in survival was 3.8 months. T he optimal dose and duration of interferon-alfa remains to be elucidated. The addition of a variety of enhancers, including lower dose intravenous or subcutaneous interleukin-2, has failed to improve survival compared to interferon-alfa alone. Two recent randomized studies have examined the role of initial nephrectomy prior to interferon-alfa therapy in highly selected fit patients with metastases at diagnosis and minimal symptoms: despite minimal improvement in the chance of remission, both studies of up-front nephrectomy improved median survival by 4.8 months over interferon-alfa alone. Recent studies have been examining anti-angiogenesis agents. A landmark study of bevacizumab, an anti-vascular endothelial growth factor antibody, was associated with significant prolongation of the time to progression of disease when given at high dose compared to low-dose or placebo therapy though frequency of remissions or survival were not improved. AUTHORS' CONCLUSIONS: interferon-alfa provides a modest survival benefit compared to other commonly used treatments and should be considered for the control arm of future studies of systemic agents. In fit patients with metatases at diagnosis and minimal symptoms, nephrectomy followed by interferon-alfa gives the best survival strategy for fully validated therapies. The need for more effective specific therapy for this condition is apparent.

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Scand J Urol Nephrol. 2004;38(4):306-14.
Prospective randomized trial comparing high lumbotomic with laparotomic access in renal cell carcinoma surgery.
Battaglia M, Ditonno P, Martino P, Palazzo S, Annunziata G, Selvaggi FP.
Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy. battaglia@urologia.uniba.it

OBJECTIVE: We compared laparotomic with lumbotomic access in renal cell carcinoma (RCC) surgery by means of a prospective randomized trial, in order to evaluate differences in surgical time, blood loss, number of lymph nodes removed, duration of postoperative ileus and hospitalization, perioperative complications and progression-free and cancer-specific survival rates. MATERIAL AND METHODS: Between November 1991 and November 1996, 94 patients with RCC were recruited and randomly assigned to undergo surgery by lumbotomic (n = 50) or laparotomic (n = 44) access. All patients underwent radical nephrectomy and lymph node dissection. RESULTS: The mean surgical time was 59.1 min (range 20-140 min) and 84.4 min (range 40-180 min) for lumbotomic and laparotomic access, respectively (p < 0.01). Blood loss was 502 ml (range 200-1800 ml) for lumbotomic and 648 ml (range 200-2000 ml) for laparotomic access (p < 0.005). Mean hospital stay was 6.8 days (range 3-13 days) for lumbotomic and 8.2 days (range 5-15 days) for laparotomic access (p < 0.001). The perioperative complication rates were 6.1% and 13.6% for lumbotomic and laparotomic access, respectively. After a mean follow-up period of 7.5 years, cancer-specific and progression-free survival rates were 88% and 75%, respectively for lumbotomic and 88% and 72.7%, respectively for laparotomic access (p = NS). Multivariate analysis of risk factors showed that pathological stage was the best prognostic indicator of tumor progression, while other variables (age, tumor grade, surgical access, tumor size and incidental diagnosis of tumor) were not predictive of the prognosis of patients with RCC. CONCLUSIONS: During radical nephrectomy, control of the renal vessels is easier and faster with high lumbotomic access. The suggested risk of tumor cell spread due to manipulation of the kidney before vessel ligature was not confirmed in our study. Because of the shorter surgical time, lower blood loss, lower perioperative and late complication rates and shorter hospital stay involved, lumbotomic access should be preferred to laparotomic access in radical nephrectomy for RCC.

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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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Int J Urol. 2004 Dec;11(12):1051-7.
Radio-frequency ablation of renal cell carcinoma in patients who were at significant risk.
Ukimura O, Kawauchi A, Fujito A, Mizutani Y, Okihara K, Mikami K, Soh J, Nakamura T, Nakanishi H, Ushijima S, Miki T.
Department of Urology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto, Japan.

Abstract Objective: Although radio-frequency ablation (RFA) has been recently applied as a minimally invasive treatment option for renal cell carcinoma (RCC), indication of this modality remains a critical issue due to the lack of complete tumor destruction as well as the uncertainty of its long-term efficacy. We report the efficacy of RFA for nine carefully selected patients with RCC who had significant reason to avoid invasive surgical treatment under general anesthesia. Methods: Radio-frequency ablation was performed under epidural or local anesthesia by ultrasound or computed tomography (CT) guidance in nine patients with biopsy proven RCC (mean diameter, 38 mm; range, 20-53 mm), who were at significant operative or anesthetic risk for invasive surgery. Follow-up enhanced CT scans or magnetic resonance images were evaluated every 3-6 months and an evaluation of metastasis was performed every 6 months. Results: At a mean follow-up of 17 months, seven (78%) of the nine patients with renal tumor showed no tumor enhancement. The renal function of all patients was well preserved. All patients were able to continue undergoing their respective treatments for active diseases in other organs in parallel to the RFA treatment. No distant metastasis, urine leakage were reported and one case of temporary hematuria and one case of peri-renal hemorrhage not requiring blood transfusion were encountered. Intra-operative ultrasonography was useful in the real-time monitoring of the minimally excessive extension of ablation into the normal parenchyma. Conclusion: Radio-frequency ablation appears to be an effective and safe minimally invasive therapeutic option for selected patients with RCC who have reason to avoid invasive surgery under general anesthesia.

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Cancer Immunol Immunother. 2004 Dec 31; [Epub ahead of print]
A phase-II study of pegylated interferon alfa-2b for patients with metastatic renal cell carcinoma and removal of the primary tumor.
Bex A, Mallo H, Kerst M, Haanen J, Horenblas S, Gast GC.
Division of Surgical Oncology, Urology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands, a.bex@nki.nl.

Twenty-two patients with metastatic renal cell carcinoma and removal of the primary tumor were treated with subcutaneous pegylated interferon alfa-2b (PEG-Intron) to evaluate toxicity and efficacy. Start dose was 3.0 mug/kg/week, escalated to 6.0 mug/kg/week. After 2 months, therapy was extended in case of response or stable disease (SD) until progressive disease (PD) or relapse for a maximum of 2 years. National Cancer Institute common toxicity criteria (NCI-CTC) were monitored every 2-4 weeks. After 2 months, nine patients did not continue (8 PD, 1 SD with grade 4 CTC) and 13 extended treatment [three partial response (PR), 10 SD], of these, 11 progressed. One patient with PR developed a durable complete response later. Overall response rate was 13.6% (3/22). Median overall survival is 13 months (range 3-35 months). Dosage was escalated to 6 mug/kg/week in three patients . NCI-CTC grade 2 and 3 required dose attenuation in 12 patients during escalation, and reduction in 10 during the trial. Three patients discontinued because of grade 4 CTC (two fatigue, one hyperglycemia). Fatigue was the major dose-limiting toxicity. These results suggest an efficacy and toxicity of PEG-Intron comparable to standard interferon alfa-2b in patients with mRCC and removal of the primary tumor.

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Cancer. 2004 Dec 20;103(3):553-558 [Epub ahead of print]
A Phase I trial of fixed dose rate gemcitabine and capecitabine in metastatic renal cell carcinoma.
Rini BI, Weinberg V, Small EJ.
Department of Hematology/Oncology, The University of California San Francisco Comprehensive Cancer Center, San Francisco, California.

BACKGROUND: Metastatic renal cell carcinoma (RCC) has modest response rates to chemotherapy with gemcitabine and 5-fluorouracil (5-FU). Fixed dose rate gemcitabine infusion leads to enhanced intracellular accumulation of drug and possible augmented clinical effect. To determine the toxicity of this combination therapy in metastatic RCC, a Phase I trial was conducted. METHODS: Patients with metastatic RCC were enrolled in a Phase I dose escalation trial. Patients received fixed dose rate gemcitabine on Days 1, 8, and 15 in combination with capecitabine, an oral 5-FU analog, given on Days 1-21 of a 28-day cycle. RESULTS: Nine patients were enrolled at one of two dose levels. The initial dose level produced dose-limiting toxicity (DLT), including prominent palmar-plantar erythrodysesthesia (hand-foot syndrome). A modified second dose level also resulted in DLT, precluding further study. No central nervous system (CNS) toxicity was observed in three patients with CNS metastases. Two patients demonstrated an objective partial response. CONCLUSIONS: Fixed dose rate gemcitabine in combination with capecitabine produced unacceptable toxicity in patients with advanced RCC. Further development of this schedule in RCC cannot be recommended. Cancer 2005. (c) 2004 American Cancer Society.

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Hinyokika Kiyo. 2004 Nov;50(11):763-6.
[Partial nephrectomy using microwave tissue coagulator--application for laparoscopic operation]
[Article in Japanese]
Yoshimichi J, Inoue K, Karashima T, Hamaguchi T, Tokinaga K, Kamada M, Komatsu F, Shuin T, Chikazawa M.
Department of Urology, Kochi Medical School.

We report our clinical findings on 12 tumors (11 patients) successfully resected by partial nephrectomy with a microwave tissue coagulator (MTC) without renal pedicle clamping, including laparoscopic operation in 4 patients. All patients presented with a renal tumor detected incidentally by ultrasonography or computed tomography. The mean size of renal tumor was 1.9 (range 0.8-3.4) cm. Pathological diagnosis was renal cell carcinoma in 9 tumors and hemorrhagic cyst in 3 tumors. Mean operative time was 249 minutes. Mean blood loss was 183 ml in cases with a laparoscopic operation, that was statistically less than 486 ml in cases with an open operation (p<0.05), and 376 ml in all cases. There was no significant change in the creatinine clearance of cases with laparoscopic operation, compared with that of cases with an open operation. There were no other serious complications postoperatively. These findings suggested that partial nephrectomy with the MTC can be safely and successfully carried out while sparing renal function. Moreover, partial nephrectomy with the MTC for a laparoscopic operation may provide these patients with more benefits.

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Curr Opin Oncol. 2004 Nov;16(6):542-6.
A review of recent findings involving interleukin-2-based cancer therapy.
Eklund JW, Kuzel TM.

PURPOSE OF REVIEW: Highlighted in this review are the important preclinical and clinical updates of interleukin (IL)-2-based cancer immunotherapy that have been published during the last year. RECENT FINDINGS: The review starts with a summary of the preclinical breakthroughs involving IL-2. The authors briefly examine two recent studies that take very different approaches to overcome the toxicities associated with IL-2 therapy. The first involves IL-2 gene transduction into tumor-infiltrating lymphocytes, and the latter discusses the use of a superoxide dismutase mimetic to ameliorate the hypotensive effects of IL-2. This is followed by a discussion of the key roles that T regulatory cells and transforming growth factor-beta have in immunosuppression, and how they interplay with IL-2. Next they review the clinical updates of IL-2 in melanoma, including IL-2 as adjuvant therapy, IL-2-based biochemotherapy, and intralesional IL-2 for soft-tissue metastases. Finally, the authors point out the recent clinical developments of IL-2 in renal cell carcinoma, including high-dose IL-2 as adjuvant therapy, and then focus on its role in the management of metastatic disease. SUMMARY: IL-2 remains a valuable treatment option for patients with metastatic melanoma or renal cell carcinoma. Some of the recent updates in IL-2 therapy address important questions regarding the use of this drug, and others generate equally important hypotheses that could lead to better clinical outcomes in the future.

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J Endourol. 2004 Oct;18(8):783-6.
Laparoscopic nephron-sparing surgery for a renal mass: 1-year minimum follow-up.
Seifman BD, Hollenbeck BK, Wolf JS Jr.
Department of Urology, University of Michigan Health System, Ann Arbor, Michigan 48109-0330, USA.

BACKGROUND AND PURPOSE: Because of the explosion of laparoscopy in urology coinciding with the excellent results of open nephron-sparing surgery (NSS) for small renal masses, laparoscopic NSS has become an alternative to an open surgical approach. We report our results with laparoscopic NSS in patients who have had a minimum of 1 year of follow-up. PATIENTS AND METHODS: All consecutive laparoscopic partial nephrectomies from November 1998 through February 2002 were assessed. The mean patient age, body mass index, and American Society of Anesthesiology score were 57.1 years, 28.5 cm/kg2, and 2.0, respectively. The procedures were performed using hand-assisted (N = 28) or standard (N = 12) laparoscopic techniques. Hospital records were reviewed in order to obtain operative, perioperative, and follow-up data. RESULTS: The median operating room time, estimated blood loss, and hospital stay were 184 minutes, 300 mL, and 2.0 days, respectively. No patients were converted to an open surgical procedure. Four patients (10%) required a blood transfusion, and one (2.5%) had a postoperative urinoma. The mean tumor size was 2.3 cm. Twenty-nine lesions were renal-cell carcinoma, and 11 were benign. With a mean CT scan follow-up of 100.0 weeks, there has not been any recurrence of renal-cell carcinoma. CONCLUSION: Laparoscopic NSS can be performed with acceptable complication rates, which will continue to decrease as newer methods of controlling hemostasis are developed. Although follow-up is fairly short, no renal-cell carcinoma recurrences have appeared. At this point in time, the oncologic efficacy of a laparoscopic approach appears to mirror that of the open surgical technique.

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Expert Opin Biol Ther. 2004 Nov;4(11):1791-801.
Antigenic targets for renal cell carcinoma immunotherapy.
Vieweg J, Jackson A.
Duke University Medical Center, MSRB, Suite 455, PO Box 2626, Durham, North Carolina 27710, USA. j.vieweg@duke.edu

Renal cell carcinoma (RCC) has been shown to respond to immunotherapeutic intervention, thus fostering continued interest in exploiting the ability of the immune system to recognise and eradicate renal malignancy. Considerable progress in the characterisation of tumour-associated antigens, coupled with the appreciation that dendritic cells act as master regulators of immunity and tolerance, has opened new possibilities for immunotherapeutic intervention against human cancer. However, in contrast to other tumour systems, clinically relevant antigens expressed by RCC have not yet been identified. Therefore, most RCC vaccine trials have employed unfractionated antigens derived from tumour cells, with the goal of eliciting T cell responses against many unknown antigens expressed by the tumour. The recent discovery of genes with critical roles in oncogenesis has facilitated the identification of novel, more universal targets that may make cancer vaccines more practical, applicable and, potentially, more effective. In addition, immunisation against tumour antigens can be combined with tumour stroma-associated targets, thereby exerting a synergistic antitumour effect. Continued identification of molecular targets, in concert with more effective vaccination protocols, is likely to produce vaccination strategies with clinical impact.

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Hematol Oncol Clin North Am. 2004 Oct;18(5):1143-59.
Renal cell carcinoma: rationale and development of therapeutic inhibitors of angiogenesis.
Ebbinghaus SW, Gordon MS.
Division of Hematology-Oncology, University of Arizona College of Medicine, Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, AZ 85724-5024, USA.

Inhibition of tumor angiogenesis is a promising therapeutic approach to treat cancer; translation of this concept into clinical practice requires an understanding of the molecular events that are responsible for the development of tumor vasculature. Renal cell carcinoma is characterized by the frequent loss of the von Hippel-Lindau tumor suppressor gene which results in the loss of one of the critical mechanisms for regulating the level of hypoxia inducible factor 1 and leads to the overproduction of vascular endothelial growth factor (VEGF) by the tumor cell. Therapeutic strategies to inhibit the function of these important pathways have been effective in preventing tumor angiogenesis in preclinical models of kidney cancer, and more recently, in the clinical setting. Strategies to treat renal cell carcinoma with agents that are designed to prevent angiogenesis have included interruption of the VEGF signaling pathway, mimics of endogenous angiogenesis inhibitors, prevention of destruction of the basement membrane, and direct inhibition of endothelial cells by a variety of agents with complex, novel, or undetermined mechanisms. Recent clinical studies of bevacizumab, the first anti-VEGF agent to be marketed for the treatment of cancer, have provided proof for the concept that these strategies can lead to tangible benefits for patients who have advanced renal cell carcinoma and likely will be applicable broadly to the treatment of cancer.

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Anticancer Drugs. 2004 Oct;15(9):819-824.
Application of retinoids in the treatment of renal cell carcinoma--a futile effort?
Schrader AJ, Knobloch RV, Heidenreich A, Buer J, Hofmann R.
Department of Urology, Philipps-University Medical School, Marburg, Germany; Department of Cell Biology and Immunology, German Research Center for Biotechnology, Braunschweig, Germany; Division of Urological Oncology, Department of Urology, Cologne University Medical School, Cologne, Germany.

The therapeutic benefit of adding retinoids such as all-trans retinoic acid (RA), 9-cis-RA or 13-cis-RA to established single-agent or combination immuno/chemotherapy regimens for the treatment of metastatic renal cell carcinoma (RCC) has been extensively investigated during the last decade. However, at present results are contradictory and their application controversial. Moreover, recent studies indicated a significantly higher incidence of toxic side-effects in patients treated with retinoids in addition to established bio/chemotherapy. This Commentary summarizes preclinical and clinical trials investigating efficacy and toxicity of retinoids in the treatment of RCC.

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Cancer. 2004 Oct 1;101(7):1545-51.
Active chemotherapy for sarcomatoid and rapidly progressing renal cell carcinoma.
Nanus DM, Garino A, Milowsky MI, Larkin M, Dutcher JP.
Department of Medicine, Weill Medical College of Cornell University, New York, New York, USA. dnanus@med.cornell.edu

BACKGROUND: Immunotherapy is generally ineffective in patients with sarcomatoid renal cell carcinoma (RCC) and in patients with rapidly progressive metastatic or locally recurrent disease, with a median time to progression of approximately 2 months and a median survival of 4-7 months. Gemcitabine-based regimens have modest antitumor activity, whereas doxorubicin is often used to treat sarcomatoid RCC. Based on the antitumor activity of doxorubicin and gemcitabine in collecting duct carcinoma of the kidney, the authors used this combination to treat selected patients with sarcomatoid or rapidly progressing RCC. METHODS: Eighteen patients (11 males and 7 females; median age, 53 years; range, 31-81 years) with RCC (56% sarcomatoid; 44% other) were treated at 2 institutions in a collaborative study that was not institutional review board reviewed. Seven patients received previous treatment with interferon or interleukin-2. Sites of metastases included the lung, soft tissue, bone, liver, and brain with 88% of patients having > or = 3 sites of disease. Treatment consisted of doxorubicin (50 mg/m2) and gemcitabine (1500 or 2000 mg/m2) every 2-3 weeks with granulocyte-colony-stimulating factor support. RESULTS: A median of 5 courses was administered (range, 2-12 cycles). Therapy was well tolerated with no Grade 4 toxicities. Two patients had a complete response, five had a partial response, three had a mixed response, and one had stable disease. The median duration of response was 5 months (range, 2-21+ months). CONCLUSIONS: These data suggested that the combination of doxorubicin and gemcitabine has antitumor activity in patients with sarcomatoid RCC or with rapidly progressing RCC. A prospective investigation of this combination in RCC is warranted. (c) 2004 American Cancer Society.

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Urol Oncol. 2004 Sep-Oct;22(5):387-92.
Combination therapy with capecitabine and interferon alfa-2A in patients with advanced renal cell carcinoma: A phase II study.
Padrik P, Leppik K, Arak A.
Clinic of Hematology & Oncology, Tartu University Clinics, Vallikraavi 7, Tartu, Estonia.

Capecitabine is a fluoropyrimidine carbamate capable of exploiting the high concentrations of thymidine phosphorylase in tumor tissue to achieve activation preferentially at the tumor site. Thymidine phosphorylase activity is high in renal cell carcinoma tissue. Interferon alfa has been proved to be the agent for standard therapy in metastatic renal cell carcinoma. The purpose of the study was to assess the efficacy and toxicity of combining capecitabine and interferon alfa-2A in patients with advanced renal cell carcinoma. Twenty-five patients with advanced renal cell carcinoma and no prior systemic therapy were treated with the combination of capecitabine at a dose of 1,250 mg/m(2) twice daily for 2 weeks after every 21 days and interferon alfa-2A 6 million U three times a week. The overall response rate was 24.0% (95% CI, 9.4-45.1%), from 6 responded patients 5 had partial responses and 1 complete response. Stable disease status was achieved in 9 patients (36.0% with 95% CI 18.0-57.5%). The median survival time was 248 days (95% CI, 173-265 days). The median time to progression was 126 days (95% CI, 49-165 days). Grade 3-4 toxicities occurred in 12 patients and included fatigue (33.3%), nausea, hand-foot syndrome (both 12.5%), anorexia (8.3%), vomiting, anemia and neutropenia (all 4.2%). The capecitabine and interferon alfa-2A combination has clinical activity and an acceptable toxicity profile in patients with metastatic renal cell carcinoma. The importance of adding capecitabine to interferon alfa needs to be confirmed in a randomized trial.

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Minerva Urol Nefrol. 2004 Sep;56(3):319-24.
[Nephron sparing surgery.]
[Article in Italian]
Salciccia S, Cirocchi R, Salciccia P.
Unita Operativa di Urologia, ASL 2, Urbino, Italy.

AIM: The role of nephron sparing surgery in patients with a solitary kidney, bilateral kidney tumors or an impaired renal function has been widely accepted. Partial nephrectomy in patients with a normal contralateral kidney is still under discussion. METHODS: We evaluated the effectiveness and safety of the nephronsparing surgery in the treatment of low stage renal cell carcinoma versus radical nephrectomy. We evaluated the records of 12 patients with localized, symptomless small renal masses (<4 cm) treated with nephronsparing surgery (group A) and 12 patients matched for age, tumor location, size, and stage who were treated with radical nephrectomy (group B). RESULTS: The operations were successfully completed in all intended cases. No major bleeding or urine leakage from the enucleation bed was observed. None of the cases presented with postoperative bleeding or urine leakage from the enucleation bed. Severe impairment of the renal function was not observed in any case evaluated by means of serum creatinine and creatinine clearance. The overall survival rate was 100% without recurrence up to 24 months of the mean follow-up. CONCLUSION: Partial nephrectomy for small peripheral lesions is a safe procedure with low morbidity. No definite recurrences are evident at an early stage of follow-up, although longer review (probably more than 10 years) will be required to assess cancer-specific survival following this procedure.

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Clin Cancer Res. 2004 Sep 15;10(18 Pt 2):6353S-9S.
Nonmyeloablative transplantation: an allogeneic-based immunotherapy for renal cell carcinoma.
Takahashi Y, Childs RW.
Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland 20892-1652, USA.

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation has been explored as a method to enhance the efficacy of chemotherapy for advanced solid tumors. The failure of autologous hematopoietic stem cell transplantation to prolong survival in patients with metastatic solid tumors has sparked interest recently in studies exploring the potential of allogeneic hematopoietic stem cell transplantation for such patients. Allogeneic hematopoietic stem cell transplantation is widely accepted as a potent form of immunotherapy capable of curing patients with chemotherapy-refractory hematologic malignancies. However, it was not until the end of the 20th century that investigators initiated trials to test the potential of allogeneic hematopoietic stem cell transplantation as immunotherapy in malignancies of epithelial origin. Early pilot trials have established proof-of-principle that graft-versus-tumor effects can induce complete or partial remission in some treatment-refractory metastatic solid tumors. In this review, we discuss the rationale for pilot trials investigating the potential of nonmyeloablative allogeneic hematopoietic stem cell transplantation in advanced cytokine-refractory renal cancer, highlighting the preliminary success, limitations, and future clinical directions of this approach.

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Clin Cancer Res. 2004 Sep 15;10(18 Pt 2):6342S-6S.
Update on the role of interleukin 2 and other cytokines in the treatment of patients with stage IV renal carcinoma.
Atkins MB, Regan M, McDermott D.
Beth Israel Deaconess Medical Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. Matkins@bidmc.harvard.edu

Immunoreactive cytokines have been the mainstay of treatment of renal cancer for the past 15 years. Most research has focused on interferon alpha (IFN-alpha) and interleukin 2 (IL-2). IFN-alpha has been shown in Phase III studies to produce a modest survival advantage over inactive or non-IFN-containing regimens. Its general tolerability, multiple proposed mechanisms of action, and familiarity have prompted IFN-alpha to be studied in combination with a variety of agents with potential activity against renal cell carcinoma. These various studies may justify an increased role for IFN-alpha in the treatment of renal cancer in the foreseeable future. High-dose bolus IL-2 remains the only treatment for stage IV renal cancer approved by the United States Food and Drug Administration. Food and Drug Administration approval was granted in 1992 based on the ability of this agent to produce durable complete responses in a small number of patients. Unfortunately, the toxicity, expense, and restricted accessibility of high-dose IL-2 make it a poor standard. Regimens involving lower doses of IL-2 either alone or in combination with IFN-alpha have generally produced fewer tumor regressions of less overall quality. Recent efforts have focused on trying to identify factors predictive of response to IL-2 therapy so that this treatment could be limited to those most likely to benefit.

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Clin Cancer Res. 2004 Sep 15;10(18 Pt 2):6335S-41S.
Debulking nephrectomy in metastatic renal cancer.
Flanigan RC.
Department of Urology, Loyola University Medical Center, Maywood, Illinois 60153, USA. rflanig@lumc.edu

Up to one third of patients with renal cell carcinoma will present with metastatic disease, and 20 to 40% of those with clinically localized disease will eventually be found to have metastatic involvement. Prognosis continues to be guarded for this population, with a 2-year survival of only 10 to 30%. Although advances are being made in the medical management of renal cell carcinoma, the role of surgery in the treatment algorithm is also being additionally refined. Palliative surgery either via nephrectomy or metastasectomy has a role in certain well-selected patients. There are also data to support total metastasectomy at the time of either nephrectomy or recurrence in a small subset of patients with minimal, resectable metastases. More controversial is the idea of cytoreductive nephrectomy as an adjunct to immunotherapy. Recent phase III trials indicate that nephrectomy may play an important role in management of metastatic renal cell carcinoma in conjunction with cytokine-based immunotherapy. Nephrectomy is also an essential component of tumor-based vaccine and adoptive immunotherapy protocols and may play a role in other novel therapies.

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Clin Cancer Res. 2004 Sep 15;10(18 Pt 2):6328S-34S.
Review of radiofrequency ablation for renal cell carcinoma.
Hines-Peralta A, Goldberg SN.
Minimally Invasive Tumor Therapy Laboratory, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

This review will discuss how minimally invasive, image-guided radiofrequency (RF) tumor ablation [i.e., coagulating tumor using short-duration heating (<15 minutes) by directly applying temperatures >50 degrees C via needle electrodes] is being incorporated as a clinical tool for the treatment of renal cell carcinoma. RF ablation has been used to treat focal liver tumors. Potential benefits of this thermal therapy include reduced morbidity and mortality compared with standard surgical resection and the ability to treat nonsurgical patients. More recently, this technique has been introduced to treat focal renal tumors, particularly incidental lesions smaller than 3 cm in elderly patients and those with comorbid conditions. Other uses have included treatment in patients with von Hippel-Lindau syndrome and other diseases that predispose patients to multiple renal carcinomas, where renal parenchymal preservation is desired. Techniques, complications, and results will be discussed. Additionally, strategies that we are currently studying to improve RF outcomes and enable the potential treatment of larger tumors will be addressed. Most notably, recent data on increased coagulation achieved by combining RF ablation with antivascular/antiangiogenic therapies, such as arsenic trioxide, that reduce blood flow and promote heat retention are provided.

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Clin Cancer Res. 2004 Sep 15;10(18 Pt 2):6322S-7S.
Laparoscopic and partial nephrectomy.
Novick AC.
Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. novicka@ccf.org

Radical nephrectomy is the gold standard curative operation for patients with localized renal cell carcinoma (RCC). Since its introduction in 1990, laparoscopic radical nephrectomy is being increasingly done at numerous institutions worldwide. In the hands of experienced laparoscopic urological surgeons and with adherence to established principles of open radical nephrectomy, laparoscopic radical nephrectomy is now a standard of care for patients with T1-3a N0 M0 RCC. Intermediate-term outcome data indicate equivalent cancer-free survival to open radical nephrectomy in such cases. Nephron-sparing surgery (NSS) is now an established approach for patients with localized RCC when there is a clinically relevant need to preserve renal function. NSS is also indicated in patients with a single, small, unilateral, localized RCC when the opposite kidney is completely normal. The technical success rate with NSS for RCC is excellent, and long-term patient survival free of cancer is comparable with that obtained after radical nephrectomy. We recently reviewed the results of NSS in 107 patients with localized sporadic RCC treated at the Cleveland Clinic before 1988 who were followed up for a minimum of 10 years. Long-term preservation of renal function was achieved in 93% of patients, and the 10-year cancer specific survival rate was 73%. Although open surgical partial nephrectomy remains the gold standard for nephron-sparing treatment of RCC, laparoscopic partial nephrectomy is now available in selected cases. The optimal indications for laparoscopic NSS are in patients with a relatively small and peripheral renal tumor. In such cases, laparoscopic NSS is proving to be an effective, minimally invasive therapeutic approach with respect to renal functional outcome, with additional advantages of reduced postoperative narcotic use, earlier hospital discharge, and a faster convalescence. The laparoscopic approach is associated with longer warm renal ischemia time, more major intraoperative complications, and more postoperative urological complications. Continued efforts are required to develop laparoscopic renal hypothermia techniques and to facilitate intrarenal suturing while minimizing the warm ischemia time.

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BJU Int. 2004 Aug;94(3):291-4.
Laparoscopic cytoreductive nephrectomy for metastatic renal cell carcinoma.
Finelli A, Kaouk JH, Fergany AF, Abreu SC, Novick AC, Gill IS.
Section of Laparoscopic and Minimally Invasive Surgery, Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.

The theme of laparoscopy, which has been strongly stated in the mini-review section, continues here with a paper from the Cleveland Clinic on a series of patients who had a laparoscopic nephrectomy as part of a cytoreductive strategy before immunotherapy for metatastic renal cancer. They found it safe and helpful in patients with tumours of <15 cm which do not have local invasion or caval thrombus. Prostate cancer continues to occupy much time and interest. Papers this month from Canada, USA, Malaysia and Scotland assess the variation in PSA doubling time in untreated prostate cancer, the role of bone scintigraphy in patients with biochemical recurrence, the association between age and stage or grade, and the much-vexed question of biopsy technique. There are also three papers on superficial bladder cancer, evaluating the difference between tumours in young and elderly patients, intravesical epirubicin to prevent recurrence, and the use of the holmium laser to treat recurrent tumours. OBJECTIVE To critically analyse the results of laparoscopic cytoreductive surgery for renal cell carcinoma (RCC), as phase III evidence supports cytoreductive nephrectomy before immunotherapy, and there is an overall shift towards minimally invasive renal surgery for this disease. PATIENTS AND METHODS Since October 2000, 22 patients were treated by laparoscopic cytoreductive nephrectomy for metastatic RCC (group 1). All patients had radiological evidence of metastatic disease, with biopsy confirmation in 10. To put the results into perspective, 25 consecutive contemporary patients with large organ-confined nonmetastatic RCC (>7 cm, clinical stage T2) undergoing laparoscopic radical nephrectomy (group 2) were compared retrospectively. The baseline demographics were comparable between the groups. RESULTS The mean tumour size was 8 cm in group 1 and 9.6 cm in group 2 (P = 0.07). Variables during and after surgery were comparable between the groups, with a mean operative duration of 3.1 vs 3.2 h (P = 0.82), blood loss of 285 vs 308 mL (P = 0.79), complications in two vs eight (P = 0.08), morphine sulphate equivalent requirements of 51.7 vs 44.1 mg (P = 0.1) and a median length of hospital stay of 1.7 vs 1.6 days (P = 0.68). In group 1 the median (range) time to immunotherapy was 35 (13-136) days. CONCLUSIONS Laparoscopic cytoreductive nephrectomy is safe and effective in selected patients. Currently the procedure is offered to candidates eligible for immunotherapy and with tumours of </= 15 cm, and no evidence of adjacent organ invasion or inferior vena caval thrombus. Significant perihilar adenopathy and numerous parasitic vessels can increase the complexity of the surgery. Adequate laparoscopic experience is necessary.

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Scand J Surg. 2004;93(2):163-9.
Vaccination immunotherapy--an update.
Doehn C, Jocham D.
Department of Urology, University of Lubeck Medical School, Lubeck, Germany. doehn@medinf.mu-luebeck.de

Renal cell carcinoma is often regarded as an "immunogenic tumor". Organ-confined tumors are best treated by operative removal. Adjuvant strategies, however, may improve the outcome after operative therapy. Recently, a phase-III trial using an autologous renal tumor cell vaccine was able to demonstrate a reduction of the risk of progression in patients after radical nephrectomy for renal cell carcinoma larger than 2.5 cm. These results were achieved with minimal side effects. Patients with metastases have a poor prognosis. Thirty years ago autologous tumor cell vaccination resulted in remissions in a small number of patients. Almost all vaccination reports focus on patients with metastatic renal cell carcinoma. These reports differ considerably in their modes of preparation, stimulation, application route and intervals and other relevant parameters. More important, clinical response is limited in most studies. For metastatic renal cell carcinoma none of the various vaccination approaches are being currently investigated in phase-III trials. Ongoing efforts focus on development of more powerful vaccines. This review summarizes vaccination approaches for renal cell carcinomas published in the past 4 years.

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Scand J Surg. 2004;93(2):156-61.
Systemic therapy in metastatic renal cell carcinoma.
Pyrhonen SO.
Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland. seppo.pyrhonen@tyks.fi

During the last two decades considerable advances have been made in the understanding of the biology of RCC. Although the best therapeutic options for patients with metastatic RCC have not been defined, it is apparent that use of immunomodulating cytokines like interferon-alpha and interleukin-2 either alone or combined with chemotherapeutic agents provides the best available results in routine clinical practice. Numerous studies have confirmed that objective tumour responses are seen only in a small fraction of patients (averagely in 15-20%). In spite of a lot of evidence that these treatments prolong survival, expectations of only 5-10% long-term survivals with complete and durable regression of tumours are realistic. Recently, some new promising investigational approaches have been reported. These may already in near future further improve overall treatment results.

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Scand J Surg. 2004;93(2):150-5.
Surgery for metastases of renal cell carcinoma.
Swanson DA.
Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. dswanson@mdanderson.org

The role of surgery for RCC in the era of emerging effective systemic therapy (usually immunotherapy) is not yet defined except for solitary metastasis. The retrospective analysis of patients subjected to aggressive surgical management after systemic therapy reinforces the need to find better therapeutic modalities in order to achieve complete eradication of metastatic disease. In the meantime, however, we propose these guidelines. First, we would encourage aggressive surgical resection of the clinically solitary metastasis, whether synchronous or metachronous. Continue to follow those patients indefinitely, because relapse is quite likely, but do not give adjuvant systemic therapy unless on protocol. Second, limited metastases in only one organ may behave similarly to a solitary metastasis, and if the metastases are in a site amenable to surgical resection, e.g., lung, initial surgery might be reasonable. Systemic therapy for these patients is highly recommended and need not necessarily wait for recurrence. Third, for patients with multiple metastases, initial systemic therapy followed then by resection of any residual disease in selected patients seems to be supported by the experience at several medical centers. Apparently prolonged survival times have been observed after systemic therapy followed by surgery in highly selected patients, despite finding viable cancer in the overwhelming majority of specimens. One must be mindful of the morbidity of an attempt to remove all known disease, however, and try to weigh this against potential benefit. Only a prospective, randomized trial could ever confirm the value of an aggressive surgical approach to metastatic RCC. In the meantime, however, metastasectomy offers, at the very least, the opportunity to confirm the histologic response to systemic therapy, render some patients disease-free, and possibly promote long-term survival in selected patients.

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Scand J Surg. 2004;93(2):132-6.
Laparoscopic versus open nephrectomy for renal cell carcinoma?
Taari K, Perttila I, Nisen H.
Department of Urology, Helsinki University Hospital, Helsinki, Finland. kimmo.taari@hus.fi

Laparoscopic radical nephrectomy has become a well-standardized and reproducible, but technically demanding procedure. It is rapidly replacing the traditional open technique in radical nephrectomy with T1-2 tumours. Open operation will mainly be reserved for T3 tumours. Nephron-sparing surgery will play a major role in small (<4 cm) peripheral tumours. Open technique is still the standard for NSS, but with the refined techniques, laparoscopy may be soon coming.

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Scand J Surg. 2004;93(2):126-31.
Nephron-sparing surgery--strategies for partial nephrectomy in renal cell carcinoma.
Ljungberg B.
Department of Surgical and Perioperative Sciences, Urology and Andrology, Umea University, Umea, Sweden. Borje.Ljungberg@urologi.umu.se

The use of partial nephrectomy for renal cell carcinoma has continuously changed in the clinical practice. Previously it was mostly used in imperative cases, in patients with a solitary kidney or in patients with a risk of renal failure. An increased number of incidentally detected renal cell carcinomas are diagnosed due to the advances of the radiological methods. These tumours tend to be smaller and generally with a lower stage. The reported excellent results of partial nephrectomy have promoted the use of nephron-sparing surgery also in patients with a normal contralateral kidney and tumours smaller than 4-5 cm. The technical outcome is excellent with a low operative morbidity and a good oncologic control. Therefore partial nephrectomy has become a standard technique in the treatment of properly selected patients. Laparoscopy with its reduced postoperative pain and shorter rehabilitation time, has encouraged the interest in minimally invasive nephron sparing surgical techniques. Although low, the risk of local tumour recurrence and surgical complications are higher after nephron-sparing surgery compared with radical nephrectomy. Furthermore, long-term renal function remains adequate in most patients with a normally functioning contralateral kidney also after radical nephrectomy. Albeit these facts, there is convincing evidence justifying nephron-sparing surgery to be used routinely for patients with a small renal cell carcinoma and a normal functioning contralateral kidney.

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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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Urol Oncol. 2004 May-Jun;22(3):214-23.
The role of lymphadenectomy in the surgical management of renal cell carcinoma.
Phillips CK, Taneja SS.
Department of Urology, New York University School of Medicine, New York, NY, USA.

After decades of evaluation, the role of lymphadenectomy in the management of renal cell carcinoma remains a controversy. Contemporary series suggest that the true incidence of isolated lymph node metastases in clinically localized disease is small, and the location of such metastases is unpredictable. While several institutional series have suggested a therapeutic benefit for extended lymphadenectomy, there remains a lack of randomized data to support its routine use. Despite this, there remains a role for lymphadenectomy in individuals with high risk of lymph node metastasis or known lymphadenopathy in whom few other options exist for aggressive, potentially curative therapy.

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Urol Int. 2004;73(1):54-8.
Does radical nephrectomy with immunochemotherapy have any superiority over embolization alone in metastatic renal cell carcinoma? A preliminary report.
Demirci D, Tatlisen A, Ekmekcioglu O, Ozcan N, Kaya R.
Department of Urology, Erciyes University Medical Faculty, Kayseri, Turkey. demirci@erciyes.edu.tr

INTRODUCTION: We evaluated the results and effects of radical nephrectomy followed by immunochemotherapy and embolization alone on the survival of patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: The study included 20 patients with histologically confirmed renal cell carcinoma. Ten patients were in the combined therapy group and the other 10 patients who were unable to undergo nephrectomy because of poor performance status or unresectable tumor were in the embolization group. Radical nephrectomy was performed on patients with good performance status (WHO criteria 0-1). Immunochemotherapy (interferon alpha 2a and 5-fluorouracil) was started within 1 month after surgery. A dose of 9 x 10(6) U/day interferon alpha 2a was subcutaneously administered 3 times a week. A dose of 750 mg/m2 5-fluorouracil was administered intravenously during 4 h in the first 5 days of treatment. 5-Fluorouracil therapy was converted to weekly intervals after the first 12 days. Combined therapy was continued for 3 months. Ethanol was used for transarterial embolization. The main renal arteries and parasitic arteries of the tumor were embolized. RESULTS: There were no significant differences in age distribution, sex, affected side, tumor size and T stage between the groups. After completion of the combined therapy, 6 patients showed progression at the first control. Only 1 patient (10 %) had stable disease throughout the 10 months after combined therapy. One patient died of myocardial infarction on the 4th day in the embolization group. While progressive disease within the first 3 months was detected in 6 patients, the other 3 patients (30%) had stable disease for 14, 17 and 55 months, respectively. There was no complete response in any group and no patient was alive (died of renal cell carcinoma) at the time of the analysis of the study data. Whereas the median survival time was 11 months (1-80) (mean +/- SE: 22.2 +/- 9.1) in the combined group, this time was a median of 1 month (1-74) (mean +/- SE: 17.5 +/- 8.6) in the embolization group. There was no statistically significant difference in survival time between the groups (p > 0.05). CONCLUSION: In this preliminary report, the clinical findings in embolization-group patients were definitively worse than the nephrectomy plus immunochemotherapy-group patients. In spite of these differences, combination therapy using radical nephrectomy and immunochemotherapy could not show superiority to embolization alone, especially in terms of survival time. Copyright 2004 S. Karger AG, Basel

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Curr Opin Oncol. 2004 May;16(3):247-52.
Renal cell carcinoma.
Rathmell WK, Godley PA.
Division of Hematology/Oncology, University of North Carolina at Chapel Hill, and the Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.

PURPOSE OF REVIEW: Renal cell carcinoma continues to be a devastating cancer, which currently has few effective treatment options. Recent developments in our understanding of the molecular biology of renal cell carcinoma, particularly clear cell renal cell carcinoma, have led to the development of new agents targeting portions of the hypoxic response pathway. RECENT FINDINGS: Although high-dose bolus interleukin-2 remains the mainstay of treatment for metastatic disease, the number of patients deriving long-term benefit from this treatment are few, and the use of cytokine therapy in the adjuvant setting has been disappointing. However, the expanding use of minimally invasive surgical techniques has continued to improve patient care. Systemic advances include antibody therapeutics such as bevacizumab, which targets vascular endothelial growth factor signaling, as well as emerging small molecule inhibitors of angiogenesis-related signaling events. SUMMARY: In addition to progress in surgical techniques and supportive care of patients with renal cell carcinoma, a host of promising targeted therapies for renal cell carcinoma are on the horizon.

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Zhonghua Wai Ke Za Zhi. 2004 Apr;42(4):205-6.
[Immunotherapy of metastatic renal cell carcinoma: report of 28 cases]
[Article in Chinese]
Wang HJ, Wang H, Li HZ, Shi BB, Song ZL.
Department of Urology, Peking Union Medical College Hospital, Beijing 100230, China.

OBJECTIVE: To determine the efficacy of IL-2, IFN and Furtulon in patients with metastatic renal cell carcinoma. METHODS: During the induction phase of the treatment of 28 patients, which lasted 3 months, IL-2 and IFN were administered subcutaneously three times a week at doses of 5 approximately 20 MU/m(2) and 6 approximately 9 MU/m(2), Furtulon was administered at doses of 800 approximately 1 200 mg daily by oral during 28 days a month. RESULTS: The response rate was 46.4%, including 4 complete response (CR), 9 presented with partial response (PR). CONCLUSION: The three-drugs combination described in this study demonstrates activity. Based on the present data, combined biochemotherapy may be a promising new approach to the therapy of the metastatic renal cell carcinoma.

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J Vasc Surg. 2004 Apr;39(4):829-35.
Surgical strategy for treating renal cell carcinoma with thrombus extending into the inferior vena cava.
Jibiki M, Iwai T, Inoue Y, Sugano N, Kihara K, Hyochi N, Sunamori M.
Department of Surgery, Tokyo Medical and Dental University Graduate School, Japan. jibiki.srg1@tmd.ac.jp

OBJECTIVE: A surgical strategy for treating malignant renal tumors with thrombus extending into the inferior vena cava (IVC) was assessed. METHODS: We retrospectively reviewed the records for all patients with renal cell carcinoma (RCC; n=30) or Wilms tumor (n=1) with tumor thrombus extending into the IVC who underwent surgical intervention at our institution between January 1980 and December 2001. Tumors were classified preoperatively according to the cephalad extension of thrombus, and intraoperative procedures were selected on the basis of degree of extension. Patients with RCC underwent radical nephrectomy and removal of thrombus with (n=11) or without (n=19) IVC resection. Partial normothermic cardiopulmonary bypass without cardiac arrest was used in 4 patients. The Pringle maneuver was performed in 8 patients. Infrarenal abdominal aortic cross-clamping was used in 8 patients to maintain systemic blood pressure. IVC cross-clamping and the Pringle maneuver were performed in 5 patients with suprahepatic thrombus extension. Temporary placement of a filter in the IVC or plication of the IVC above the hepatic vein was performed before hepatic mobilization, to decrease the risk for pulmonary embolism. RESULTS: One patient died intraoperatively of pulmonary embolism. Postoperative complications occurred in 11 patients; all resolved with conservative therapy. The postoperative duration of survival in patients with RCC was 37 +/- 44 months (range, 4-180 months); the 5-year survival rate was 42%. CONCLUSION: Aortic cross-clamping during IVC occlusion prevented hypotension and maintained hemodynamic stability that has required bypass in other series. This surgical treatment with the less extensive approach could result in long-term survival of patients with RCC in whom tumor thrombus extends into the IVC. We recommend that radical nephrectomy and tumor thrombectomy, with or without caval resection, be performed in these patients, with less invasive additional maneuvers.

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Int J Eat Disord. 2004 Jan;35(1):10-5.
Use of nutritional supplements to increase the efficacy of fluoxetine in the treatment of anorexia nervosa.
Barbarich NC, McConaha CW, Halmi KA, Gendall K, Sunday SR, Gaskill J, La Via M, Frank GK, Brooks S, Plotnicov KH, Kaye WH.
Department of Psychiatry, University of Pittsburgh Medical School, Anorexia and Bulimia Nervosa Research Module, Pittsburgh, Pennsylvania 15213, USA.

OBJECTIVE: Selective serotonin reuptake inhibitor (SSRI) medication does not appear to be effective in ill, malnourished anorexia nervosa (AN) patients. However, it may be effective in preventing relapse after weight restoration. The purpose of this study was to determine whether nutritional supplements could potentiate the effects of fluoxetine in underweight AN subjects. METHOD: Twenty-six subjects with AN participated in a trial of fluoxetine. In a double-blind, placebo-controlled manner, subjects received either nutritional supplements or a nutritional placebo. The nutritional supplement included tryptophan (the precursor of serotonin), vitamins, minerals, and essential fatty acids believed to influence serotonin pathway function. RESULTS: There was no significant difference in weight gain between subjects treated with fluoxetine plus nutritional supplements versus fluoxetine plus a nutritional placebo. Moreover, there were no significant differences between groups on mean changes in anxiety or obsessive and compulsive symptoms. DISCUSSION: The results of this study suggest that supplement strategies are not a substitute for adequate nutrition and are ineffective in increasing the efficacy of fluoxetine in underweight AN subjects. Copyright 2003 by Wiley Periodicals, Inc. Int J Eat Disord 35: 10-15, 2004.

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Curr Sports Med Rep. 2003 Dec;2(6):331-6.
The multidisciplinary team approach to the outpatient treatment of disordered eating.
Joy EA, Wilson C, Varechok S.
Department of Family and Preventive Medicine, University of Utah, 555 Foothill Drive, Salt Lake City, UT 84112, USA. eajslc@aol.com

The multidisciplinary team approach to the patient with disordered eating is widely recognized as the best practice. Team members include a physician, a nutritionist, and a mental health professional. All should be experienced in the care of individuals with disordered eating. Each member of the treatment team has unique skills and responsibilities with respect to patient care. However, there is considerable overlap in what each member of the treatment team does to promote recovery from disordered eating. It is important to remember that eating problems exist on a spectrum from disordered eating behaviors that do not meet the Diagnostic and Statistical Manual of Mental Disorders criteria, to anorexia nervosa, and bulimia nervosa. Prognosis is directly related to duration of illness, so early intervention, even when symptoms may be minimal, is preferable. Despite multi- disciplinary treatment efforts, overall prognosis is poor, with only 40% to 50% of patients with anorexia nervosa and bulimia nervosa progressing to complete recovery. Continued efforts and early, comprehensive intervention must be undertaken by all practitioners.

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Lancet Oncol. 2003 Nov;4(11):686-94.
Cancer anorexia: clinical implications, pathogenesis, and therapeutic strategies.
Laviano A, Meguid MM, Rossi-Fanelli F.
Department of Clinical Medicine, University La Sapienza, Rome, Italy. alessandro.laviano@uniroma1.it

Anorexia and reduced food intake are important issues in the management of patients with cancer because they contribute to the development of malnutrition, increase morbidity and mortality, and impinge on quality of life. Accumulating evidence indicates that cancer anorexia is multifactorial in its pathogenesis, and most of the hypothalamic neuronal signalling pathways modulating energy intake are likely to be involved. Several factors are considered to be putative mediators of cancer anorexia, including hormones (eg, leptin), neuropeptides (eg, neuropeptide Y), cytokines (eg, interleukin 1 and 6, and tumour necrosis factor), and neurotransmitters (eg, serotonin and dopamine). These pathways are not isolated and distinct pathogenic mechanisms but are closely inter-related. However, convincing evidence suggests that cytokines have a vital role, triggering the complex neurochemical cascade which leads to the onset of cancer anorexia. Increased expression of cytokines during tumour growth prevents the hypothalamus from responding appropriately to peripheral signals, by persistently activating anorexigenic systems and inhibiting prophagic pathways. Hypothalamic monoaminergic neurotransmission may contribute to these effects. Thus, the optimum therapeutic approach to anorectic cancer patients should include changes in dietary habits, achieved via nutritional counselling, and drug therapy, aimed at interfering with cytokine expression or hypothalamic monoaminergic neurotransmission.

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Minn Med. 2003 Nov;86(11):34-9.
Current challenges in recognizing and treating eating disorders.
Johnson CJ.
Eating Disorders Institute, Methodist Hospital, Park Nicollet Health Services, USA.

Anorexia nervosa and bulimia nervosa are serious, life-threatening illnesses that often require several years of treatment. Although classified as mental health diagnoses, they are associated with significant medical consequences and have the highest rate of premature death of any mental health diagnosis. They also are associated with the highest rate of short- and long-term physiological complications. Eating disorders disproportionately affect young women. With early intervention and aggressive treatment, affected adolescents and young adults can recover and be free of the disorder. This article reviews the difficulties in recognizing that a patient has an eating disorder and the signs and symptoms providers should look for. It also discusses our current understanding of the causes of eating disorders as well as current treatment methods, which involve a multidisciplinary approach.

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Am J Psychiatry. 2003 Nov;160(11):2046-9.
Cognitive behavior therapy in the posthospitalization treatment of anorexia nervosa.
Pike KM, Walsh BT, Vitousek K, Wilson GT, Bauer J.
Department of Psychiatry, Columbia University College of Physicians and Surgeons, 1051 Riverside Drive, New York, NY 10032, USA. kmp2@columbia.edu

OBJECTIVE: This study provides what the authors believe is the first empirical evaluation of cognitive behavior therapy as a posthospitalization treatment for anorexia nervosa in adults. METHOD: After hospitalization, 33 patients with DSM-IV anorexia nervosa were randomly assigned to 1 year of outpatient cognitive behavior therapy or nutritional counseling. RESULTS: The group receiving nutritional counseling relapsed significantly earlier and at a higher rate than the group receiving cognitive behavior therapy (53% versus 22%). The overall treatment failure rate (relapse and dropping out combined) was significantly lower for cognitive behavior therapy (22%) than for nutritional counseling (73%). The criteria for "good outcome" were met by significantly more of the patients receiving cognitive behavior therapy (44%) than nutritional counseling (7%). CONCLUSIONS: Cognitive behavior therapy was significantly more effective than nutritional counseling in improving outcome and preventing relapse. To the authors' knowledge, these data provide the first empirical documentation of the efficacy of any psychotherapy, and cognitive behavior therapy in particular, in posthospitalization care and relapse prevention of adult anorexia nervosa.

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Seishin Shinkeigaku Zasshi. 2003;105(11):1363-86.
[Efficacy of intervention with externalization therapy for eating disorders]
[Article in Japanese]
Ono H, Kojima K, Higashi Y, Yoshioka S, Kawahara R.
Department of Neuropsychiatry, Faculty of Medicine, Tottori University.

Externalization has been one of the effective methods in the fields of brief therapy, family therapy, and psycho-education in recent years. In this study, we investigated the efficacy of intervention with externalization at the first stage of therapy in 25 patients with eating disorders. The subjects consisted of 11 patients with anorexia nervosa (AN) and 14 with bulimia nervosa (BN). The Eating Disorder Inventory (EDI) was evaluated at the first session, the 10th session, and six months later. The obtained results showed intervention with externalization resulted in significant decreases in not only total EDI score but also all the EDI subscale scores. We also found that there were great differences between the EDI subscale scores of anorexia nervosa and bulimia nervosa patients. Therapy was significantly less effective for patients with anorexia nervosa than for those with bulimia nervosa, and much less effective for the restricting type of anorexia nervosa. In addition, all the EDI subscale scores were significantly decreased, irrespective of the complication of personality disorder. The efficacy of intervention with externalization continued for six months. Especially in patients with anorexia nervosa, there were significant decreases in the EDI subscale scores when compared with the scores in the 10th session. The present findings indicates that initial intervention with externalization is effective for treating eating disorders, regardless of the severity of illness.

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Expert Opin Pharmacother. 2003 Oct;4(10):1659-78.
Towards the pharmacotherapy of eating disorders.
Pederson KJ, Roerig JL, Mitchell JE.
The Neuropsychiatric Research Institute, 700 First Avenue South, Fargo, ND 58103, USA.

The purpose of this review is to discuss pharmacological options for the treatment of patients with eating disorders. Sequentially described are pharmacotherapy studies of anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED). The quantity of drug trials performed with AN patients has been very limited. While the majority of studies have failed to show medication efficacy for the acute treatment of AN, there is data which suggests that fluoxetine hydrochloride may play a role in preventing relapse during maintenance therapy. Atypical antipsychotics, most often olanzapine, have shown promise in a number of uncontrolled studies. BN has been most extensively studied, with the majority of pharmacological trials focusing on antidepressants. Fluoxetine, at a dose of 60 mg/day, is FDA-approved for the treatment of BN. Psychotherapy, particularly cognitive behavioural therapy (CBT) is of well-established utility in BN and data suggests that the combination of an antidepressant plus CBT is superior to either treatment alone. Recently, there has been interest in the 5-HT3 antagonist, ondansetron, and the anticonvulsant, topiramate. BED investigators have focused largely on antidepressants, which may reduce symptoms of depression and augment psychotherapy. While sibutramine and topiramate have both been associated with weight loss in controlled trials, the former appears to be fairly well-tolerated and the latter appears to be responsible for the emergence of significant cognitive and peripheral nervous system side effects in some patients. Further pharmacological research with eating disorder patients is needed, particularly in the areas of AN and BED. Also, pharmacological augmentation strategies for those not responding to primary therapies should be explored.

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Eat Weight Disord. 2003 Sep;8(3):242-8.
Adolescents and eating disorders: an examination of a day treatment program.
Dancyger I, Fornari V, Schneider M, Fisher M, Frank S, Goodman B, Sison C, Wisotsky W.
Division of Child and Adolescent Psychiatry, North Shore University Hospital, New York University School of Medicine, Manhasset, USA. IDancyge@nshs.edu

OBJECTIVE: In this study, we report on our day treatment program (DTP) for adolescents and young adults with eating disorders (EDs). METHOD: Data for the 82 female patients in DTP were examined, compared across ED diagnosis and by age (adolescents vs. young adults). At admission, patients completed the Eating Disorder Inventory-2 (EDI-2) and the Beck Depression Inventory (BDI) and the Family Adaptability and Cohesion Evaluation Scale- II (FACES-II). RESULTS: Forty-nine percent of patients successfully completed the day program and 13% required hospitalization following day treatment. Overall, there were no significant differences between the adolescents and adults at discharge of the day program. DISCUSSION: With shortened inpatient (IP) hospitalizations, DTPs can provide the long-term care required by many adolescent patients for psychological and physical recovery. This may be particularly important for the development of children and adolescents.

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Ann Med. 2003;35(7):488-501.
A practice guideline for treatment of eating disorders in children and adolescents.
Ebeling H, Tapanainen P, Joutsenoja A, Koskinen M, Morin-Papunen L, Jarvi L, Hassinen R, Keski-Rahkonen A, Rissanen A, Wahlbeck K.
Unit for Child Psychiatry, University of Oulu, University Hospital of Oulu, PO Box 26, FIN-90029 OYS, Finland.

Eating disorders are diseases of both the body and the psyche. Early treatment focuses on restoration of nutritional status and somatic health, including psycho-educational counselling and support offered to the patient and his/her family. Diagnosis and treatment require a multidisciplinary approach. Psychological factors related to the condition should be assessed. The most severe weight loss should be reversed before psychotherapeutic treatment. Nutritional counselling is recommended, and the benefits of individual and/or family therapy are considered in accordance with the patient's age, development, symptomatology and comorbid psychiatric disorders. Medication is useful in the treatment of bulimia nervosa and certain comorbid symptoms of anorexia nervosa. Early admission to treatment and active therapy are associated with a more favourable prognosis.

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J Clin Oncol. 2004 Jan 1;22(1):115-9.
Phase II trial of PS-341 in patients with renal cell cancer: a University of Chicago phase II
consortium study.
Davis NB, Taber DA, Ansari RH, Ryan CW, George C, Vokes EE, Vogelzang NJ, Stadler WM.
Section of Hematology/Oncology, University of Chicago Medical Center, 5841 S Maryland Avenue, MC 2115, Chicago, IL 60637, USA.

PURPOSE: Determine response rate, time to disease progression, and toxicity of the proteasome inhibitor PS-341 in patients with stage IV renal cell cancer. PATIENTS AND METHODS: PS-341 1.5 mg/m(2) was administered intravenously twice weekly for 2 weeks every 21 days. Dose escalation to 1.7 mg/m(2) ensued in the absence of grade 3 to 4 toxicities. Re-evaluation took place after three cycles. To assess proteasome inhibition, patients were randomly assigned to tumor core biopsy either before the first dose or after the third cycle of PS-341. Additionally, whole blood was collected at the same time intervals. RESULTS: Twenty-three patients were enrolled; 21 were assessable for response. Two patients were never treated (one patient refused treatment and one had insufficient tumor for biopsy). Eighteen patients completed at least three cycles of therapy; three patients experienced disease progression after two cycles. Grade 4 toxicities were arthralgia, diarrhea, and vomiting. Grade 3 toxicities included thrombocytopenia with one hemorrhage, anemia, febrile neutropenia, gastrointestinal toxicity, pain, fatigue, neuropathy (one sensory, one mixed sensorimotor), and electrolyte disturbances. Grade 1 to 2 neuropathy occurred in seven patients. One case of thrombosis and one case of pleural effusion occurred. Only one objective response was seen. Proteasome activity was measured by specific chymotryptic activity (SpA) and chymotryptic/tryptic activity (ChT:T). After PS-341, there was a decrease in mean whole blood SpA and ChT:T (P =.07 and.11, respectively). CONCLUSION: Evidence is lacking for clinically significant activity of PS-341 in metastatic renal cell cancer. Insufficient biopsy and whole blood sample numbers preclude conclusions regarding proteasome inhibition within tumor. Further evaluation in this disease setting is not recommended

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Expert Rev Anticancer Ther. 2003 Dec;3(6):830-6.
Laparoscopic surgery for renal cell carcinoma.
Hasan WA, Abreu SC, Gill IS.
Section of Laparoscopic and Minimally Invasive Surgery, Glickman Urological Institute, Cleveland Clinic Foundation, Ohio 44195, USA. hasanw@ccf.org

New minimally invasive technologies are currently being applied to the management of renal cell carcinoma in an effort to decrease operative time, pain, morbidity and hospital stay. Foremost among these is the burgeoning role of laparoscopy in tumor destruction and complete in vivo resection. The primary modalities in clinical use today are laparoscopic radical nephrectomy, laparoscopic partial nephrectomy, laparoscopic renal cryoablation and laparoscopic radiofrequency ablation. Most initial reports include only highly selected patients with unifocal, small, exophytic, peripheral lesions away from the collecting system. As experience with these techniques increases, larger and more difficult lesions are being approached laparoscopically, with promising anecdotal results reported. Laparoscopic access to the kidney may be retroperitoneal or transperitoneal. Complete tumor destruction with maximal preservation of unaffected nephrons remains the goal. Herein, an update on laparoscopic surgery for renal cell carcinoma is presented. For each procedure, the current indications and contraindications, perioperative data, complications and oncological outcomes are described. In the future, it appears likely that laparoscopy will play a major role in the established treatment options for renal cell carcinoma, with open surgery being reserved for specific indications.

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Urology. 2003 Nov;62(5):821-6.
Surgical treatment of renal neoplasia: evolving toward a laparoscopic standard of care.
Bhayani SB, Clayman RV, Sundaram CP, Landman J, Andriole G, Figenshau RS, Bullock A, Brandes S, Shalhav A, McDougall E, Kibel AS.
Division of Urology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

OBJECTIVES: To determine the extent to which laparoscopy has replaced open surgery for renal malignancy. METHODS: The records of all 537 patients at Washington University who underwent surgery for localized renal malignancies from January 1997 to December 2001 were examined for clinical and pathologic information. RESULTS: The total procedures per year increased from 1997 to 2001, but the distribution of pathologic stages throughout the 5 years was similar. In 1997, laparoscopic approaches were used in 15% of cases; this increased to 65% by 2001. Nephron-sparing surgery (NSS) was used in 31% to 42% of patients yearly, but laparoscopic NSS increased in frequency. By 2001, only 3.3% of T1 tumors were removed by open radical nephrectomy compared with 55% treated by laparoscopic nephrectomy. The rest of the T1 tumors in 2001 were treated by open partial nephrectomy (20.2%) or laparoscopic NSS (21.3%). In 2001, 61% of T2 lesions were treated laparoscopically, an increase from 37% in 1997. Most open radical nephrectomies in 2001 were performed for T3 disease. The number of surgeons performing laparoscopic renal surgery has increased at our institution, from two in 1997, both endourologists, to eight in 2001, representing the entire urology faculty that treats renal cancer. CONCLUSIONS: Laparoscopic radical nephrectomy has replaced open radical nephrectomy for low-stage renal neoplasia. Although laparoscopic NSS is increasing in frequency, it has not yet replaced open partial nephrectomy. At our institution, the laparoscopic approach has become the standard of care when radical nephrectomy is needed for T1 or T2 renal cancer.

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Cancer. 2003 Nov 1;98(9):1837-41.
Vinblastine and estramustine phosphate in metastatic renal cell carcinoma: a phase II trial of the Fox Chase Network.
Haas NB, Giantonio BJ, Litwin S, Minniti CJ Jr, Fox S, Yeslow G, Reilly R, Nahum K, Greenberg R, Halbherr T, Hudes GR.
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. nb_haas@fccc.edu

BACKGROUND: It is well known that metastatic renal cell carcinoma (RCC) exhibits constitutive resistance to chemotherapeutic agents. Antimicrotubule agents such as vinblastine are associated with low but reproducible response rates (approximately 12%) in patients with RCC. Estramustine has been shown to potentiate the antimicrotubule effects of vinblastine. The authors sought to increase the activity of vinblastine in RCC through the addition of estramustine. METHODS: Twenty-one patients with metastatic RCC not previously treated with chemotherapy received oral estramustine phosphate, 600 mg/m(2), on Days 1, 2, and 3 weekly for 6 weeks, and intravenous vinblastine, 4 mg/m(2) on Day 2 weekly for 6 weeks, repeated every 8 weeks. Twenty-one patients received 31 cycles of therapy. RESULTS: Two patients experienced Grade 3 and 4 hematologic toxicity, and three patients had Grade 3 nonhematologic toxicity consisting of neurologic toxicity, hepatic toxicity, or angioneurotic edema. One patient had a partial response with decreased liver metastases for 48 weeks; 9 patients had stable disease, for a median duration of 14 weeks (range, 11-31 weeks); and 11 patients demonstrated disease progression. The median overall time to progression was 8 weeks and the median overall survival period was 24 weeks. CONCLUSIONS: Although well tolerated, the combination of oral estramustine phosphate with vinblastine administered on this schedule had minimal activity in patients with metastatic RCC. Copyright 2003 American Cancer Society.

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Urology. 2003 Nov;62(5):814-20.
Quality of life after surgery for localized renal cell carcinoma: comparison between radical nephrectomy and nephron-sparing surgery.
Poulakis V, Witzsch U, de Vries R, Moeckel M, Becht E.
Department of Urology and Pediatric Urology, Krankenhaus Nordwest, Teaching Hospital Johann-Wolfgang-Goethe-University Frankfurt, Frankfurt/Main, Germany.

OBJECTIVES: To compare the impact of radical nephrectomy and nephron-sparing surgery (NSS) for localized renal cell carcinoma on quality of life (QOL). METHODS: Retrospectively, 357 patients who had undergone NSS (n = 158) or radical nephrectomy (n = 199) for localized renal cell carcinoma completed postal questionnaires, including measures of QOL with validated instruments (SF-36, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 [EORTC QLQ-C30]), the impact of the stress of cancer, fear of recurrence, and worry about having fewer than two normal kidneys. A subset of 51 patients diagnosed after 2000 were followed up prospectively for at least 1 year. RESULTS: The mental and physical health composite scores were not significantly different from the validated norms for an age and sex-matched community sample. Although the type of operation had no influence on patients' overall QOL, all patients who underwent elective NSS showed a significantly greater score on physical function than patients treated with radical nephrectomy (P <0.001). Predictors for higher scores included elective NSS, comorbidity (assessed with standardized checklist), tumor size, and time since nephrectomy. The overall QOL scores and recovery of stress from cancer in patients treated with NSS for tumor less than 4 cm with a normal contralateral kidney were significantly superior to those who underwent NSS for tumor greater than 4 cm (P <0.05). Patients questioned after mandatory NSS were significantly more concerned about cancer recurrence. CONCLUSIONS: Patients without evidence of disease have relatively normal physical and mental health after operative treatment for localized renal cell carcinoma, independent of the kind of surgery. The QOL correlates proportionally with the size of tumor and is significantly better for patients undergoing NSS for tumor less than 4 cm with a normal contralateral kidney.

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Urology. 2003 Oct;62(4):641-6.
Nephron-sparing surgery for renal cell carcinoma: clinicopathologic features predictive of patient outcome.
Krejci KG, Blute ML, Cheville JC, Sebo TJ, Lohse CM, Zincke H.
Department of Urology, Mayo Clinic, Rochester, Minnesota 55905, USA.

OBJECTIVES: To determine the clinicopathologic features associated with outcome in patients with sporadic renal cell carcinoma (RCC) treated with nephron-sparing surgery. METHODS: We studied 344 patients treated with nephron-sparing surgery between 1970 and 2000. The pathologic features of the tumors were reviewed by two urologic pathologists who recorded the histologic subtype, 2003 TNM stage, tumor size, and grade. Cancer-specific survival (CSS) was estimated using the Kaplan-Meier method, and log-rank tests were used to compare the outcome by histologic subtype. Univariate Cox proportional hazards models were fit to assess the associations between the clinicopathologic features and death from RCC, distant metastases, and local recurrence. RESULTS: The CSS rate at 5 and 10 years for patients with clear cell RCC was 94.4% and 91.5%, respectively. In contrast, the CSS rate at 5 and 10 years for patients with papillary or chromophobe RCC was 99.0%, because only 1 patient died of papillary RCC and no patient died of chromophobe RCC (P = 0.029). Among the patients with localized clear cell RCC, tumor stage and grade were significantly associated with death from RCC and metastases. Grade was significantly associated with local recurrence for clear cell RCC, but not for papillary RCC. CONCLUSIONS: In our series of patients with RCC treated with nephron-sparing surgery, patients with clear cell RCC had a significantly worse CSS than did patients with papillary and chromophobe RCC. Tumor stage and grade were associated with outcome among patients with localized clear cell RCC. These findings are similar to the results for patients with localized clear cell RCC treated with radical nephrectomy.

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Urology. 2003 Oct;62(4):636-40.
Nephrectomy for metastatic renal cell carcinoma: Indiana University experience.
Mosharafa A, Koch M, Shalhav A, Gardner T, Logan T, Bihrle R, Foster R.
Department of Urology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5289, USA.

OBJECTIVES: To report on the short-term morbidity of radical nephrectomy in 32 patients with poorer performance status and more advanced primary renal cell carcinoma (RCC). Nephrectomy followed by immunotherapy has been shown to improve survival in selected, good performance status patients with metastatic RCC. METHODS: We report on 32 patients who underwent radical nephrectomy (20 open procedures and 12 laparoscopic) in the setting of metastatic RCC at Indiana University between 1999 and 2002. The study group included patients with advanced primary tumors (inferior vena cava involvement, large size, and involvement of adjacent structures). The patients' performance status score ranged from 0 to 2. RESULTS: The average hospital stay was 5.1 days. No significant intraoperative complications were encountered, and postoperative complications occurred in 6 patients, including one perioperative death. At 4 weeks postoperatively, 21 (72.4%) of 29 assessable patients had a performance status equal to, or better than, their preoperative status, including 4 patients who converted from a preoperative performance status of 2 to 0 or 1 postoperatively. Eleven patients (34.4%) went on to receive postoperative immunotherapy. CONCLUSIONS: The results of our study demonstrated that radical nephrectomy in the setting of metastatic RCC has a low morbidity and acceptable recovery in these patients with advanced primary tumors and poorer performance status.

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J Clin Oncol. 2003 Oct 15;21(20):3770-6.
Interferon alfa-2b three times daily and thalidomide in the treatment of metastatic renal cell carcinoma.
Hernberg M, Virkkunen P, Bono P, Ahtinen H, Maenpaa H, joensuu H.
Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland. micaela.hernberg@hus.fi

PURPOSE: The antiangiogenic effect of interferon (IFN) may improve with frequent dosing and by combination with other agents with antiangiogenic activity. To evaluate this potential, we treated patients with metastatic renal cell carcinoma (RCC) with frequently dosed IFN and thalidomide. PATIENTS AND METHODS: Thirty patients were given IFN-alpha-2b 0.9 MU subcutaneously three times daily for 1 month and subsequently 1.2 MU tid unless serious toxicity was encountered. Thalidomide was first given 100 mg/d for 1 week and 300 mg/d thereafter. Sera were collected before and during treatment for serum vascular endothelial growth factor (S-VEGF) analyses performed using enzyme-linked immunosorbent assay. RESULTS: The intention-to-treat response rate was 20% (95% CI, 6% to 34%) and response rate for assessable patients (n = 27) was 22% (95% CI, 6% to 38%). All responses were partial. In addition, 17 patients (63%; 95% CI, 45% to 81%) had stable disease for 3 months or longer. The median time to treatment failure was 7.7 months, and median survival time was 14.9 months. The most common cause of thalidomide discontinuation was neuropathy. S-VEGF levels decreased more in patients who responded to therapy compared with those in patients whose condition had stabilized or who had progressive disease (P =.036). CONCLUSION: The combination of frequently dosed IFN-alpha-2b and low-dose thalidomide is feasible and active in advanced RCC, but the clinical benefit may remain small compared with that of IFN alone. Results from an ongoing phase III trial comparing IFN-alpha with or without thalidomide need to be analyzed before this combination can be recommended for use outside clinical studies.

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Med Oncol. 2003;20(4):325-34.
Prognostic factors of immunotherapy in metastatic renal cell carcinoma.
Padrik P.
Clinic of Hematology & Oncology, Tartu University Clinics, Vallikraavi 7, Tartu, 51003 ESTONIA. peeter.padrik@kliinikum.ee

The prognosis of the majority of patients with metastatic renal cell carcinoma is poor, and there is no internationally recognized standard therapy for these patients. Patients are treated with interferon alpha or interleukin- 2 monotherapy, or combinations outside of clinical trials and a subgroup of patients responds to these therapies. Because immunotherapy induces adverse effects in almost every patient, it is necessary to avoid treating patients who will not, in the end, benefit from the treatment. It is therefore sensible to carefully select patients prior to the initiation of immunotherapy. Determining prognostic factors of survival or of rapid progression under treatment would be of help for selecting patients for immunotherapy. This article reviews current data about prognostic and predictive factors from immunotherapy studies in metastatic renal cell carcinoma comparing all analyzed factors with those that demonstrated an independent prognostic significance in multivariate analyses.

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BJU Int. 2003 Oct;92(6):567-71.
Long-term results of nephron-sparing surgery for renal cell carcinoma in 114 patients: risk factors for progressive disease.
Zigeuner R, Quehenberger F, Pummer K, Petritsch P, Hubmer G.
Department of Urology, University Hospital of Graz, Karl-Franzens University Graz, Graz, Austria. richard.zigeuner@kfunigraz.ac.at

OBJECTIVES: To evaluate risk factors for metastatic disease after nephron-sparing surgery (NSS) for renal cell carcinoma (RCC). PATIENTS AND METHODS: NSS for RCC was used 117 times in 114 patients at our institution; 61 had a normal contralateral kidney and were selected for elective NSS, and in 56 cases (53 patients) the indication for NSS was imperative. Univariate and multiple regression analysis was used to evaluate the risk factors for metastatic disease. RESULTS: After a mean follow-up of 80 months, there was tumour progression in 17 of the 114 patients (15%). In the univariate analysis, the tumour diameter (P = 0.03) and imperative indication (P = 0.009), and in multiple regression analysis only imperative indication, were significant risk factors for metastatic disease (P = 0.016). CONCLUSIONS: Elective NSS for RCC provides excellent long-term results in selected patients, whereas those undergoing NSS imperatively are at a significantly higher risk of metastatic disease and require a close follow-up.

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Radiol Clin North Am. 2003 Sep;41(5):1053-65, vii.
Surgical management of renal tumors.
El-Galley R.
Department of Surgery, Division of Urology, University of Alabama at Birmingham, 1530 3rd Avenue South, MEB 602, Birmingham, AL 35294-3296, USA. rizk.el-galley@ccc.uab.edu

Renal cell carcinoma is a relatively rare tumor, accounting for approximately 3% of malignancies in adults, but is the most common tumor of the kidney and the third most common tumor seen by urologists. Renal cell carcinoma is refractory to most traditional oncologic treatments, including chemotherapy, radiation therapy, and hormonal therapy. Because of recent advances in sophisticated radiologic studies, the surgeon can now make an accurate preoperative assessment of the nature and extent of kidney tumors. When evaluating renal tumors, the urologist looks for certain information to help in constructing a management plan. This article explores some of the points that contribute in the surgical decision-making.

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Nippon Rinsho. 2003 Sep;61(9):1619-34.
[Allogeneic hematopoietic stem cell transplantation for solid tumors in the United States: a review]
[Article in Japanese]
Cheng YC, Ueno NT.
Departments of Blood and Marrow Transplantation, Breast Cancer Research Program, University of Texas M.D. Anderson Cancer Center, USA.

The field of bone marrow transplantation has undergone dramatic changes over the past few decades. Not only has the terminology changed (e.g., hematopoietic stem-cell transplantation), but the role of allogeneic transplantation has been modified from supportive to immunotherapeutic and the applications have expanded from hematologic malignancies to solid tumors. The development of nonmyeloablative conditioning regimen has greatly increased the number of patients eligible for this kind of treatment. Use of hematopoietic stem-cell transplantation as a form of adoptive immunotherapy in the treatment of cancer depends on advances in tumor immunology, particularly the identification of tumor antigens and mechanisms of immunotherapy. The earliest use of allogeneic transplantation of immunogenic cells for the treatment of solid tumors in the late 1960s and early 1970s produced no definite graft-versus-tumor effects. However, as conventional allogeneic hematopoietic stem-cell transplantation methods for the treatment of hematologic malignancies have matured, these methods have reestablished the foundation for expanding their application to solid tumors. From the first case reports on medulloblastoma and breast cancer to subsequent case series reports on breast cancer and renal cell carcinoma, allogeneic hematopoietic stem-cell transplants have demonstrated graft-versus-tumor effect. At present, the most common solid tumor for which this treatment is used is advanced renal cell carcinoma, but allogeneic hematopoietic stem-cell transplants have proven feasible for other solid tumors as well. Directions for future study include the identification of the definitive tumor antigens involved in the graft-versus-tumor effect and means of selecting those patients who will benefit the most from this form of treatment. This review summarizes the peer-reviewed literature on the use of allogeneic transplantation for solid tumors based on US studies.

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Tumori. 2003 Jul-Aug;89(4):400-4.
Long-term survival in patients with metastatic renal cell carcinoma treated with continuous intravenous infusion of recombinant interleukin-2: the experience of a single institution.
Libra M, Talamini R, Crivellari D, Buonadonna A, Freschi A, Stefanovski P, Berretta M, De Cicco M, Balestreri L, Merlo A, Volpe R, Galligioni E, Sorio R.
Division of Medical Oncology, Centro di Riferimento Oncologico, IRCCS, Aviano, PN, Italy.

AIM AND BACKGROUND: Metastatic renal cell carcinoma is one of the few tumors for which a clear benefit of immunotherapy has been demonstrated. The aim of this study was to evaluate the long-term survival of patients with metastatic renal cell carcinoma, along with response rate and other prognostic and predictive factors. PATIENTS AND METHODS: Between July 1989 and May 1995, 56 patients with metastatic renal cell carcinoma were treated in a single institution with high-dose recombinant interleukin-2 in continuous infusion. Survival was measured by the Kaplan and Meier method. Prognostic factors were assessed by univariate and multivariate analyses of survival (Cox proportional hazard ratio model). RESULTS: Of 56 patients, 15 had objective responses (26.8%), 16 stable disease (28.6%), 18 disease progressions (32.1%), and 7 (12.5%) were not valuable for response. Median overall survival was 20 months, and probability of 2- and 5-year survival was 41% and 21%, respectively. At multivariate analysis, the increased risk of death for: performance status > or = 2 vs 0 (HR = 6.20), stable disease (HR = 1.87), disease progression (HR = 10.61) vs partial or complete remission, and for hypotension and oliguria toxicity, G3 + G4 vs G1 + G2 (HR = 2.19). CONCLUSIONS: Our study confirms the activity of IL-2 based immunotherapy in renal cell carcinoma. Moreover, ECOG performance status, clinical response, hypotension and oliguria toxicity resulted as independent survival prognostic factors.

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Aktuel Urol. 2003 Jul;34(4):244-6.
Laparoscopic radical nephrectomy for renal cell carcinoma.
Kuriki O, Ono Y, Kinukawa T, Hattori R, Nishiyama N, Yamada S, Ohshima S.
Department of Urology, Okazaki City Hospital, Aichi Prefecture, Japan.

PURPOSE: To estimate the efficacy of the laparoscopic radical nephrectomy we analyzed the clinical data of our series. PATIENTS AND METHODS: One hundred eighty five patients were enrolled in our laparoscopic radical nephrectomy program between July, 1992 and July, 2001. Of the 185 patients, 146 had small renal tumors (smaller than 5 cm in diameter) and 39 had large tumors (equal to or more than, 5 cm in diameter). Under a laparoscope the kidney, adrenal gland, and perirenal fatty tissue were dissected in an en bloc fashion. In case of taking out a small tumor, the specimen was fractionated within the sack to avoid an additional skin incision after entrapping in the laparoscopy sack in the working space. In case of a large tumor, regional lymph nodes dissection was done and the specimen was taken out intact in the sack through an enlarged incision. RESULTS: Our laparoscopic procedure was successful in 171 of the 185 cases; 14 patients required open surgery because of bleeding from an injured vessels or treatment for other injured organs. The mean operative time was 4.7 hours for both small and large tumors. Estimated blood loss was between 237 and 380 ml on average for small and large tumors, respectively. Full convalescence was achieved around 3 weeks after operation in both groups. Only one patient who had large tumor was found to have micrometastasis in 1 of 5 regional lymph nodes. Recurrences were observed in 4 cases of the small tumor group and in 2 cases of the large tumor group during 1 to 108 months of follow-up. CONCLUSION: Laparoscopic radical nephrectomy is a very useful and safe surgical procedure for renal cell carcinoma.

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BJU Int. 2003 Aug;92(3):240-4.
The role of transarterial embolization in the treatment of renal cell carcinoma.
Munro NP, Woodhams S, Nawrocki JD, Fletcher MS, Thomas PJ.
Cancer Research UK, St James's University Hospital, Leeds, UK. n.munro@cancer.org.uk

OBJECTIVE: To review the role of transarterial renal embolization in our unit, assessing the indications, tolerability and efficacy of this technique for treating renal cell carcinoma (RCC). PATIENTS AND METHODS: Thirty patients undergoing transarterial embolization between 1991 and 1999 were identified and 25 case notes analysed retrospectively. RESULTS: Most patients (14 of 25) presented with less advanced (stage I-III) RCC who were unable or unwilling to undergo radical surgery; the remainder (11) presented with advanced (stage IV) disease. The embolizing agent was ethanol, usually combined with stainless steel coils (85% of cases). Procedural pain and fever was controlled successfully. The median hospital stay associated with the procedure was 4 days. At the time of analysis six of 11 stage IV and 11 of 14 stage I-III patients were alive (median follow-up 27 and 39 months, respectively). Symptoms from the primary tumour were well controlled. Overall, 17 of 25 (68%) of patients reported no problems while three (12%) required brief hospital admission for treatment of persistent haematuria. Fourteen patients were subsequently re-staged; the primary tumour in two had increased, in seven remained unchanged and in five it decreased. No patients without metastases developed them and metastases in two patients regressed. CONCLUSION: Transarterial embolization is associated with minimal morbidity and complications, and subsequent symptom control is good. The effect of palliative embolization on RCC progression is unknown and requires prospective investigation. Presently, there is no role for cytoreductive embolization; it should be included as a treatment option in clinical trials evaluating such options in patients with metastatic RCC.

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J Urol. 2003 Jul;170(1):64-8.
Comparative analysis of laparoscopic versus open partial nephrectomy for renal tumors in 200 patients.
Gill IS, Matin SF, Desai MM, Kaouk JH, Steinberg A, Mascha E, Thornton J, Sherief MH, Strzempkowski B, Novick AC.
Glickman Urological Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue A-100, Cleveland, OH 44195, USA.

PURPOSE: Laparoscopic partial nephrectomy is an emerging minimally invasive, nephron sparing approach for renal cell carcinoma. We compared perioperative outcomes after laparoscopic and open nephron sparing surgery (NSS) for patients with a solitary renal tumor of 7 cm or less at a single institution. MATERIALS AND METHODS: Since September 1999, 100 consecutive patients have undergone laparoscopic partial nephrectomy for a sporadic single renal tumor of 7 cm or less at our institution. A contemporary cohort of 100 consecutive patients with similar inclusion criteria have undergone open NSS since April 1998. Since our laparoscopic technique was based on our established open surgical principles, the 2 approaches were similar, including transient renal vascular control, sharp tumor excision in a bloodless field, pelvicaliceal repair when necessary, suture ligation of transected intrarenal blood vessels and suture repair of the renal parenchymal defect over a bolster. Demographic, intraoperative, postoperative and short-term followup data were retrospectively compared between the 2 groups. RESULTS: Median tumor size was 2.8 cm in the laparoscopic group and 3.3 cm in the open group (p = 0.005). There were significantly more tumors greater than 4 cm in the open group (p <0.001). There were more patients with a solitary kidney in the open surgical group (p = 0.002). More patients in the open group underwent NSS for a malignant tumor (p = 002). Comparing the laparoscopic versus open groups, median surgical time was 3 vs 3.9 hours (p <0.001), blood loss was 125 vs 250 ml (p <0.001) and mean warm ischemia time was 27.8 vs 17.5 minutes (p <0.001), respectively. In the laparoscopic and open groups median analgesic requirement was 20.2 vs 252.5 mg morphine sulfate equivalents (p <0.001), hospital stay was 2 vs 5 days (p <0.001) and average convalescence was 4 vs 6 weeks (p <0.001). Median preoperative serum creatinine (1.0 vs 1.0 mg/dl, p = 0.52) and postoperative serum creatinine (1.1 vs 1.2 mg/dl, p = 0.65) were similar in the 2 groups. No kidney was lost due to warm ischemic injury. Three patients in the laparoscopic group had a positive surgical margin compared to none in the open groups (3% vs 0%, p = 0.1). Laparoscopic NSS was associated with a higher rate of major intraoperative complications (5% vs 0%, p = 0.02). There were no significant differences in overall postoperative complications, although renal/urological complications were more common in the laparoscopic group (11% vs 2%, p = 0.01). CONCLUSIONS: Open surgical partial nephrectomy remains the established standard for nephron sparing treatment of renal tumors. When applied to small renal tumors, the laparoscopic approach is associated with longer warm renal ischemia time, more major intraoperative complications and more postoperative urological complications. Our data also suggest that more deliberate efforts to achieve a wider surgical margin are necessary with the laparoscopic approach. Nevertheless, our data suggest that laparoscopic NSS is emerging as an effective, minimally invasive therapeutic approach with respect to renal functional outcome with the additional advantages of decreased postoperative narcotic use, earlier hospital discharge and a more rapid convalescence. Continued efforts are required to develop laparoscopic renal hypothermia techniques and facilitate intrarenal suturing, while minimizing warm ischemia time.

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J Clin Oncol. 2003 Aug 15;21(16):3127-32.
Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer.
Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers-Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA.
Surgery Branch, Biostatistics and Data Management Section, Department of Pathology, National Cancer Institute/NIH, Room 2B-37, Building 10, 9000 Rockville Pike, Bethesda, MD 20892, USA. james_yang@nih.gov

PURPOSE: This three-arm randomized study compares response rates and overall survival of patients with metastatic renal cell cancer (RCC) receiving high-dose or one of two low-dose interleukin-2 (IL-2) regimens. PATIENTS AND METHODS: Patients with measurable metastatic RCC and a good performance status were randomized to receive either 720,000 U/kg (high-dose [HD]) or 72,000 U/kg (low-dose [LD]), both given by intravenous (IV) bolus every 8 hours. After randomly assigning 117 patients, a third arm of low-dose daily subcutaneous IL-2 was added, and an additional 283 patients were randomly assigned. RESULTS: A total of 156 patients were randomly assigned to HD IV IL-2, and 150 patients to LD IV IL-2. Toxicities were less frequent with LD IV IL-2 (especially hypotension), but there were no IL-2-related deaths in any arm. There was a higher response proportion with HD IV IL-2 (21%) versus LD IV IL-2 (13%; P =.048) but no overall survival difference. The response rate of subcutaneous IL-2 (10%, partial response and complete response) was similar to that of LD IV IL-2, differing from HD IV (P =.033). Response durability and survival in completely responding patients was superior with HD IV compared with LD IV therapy (P =.04). CONCLUSION: Major tumor regressions, as well as complete responses, were seen with all regimens tested. IL-2 was more clinically active at maximal doses, although this did not produce an overall survival benefit. The immunological factors which constrain the curative potential of IL-2 to only a small percentage of patients need to be further elucidated.

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N Engl J Med. 2003 Jul 31;349(5):427-34.
A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer.
Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA.
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md 20892, USA. james_yang@nih.gov

BACKGROUND: Mutations in the tumor-suppressor gene VHL cause oversecretion of vascular endothelial growth factor by clear-cell renal carcinomas. We conducted a clinical trial to evaluate bevacizumab, a neutralizing antibody against vascular endothelial growth factor, in patients with metastatic renal-cell carcinoma. METHODS: A randomized, double-blind, phase 2 trial was conducted comparing placebo with bevacizumab at doses of 3 and 10 mg per kilogram of body weight, given every two weeks; the time to progression of disease and the response rate were primary end points. Crossover from placebo to antibody treatment was allowed, and survival was a secondary end point. RESULTS: Minimal toxic effects were seen, with hypertension and asymptomatic proteinuria predominating. The trial was stopped after the interim analysis met the criteria for early stopping. With 116 patients randomly assigned to treatment groups (40 to placebo, 37 to low-dose antibody, and 39 to high-dose antibody), there was a significant prolongation of the time to progression of disease in the high-dose--antibody group as compared with the placebo group (hazard ratio, 2.55; P<0.001). There was a small difference, of borderline significance, between the time to progression of disease in the low-dose--antibody group and that in the placebo group (hazard ratio, 1.26; P=0.053). The probability of being progression-free for patients given high-dose antibody, low-dose--antibody, and placebo was 64 percent, 39 percent, and 20 percent, respectively, at four months and 30 percent, 14 percent, and 5 percent at eight months. At the last analysis, there were no significant differences in overall survival between groups (P>0.20 for all comparisons). CONCLUSIONS: Bevacizumab can significantly prolong the time to progression of disease in patients with metastatic renal-cell cancer. Copyright 2003 Massachusetts Medical Society

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J Urol. 2003 Aug;170(2 Pt 1):408-11.
Laparoscopic radical versus partial nephrectomy: assessment of complications.
Kim FJ, Rha KH, Hernandez F, Jarrett TW, Pinto PA, Kavoussi LR.
Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-2101, USA.

PURPOSE: We evaluated the short-term morbidity and complications of laparoscopic radical nephrectomy (LRN) compared with laparoscopic partial nephrectomy (LPN). MATERIALS AND METHODS: From May 1998 to May 2002, 114 patients were identified with a single unilateral sporadic renal tumor and a normal contralateral kidney. These individuals had undergone LRN (35) or LPN (79). RESULTS: The LRN and LPN groups were analyzed for age, sex, American Society of Anesthesiologists score and body mass index. Mean tumor size in patients undergoing LRN and LPN was 2.8 +/- 1.2 (range 0.9 to 4.5) and 2.5 +/- 1.0 cm (range 1 to 4.5), respectively (p = 0.17). There were no differences between the 2 groups in terms of mean hospital stay, blood transfusion or surgical complications. There was no difference in mean preoperative and postoperative serum creatinine in patients in the LPN group. Mean postoperative serum creatinine was significantly higher than the mean preoperative level in patients in the LRN group (1.51 +/- 0.22 vs 1.18 +/- 0.37 mg/ml, range 0.6 to 2.4, p = 0.02). In each group 1 case was converted to open surgery due to bleeding. CONCLUSIONS: LPN is associated with similar postoperative convalescence and complications compared with LRN. The increase in serum creatinine noted in patients undergoing radical extirpation supports the use of LPN when clinically indicated.

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Br J Cancer. 2003 Jul 7;89(1):50-4.
Rapid deterioration in quality of life during interleukin-2- and alpha-interferon-based home therapy of renal cell carcinoma is associated with a good outcome.
Atzpodien J, Kuchler T, Wandert T, Reitz M.
Fachklinik Hornheide der Universitat Munster, Dorbaumstr. 300, 48157 Munster, Germany. SekrProfAtzpodien@yahoo.de

We conducted a prospective quality-of-life analysis during outpatient immunotherapy in 22 patients with progressive metastatic renal cell carcinoma (RCC) treated with subcutaneous interferon-alpha2a and subcutaneous interleukin-2. Patients' quality of life was assessed by the European Organization for Research and Treatment of Cancer quality-of-life questionnaire QLQ-C30 before (week 0) and once during immunotherapy (week 3). Advanced renal cancer patients completed a total of 30 questionnaires before therapy (week 0) and after 3 weeks of therapy. Their mean quality of life (global-quality-of-health status) deteriorated significantly, from 64 to 41 (P</=0.001) during the first 3 weeks after treatment initiation, due to a mean reduction in physical (from 82 to 65; P</=0.001), emotional (from 77 to 61; P</=0.01), social (from 78 to 55; P</=0.01), and role functioning (from 82 to 58; P</=0.01). In contrast, cognitive functioning did not differ significantly from pretreatment scores after 3 weeks of therapy. In addition, during the first 3 weeks, appetite loss (from 18 to 59; P</=0.01), fatigue (from 33 to 56; P</=0.01), nausea/vomiting (from 10 to 26; P</=0.01), sleep disturbance (from 27 to 47; P</=0.01), diarrhoea (from five to 27; P</=0.01), and pain (from 20 to 32; P</=0.05) were significantly increased, while quality-of-life symptoms such as dyspnoea, and constipation were not significantly influenced by therapy. Complete response to RCC outpatient immunotherapy was associated with the most predominant reduction in functional quality of life when compared against patients in progressive or stable disease or partial tumour response. In conclusion, quality-of-life analysis during outpatient immunotherapy yielded modest changes in patients' health status 3 weeks after therapy initiation. Since the rapid decline in functional quality-of-life was associated with therapeutic efficacy, it is suggested that quality-of-life analysis might serve as an early indicator for immunotherapy response in metastatic RCC.British Journal of Cancer (2003) 89, 50-54. doi:10.1038/sj.bjc.6600996 www.bjcancer.com

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J Clin Oncol. 2003 Jul 1;21(13):2564-73.
Phase I trial of concurrent twice-weekly recombinant human interleukin-12 plus low-dose IL-2 in patients with melanoma or renal cell carcinoma.
Gollob JA, Veenstra KG, Parker RA, Mier JW, McDermott DF, Clancy D, Tutin L, Koon H, Atkins MB.
Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. gollo001@mc.duke.edu

PURPOSE: To maintain interferon gamma (IFNgamma) induction by recombinant human interleukin-12 (rhIL-12) and enhance its activity against melanoma and renal cell cancer, a regimen of twice-weekly intravenous (IV) rhIL-12 was modified to include concurrent low-dose subcutaneous (SC) IL-2 in a phase I dose escalation study. PATIENTS AND METHODS: Patients received 6-week cycles of twice-weekly IV rhIL-12 at doses of 300 to 500 ng/kg. Midway through cycle 1, low-dose SC IL-2 was added. The IL-2 was escalated from 0.5 to 6.0 MU/m2. Grade 3 elevations of hepatic ALT, AST, or alkaline phosphatase were not considered dose-limiting unless values were more than 10 times normal. During cycle 1, patients underwent immune monitoring to assess the effect of IL-2 on lymphocyte activation and cytokine production induced by rhIL-12. RESULTS: Twenty-eight patients were enrolled onto the study. The maximum-tolerated dose (MTD) was 500 ng/kg rhIL-12 plus 3 MU/m2 IL-2. Toxicities related to the addition of IL-2 at the MTD included fever or chills, anemia, fatigue, nausea or vomiting, and orthostatic hypotension. At the MTD, IL-2 significantly augmented IFNgamma and IFNgamma-inducible protein-10 production by rhIL-12 and led to a three-fold expansion of natural killer cells. There was one major clinical response (partial response) as well as two pathologic responses; all occurred in melanoma patients. Stable disease for three to six cycles was only observed at or above the MTD in melanoma and renal cell cancer patients. CONCLUSION: The addition of concurrent low-dose IL-2 to rhIL-12 is well tolerated, restores and maintains immune activation by rhIL-12, and has clinical activity. This regimen should be further investigated in phase II studies in untreated patients with melanoma or renal cell cancer and in other rhIL-12-responsive malignancies.

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J Clin Oncol. 2003 Aug 15;21(16):3133-40. Epub 2003 Jun 16.
Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine working group randomized trial.
Clark JI, Atkins MB, Urba WJ, Creech S, Figlin RA, Dutcher JP, Flaherty L, Sosman JA, Logan TF, White R, Weiss GR, Redman BG, Tretter CP, McDermott D, Smith JW, Gordon MS, Margolin KA.
Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA. jclark@lumc.edu

PURPOSE: This prospective, randomized, controlled phase III trial assessed high-dose bolus interleukin-2 (IL-2) postoperatively in patients with high-risk renal cell carcinoma (RCC). PATIENTS AND METHODS: Eligibility requirements were resected locally advanced (LA; T3b-4 or N1-3) or metastatic (M1) RCC, no prior systemic therapy, and excellent organ function. Randomized assignment was to one course of IL-2 (600,000 U/kg every 8 hours on days 1 to 5 and days 15 to 19 [maximum 28 doses]) or observation. The study was designed and powered to show an improvement in predicted 2-year disease-free survival (DFS) from 40% for the observation group to 70% for the treatment group. The accrual goal was 68 patients with LA disease, with 34 patients per treatment arm. Metastasectomy patients were to be analyzed separately because of their unpredictable natural history. RESULTS: Sixty-nine patients were enrolled onto the study (44 LA and 25 M1 patients). Toxic effects of IL-2 were as anticipated; no unexpected serious adverse events or treatment-related deaths occurred. Early closure occurred when an interim analysis determined that the 30% improvement in 2-year DFS could not be achieved despite full accrual. Sixteen of 21 LA patients receiving IL-2 experienced relapse, compared with 15 of 23 patients in the observation arm (P =.73); in the LA group, three deaths occurred in the IL-2 arm, and five deaths occurred in the observation arm (P =.38). Analysis including metastasectomy patients made no difference in DFS or overall survival. CONCLUSION: One course of high-dose bolus IL-2, though feasible, did not produce the ambitious clinically meaningful benefit anticipated when administered postoperatively to patients with resected high-risk RCC.

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Cancer. 2003 Jun 15;97(12):2995-3002.
Renal cell carcinoma with retroperitoneal lymph nodes. Impact on survival and benefits of immunotherapy.
Pantuck AJ, Zisman A, Dorey F, Chao DH, Han KR, Said J, Gitlitz B, Belldegrun AS, Figlin RA.
Department of Urology, University of California School of Medicine, Los Angeles, California 90095-1738, USA.

BACKGROUND: The current study was performed to determine the impact of the presence of retroperitoneal lymphadenopathy on the survival and response to immunotherapy of patients with metastatic renal cell carcinoma (RCC). METHODS: A retrospective cohort study was performed with outcome assessment based on the chart review of demographic, clinical, and pathologic data from 1087 patients. Patients with RCC who did not present with metastatic disease, who did not undergo nephrectomy as part of their cancer treatment, and those in whom either the lymph node (N) or metastatic (M) status was unknown, were excluded. A total of 322 M1 patients who met these criteria and who underwent nephrectomy for unilateral RCC formed the principal study population. RESULTS: Two hundred thirty-six patients presented with N0M1 disease and 86 patients presented with N+M1 disease. In M1 patients, the presence of positive regional lymph nodes was associated with larger sized, higher grade, locally advanced primary tumors that were more commonly associated with sarcomatoid features. N0M1 patients were more likely to achieve an objective response to systemic immunotherapy compared with N+M1 patients (P = 0.01). N+M1 patients overall had worse short-term and long-term survival compared with N0M1 patients, with a median survival of 10.5 months compared with 20.4 months, respectively. The median survival of N0M1 patients was improved to 28 months in those who received adjunctive immunotherapy (P = 0.0008), whereas the median survival of patients with N+M1 disease was the same in those treated with and those treated without adjunctive immunotherapy (P = 0.18). CONCLUSIONS: Even in the modern era of systemic immunotherapy, the presence of regional lymphadenopathy exerts a detrimental effect on the survival of patients with metastatic RCC. Lymph node status is a strong predictor of the failure to achieve either an objective immunotherapy response or an improvement in survival when immunotherapy is given as an adjunctive treatment after cytoreductive nephrectomy. However, in multivariate analysis, including both clinical and pathologic variables, lymph node status was found to have less of an impact on survival than primary tumor stage and grade and patient performance status. Copyright 2003 American Cancer Society.

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Technol Cancer Res Treat. 2003 Jun;2(3):205-10.
The timing of immunotherapy and nephrectomy in multimodality treatment of metastatic
renal cell carcinoma.
Bex A, Horenblas S, de Gast GC.
Division of Surgical Oncology, Urology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. a.bex@nki.nl

Multimodality treatment of metastatic renal cell carcinoma with immunotherapy and cytoreductive surgery is controversial. Especially the benefit of removing asymptomatic primary tumors in synchronous metastatic renal cell cancer has been debated since several non-randomized, retrospective studies revealed an improved response to immunotherapy and prolonged survival following initial nephrectomy. Two recent randomized prospective trials both demonstrated a prolonged survival in those who were randomly assigned to undergo nephrectomy of the primary tumor prior to treatment with interferon alfa-2b than in those who were assigned to undergo treatment with interferon alfa-2b alone. In these trials the survival benefit was limited and strongly influenced by overall performance score. The timing of immunotherapy, either as neoadjuvant (prior to nephrectomy) or adjuvant treatment (following nephrectomy) in the multimodality approach of synchronous metastatic renal cell carcinoma remains controversial. Selection of patients, the possible mechanisms underlying the survival advantage of the combination of nephrectomy and immunotherapy, and the timing of the treatment modalities are discussed herein.

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Br J Cancer. 2003 May 6;88(9):1346-51.
Immunotherapy with concurrent subcutaneous GM-CSF, low-dose IL-2 and IFN-alpha in patients with progressive metastatic renal cell carcinoma.
Verra N, Jansen R, Groenewegen G, Mallo H, Kersten MJ, Bex A, Vyth-Dreese FA, Sein J, van de Kasteele W, Nooijen WJ, de Waal M, Horenblas S, de Gast GC.
Division of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

The purpose of the study was to determine toxicity, efficacy and immunologic effects of concurrent subcutaneous injections of low-dose interleukin-2 (LD-IL-2), granulocyte-monocyte colony-stimulating factor (GM-CSF) and interferon-alpha 2b (IFNalpha) in progressive metastatic renal cell carcinoma. In a multicentre phase II study, 59 evaluable patients received two to six cycles of subcutaneous IL-2 (4 mIU m(-2)), GM-CSF (2.5 microg kg(-1)) and IFNalpha (5 mIU flat(-1)) for 12 days per 3 weeks with evaluation after every two cycles. Cycles were repeated in responding or stable patients. Data were analysed after a median of 30 months follow-up (range 16-48 months). In 42 patients, the immunologic response was studied and related to response and survival. The main toxicity were flu-like symptoms, malaise and transient liver enzyme elevations, necessitating IL-2 reduction to 2 mIU m(-2) in 29 patients, which should be considered the maximal tolerable dose. The response was 24% (eight out of 34, three complete response (CR), five partial response (PR)) in patients with metachronic metastases and 12% (three out of 25, 2CR, 1PR) in patients with synchronic metastases. Overall response was 19% (11 out of 59). Median survival was 9.5 months. All tested patients showed expansion and/or activation of lymphocytes, T cells and subsets, NK cells, eosinophils and monocytes. Pretreatment HLA-DR levels on monocytes and number of CD4(+)HLA-DR(+) cells correlated with response. Pretreatment number of CD4(+)HLA-DR(+) cells and postimmunotherapy levels of lymphocytes, CD3(+), CD4(+) and CD8(+) T cells, but not of NK or B cells, correlated with prolonged survival. Immunotherapy with concurrent subcutaneous GM-CSF, LD-IL-2 and IFNalpha has limited toxicity, can be given as outpatient treatment and can induce durable CR. Response and survival with this form of immunotherapy seem to be more dependent on expansion/activation of T cells than of NK cells.

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Curr Opin Oncol. 2003 May;15(3):213-6.
Renal cell carcinoma.
Whang YE, Godley PA.
Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7305, USA.

Renal cell carcinoma (RCC) continues to present a diagnostic and therapeutic challenge. The increased use of abdominal imaging studies does not appear to completely account for the rising incidence of RCC. Alcohol consumption has been found to be a possible protective factor among women in a recent study, but among women with children, RCC risk may increase with each child born when compared with nulliparous women. An alternative staging system shows promise, and two randomized clinical trials clarify the role of removing the primary tumor in the setting of metastatic RCC. New agents have shown promise in early clinical trials such as CCI-779, pegylated interferon, thalidomide, and anti-VEGF antibody.

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Br J Cancer. 2003 May 19;88(10):1516-21.
IPM chemotherapy in cytokine refractory renal cell cancer.
Shamash J, Steele JP, Wilson P, Nystrom M, Ansell W, Oliver RT.
Department of Medical Oncology, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK. jonathan@jshamash.demon.co.uk

Renal cell carcinoma (RCC) is notoriously chemoresistant. Current management of metastatic disease usually includes immunological agents of which the most clearly evaluated is alpha interferon. Following the failure of such agents no clear second-line therapy exists. The use of a novel combination of cisplatin, irinotecan and mitomycin may offer some palliative benefit in this situation. Thirty-three patients with cytokine refractory RCC and documented progression and documented active progressive disease with performance status 0-3 were enrolled. Therapy consisted of cisplatin 40 mg m(-2) on day 1 and day 15, irinotecan 100 mg m(-2) on day 1 and day 15, and mitomycin 6 mg m(-2) on day 1 of a 28-day cycle. The results showed that one patient (3%) had a partial response, eight (24%) had minor responses and nine (27%) had stable disease, overall 61% had symptomatic responses. Quality-of-life (QOL) assessment did not change significantly during therapy. Seventy-one percent of those who had primary refractory disease to cytokine therapy subsequently responded to IPM. The median progression-free interval was 4.8 months in this cohort on chemotherapy, compared to 3.9 months with their previous cytokine treatment. In conclusion, IPM produced symptomatic relief for a majority of patients with cytokine refractory RCC without any deterioration in QOL. Disease stabilisation on radiological assessment and symptomatic improvement were associated with prolonged survival. A degree of non-crossresistance to cytokine therapy was seen. IPM may be considered in patients with renal cancer following failure of cytokines.

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J Urol. 2003 Jun;169(6):2076-83.
Renal cell carcinoma with retroperitoneal lymph nodes: role of lymph node dissection.
Pantuck AJ, Zisman A, Dorey F, Chao DH, Han KR, Said J, Gitlitz BJ, Figlin RA, Belldegrun AS.
Department of Urology, University of California School of Medicine, Los Angeles, California, USA.

PURPOSE: We better defined the benefits and morbidity of lymph node dissection in patients with localized renal cell carcinoma using the experience of patients treated at our institution. MATERIALS AND METHODS: A retrospective cohort study was performed with outcome assessment based on the chart review of demographic, clinical and pathological data in 1,087 patients with renal cell carcinoma treated at our institution. Patients with renal cell carcinoma who did not undergo nephrectomy as part of cancer treatment, those with bilateral disease and those for whom nodal status was unknown were not included in this study. A total of 900 patients meeting these criteria who underwent nephrectomy for unilateral renal cell carcinoma at our medical center form the principal study population. RESULTS: Positive lymph nodes were associated with larger, higher grade, locally advanced primary tumors that were more commonly associated with sarcomatoid features. Positive nodes were 3 to 4 times more common in patients with metastatic disease and the majority of these patients could be identified preoperatively. The survival of patients with regional lymph node involvement only was identical to that of patients with distant metastatic disease only. Patients with regional nodes and distant metastases had significantly inferior survival to those with either condition alone. In node negative cases lymph node dissection can be performed with no additional morbidity but it confers no survival advantage. In node positive cases lymph node dissection can also be performed safely but it is associated with improved survival and a trend toward an improved response to immunotherapy. CONCLUSIONS: Regional lymph node dissection is unnecessary in patients with clinically negative lymph nodes since it offers extremely limited staging information and no benefit in terms of decreasing disease recurrence or improving survival. In patients with positive lymph nodes lymph node dissection is associated with improved survival when it is performed in carefully selected patients undergoing cytoreductive nephrectomy and postoperative immunotherapy. When lymph nodes are present, they should be resected when technically feasible.

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Anticancer Res. 2003 Mar-Apr;23(2A):969-74.
Adjuvant therapy of renal cell carcinoma patients with an autologous tumor cell lysate vaccine: a 5-year follow-up analysis.
Repmann R, Goldschmidt AJ, Richter A.
Department of Urology, St. Georg Hospital Leipzig, Delitzscher Str. 141, 04129 Leipzig, Germany. repi@surfEU.de

BACKGROUND: Non-metastasized renal cell carcinoma (RCC) is associated with postoperative progression in 1 out of 3 patients. However, no adjuvant therapy after radical nephrectomy has been established. We investigated the impact of an adjuvant autologous tumor cell lysate vaccination on the 5-year survival rates of patients with non-metastasized RCC. PATIENTS AND METHODS: Between 1990 and 1995, a total of 360 patients with RCC underwent a radical nephrectomy at the St. Georg Hospital Leipzig, Germany. There were 236 patients with RCC stages T2N0M0 or T3N0M0. Out of this group, 148 consecutive patients received an adjuvant autologous tumor cell lysate vaccine (vaccine group, 72 patients with T2N0M0 and 76 patients with T3N0M0), while the remaining 88 patients had no adjuvant therapy (control group, 52 patients with T2N0M0 and 36 patients with T3N0M0). Both groups were comparable for parameters such as age, sex, tumor localization and size, and Storkel-score (p > 0.05 for each parameter; Chi-Square test and Wilcoxon-Mann-Whitney test). RESULTS: For RCC stage T2N0M0, the 5-year progression-free survival rate in the control group was 65.3% compared to 84.6% in the vaccine group (p = 0.0023, log-rank test). The 5-year overall survival was 71.4% in the control group compared to 86% in the vaccine group (p = 0.0059, log-rank test). Patients with RCC stage T3N0M0 in the vaccine group demonstrated a clear advantage in terms of 5-year overall survival (77.5% vs. 25% in the control group, p < 0.0001, log-rank test) and 5-year progression-free survival (68.2% in the vaccine group vs. 19.4% in the control group, p < 0.0001, log-rank test). CONCLUSION: Adjuvant autologous tumor cell lysate vaccination may improve the outcome of patients with non-metastasized RCC after radical nephrectomy. A prospective randomized and multicenter phase III trial was started in 1997 to confirm these results.

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AJR Am J Roentgenol. 2003 Jun;180(6):1509-13.
Imaging-guided radiofrequency ablation of solid renal tumors.
Farrell MA, Charboneau WJ, DiMarco DS, Chow GK, Zincke H, Callstrom MR, Lewis BD, Lee RA, Reading CC.
Department of Radiology, Mayo Clinic, 200 First St., Rochester, MN 55902, USA.

OBJECTIVE: We performed a retrospective review of imaging-guided radiofrequency ablation of solid renal tumors. MATERIALS AND METHODS: Since May 2000, 35 tumors in 20 patients have been treated with radiofrequency ablation. The size range of treated tumors was 0.9-3.6 cm (mean, 1.7 cm). Reasons for patient referrals were a prior partial or total nephrectomy (nine patients), a comorbidity excluding nephrectomy or partial nephrectomy (10 patients), or a treatment alterative to nephron-sparing surgery (one patient who refused surgery). Tumors were classified as exophytic, intraparenchymal, or central. Sixteen patients had 31 lesions that showed serial growth on CT or MR imaging. Of these 16 patients, four patients with 10 lesions had a history of renal cell carcinoma, and two patients with 11 lesions had a history of von Hippel-Lindau disease. Four patients had incidental solid masses, two of which were biopsied and shown to represent renal cell carcinoma, and the remaining two masses were presumed malignant on the basis of imaging features. Successful ablation was regarded as any lesion showing less than 10 H of contrast enhancement on CT or no qualitative evidence of enhancement after IV gadolinium contrast-enhanced MR imaging. RESULTS: Of the 35 tumors, 22 were exophytic and 13 were intraparenchymal. Twenty-seven of the 35 were treated percutaneously using either sonography (n = 22) or CT (n = 5). Two patients had eight tumors treated intraoperatively using sonography. Patients were followed up with contrast-enhanced CT (n = 18), MR imaging (n = 5), or both (n = 5) with a follow-up range of 1-23 months (mean, 9 months). No residual or recurrent tumor and no major side effects were seen. CONCLUSION: Preliminary results with radiofrequency ablation of exophytic and intraparenchymal renal tumors are promising. Radiofrequency ablation is not associated with significant side effects. Further follow-up is necessary to determine the long-term efficacy of radiofrequency ablation.

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AJR Am J Roentgenol. 2003 Jun;180(6):1503-8.
Imaging-guided percutaneous radiofrequency ablation of solid renal masses: techniques and outcomes of 38 treatment sessions in 32 consecutive patients.
Mayo-Smith WW, Dupuy DE, Parikh PM, Pezzullo JA, Cronan JJ.
Department of Diagnostic Imaging, Rhode Island Hospital, Brown Medical School, 593 Eddy St., Providence 02903, USA.

OBJECTIVE: The purpose of this study was to describe the treatment techniques and results of 38 consecutive imaging-guided percutaneous radiofrequency ablations of solid renal masses performed in 32 patients. MATERIALS AND METHODS: Solid renal masses in 32 patients underwent 38 treatment sessions using imaging-guided percutaneous radiofrequency ablation. During 36 sessions, radiofrequency ablation was performed using CT guidance, and two, using sonographic guidance. The average patient age was 76 years (range, 52-87 years), and the average renal mass size was 2.6 cm (range, 1-5 cm). The average number of radiofrequency treatments per solid mass at each session was 2.4 (range, 1-6 treatments), and the average time per treatment was 9.2 min (range, 3-14 min). A single electrode was used in 12 sessions, and a cluster electrode was used in 26 sessions. The average follow-up time was 9 months (range, 1-36 months). RESULTS: Twenty-six of 32 patients had successful treatment of the solid renal mass using percutaneous imaging-guided radiofrequency ablation after one treatment session. Successful treatment was defined as lack of enhancement of the treated region on follow-up CT. Six of 32 patients had residual enhancing tissue after the first treatment session and returned for a second session. Five of these six retreatments were successful. Masses requiring a second treatment session were significantly larger than masses treated in a single session (3.5 vs 2.4 cm, respectively; p = 0.0013). Two patients had perinephric hematomas (which did not require transfusion), and one patient developed a 5-mm skin metastasis at the electrode insertion site, which was resected without recurrence. CONCLUSION: Percutaneous imaging-guided radiofrequency ablation shows promise in the treatment of solid renal malignancies.

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BJU Int. 2003 May;91(7):600-2.
Outcome and survival with nonsurgical management of renal cell carcinoma.
Baird AD, Woolfenden KA, Desmond AD, Fordham MV, Parsons KF.
Department of Urology, Royal Liverpool University Hospital, Liverpool, UK. andy.baird@breathemail.net

OBJECTIVE: To document long-term survival in patients with renal cell carcinoma (RCC) in whom the primary tumour was left in situ and treatment limited to palliative and symptomatic measures. PATIENTS AND METHODS: All patients with a diagnosis of RCC from January 1994 to January 1999 and in whom the primary tumour was left in situ were identified from hospital records (nine women and 16 men, mean age 69 years). The tumour stage was T1-T4. RESULTS: The mean survival overall was 19.3 months; patients with locally advanced disease, i.e. stage >or= T3a, had a mean survival of 16.9 months. CONCLUSIONS: There is renewed interest in the management of advanced RCC, with data supporting cytoreductive nephrectomy with systemic biological therapy. These results confirm that such patients with or without metastatic disease can survive for a considerable period with no aggressive surgical or systemic measures, and such intervention may offer no significant advantage in outcome and survival over supportive treatment alone.

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J Clin Oncol. 2003 Apr 15;21(8):1524-9.
Phase II study of troxacitabine (BCH-4556) in patients with advanced and/or metastatic renal cell carcinoma: a trial of the National Cancer Institute of Canada-Clinical Trials Group.
Townsley CA, Chi K, Ernst DS, Belanger K, Tannock I, Bjarnason GA, Stewart D, Goel R, Ruether JD, Siu LL, Jolivet J, McIntosh L, Seymour L, Moore MJ; National Cancer Institute of Canada-Clinical Trials Group.
Department of Medical Oncology, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, M5G 2M9 Canada. malcolm.moore@uhn.on.ca

PURPOSE: A multi-institution phase II study was undertaken by National Cancer Institute of Canada-Clinical Trials Group to evaluate the efficacy and toxicity of intravenous troxacitabine (Troxatyl; Shire Pharmaceuticals Plc, Laval, Quebec, Canada), in patients with renal cell carcinoma. PATIENTS AND METHODS: Between June 1999 and March 2000, 35 patients (24 male) with a mean age of 60 years who had advanced and/or metastatic disease were treated with troxacitabine given as an intravenous infusion over 30 minutes at a dose of 10 mg/m2 intravenously, once every 3 weeks. RESULTS: Of the 33 of 35 patients evaluable for response, there were two confirmed partial responses, 21 patients had stable disease (median duration, 4.4 months), and 10 patients had progressive disease. Eight patients remained stable for more than 6 months, of whom six remain free of progression. The most common drug-related nonhematologic toxicities observed were skin rash (77.1%), hand-foot syndrome (68.6%), alopecia (51.4%), fatigue (51.4%), and nausea (57.1%). Out of a total of 145 cycles of treatment, 98 were given without steroid premedication, whereas 47 cycles were given with steroid premedication. Without premedication, skin rash occurred in 37% of cycles compared with 26% when steroids were given prophylactically. CONCLUSION: Troxacitabine given at a dose of 10 mg/m2 once every 3 weeks was well tolerated in patients with metastatic renal cell cancer, with common toxicities being a moderate to severe granulocytopenia and skin rash. Steroid premedication may reduce the frequency and severity of the skin rash. Our current study suggests that the nucleoside analog troxacitabine may have modest activity against renal cell carcinoma; however, larger studies are required to confirm this.

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Curr Opin Urol. 2003 May;13(3):203-8.
Laparoscopic wedge resection for renal cell carcinoma.
Janetschek G, Abdelmaksoud AA.
Urology Department, Elisabethinen Hospital, Linz, Austria. guenter.janetschek@elisabethinen.or.at

PURPOSE OF REVIEW: Because an increasing number of small renal cell tumors suitable for nephron sparing surgery are being diagnosed incidentally, the standardization of laparoscopic wedge resection has now become a major issue. RECENT FINDINGS: In this article we reviewed mainly recent literature published since November 2001 focusing our interest to clearly present the different techniques for wedge resection. These techniques are shown under two main subtitles: resection with or without ischemia. Also new alternative techniques for resection without ischemia are reviewed. SUMMARY: Wedge resection can be done laparoscopically by different techniques. Each technique has its inherent advantages and disadvantages. Further studies and modifications on each technique are expected in the future.

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Curr Opin Urol. 2003 May;13(3):193-7.
Renal cryotherapy: 2003 clinical status.
Lowry PS, Nakada SY.
The University of Wisconsin Medical School, USA.

PURPOSE OF REVIEW: Traditionally, curative therapy for most renal cancers involved open radical nephrectomy. However, as increased radiological monitoring has led to more incidentally discovered small renal masses, the optimal treatment has evolved. Nephron-sparing surgery, initially developed for patients with solitary kidneys or compromised renal function, emerged as the treatment of choice for small renal masses. It has been shown that long-term cancer control and renal function after partial nephrectomy equals the results of radical nephrectomy. Cryoablation of small renal masses represents an alternative method for performing nephron-sparing surgery. RECENT FINDINGS: Cryoablation of renal tumors with ultrasound monitoring may be performed under open exposure, but laparoscopy provides equivalent exposure with less morbidity. Cryotherapy may also be performed percutaneously with magnetic resonance image monitoring. After treatment, patients require diligent radiographic monitoring, more frequently than after surgical extirpation. SUMMARY: The durability of renal cryotherapy appears promising. More data are required to provide reliable treatment of tumor margins for larger lesions, and further to determine the safety of use near the collecting system and renal hilum. Currently, cryoablation of small renal lesions is minimally invasive, safe, and efficacious for select peripheral lesions in carefully selected patients.

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Curr Oncol Rep. 2003 May;5(3):239-44.
The evolving role of partial nephrectomy in the management of renal cell carcinoma.
Gilbert SM, Russo P, Benson MC, Olsson CA, McKiernan JM.
Department of Urology, Columbia-Presbyterian Medical Center, 161 Fort Washington Avenue, Atchley Pavilion, 11th floor, New York, NY 10032, USA.

The surgical management of renal cell carcinoma has undergone critical review over the past decade. Initially treated with radical nephrectomy, renal cell carcinoma is now approached with nephron-sparing surgical techniques. Improved imaging modalities have substantially increased the number of incidental renal tumors detected, and with the increasing number of incidentally detected kidney tumors, a size and stage migration has occurred in renal cell carcinoma. Early studies showed that disease-free survival rates were similar between cancers treated with radical and partial nephrectomy. The standard now is to offer partial nephrectomy as a surgical option to all patients with renal lesions measuring 4.0 cm or smaller in the setting of a normal contralateral kidney. More recent issues regarding partial nephrectomy concern complication rates and management, renal cell carcinoma multifocality, margin status and distance to normal renal parenchyma, cost analysis, and the development of laparoscopic techniques that duplicate open partial nephrectomy. The purpose of this review is to outline and analyze these more recent concerns regarding partial nephrectomy.

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J Clin Oncol. 2003 Apr 1;21(7):1214-22.
Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: an Eastern Cooperative Oncology Group/Intergroup trial.
Messing EM, Manola J, Wilding G, Propert K, Fleischmann J, Crawford ED, Pontes JE, Hahn R, Trump D; Eastern Cooperative Oncology Group/Intergroup trial.
University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. edward_messing@urmc.rochester.edu

PURPOSE: To evaluate the role of adjuvant interferon alfa after complete resection of locally extensive renal cell carcinoma. PATIENTS AND METHODS: A total of 283 eligible patients with pT3-4a and/or node-positive disease were randomly assigned after radical nephrectomy and lymphadenectomy to observation or to interferon alfa-NL (Wellferon, Burroughs-Wellcome, Research Park, NC) given daily for 5 days every 3 weeks for up to 12 cycles. Patients were stratified on the basis of pathologic stage. Patients remained on treatment until documented recurrence, excessive toxicity, or patient/physician preference deemed removal appropriate. RESULTS: At median follow-up of 10.4 years, median survival was 7.4 years in the observation arm and 5.1 year in the treatment arm (log-rank P =.09). Median recurrence-free survival was 3.0 years in the observation arm and 2.2 years in the interferon arm (P =.33). Performance status (P =.003), nodal status (N2 v N0, P <.0001), and tumor stage (P =.0002) were significant prognostic factors in multivariate analysis. A proportional hazards model examining the effects of treatment arm and time to recurrence on survival after recurrence among patients who recurred found that random assignment to interferon treatment (P =.009) and shorter time to recurrence (P <.0001) were independent predictors of shorter survival after recurrence. Although no lethal toxicities were observed, severe (grade 4) toxicities including neutropenia, myalgia, fatigue, depression, and other neurologic toxicities occurred in 11.4% of those randomly assigned to interferon treatment. CONCLUSION: Adjuvant treatment with interferon did not contribute to survival or relapse-free survival in this group of patients.

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AJR Am J Roentgenol. 2003 Apr;180(4):1055-61.
Early experience with percutaneous radiofrequency ablation of small solid renal masses.
Roy-Choudhury SH, Cast JE, Cooksey G, Puri S, Breen DJ.
Department of Radiology, Hull and East Yorkshire Hospitals NHS Trust, Anlaby Rd., Kingston Upon Hull, HU3 2JZ, United Kingdom.

OBJECTIVE: Incidental small renal-cell masses are often seen in elderly patients with significant comorbidity who are unfit to undergo major surgery. This study was conducted to determine the safety and efficacy of percutaneous imaging-guided radiofrequency ablation in the management of small solid renal masses, almost all of which are renal cell cancers. CONCLUSION: Early experience suggests that radiofrequency ablation is a safe, well-tolerated, and minimally invasive therapy for patients with solid renal masses. In the era of nephron-sparing surgery, radiofrequency ablation may have a role in the management of small problematic renal masses.

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Harefuah. 2003 Mar;142(3):208-11, 237.
[The role of nephron sparing surgery for renal cancer]
[Article in Hebrew]
Meyer G, Mullerad M, Nativ O.
Department of Urology, Bnei-Zion Medical Center, Israel.

AIM: A contemporary review of the indications, techniques and outcome of the nephron sparing surgical approach in the management of solid renal masses. MATERIAL AND METHODS: Pertinent articles were reviewed using the MEDLINE. RESULTS: Nephron sparing surgery is increasingly being used to treat patients with solid renal lesions. The technical success rate of nephron sparing surgery is excellent, and operative morbidity and mortality are low. For renal cell carcinoma, long-term cancer-free survival is comparable to radical nephrectomy, particularly in patients with low stage disease. The reported incidence of multifocal renal cell carcinoma is approximately 15%, and it depends on tumor size, histology and stage. The risk of multifocal disease is low (less than 5%), when the maximal diameter of the primary tumor is 4 cm or less. Minimally invasive modalities of tumor resection or destruction show promising results, however they should be reserved for selected patients and await improvement in technology. Only when long-term follow-up data is available these methods might become routine clinical practice. CONCLUSIONS: Nephron sparing surgery provides effective therapy for patients in whom preservation of renal function is a relevant clinical consideration. Accumulating data in appropriately selected patients suggest a long-term functional advantage gained by the maximal preservation of unaffected renal parenchyma without sacrificing cancer control.

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Urology 2003 Jan;61(1):83-8
Retroperitoneal laparoscopic cryoablation of small renal tumors: intermediate results.
Lee DI, McGinnis DE, Feld R, Strup SE.
Department of Urology, University of California, Irvine Medical Center, Orange, California, USA.

OBJECTIVES: To present our experience with laparoscopic renal cryoablation with up to 3 years of follow-up. Laparoscopic renal cryoablation remains a viable option for the treatment of small peripheral renal masses in patients with significant comorbidities. Although partial nephrectomy has been shown to be a safe and reliable method of renal parenchymal preservation, laparoscopic cryoablation still requires longer term data to prove its efficacy. METHODS: Twenty patients with small renal masses (1.4 to 4.5 cm) underwent laparoscopic renal cryosurgery at our institution. A retroperitoneal laparoscopic approach was used to expose the kidney. Intraoperative ultrasound guidance was used to localize the lesions and monitor iceball formation. A double-freeze technique was used. Needle biopsies of solid masses were performed intraoperatively. RESULTS: Renal biopsies revealed renal cell carcinoma in 11 of the 20 patients. Of these 11 patients, none had evidence of recurrent disease at last follow-up, and follow-up scans showed no enhancement of any lesions. Of the 8 patients with follow-up of 2 years or greater, 4 had complete resolution of the renal lesions. The remainder had lesions that were reduced and stable in size. Complications included surgical re-exploration to evaluate pancreatic injury in 1 patient and failure to ablate a lesion in another. CONCLUSIONS: Laparoscopic renal cryoablation appears to be an effective tool for ablation of small renal lesions. A moderate length of follow-up continues to demonstrate efficacy because no patients had growth of treated pathologic lesions or developed metastasis to date. Continued maturation of data is necessary to determine the long-term efficacy.

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Urology 2003 Jan;61(1):78-82
Hand-assisted laparoscopy for large renal specimens: a multi-institutional study.
Stifelman MD, Handler T, Nieder AM, Del Pizzo J, Taneja S, Sosa RE, Shichman SJ.
Department of Urology, New York University Medical Center, New York, New York 10016, USA.

OBJECTIVES: To present our experience with hand-assisted laparoscopy (HAL) for larger renal specimens. One of the theoretical benefits of HAL is the ability to manage large renal specimens, which we defined as tumors greater than 7 cm, and tumors in obese patients. METHODS: Between March 1998 and October 2000, 106 HAL radical nephrectomies were performed for enhancing renal masses, for which 95 patients had complete preoperative, intraoperative, and postoperative data. Of the 95 patients, 32 underwent HAL for large tumors (7 cm or greater) and 41 had a body mass index of 31 or greater. The demographic and outcome data of these two groups were compared with 63 patients who underwent HAL for tumors less than 7 cm and 54 patients with a body mass index of less than 31. RESULTS: When comparing cohorts by tumor size, the only statistically significant differences were in convalescence and specimen weight. Patients with lesions 7 cm or greater required 21 days to recover compared with 18 days for patients with lesions less than 7 cm. Obese patients had statistically significantly higher American Society of Anesthesiologists classifications, longer operative times (214 versus 176 minutes), and longer convalescences (21 versus 17.5 days) compared with nonobese patients. The estimated blood loss and conversion rate was not different between the groups. Furthermore, no difference was noted between the groups in the incidence of positive margins, local recurrence, or metastatic recurrence at a mean follow-up of 12.2 months. CONCLUSIONS: HAL provides a safe, reproducible, and minimally invasive technique to remove large renal tumors and renal tumors in the obese.

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Radiology 2003 Feb;226(2):417-24
Renal cell carcinoma: clinical experience and technical success with radio-frequency ablation
of 42 tumors.
Gervais DA, McGovern FJ, Arellano RS, McDougal WS, Mueller PR.
Departments of Radiology, White 270, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114, USA. dgervais@partners.org

PURPOSE: To evaluate clinical experience with percutaneous image-guided radio-frequency (RF) ablation of renal cell carcinoma (RCC) and to assess factors that may influence technical success. MATERIALS AND METHODS: Thirty-four patients who underwent RF ablation of 42 RCC tumors during a 3.5-year period were evaluated. Overlapping ablations were performed on the basis of tumor size and geometry. Technical success was defined as elimination of areas that enhanced at imaging within the entire tumor. With the exception of those patients with renal insufficiency, who were followed up with unenhanced and gadolinium-enhanced magnetic resonance imaging, patients were followed up with unenhanced and contrast material-enhanced computed tomography. Univariate analysis of the results was performed with the Fisher exact test to assess the effect of tumor size and location on technical success. P <or=.05 was considered to represent a significant difference. Complications and the management and outcomes of the complications were recorded. RESULTS: All 29 exophytic tumors (mean size, 3.2 cm; size range, 1.1-5.0 cm) were completely ablated, as were two parenchymal tumors. The remaining 11 tumors had a component in the renal sinus. For large (>3.0 cm) tumors, presence of a tumor component in the renal sinus was a significant negative predictor of technical success (P =.004); only five of these 11 tumors were completely treated, compared with 11 of 11 tumors without a renal sinus component. A similar analysis was not possible for small tumors because no small tumors involved the renal sinus. Four complications occurred in a total of 54 ablation sessions: one minor hemorrhage, two major hemorrhages, and one ureteral stricture. CONCLUSION: RF ablation of RCC can be successful in exophytic RCC tumors up to 5.0 cm in size. Tumors larger than 3.0 cm with a component in the renal sinus are more difficult to treat but can be ablated successfully.

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J Urol 2003 Mar;169(3):905-8
Renal cell carcinoma: histological findings on surgical margins after nephron sparing surgery.
Zucchi A, Mearini L, Mearini E, Costantini E, Vivacqua C, Porena M.
Urology Department, University of Perugia, Italy.

PURPOSE: We evaluated the incidence of peritumoral satellite lesions in nephron sparing surgery and examined whether these findings have a negative effect on cancer specific survival and on the percent of local recurrence. MATERIALS AND METHODS: We performed nephron sparing surgery in 63 patients with kidney cancer, including 53 elective (group 1) and 10 imperative (group 2) operations. In all cases we removed 10 mm. of apparently healthy peritumoral parenchyma with the tumor. This tissue was subsequently examined by an anatomical pathologist to identify any satellite lesions. RESULTS: Four satellite lesions were identified, including 3 in group 1 and 1 in group 2, at a mean of 5.3 mm. from the primary lesion. None of the patients in either group had local recurrence at followup. Cancer specific survival was 96.3% in group 1 (mean followup 61 months) and 58% in group 2 (mean followup 39 months). It was not influenced by the presence of satellite micro-lesions. CONCLUSIONS: Despite common perplexities concerning the risk of multifocality in renal cell carcinoma we believe that the nephron sparing procedure in select patients is as effective as radical surgery. Based on our experience the surgical safety margin must be at least 10 mm. of macroscopically healthy, peritumoral tissue.

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J Neurosurg 2003 Feb;98(2):342-9
Radiosurgery in patients with renal cell carcinoma metastasis to the brain: long-term outcomes and prognostic factors influencing survival and local tumor control.
Sheehan JP, Sun MH, Kondziolka D, Flickinger J, Lunsford LD.
Department of Neurological Surgery, University of Pittsburgh, University of Pittsburgh Medical Center, Presbyterian Hospital, Pittsburgh, Pennsylvania, USA. jps2f@virginia.edu

OBJECT: Renal cell carcinoma is a leading cause of death from cancer and its incidence is increasing. In many patients with renal cell cancer, metastasis to the brain develops at some time during the course of the disease. Corticosteroid therapy, radiotherapy, and resection have been the mainstays of treatment. Nonetheless, the median survival in patients with renal cell carcinoma metastasis is approximately 3 to 6 months. In this study the authors examined the efficacy of gamma knife surgery in treating renal cell carcinoma metastases to the brain and evaluated factors affecting long-term survival. METHODS: The authors conducted a retrospective review of 69 patients undergoing stereotactic radiosurgery for a total of 146 renal cell cancer metastases. Clinical and radiographic data encompassing a 14-year treatment interval were collected. Multivariate analyses were used to determine significant prognostic factors influencing survival. The overall median length of survival was 15 months (range 1-65 months) from the diagnosis of brain metastasis. After radiosurgery, the median survival was 13 months in patients without and 5 months in those with active extracranial disease. In a multivariate analysis, factors significantly affecting the rate of survival included the following: 1) younger patient age (p = 0.0076); 2) preoperative Karnofsky Performance Scale score (p = 0.0012); 3) time from initial cancer diagnosis to brain metastasis diagnosis (p = 0.0017); 4) treatment dose to the tumor margin (p = 0.0252); 5) maximal treatment dose (p = 0.0127); and 6) treatment isodose (p = 0.0354). Prior tumor resection, chemotherapy, immunotherapy, or whole-brain radiation therapy did not correlate with extended survival. Postradiosurgical imaging of the brain demonstrated that 63% of the metastases had decreased, 33% remained stable, and 4% eventually increased in size. Two patients (2.9%) later underwent a craniotomy and resection for a tumor refractory to radiosurgery or a new symptomatic metastasis. Eighty-three percent of patients died of progression of extracranial disease. CONCLUSIONS: Stereotactic radiosurgery for treatment of renal cell carcinoma metastases to the brain provides effective local tumor control in approximately 96% of patients and a median length of survival of 15 months. Early detection of brain metastases, aggressive treatment of systemic disease, and a therapeutic strategy including radiosurgery can offer patients an extended survival.

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J Urol 2003 Mar;169(3):909-16
Renal cell carcinoma with tumor thrombus extension: biology, role of nephrectomy and
response to immunotherapy.
Zisman A, Wieder JA, Pantuck AJ, Chao DH, Dorey F, Said JW, Gitlitz BJ, deKernion JB, Figlin RA, Belldegrun AS.
Kimmel Cancer Center, Division of Urologic Oncology, Department of Urology, University of California School of Medicine, Los Angeles, USA.

PURPOSE: We outline the biology, prognosis and role of immunotherapy for renal cell carcinoma with gross venous tumor thrombus. MATERIALS AND METHODS: A total of 207 patients with unilateral renal cell carcinoma and tumor thrombus into the renal vein (107) and inferior vena cava (100) who underwent nephrectomy and thrombectomy were compared with 607 without tumor thrombus. RESULTS: At diagnosis 77 patients (37%) had N0M0 disease and 130 (63%) had lymph node (N+) or distant (M1) metastases. Compared with nontumor thrombus cases tumor thrombus was associated with more advanced stage, N+ (26% versus 12%), M1 (54% versus 31%) disease, higher grade and Eastern Cooperative Oncology Group performance status. In N0M0 cases with inferior vena caval tumor thrombus capsular penetration, collecting system invasion and extension into the hepatic vein were more important prognostic variables then the level of inferior vena caval thrombus. In patients with confined N0M0 tumors mean 2 and 5-year survival +/- SD was 83% +/- 8.8% and 72% +/- 10.7% in those with inferior vena caval tumor thrombus, and 90% +/- 9.4% and 68% +/- 16.1% in those with renal vein tumor thrombus, similar to the 93.4% +/- 1.7% and 81 +/- 3.1% rates, respectively, in those without thrombus who had no recurrence within 6 months after nephrectomy. Of patients with M1 disease in whom cytoreductive surgery was done those with and without thrombus showed a similar response to immunotherapy. When there was inferior vena caval and renal vein thrombus, mean 2-year survival was higher after nephrectomy and immunotherapy than after nephrectomy alone (41% +/- 9% and 52% +/- 7% versus 32% +/- 13% and 45% +/- 7%), immunotherapy alone (0% and 13% +/- 12%, respectively) and no treatment (0%). CONCLUSIONS: Renal cell carcinoma with tumor thrombus is associated with worse characteristics. Local tumor extension has greater prognostic importance than the level of inferior vena caval tumor thrombus. Survival is fair in patients with truly confined N0M0 disease and thrombus. The combination of surgery and immunotherapy has a role in thrombus cases. Our data provide the rationale for a prospective study of adjuvant immunotherapy after surgery in N0M0 cases with extensive tumor thrombus.

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J Clin Oncol 2003 Feb 1;21(3):530-5
Renal cell carcinoma in children: a clinicopathologic study.
Indolfi P, Terenziani M, Casale F, Carli M, Bisogno G, Schiavetti A, Mancini A, Rondelli R, Pession A, Jenkner A, Pierani P, Tamaro P, De Bernardi B, Ferrari A, Santoro N, Giuliano M, Cecchetto G, Piva L, Surico G, Di Tullio MT.
Pediatric Oncology Service-Pediatric Department II, University of Napoli, Napoli, Italy. paolo.indolfi@unina2.it

PURPOSE: To identify the prognostic factors, treatment, and outcome of children affected by renal cell carcinoma (RCC). PATIENTS AND METHODS: The series included 41 patients (18 males and 23 females) with a median age of 124 months observed at the 11 Italian Association for Pediatric Hematology and Oncology centers from January 1973 to January 2001. Clinical data, surgical notes, pathologic findings, and summaries of therapy were taken from the charts. RESULTS: Seven (17%) of the 41 patients had a papillary histology, and 34 (82.4%) had nonpapillary histology. Eighteen patients (43.9%) had stage I, one patient (2.4%) had stage II, two patients (4.8%) had stage IIIA, 10 patients (24.3%) had stage IIIB, and nine patients (21.9%) had stage IV disease. One patient had a bilateral involvement at diagnosis. Seven patients experienced disease recurrence. Lung and liver were the most common distant lesions and usually were fatal. In this study, the major factor influencing the prognosis was the stage. Event-free survival at 20 years was 53.5% for all patients. Overall survival at 20 years was 54.9% for all patients. CONCLUSION: RCC is a rare disease in children and adolescents. This neoplasm has a different clinical presentation in children compared with adults but the same outcome. In our experience, patients with localized disease could be cured by nephrectomy alone. Prospective studies in a larger number of patients are needed to confirm radiation therapy and biologic response modifiers as effective adjunct therapy in RCC stage III. The alternative therapy seems warranted in patients with advanced disease.

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Urology 2003 Jan;61(1):73-7
Improvement of hemostasis in open and laparoscopically performed partial nephrectomy using a gelatin matrix-thrombin tissue sealant (FloSeal).
Richter F, Schnorr D, Deger S, Trk I, Roigas J, Wille A, Loening SA.
Klinik und Poliklinik fur Urologie, Humboldt Universitat (Charite') Berlin, Berlin, Germany.

OBJECTIVES: Long-term follow-up studies have demonstrated that effective local tumor control and long-term tumor-free progression rates can be achieved by nephron-sparing surgery. However, hemostasis is a major issue, and the lack of effective means of hemostasis has limited the wider use of the laparoscopic approach to nephron-sparing surgery. METHODS: Between January 2001 and April 2002, 25 patients with renal cell carcinoma were treated with partial nephrectomy using a two-component tissue sealant (FloSeal). The median age was 54 years (range 42 to 71). The follow-up time was 1 to 12 months (median 3.5). The tumor diameter ranged from 2 to 5 cm (median 2.8). Fifteen cases were performed by open retroperitoneal surgery, and 10 cases were performed laparoscopically. The two-component tissue sealant (consisting of a gelatin matrix granula component and a thrombin component) was applied after resection of the tumor and before perfusion of the kidney. The following parameters were recorded: time until complete hemostasis was achieved; decrease in postoperative hemoglobin level; postoperative bleeding; and presence or absence of a perirenal hematoma 24 hours and 10 days postoperatively by ultrasonography. RESULTS: After application of the tissue sealant for 1 to 2 minutes to the moist resection site, hemostasis was immediate in all cases. During the laparoscopically performed partial nephrectomies, a laparoscopic applicator was used to avoid wasting the tissue sealant within the dead space of the instrument. When reperfusion of the kidney was established, hemostasis was maintained. The decrease in postoperative hemoglobin level ranged from 0.3 to 1.2 points (median 0.7). None of the patients required blood transfusions. No postoperative bleeding occurred. The ultrasound examination 24 hours and 10 days postoperatively demonstrated the absence of a significant perirenal hematoma. CONCLUSIONS: The two-component tissue sealant FloSeal provided immediate and durable hemostasis in open and laparoscopically performed partial nephrectomies. The tissue sealant may provide a tool to expand the possibilities of laparoscopic nephron-sparing surgery.

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Anticancer Res 2002 Sep-Oct;22(5):3045-51
Interleukin-2, interferon-alpha and medroxyprogesterone acetate in metastatic renal cell carcinoma.
Naglieri E, Lopez M, Lelli G, Morelli F, Amodio A, Di Tonno P, Gebbia N, Di Seri M, Chetri MC, Rizzo P, Abbate I, Casamassima A, Selvaggi FP, Colucci G.
Medical and Experimental Oncology Department, Oncology Institute, Via Amendola 209, 70126 Bari, Italy. onmes2@libero.it

BACKGROUND: Interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) are the main immuno-biological agents used in the therapy of metastatic renal cell carcinoma (RCC). Unfortunately the promising results obtained in biological studies have not yet been confirmed in clinical studies. One reason is linked to the immunosuppression of metastatic patients which is caused by macrophage products. IL-6 in particular is considered a growth factor for RCC. Medroxyprogesterone acetate (MPA) may interfere with IL-6 macrophage production, possibly causing a synergistic effect in association with IL-2 and IFN-alpha. Therefore the purpose of our study was to evaluate the toxicity and the efficacy of the association between IL-2, IFN-alpha and MPA. PATIENTS AND METHODS: Forty-two consecutive patients with metastatic RCC were enrolled. IL-2 was administered subcutaneously at doses of 4.5 million UI on days 1-5, 8-12, 15-19 and 22-26; IFN-alpha was administered s.c. at a dose of 3 million t.t.w; MPA was administered orally at a dose of 1000 mg daily. This schedule was repeated after a rest of 2 weeks. RESULTS: Toxicity was mild: the main symptoms observed were fatigue and fever. Six CR (14%), five PR (12%), thirteen SD (31%) and seventeen PD (41%) were observed for an overall response rate of 26%. Patients with good PS and low levels of CRP had a better prognosis. CONCLUSION: Considering both the good activity and the low toxicity of this scheme, we think that it could be carried out in normal clinical practice.

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Oncology 2003;64(1):25-7
A phase II study with 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX-4 regimen) in patients with metastatic renal cell carcinoma.
Bennouna J, Delva R, Gomez F, Lesimple T, Geoffrois L, Linassier C, Chevreau C, Douillard JY, Negrier S.
Centre Rene Gauducheau, Nantes, France. j-bennouna@nantes.fnclcc.fr

PURPOSE: To investigate the efficacy and safety of the FOLFOX-4 regimen for patients with metastatic renal cell carcinoma (MRCC). PATIENTS AND METHODS: Fifty-nine patients (median age 59 years) pre-treated or not by cytokines (29 vs. 30) received the FOLFOX-4 regimen every 2 weeks. RESULTS: Three minor responses, and no complete or partial responses were obtained. The median progression-free survival was 3 months (95% CI: 2.6-3.4), the median survival 10.6 months (95% CI: 8.7-12.4), with no difference between pre-treated patients and others. Treatment was well tolerated. CONCLUSION: The FOLFOX-4 regimen is ineffective in patients with MRCC. We believe that oxaliplatin should no longer be explored in renal carcinoma. Copyright 2003 S. Karger AG, Basel

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J Urol 2002 Dec;168(6):2401-5
Phase II trial of radio frequency ablation of renal cancer: evaluation of the kill zone.
Matlaga BR, Zagoria RJ, Woodruff RD, Torti FM, Hall MC.
Department of Urology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.

PURPOSE: We report on the pathological evaluation of renal tumors after intraoperative radio frequency ablation performed immediately before surgical nephrectomy. MATERIALS AND METHODS: Ten patients with renal tumors were enrolled in a prospective, Institutional Review Board approved phase II trial of radio frequency ablation. Following surgical exposure of the kidney a single 12-minute radio frequency ablation of the tumor was performed using the Radionics Cool-tip RF Radio Frequency Ablation System (Radionics, Burlington, Massachusetts). The tumor was then excised via radical or partial nephrectomy. Gross and histological evaluations of the tumor were performed, including evaluation with nicotinamide adenine dinucleotide vital staining. RESULTS: All 10 tumors were confirmed histologically to be renal cell carcinoma. Mean tumor size was 3.2 cm. (range 1.4 to 8.0). Of the 10 tumors 8 were completely ablated with a mean treatment margin of 6.75 mm. (range 2 to 13). Of the 2 tumors that were incompletely treated 1 never attained a temperature sufficient for tissue destruction and the other measured 8 cm., far exceeding the expected ablation volume of treatment protocol. CONCLUSIONS: This study represents the initial report of the histological outcome of saline cooled radio frequency ablation of renal tumors. Our data indicate that it can completely destroy renal cancers while transmitting minimal collateral damage to surrounding renal parenchyma. Further investigation is required to determine long-term oncological outcome.

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Cancer Immunol Immunother 2002 Dec;51(11-12):637-44
Therapeutic vaccination against metastatic renal cell carcinoma by autologous dendritic cells: preclinical results and outcome of a first clinical phase I/II trial.
Marten A, Flieger D, Renoth S, Weineck S, Albers P, Compes M, Schottker B, Ziske C, Engelhart S, Hanfland P, Krizek L, Faber C, von Ruecker A, Muller S, Sauerbruch T, Schmidt-Wolf IG.
Department of Internal Medicine I, University of Bonn, Sigmung Freud-Strasse 25, 53105 Bonn, Germany.

In this study we have presented in vitro data and results of a preliminary clinical trial using dendritic cells (DC) in patients with progressive metastatic renal cell carcinoma. DC precursor cells were obtained from peripheral blood mononuclear cells (PBMC). DC were pulsed with autologous tumor cell lysate if available. In total, 15 patients were treated with a median of 3.95 x 10(6) DC administered and ultrasound-guided into a lymph node or into adjacent tissue. Seven patients remained with progressive disease (PD), 7 patients showed stable disease (SD), and one patient displayed a partial response (PR). Most interestingly, the patient who was treated with the highest number of DC (14.4 x 10(6) DC/vaccine) displayed a PR. Delayed-type hypersensitivity (DTH) reaction using autologous tumor lysate was positive in 3 out of 13 patients, including the patient with PR. Two out of 3 patients receiving additional treatment with keyhole limpet hemocyanin (KLH) showed reactivity to KLH after vaccination. CD3+CD4+ and CD3+CD28+ cells as well as the proliferation rate of peripheral blood lymphocytes (PBL) increased significantly in the blood of patients during therapy. In conclusion, our observations confirm the capability of tumor-lysate pulsed autologous DC vaccines to stimulate an immune response in patients with metastatic renal cell carcinoma even in the presence of a large tumor burden. The lack of adverse effects together with immunologic effects support further investigation of this novel therapeutic approach. Further studies are necessary to demonstrate clinical effectiveness in cancer patients, in particular in patients with less advanced disease.

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Urol Nefrol (Mosk) 1999 Mar-Apr;(2):51-2
[Surgical treatment of late metastases of kidney cancer]
[Article in Russian]
Matveev VB, Gurarii LL, Began-Bogatskii KM.

Whereas 25-57% of patients diagnosed with renal cell carcinoma (RCC) present with metastatic disease, about 50% of (RCC) patients develop metastases after potentially curative radical nephrectomy. Five-year survival at following surgical removal of solitary metastases is approximately 35-50%. Our experience demonstrate that a small cohort of patients benefit from aggressive surgical therapy for consequtively arising solitary distant metastases with long-term palliation.

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Cas Lek Cesk 2002 Sep 13;141(18):578-80
[Adjuvant therapy of renal carcinoma]
[Article in Czech]
Novak J, Stolz J, Dvoracek J.
Urologicka klinika 1. LF UK a VFN, Praha. jaroslav.novak@lf1.cuni.cz

A treatment approach in a group of 1498 patients with renal cell carcinoma (RCC) was studied. Out of these, 86 patients had the primarily generalised form. For the therapy of primary advanced metastasis, the treatment strategy was changed from conservative to an active approach. Such approach is based on the removal of 75% of the tumor mass, the patient should be in good conditions with no metastases in CNS, bone and liver, and the primary tumor should not be a sarcoma. The new treatment strategy of patients with advanced RCC combines surgery and chemoimmunotherapy. 47 patients from the studied group were treated with combined INF alpha + IL-2 + 5FU + isotretinoin using the Atzpodien scheme. The toxicity was minimal and only in six patients the treatment was interrupted because of the disease progression. Results of this treatment strategy are encouraging, however, further randomised trials are recommended.

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Gan To Kagaku Ryoho 2002 Oct;29(10):1745-51
[Cell therapy for renal cell carcinoma]
[Article in Japanese]
Kawai K.
Department of Urology, Institute of Clinical Medicine, University of Tukuba, 1-1-1 Tennoudai, Tsukuba, Ibaragi 305-8575, Japan.

Renal cell carcinoma (RCC) is an immunogenic tumor that has shown some response to cytokine-therapy and other types of immune-based treatment. Since the advent of lymphocyte culture techniques in the 1980s, clinical trials of lymphokine-activatedkiller cells and tumor infiltrating lymphocytes have been conducted. Although these approaches have not shown apparent benefit compared to the standard cytokine therapy, further trials are ongoing using dendritic cell or gene-modified tumor vaccines in order to induce a tumor-specific cytotoxic T cell response in vivo. Recently, several investigators have indicated that RCC is susceptible to a graft-versus-tumor effect promoted by allogeneic stem-cell transplantation. This article reviews the clinical results of these cell therapies for metastaic RCC.

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Arch Esp Urol 2002 Sep;55(7):868-80
Laparoscopic partial nephrectomy: current status.
Bernardo NO, Gill IS.
Section of Laparoscopic and Minimally Invasive Surgery, Urological Institute, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, Ohio 44195, USA.

OBJECTIVE: Increasingly nephro-sparing partial nephrectomy has became widely accepted as a preferred treatment option for the select patient when the adenocarcinoma involves a solitary kidney or poorly functioning contralateral kidney, and in patients with synchronous bilateral tumors. While open partial nephrectomy is currently the standard nephron sparing procedure for treatment of renal tumors, laparoscopic partial nephrectomy has emerged as a potential alternative recently. METHODS: This review seeks a critical assessment of the current status of laparoscopic partial nephrectomy, worldwide results and a brief description of energy based in-situ tumor ablation systems. We have duplicated laparoscopically, the open surgical techniques. While choice of laparoscopic approach depends upon the surgeon's personal preference, the precise location of the tumor on the kidney is the main factor determining our either retroperitoneal or transperitoneal approach. Hilar clamping reliably achieves a bloodless field, decreases renal turgor and allows surgical precision during tumor excision and control of larger vessels, which represents a real, practical and significant advantage. Precise suture repair currently remains the optimal and most reliable method for sealing a collecting system entry during the course of a laparoscopic partial nephrectomy. With increasing experience, laparoscopic partial nephrectomy can be safely applied to renal tumors that extend deeply, even upto the renal sinus. CONCLUSIONS: As more data emerges and the technical success rates of laparoscopic partial nephrectomy improve this minimally invasive technique will gain a wider role in the treatment of select renal cell carcinomas.

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Cancer 2002 Oct 15;95(8):1644-9
Interleukin-2, interferon-alpha, 5-fluorouracil, and vinblastine in the treatment of metastatic renal cell carcinoma: a prospective phase II study: the experience of Rambam and Lin Medical Centers 1996-2000.
Gez E, Rubinov R, Gaitini D, Meretyk S, Best LA, Native O, Stein A, Erlich N, Beny A, Zidan J, Haim N, Kuten A.
Department of Oncology, Rambam Medical Center, Haifa, Israel. e_gez@rambam.health.gov.il

BACKGROUND: The current study evaluated the efficacy and toxicity of interleukin-2 (IL-2), interferon-alpha (IFN-alpha), 5-fluorouracil (5-FU), and vinblastine (VBL) in the treatment of metastatic renal cell carcinoma (MRCC). METHODS: Sixty-two MRCC patients, median age 63 years, received immunochemotherapy. Eastern Cooperative Oncology Group performance status was 1 for 45 patients and 2 for 17 patients. Fifty-four patients underwent nephrectomy prior to treatment. Sites of disease were lungs, lymph nodes, bone, kidney, and liver. Treatment consisted of IL-2 10 MIU/m(2) subcutaneous (SC), three times per week, Weeks 1-4; IFN-alpha 6 MIU/m(2) SC, once per week, Weeks 1-4 and 9 MIU/m(2), three times per week, Weeks 5-7; 5-FU 600 mg/m(2) and VBL 6 mg/m(2), intravenous bolus, Day 1 of Weeks 5 and 7. RESULTS: In a median followup of 34 months, 62 patients were evaluated for tumor response. Four patients achieved complete response for 26+, 34+, 51+, and 56+ months, respectively; 14 patients achieved partial response for a median of 14 months; and 20 patients achieved stable disease for a median of 9 months. Seven patients (5 partial response, 2 stable disease) underwent complete resection of residual tumor. Five patients remained alive with no evidence of disease for 27, 32, 36, 42, and 48 months, respectively. Nine patients achieved long-term complete response for a median of 36 months. Three-year survival rate for the entire group and for 11 complete responders was 88%. Common side effects were flu-like symptoms, nausea, headache, and depression. Four patients were excluded because of treatment intolerance, and one patient died after nephrectomy. CONCLUSIONS: Immunochemotherapy is effective and well-tolerated by patients with MRCC. Surgical intervention for resection of residual disease is justified. Copyright 2002 American Cancer Society.

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Cancer 2002 Oct 15;95(8):1629-36
A high rate of venous thromboembolism in a multi-institutional phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil and daily thalidomide in patients with metastatic renal cell carcinoma.
Desai AA, Vogelzang NJ, Rini BI, Ansari R, Krauss S, Stadler WM.
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois, USA. adesai@medicine.bsd.uchicago.edu

BACKGROUND: The objective of this study was to determine the clinical response rate of the combination of weekly intravenous (IV) gemcitabine with continuous infusion fluorouracil (5-FU) and daily oral thalidomide in patients with metastatic renal cell carcinoma (RCC). METHODS: Between June, 2000 and January, 2001, 21 patients with metastatic RCC were enrolled onto this multi-institutional Phase II study of gemcitabine at 600 mg/m(2) per day on Days 1, 8, and 15; 5-FU at 150 mg/m(2) per day by continuous IV infusion through a permanent catheter on Days 1-21; and oral thalidomide on Days 1-28 starting at a dose of 200 mg daily. After the first 2 weeks of therapy, the thalidomide dose was escalated by 100 mg per day every week to a maximum dose of 400 mg per day unless it was precluded by toxicity. Treatment cycles were repeated every 28 days. RESULTS: A high rate of venous thromboembolism (VTE) was observed. Five patients developed deep vein thrombosis (DVT), three patients developed pulmonary embolization (PE), and one patient suffered a fatal cardiac arrest preceded by hemoptysis, for an overall VTE rate of 43%. Of the 18 assessable patients, there were no complete responses and 2 partial responses (objective response rate, 10%; 95% confidence interval, 1-30%). CONCLUSIONS: The addition of thalidomide to gemcitabine and 5-FU did not improve the objective response rate previously observed with gemcitabine and 5-FU alone and added significant vascular toxicity. The authors recommend against further development or use of this three-drug regimen. Copyright 2002 American Cancer Society.

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Oncology 2002;63(2):130-8
Vinblastine and interferon-gamma combination with and without 13-cis retinoic acid for patients with advanced renal cell carcinoma. Results of two phase II clinical trials.
Bacoyiannis C, Dimopoulos MA, Kalofonos HP, Nicolaides C, Aravantinos G, Bafaloukos D, Samelis G, Onyenadum A, Kiamouris Ch, Skarlos D, Pavlidis N, Triantafillidis A, Kosmidis P; Hellenic Cooperative Oncology Group.
Medical Oncology Department, Hygeia Hospital, Athens, Greece. ParisKosmidis/Hygeia/30@Hygeia.gr

BACKGROUND: The aim of this study is firstly to determine the response rates and toxicity of two regimens containing vinblastine (VBL) in combination with interferon-gamma (IFN-gamma) in the treatment of patients with advanced renal cell carcinoma (RCC), and secondly to evaluate the additional efficacy of 13-cis retinoic acid (13-CRA) in RCC. METHODS: Twenty-nine patients were included in the first trial (Trial 1) and 40 in the second one (Trial 2). The therapy given in Trial 1 consisted of VBL 0.15 mg/kg i.v. every 2 weeks and IFN-gamma 100 microg s.c. 3 times weekly. In Trial 2, the therapy consisted of the same two drugs, in the same doses, plus oral 13-CRA 40 mg/day. RESULTS: In Trial 1 there were 3 (10.3%) patients with complete response, 3 (10.3%) patients with partial response, 8 (27.6%) patients with stable disease and 15 (51.7%) patients with progressive disease. In Trial 2, there was no complete response, however, 3 (7.5%) patients had partial response. Additionally, 15 (37.5%) patients maintained stable disease and 14 (35%) patients had progressive disease. In Trial 1, the median survival was 12.56 months (95% CI, 6.8-18.3, range 0.59-42.49) and the median time to progression was 3.21 months (95% CI, 1.7-4.7, range 0.03-42.49). In Trial 2, the median survival was 9.54 months (95% CI, 5.9-13.1, range 0.43-24.1) and the median time to progression was 3.9 months (95% CI, 0.8-7, range 0.26-24.1). In Trial 1, granulocytopenia grade 3 and 4 appeared in 5 (17.2%) patients and anaemia grade 3 in 1 (3.4%) patient. In Trial 2, there were grade 3 toxicities, as granulocytopenia in 5 (12.5%) patients, anemia in 4 (10.0%) patients, stomatitis in 3 (7.5%) patients, fatigue/malaise in 3 (7.5%) patients and 1 (2.5%) had diarrhea. No toxic deaths occurred in both studies. CONCLUSION: The use of IFN-gamma does not enhance the low response of VBL-based chemotherapy. The additional administration of 13-CRA with the combination of VBL and IFN-gamma does not add to the efficacy of this combination in patients with advanced renal cell carcinoma. New active agents are needed to treat patients with this disease. Copyright 2002 S. Karger AG, Basel

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Cancer Control 2002 Jul-Aug;9(4):293-304
Immunotherapy of metastatic renal cell cancer.
Fishman M, Seigne J.
Genitourinary Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.

BACKGROUND: The management of metastatic renal cancer remains a therapeutic challenge. Conventional cytotoxic chemotherapy is rarely effective, and the most promising approaches appear to lie in the field of immunotherapy. METHODS: The authors review the literature regarding current and investigational immunotherapy approaches to the management of metastatic renal cancer. RESULTS: The mechanism of action, methods of delivery, efficacy, and side effect profile of the cytokines IL-2 and interferon alfa are discussed. The role of investigational approaches such as tumor vaccines, antibody-based therapy, lymphocyte infusions, and bone marrow transplantation is addressed. The rationale for nephrectomy as an adjunctive procedure to immunotherapy is also discussed. CONCLUSIONS: Ongoing laboratory investigation of the cause of the immune deficit in patients with metastatic renal cell cancer will result in the development of novel therapies to enhance tumor cell recognition as well as host antitumor response. Translation of laboratory findings into the clinic will be facilitated by the presence of an already well-developed infrastructure for the performance of clinical trials for patients with this difficult diagnosis.

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Arch Esp Urol 2002 Jul-Aug;55(6):756-66
Hand-assisted laparoscopic renal surgery: current trends and applications.
Yohannes P, Smith AD, Lee BR.
Long Island Jewish Medical Center, New Hyde Park, New York, USA.

OBJECTIVE: Hand-assisted laparoscopic surgery has recently been introduced in order to help ease the learning process associated with standard laparoscopic surgery. It has various urological applications in the management of malignant and benign disease of the kidney. The purpose of this study is to review the applications and the success rate associated with hand-assisted laparoscopic surgery. METHODS: A comprehensive literature review of hand-assisted urological surgery was performed using MEDLINE search. RESULTS: Hand-assisted laparoscopic nephrectomy has been performed for benign and malignant disease, donor renal transplant, and nephron sparing surgery with good success. Patients who undergo the hand-assisted procedure seem to have less perioperative morbidity than those who undergo an open procedure. This approach minimized the warm-ischemia time in renal transplantation. CONCLUSION: Hand-assisted nephrectomy is a useful tool facilitating the learning process in laparoscopy.

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J Radiol 2002 Jun;83(6 Pt 2):805-22, discussion 823-4
[Staging and follow-up of renal cell carcinoma]
[Article in French]
Rouviere O, Brunereau L, Lyonnet D, Rouleau P.
Service de radiologie urinaire et vasculaire - P Radio, Hopital E. Herriot, 69437 Lyon Cedex 03, France. olivier.rouviere2netcourrier.com

Surgery is the only curative treatment of renal cell carcinoma (RCC). Preoperative staging is aimed at evaluating surgical possibilities and optimal surgical technique. Thoracic and abdominal CT is the best way to routinely evaluate locoregional and metastatic extension of the tumor. However, there is no consensus concerning which laboratory and imaging studies should be obtained to assess patients after radical nephrectomy or conservative surgery. Objectives of this review

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Cancer 2002 Sep 15;95(6):1220-7
Phase I trial of interferon alpha2b and liposome-encapsulated all-trans retinoic acid in the treatment of patients with advanced renal cell carcinoma.
Goldberg JS, Vargas M, Rosmarin AS, Milowsky MI, Papanicoloau N, Gudas LJ, Shelton G, Feit K, Petrylak D, Nanus DM.
Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.

BACKGROUND: Studies suggest that retinoic acid (RA) can augment the antitumor effects of interferon-based therapy in patients with advanced renal cell carcinoma (RC); however, this benefit has not been achieved convincingly using oral formulations of 13-cis RA and all-trans RA. Liposome-encapsulated all-trans RA (ATRA-IV) has improved pharmacokinetics with increased and prolonged ATRA serum levels compared with oral retinoids. METHODS: Cohorts of 3-6 patients with progressive metastatic RC received a dose of 3 MU interferon alpha2b per day subcutaneously, which was escalated weekly to 5 MU and then to 10 MU, plus ATRA-IV beginning at a dose of 90 mg/m(2) intravenously three times per week (Monday, Wednesday, and Friday), with a planned escalation to a maximum of 140 mg/m(2). RESULTS: Two of the initial five patients experienced Grade 3 leukopenia while receiving 3 MU interferon and 90 mg/m(2) ATRA-IV. Therefore, the trial was amended to begin ATRA-IV at a dose of 15 mg/m(2) three times per week with a planned escalation by 15 mg/m(2) per cohort plus interferon-alpha at a dose of 3 MU subcutaneously 5 days per week (Monday through Friday), which was escalated weekly to 5 MU and then to 10 MU. Twelve patients were treated on the revised schedule. Toxicity was mild and included Grade 2 anemia (n = 7 patients), leukopenia (n = 2 patients), nausea (n = 2 patients), fatigue (n = 2 patients), fever (n = 2 patients), hepatic toxicity (n = 1 patient), edema (n = 1 patient), neurocortical toxicity (n = 1 patient), headache (n = 1 patient), and infection (n = 1 patient). One patient developed hyperthyroidism, and one patient required admission for bacteremia from a line infection. Dose limiting toxicity was Grade 3 hepatic toxicity, which was observed at a dose of 30 mg/m(2) ATRA-IV in 2 of 6 patients. Only 2 of 12 patients agreed to a dose escalation up to 10 MU interferon-alpha. Of 12 patients who were evaluable for response, 2 patients (17%) had a partial response in bone and lung, including 1 partial response of > 91 weeks' duration, at a dose of 15 mg/m(2) ATRA-IV three times per week and 5 MU interferon-alpha. Five additional patients experienced stable disease, two of whom had disease progression in bone only. CONCLUSIONS: The acceptable toxicity profile and preliminary efficacy results suggest that this regimen warrants further evaluation. ATRA-IV (15 mg/m(2) TIW) and interferon-alpha (3 MU Monday through Friday escalated weekly to 5 MU and to 7 MU) are recommended for further study in patients with advanced RC. Copyright 2002 American Cancer Society.

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Cancer 2002 Aug 15;95(4):758-65
A pilot study of thalidomide in patients with progressive metastatic renal cell carcinoma.
Daliani DD, Papandreou CN, Thall PF, Wang X, Perez C, Oliva R, Pagliaro L, Amato R.
Department of Genitourinary Medical Oncology, M. D. Anderson Cancer Center, Houston, Texas 77030, USA. ddaliani@notes.mdacc.org

BACKGROUND: The highly vascular nature of renal cell carcinoma (RCC) suggests that angiogenesis inhibition may be therapeutic for patients with this disease. Thalidomide inhibits basic fibroblast growth factor and vascular endothelial growth factor (VEGF)-induced angiogenesis. METHODS: In a pilot study, we evaluated the safety and efficacy of escalating doses of thalidomide in patients with progressive metastatic RCC (mRCC), measurable disease, and good organ function. Patients received oral thalidomide starting at 200 mg per day and increasing by 100-200 mg per day weekly until a target dose of 1200 mg per day was reached. Study endpoints were objective tumor response and toxicity. RESULTS: Of the 20 patients enrolled, 19 were evaluable for response. Eighteen achieved the target dose. The most common, but reversible, toxicities were constipation, somnolence, and fatigue. Peripheral neuropathy was seen after prolonged therapy, necessitating dose reduction. Two patients achieved a partial response and nine had stable disease for a median of 14 months (range, 3-17 months). Median time to progression was 4.7 months (range, 0.7-31.3 months). Fifteen patients died (median survival, 18.1 months; 95% lower confidence bound 10.7). Survival was significantly longer in patients with higher hemoglobin level and longer time from first metastasis to start of thalidomide, but significantly shorter in patients with multiple organ involvement and previous treatments. CONCLUSIONS: Thalidomide at this dose is associated with manageable acute toxicities but long-term dose-limiting neuropathy. Objective responses are rare in patients with mRCC and are characterized by delay in achieving maximum tumor reduction. Prolonged stable disease is seen in some patients, but the benefit of thalidomide, as well as other angiogenesis inhibitors, in that setting needs to be studied in controlled, randomized trials. Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10740

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Cancer 2002 Sep 1;95(5):1045-50
Thirteen-year, long-term efficacy of interferon 2alpha and interleukin 2-based home therapy in patients with advanced renal cell carcinoma.
Atzpodien J, Hoffmann R, Franzke M, Stief C, Wandert T, Reitz M.
Medizinische Hochschule Hannover, Germany. sekrprofatzpodien@yahoo.de

BACKGROUND: The goal of the current report was to demonstrate the long-term efficacy of outpatient subcutaneous (sc) interferon alpha (IFN-alpha) and sc interleukin 2 (IL-2)-based combination regimens in patients with metastatic renal cell carcinoma. METHODS: In three consecutive clinical trials, 443 patients received combined sc IFN-alpha and sc IL-2 (n = 97 patients); combined sc IFN-alpha, sc IL-2, and intravenous (iv) 5-fluorouracil (5-FU) (n = 260 patients); or combined sc IFN-alpha, sc IL-2, and iv 5-FU with oral 13cis-retinoic acid (n = 86 patients). RESULTS: The median overall survival was 21+ months. The 2-year, 5-year, and 13-year survival rates were calculated at 45.26%, 15.96%, and 8.96%, respectively. The median time to disease progression was 6 months. The 2-year, 5-year, and 13-year progression free survival rates were 17.84%, 9.54%, and 9.20%, respectively. CONCLUSIONS: The current data suggest that combined outpatient sc IFN-alpha and sc IL-2, according to the Atzpodien regimen, achieves long-term survival benefits in a subset of patients with metastatic renal cell carcinoma, both with and without 13-cis-retinoic acid and/or 5-fluorouracil. Copyright 2002 American Cancer Society.

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J Exp Med 2002 Sep 2;196(5):619-28
Disease-associated bias in T helper type 1 (Th1)/Th2 CD4(+) T cell responses against MAGE-6 in HLA-DRB10401(+) patients with renal cell carcinoma or melanoma.
Tatsumi T, Kierstead LS, Ranieri E, Gesualdo L, Schena FP, Finke JH, Bukowski RM, Mueller-Berghaus J, Kirkwood JM, Kwok WW, Storkus WJ.
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.

T helper type 1 (Th1)-type CD4(+) antitumor T cell help appears critical to the induction and maintenance of antitumor cytotoxic T lymphocyte (CTL) responses in vivo. In contrast, Th2- or Th3/Tr-type CD4(+) T cell responses may subvert Th1-type cell-mediated immunity, providing a microenvironment conducive to disease progression. We have recently identified helper T cell epitopes derived from the MAGE-6 gene product; a tumor-associated antigen expressed by most melanomas and renal cell carcinomas. In this study, we have assessed whether peripheral blood CD4(+) T cells from human histocompatibility leukocyte antigens (HLA)-DRbeta1*0401(+) patients are Th1- or Th2-biased to MAGE-6 epitopes using interferon (IFN)-gamma and interleukin (IL)-5 enzyme-linked immunospot assays, respectively. Strikingly, the vast majority of patients with active disease were highly-skewed toward Th2-type responses against MAGE-6-derived epitopes, regardless of their stage (stage I versus IV) of disease, but retained Th1-type responses against Epstein-Barr virus- or influenza-derived epitopes. In marked contrast, normal donors and cancer patients with no current evidence of disease tended to exhibit either mixed Th1/Th2 or strongly Th1-polarized responses to MAGE-6 peptides, respectively. CD4(+) T cell secretion of IL-10 and transforming growth factor (TGF)-beta1 against MAGE-6 peptides was not observed, suggesting that specific Th3/Tr-type CD4(+) subsets were not common events in these patients. Our data suggest that immunotherapeutic approaches will likely have to overcome or complement systemic Th2-dominated, tumor-reactive CD4(+) T cell responses to provide optimal clinical benefit.

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Scand J Urol Nephrol 2002;36(4):273-7
Real indications for adrenalectomy in renal cell carcinoma.
Moudouni SM, En-Nia I, Patard JJ, Manunta A, Guille F, Lobel B.
Department of Urology, Hospital Pontchaillou, CHU Rennes, France.

OBJECTIVES: We determined the incidence and characteristics of adrenal involvement in localized and advanced renal cell carcinoma, and evaluated the role of adrenalectomy as part of radical nephrectomy. PATIENTS AND METHODS: From 1993 to 1999, 210 patients with renal cell carcinoma (RCC) (139 men and 71 women, mean age 60.8 years, range 12-96 years) underwent radical nephrectomy with associated adrenalectomy. Patients were divided into two subgroups of 106 with localized (stage T1-2 tumor, group 1) and 104 with advanced (stage T3-4N01M01, group 2) renal cell carcinoma. A retrospective review of preoperative computerized tomography (CT) of the abdomen was performed. Radiographic findings were subsequently compared with postoperative histopathological results to assess the predictive value of tumor characteristics and imaging in determining adrenal metastasis. RESULTS: Of the 210 patients, 15 (7.1%) had adrenal involvement. Tumor stage correlated with probability of adrenal spread, with T3-4 and T1-2 accounting for 13.4% and 0.9% of cases, respectively (p < 0.001). Upper pole intrarenal RCC most likely to spread was local extension to the adrenal gland, representing 53.3% of adrenal involvement. In contrast, multifocal, lower pole and mid region RCC tumors metastasized hematogenously, representing 21.4%, 7%, and 14% of adrenal metastasis, respectively. The relationship between intrarenal tumor size (mean 7.8 cm, range 4-21) and adrenal involvement was not statistically significant. Preoperative CT demonstrated 97.7% specificity, 98.4% negative predictive value, 87% sensitivity and 80% positive value for adrenal involvement by RCC. CONCLUSIONS: Ipsilateral adrenalectomy should only be performed if a lesion is seen preoperatively on CT scan or if gross disease is seen at the time of nephrectomy. The prognosis is poor for RCC with ipsilateral involvement even with complete removal. Because of this poor prognosis we believe that adrenal involvement should constitute a separate stage category.

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Ann Oncol 2002 Sep;13(9):1460-8
Prognostic factors of survival and rapid progression in 782 patients with metastatic renal carcinomas treated by cytokines: a report from the Groupe Francais d'Immunotherapie.
Negrier S, Escudier B, Gomez F, Douillard JY, Ravaud A, Chevreau C, Buclon M, Perol D, Lasset C.
Departments of Biostatistics and Medicine, Centre Leon Berard, Lyon, France. negrier@lyon.fnclcc.fr

Interleukin-2 (IL-2) or/and interferon (IFN) are routinely used for treating patients with metastatic renal cell cancer. However, results have been disappointing, with a majority of treatment failure. Over 6 years, the Groupe Francais d'Immunotherapie enrolled 782 patients in successive multicenter trials using cytokine regimens. Univariate and multivariate analyses were performed on this large prospective database to identify prognostic factors for survival. The presence of biological signs of inflammation, short time interval from renal tumor to metastases (<1 year), elevated neutrophil counts, liver metastases, bone metastases, patient performance status (PS), the number of metastatic sites, alkaline phosphatases and hemoglobin levels were predictive of survival outcome. When compared with previous results, our study showed that PS, number of metastatic sites, disease-free interval, biological signs of inflammation and hemoglobin levels can be considered as validated prognostic factors. We also identified four independent factors predictive of rapid progression under cytokine treatment: presence of hepatic metastases, short interval from renal tumor to metastases (<1 year), more than one metastatic site and elevated neutrophil counts. Patients who combined at least three of these factors have >80% probability of rapid progression despite treatment. We think that these results must be taken into account when making the decision to treat with cytokine.

   

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