Lung Cancer Research: 2002-2006
     
J Surg Oncol. 2006 Oct 12; [Epub ahead of print]
Nodal downstaging predicts survival following induction chemotherapy for stage IIIA (N2) non-small cell lung cancer in CALGB protocol #8935.
Jaklitsch MT, Herndon JE 2nd, Decamp MM Jr, Richards WG, Kumar P, Krasna MJ, Green MR, Sugarbaker DJ.
Division of Thoracic Surgery, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts.

BACKGROUND AND OBJECTIVES: CALGB 8935 was a phase II protocol for mediastinoscopically staged IIIA (N2) non-small cell lung cancer. Induction cisplatin/vinblastine chemotherapy was followed by surgical resection, adjuvant cisplatin/vinblastine, and radiotherapy. We now evaluate the prognosis of pathologic nodes. METHODS: Failure-free survival was calculated from a landmark 3 months after resection to account for heterogeneity in adjuvant therapy. RESULTS: Nine of 42 (21%) resected patients had no residual N2 disease. This subset of 9 had a median failure-free interval of 47.8 months from landmark, whereas the 33 patients (79%) with persistent N2 disease had a median failure-free survival of 8.2 months from landmark (P=0.01). Although 21/42 (50%) had an incomplete resection (positive highest resected node and/or margin), completeness of resection did not influence failure-free survival. There were 3 distant and no local recurrences among the N2 negative group, and 12 local recurrences among patients with residual N2 disease (P=0.041). CONCLUSIONS: These data suggest: (1) persistent N2 disease following induction chemotherapy is unfavorable; (2) patients downstaged to N2 negative may benefit from surgical resection; however, (3) 33% of N2 negative patients suffered disease relapse. (c) 2006 Wiley-Liss, Inc.

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Chest. 2006 Oct;130(4):1211-9.
Advances in Chemotherapy of Non-small Cell Lung Cancer.
Molina JR, Adjei AA, Jett JR.
Mayo Clinic and Foundation, Rochester, MN 55905. molina.julian@mayo.edu.

In the United States, lung cancer kills more men and woman than the next three most common cancers combined. Unfortunately, the long-term outcome of lung cancer is still dismal with a 5-year survival rate of 15%. However, significant improvements in median survival times and 1-year and 2-year survival rates have been achieved in the last decade. This progress has been accomplished not only because of better surgical techniques but also because of the use of platinum-based regimens with newer chemotherapy agents and, more recently, targeted therapy. The role of chemotherapy as an integral part of the treatment of lung cancer has expanded significantly, particularly in the last few years with the proven benefit of adjuvant chemotherapy. For advanced stage non-small cell lung cancer (NSCLC), chemotherapy prolongs survival and improves quality of life in patients with good performance status, and appears to provide symptomatic improvement in patients with decreased performance status. Platinum-based doublet chemotherapy regimens are now the standard of care in patients with advanced stage NSCLC, and non-platinum-based combination therapies are reasonable alternatives in certain populations. The combination of the vascular endothelial growth factor inhibitor bevacizumab and chemotherapy has proven to prolong survival. As agents such as monoclonal antibodies, small molecules inhibitors of tyrosine kinase, and direct inhibitors of proteins involved in lung cancer proliferation are being developed and tested, we are optimistic that these agents will result in improvement in the survival and quality of life of lung cancer patients.

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Cancer Radiother. 2006 Oct 9; [Epub ahead of print]
[Lung cancer: is there a place for elective nodal irradiation?]
[Article in French]
Le Pechoux C, Ferreira I, Bruna A, Roberti E, Besse B, Bretel JJ.
Departement de radiotherapie, institut Gustave-Roussy, 39, rue Camille-Desmoulins, Villejuif, France.

The use of conformal radiotherapy in lung cancer has considerably evolved with the advent of improved staging technologies and methods of radiation delivery. Patients with limited disease, inoperable for medical reasons, may be treated with conformal radiotherapy alone; patients with more advanced disease are treated with combined chemo-radiotherapy. If local control may be improved by radiotherapy dose escalation according to several studies, toxicity and more particularly pulmonary toxicity seems to be related to radiation volume. Thus the use of elective nodal irradiation is being questioned. Data for early stage (stage I) non-small-cell lung cancer treated with conformal radiotherapy or stereotactic hypofractionated radiotherapy strongly supports the use of smaller fields that do not incorporate elective nodal regions; local control and survival rates approach those of surgical series. In locally advanced non-small cell lung cancer, eliminating elective nodal irradiation allows to maximize tumor dose and minimize normal tissue toxicity in combined modality treatments; results are encouraging. The use of staging modalities such as positron emission tomography and eventually oesophageal ultrasonography is increasing, allowing to encompass the tumor volume with more accuracy. Several studies have confirmed that involved-field irradiation results into a regional nodal rate of less than 10%. Further larger-scale studies would be needed to definitely establish "no elective nodal irradiation" as a standard in non-small cell lung cancer. There are very few data concerning small cell lung cancer.

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Gan To Kagaku Ryoho. 2006 Oct;33(10):1437-40.
[Prolonged survival of gefitinib treatment in patients with advanced and previously treated non-small cell lung cancer.]
[Article in Japanese]
Nishikawa M, Kusano N, Yoshimoto N, Ito M, Kakemizu N, Nozaki M, Fujiwara M, Momiyama M, Kido Y.
Dept. of Respiratory Medicine, Fujisawa City Hospital.

The purpose of this study was to evaluate the survival outcome in patients with advanced and previously treated non-small cell lung cancer given gefitinib (GEF) at our institution.We reviewed the clinical records of 70 Japanese patients,among whom 33 received several chemotherapy treatment modalities including GEF monotherapy (GEF group),and the other 37 were given several chemotherapy treatment modalities without GEF monotherapy (non-GEF group). The median survival time (MST) after second-line chemotherapy in the GEF group was 527 days with 1-year and 2-year survival rates of 59% and 26%,respectively.The MST in the non-GEF group was 175 days with 1-year and 2-year survival rates of 21% and 16%,respectively.Overall survival after second-line chemotherapy in the GEF group was significantly longer than in the non-GEF group (hazard ratio 1.9 3;9 5% confidence interval 1.15-3.53, p=0.014). In our limited clinical experience, chemotherapy treatment including GEF monotherapy appeared to have longer survival than non-GEF treatment.

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Cancer Chemother Pharmacol. 2006 Oct 10; [Epub ahead of print]
A phase I/randomized phase II, non-comparative, multicenter, open label trial of CP-547,632 in combination with paclitaxel and carboplatin or paclitaxel and carboplatin alone as first-line treatment for advanced non-small cell lung cancer (NSCLC).
Cohen RB, Langer CJ, Simon GR, Eisenberg PD, Hainsworth JD, Madajewicz S, Cosgriff TM, Pierce K, Xu H, Liau K, Healey D.
Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, 19111, USA, roger.cohen@fccc.edu.

PURPOSE: To evaluate the toxicity profile and pharmacological properties of oral CP-547,632 alone and in combination with paclitaxel and carboplatin administered every 3 weeks, and to assess efficacy as measured by the objective response and progressive disease rates of oral CP-547,632 administered in combination with paclitaxel and carboplatin. PATIENTS AND METHODS: Patients with stage IIIB/IV or recurrent non-small cell lung cancer receiving first-line chemotherapy were treated with oral daily CP-547,632 in combination with paclitaxel 225 mg/m(2) and carboplatin AUC = 6 every 3 weeks. Pharmacokinetics parameters for CP-547,632 and paclitaxel were determined independently and during co-administration. RESULTS: Seventy patients were enrolled and 68 patients were treated, 37 in phase 1 and 31 in phase 2 (14 with the combination and 17 with chemotherapy alone). Dose-limiting toxicity of CP-547,632 250 mg by mouth daily in combination with paclitaxel and carboplatin was grade 3 rash and grade 3 diarrhea despite medical intervention. CP-547,632 did not significantly affect the pharmacologic profiles of paclitaxel and carboplatin. No subject had CR. In phase I, seven subjects (22.6%) had a confirmed partial response. In phase II, four subjects (28.6%) receiving CP-547,632 plus chemotherapy had a confirmed partial response. In the phase II chemotherapy alone group, four subjects (25%) had a confirmed partial response. CONCLUSION: The combination of CP-547,632 and paclitaxel and carboplatin was well-tolerated at doses up to 200 mg by mouth daily. Dose-limiting toxicity of CP-547,632 at 250 mg consisted of diarrhea and rash. CP-547,632 did not increase the objective response rate to chemotherapy alone in patients with advanced non-small cell lung cancer.

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Cancer Chemother Pharmacol. 2006 Oct 10; [Epub ahead of print]
Docetaxel/gemcitabine or cisplatin/gemcitabine followed by docetaxel in the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC): results of a multicentre randomized phase II trial.
Binder D, Schweisfurth H, Grah C, Schaper C, Temmesfeld-Wollbruck B, Siebert G, Suttorp N, Beinert T.
Medizinische Klinik m. S. Infektiologie und Pneumologie, Charite-Universitatsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany, daniel.binder@charite.de.

BACKGROUND: Most patients (pts) with metastatic non-small cell lung cancer (NSCLC) receive either single agents or chemotherapy doublets. Recent studies have demonstrated that triple-agent therapies may improve the response rate, but are associated with significant toxicity, and frequently do not prolong survival. A sequential triple-agent schedule may combine acceptable tolerability and good efficacy. We therefore conducted a multicentre, prospectively randomized study that evaluates a sequential three-drug schedule and a platinum-free doublet regimen. PATIENTS AND METHODS: The pts with union international contre le cancer (UICC) stage IV NSCLC were randomized to one of two schedules: in arm Doc-Gem, they received gemcitabine (900 mg/m(2), 30 min infusion) on days 1 and 8, and docetaxel (75 mg/m(2), 1 h infusion) on day 1, repeated every 3 weeks up to six cycles. In arm Cis-Gem-->Doc, gemcitabine (900 mg/m(2), days 1 and 8) and cisplatin (70 mg/m(2), 1 h infusion, day 1) were given for three cycles, followed by three cycles of docetaxel (100 mg/m(2), day 1, repeated every 3 weeks). RESULTS: One hundred and thirteen pts were randomized to arms Doc-Gem (55 pts) and Cis-Gem-->Doc (58 pts). With Doc-Gem, 20.4% of pts responded to the treatment whereas 31.0% responded in arm Cis-Gem-->Doc (overall response, intent-to-treat, difference not significant). The median time to progression was 3.6 months in arm Doc-Gem [95% confidence interval (CI) 1.4, 5.9] and 5.2 months in arm Cis-Gem-->Doc (95% CI 3.1, 7.3). The median survival was 8.7 months with treatment Doc-Gem (95% CI 5.7, 11.6) and 9.4 months with treatment Cis-Gem-->Doc (95% CI 7.8, 11.0). The 1-year survival rates were 34 and 35%, respectively. Mild to moderate leukopenia was frequently seen with both schedules. Other common adverse events (AE) were nausea/vomiting, thrombocytopenia, anaemia, diarrhoea, and infections. No significant differences in AEs were observed between the schedules except for nausea/vomiting, which occurred more frequently with Cis-Gem-->Doc. CONCLUSION: The sequential therapy comprising cisplatin, gemcitabine, and docetaxel demonstrated promising tumour control whereas the platinum-free combination (docetaxel/gemcitabine) was very well tolerated. However, the schedules resulted in comparable survival to recent large trials in pts with advanced NSCLC. The present results do not justify further phase III investigation.

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Lung Cancer. 2006 Oct 7; [Epub ahead of print]
Gemcitabine plus oxaliplatin combination (GEMOX regimen) in pretreated patients with advanced non-small cell lung cancer (NSCLC): A multicenter phase II study.
Kakolyris S, Ziras N, Vamvakas L, Varthalitis J, Papakotoulas P, Syrigos K, Vardakis N, Kalykaki A, Amarantidis K, Georgoulias V.
Department of Medical Oncology, University General Hospital of Alexandroupolis, Greece.

PURPOSE: To evaluate the activity and tolerance of gemcitabine in combination with oxaliplatin (GEMOX regimen) in pretreated patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Thirty-two patients with advanced NSCLC who had disease progression after a cisplatin- and taxane-based front-line regimen were treated with gemcitabine (1500mg/m(2) on days 1 and 8) and oxaliplatin (130mg/m(2) on day 8) every 3 weeks. The patients' median age was 62 years and the performance status (WHO) was 0 for 11, 1 for 17 and 2 for 4 patients. The treatment was second line for 22 (69%) and >/=third line for 10 (31%) patients. RESULTS: Partial response was achieved in 5 (16%) patients, stable disease in 8 (25%) and progressive disease in 19 (59%). Two patients with stable disease and one patient with progressive disease while on previous chemotherapy experienced a partial response with GEMOX regimen. The median duration of response was 2.5 months (range, 1-11.5), the median time to tumor progression 3 months (range, 1-18) and the median survival 5.6 months (range, 1-31). Grade III neutropenia occurred in five (16%) patients, grade III thrombocytopenia in two (6%) and grade III anemia in three (9%); moreover, grades II-III asthenia was reported in eight (25%) patients and grades II-III neurotoxicity in three (9%). CONCLUSION: The GEMOX combination is a relatively active and well tolerated second-line regimen in NSCLC patients pretreated with a taxane- and/or platinum-based chemotherapy.

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Pathol Biol (Paris). 2006 Oct 4; [Epub ahead of print]
[Treatment of localised lung cancer.]
[Article in French]
Depierre A, Westeel V.
Delegation a la recherche clinique, universite de Franche-Comte, hopital Saint-Jacques, CHU de Besancon, 2, place Saint-Jacques, 25030 Besancon cedex, France.

This paper focuses on stage I, II and IIIA non-small cell lung cancer treatable with local treatment. It addresses five questions raised by strategies combining local treatments with chemotherapy. Even if chemotherapy increases resectability of stage III disease, the chemotherapy-surgery combination has not been demonstrated to increase survival compared to the standard chemo-radiation treatment. The results of the study by Van Meerbeeck do not support this hypothesis. Does surgery, added to chemo-radiotherapy, improve the outcome in stage IIIAN2 disease? This was the question addressed by the study by K. Albain. There is probably not clear cut answer. However, the trimodality strategy might be interesting in patients undergoing a lobectomy and might have a negative impact when a pneumonectomy has been performed. In patients with a non resectable/inoperable cancer treated with standard chemoradiation, the concomitant strategy has been shown to be superior to sequential treatment. However, due to acute toxicity, it should be delivered to selected patients, who still need to be better defined. The chemotherapy-surgery combination is becoming standard (in stage II disease) and most cooperative groups will probably stand in favour of it in 2006. The best respective timing for chemotherapy and surgery is still debated. There are many advantages in favour of preoperative chemotherapy, including better feasibility and the higher proportion of patients who can benefit. However, there is no statistically reliable demonstration of such superiority.

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Clin Lung Cancer. 2006 Sep;8(2):135-9.
Randomized, Multicenter, Open-Label Phase II Study of Gemcitabine plus Single-Dose Versus Split-Dose Carboplatin in the Treatment of Patients with Advanced-Stage Non-Small-Cell Lung Cancer.
Schuette W, Blankenburg T, Schneider CP, Weikersthal LF, Guetz S, Laier-Groeneveld G, Virchow JC, Chemaissani A, Reck M.
City Hospital Martha-Maria Halle Doelau, Germany ; e-mail: schuette-wolfgang@web.de.

BACKGROUND: Gemcitabine/carboplatin is a convenient and effective treatment for advanced-stage non-small-cell lung cancer (NSCLC), but modification of the schedule to diminish thrombocytopenia is worthwhile. PATIENTS AND METHODS: One hundred fifty-eight chemotherapy-naive patients with stage IIIB/IV NSCLC were randomized from 15 centers in Germany to receive gemcitabine 1250 mg/m(2) on days 1 and 8 plus carboplatin area under the curve 5 on day 1 (arm A) or carboplatin area under the curve 2.5 on days 1 and 8 (arm B), every 21 days for 4 cycles. RESULTS: The 2 arms (A vs. B) were well balanced with regard to patient baseline characteristics: stage IV 72.5% versus 69%, median Eastern Cooperative Oncology Group performance status 1 versus 1. The incidence of grade 3/4 hematologic toxicity was as follows (percentage of patients in arm A vs. B): leukopenia 37.5% versus 27% (P = 0.075), granulocytopenia 36% versus 36%, and thrombocytopenia 51% versus 35% (P = 0.017). Nonhematologic toxicity was modest and comparable with both schedules. The overall response rate was 46% versus 36% (P = 0.12), and 24% versus 42% had stable disease. Median progression-free survival (5.8 months vs. 6.1 months) and overall survival (11.7 months vs. 10.7 months) were not significantly different between arms A and B. CONCLUSION: Splitting the dose of carboplatin between days 1 and 8 on the same days as gemcitabine results in a significantly decreased incidence of severe thrombocytopenia, without compromising the activity of the combination.

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Clin Lung Cancer. 2006 Sep;8(2):130-4.
Topotecan therapy in patients with relapsed small-cell lung cancer and poor performance status.
Lilenbaum RC, Huber RM, Treat J, Masters G, Kaubitzsch S, Lane S, Wissel P.
The Mount Sinai Comprehensive Cancer Center, Miami Beach, FL; e-mail: rlilenbaum@aptiumoncology.com.

Purpose: Topotecan is generally well tolerated and active in patients with relapsed small-cell lung cancer (SCLC) and poor performance status (PS). In this study, we investigated whether treatment with topotecan is associated with improvement in PS as measured by the rate of conversion from PS 2 to PS 0/1. Patients and Methods: A retrospective analysis of data from 7 clinical trials (N = 795) investigating topotecan in patients with relapsed SCLC was performed. All patients received topotecan 1.25-1.5 mg/m2 daily on days 1-5 of a 21-day cycle. Demographics were similar for patients with PS 2 and PS 0/1. A total of 152 patients with PS 2 at baseline received 502 cycles (median, 2 cycles; range, 1-14 cycles) of therapy, and 32 (21%) experienced PS improvement to PS 0/1 that lasted for >/= 2 cycles. Results: Overall, 50% of patients who experienced PS conversion also exhibited an objective antitumor response, compared with 8% of patients with PS 2 who had no improvement in PS and achieved a response. Similarly, median overall survival was longer for patients with PS improvement (37 weeks; 95% confidence interval, 29.6-49.4 weeks) compared with patients with PS 2 who had a response but no PS improvement (10.4 weeks; 95% confidence interval, 8.7-13.6 weeks). A substantial proportion of patients with PS 2 and relapsed SCLC experienced PS improvement during topotecan treatment. These patients had a substantially longer median survival and a higher response rate compared with the overall trial population. Conclusion: Improvement in PS appears to be a good indicator of benefit from topotecan therapy.

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Oncology (Williston Park). 2006 Sep;20(10):1210-9; discussion 1219, 1223, 1225.
Stage III lung cancer: two or three modalities? The continued role of thoracic radiotherapy.
Kelsey CR, Werner-Wasik M, Marks LB.
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA.

Lung cancer is the leading cause of cancer mortality in the United States. A significant number of patients present with disease involving mediastinal lymph nodes. As survival after surgery alone for stage III disease is poor, radiation therapy and chemotherapy have been evaluated in the neoadjuvant and adjuvant settings to improve outcomes. The benefit of adjuvant chemotherapy in the subgroup of patients with N2 disease is uncertain. Small randomized trials enrolling patients with stage III disease have shown a benefit of neoadjuvant chemotherapy over surgery alone. Whether neoadjuvant chemotherapy is superior to adjuvant chemotherapy is under investigation. Furthermore, whether neoadjuvant chemoradiotherapy is superior to neoadjuvant chemotherapy is controversial, and few randomized studies comparing these approaches have been reported. Nevertheless, neoadjuvant chemoradiotherapy appears to be associated with higher rates of resection, higher rates of clearance of mediastinal nodal disease, and better local/regional control. The use of postoperative radiation therapy (PORT) has declined since the publication of the 1998 meta-analysis suggested a detriment in survival with this strategy. However, radiation techniques are improving and emerging data support the use of carefully delivered PORT Finally, it remains unclear whether surgical resection offers an advantage over definitive chemoradiotherapy alone for stage III disease. In summary, locally advanced NSCLC remains a formidable challenge with few cures, and optimal treatment requires the careful use of surgery, chemotherapy, and radiation therapy.

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Med Dosim. 2006 Summer;31(2):152-62.
The clinical implementation of respiratory-gated intensity-modulated radiotherapy.
Keall P, Vedam S, George R, Bartee C, Siebers J, Lerma F, Weiss E, Chung T.
Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA.

The clinical use of respiratory-gated radiotherapy and the application of intensity-modulated radiotherapy (IMRT) are 2 relatively new innovations to the treatment of lung cancer. Respiratory gating can reduce the deleterious effects of intrafraction motion, and IMRT can concurrently increase tumor dose homogeneity and reduce dose to critical structures including the lungs, spinal cord, esophagus, and heart. The aim of this work is to describe the clinical implementation of respiratory-gated IMRT for the treatment of non-small cell lung cancer. Documented clinical procedures were developed to include a tumor motion study, gated CT imaging, IMRT treatment planning, and gated IMRT delivery. Treatment planning procedures for respiratory-gated IMRT including beam arrangements and dose-volume constraints were developed. Quality assurance procedures were designed to quantify both the dosimetric and positional accuracy of respiratory-gated IMRT, including film dosimetry dose measurements and Monte Carlo dose calculations for verification and validation of individual patient treatments. Respiratory-gated IMRT is accepted by both treatment staff and patients. The dosimetric and positional quality assurance test results indicate that respiratory-gated IMRT can be delivered accurately. If carefully implemented, respiratory-gated IMRT is a practical alternative to conventional thoracic radiotherapy. For mobile tumors, respiratory-gated radiotherapy is used as the standard of care at our institution. Due to the increased workload, the choice of IMRT is taken on a case-by-case basis, with approximately half of the non-small cell lung cancer patients receiving respiratory-gated IMRT. We are currently evaluating whether superior tumor coverage and limited normal tissue dosing will lead to improvements in local control and survival in non-small cell lung cancer.

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Invest New Drugs. 2006 May 11; [Epub ahead of print]
Cisplatin plus gemcitabine on days 1 and 4 every 21 days for solid tumors: Result of a dose-intensity study.
Parra HS, Cavina R, Latteri F, Campagnoli E, Morenghi E, Torri W, Brambilla G, Alloisio M, Santoro A.
Department of Medical Oncology and Hematology, Istituto Clinico Humanitas, Via Manzoni, 56 Rozzano-Milan, Rozzano, 20089, Italy, sotolatteri@hotmail.com.

Background: Three and 4-week cisplatin-gemcitabine schedules have shown similar dose-intensity (DI) and activity in non-small-cell lung cancer (NSCLC). The 3-week schedule is generally preferred because it enables better treatment compliance. To improve DI and compliance further, we delivered gemcitabine plus cisplatin over 4 days every 21 days.Methods: Patients with any stage NSCLC or epithelial neoplasms and an ECOG PS </=2 were given gemcitabine 1000 mg/m(2) on days 1 and 4 plus cisplatin 70 mg/m(2) on day 2 of a 21-day cycle. Minimax design was used and a received DI for gemcitabine of >/=580 mg/m(2)/wk was considered successful.Results: Thirty-nine patients (34 NSCLC, 5 epithelial neoplasias) were enrolled. SWOG grade 3-4 neutropenia and thrombocytopenia were observed in 17.9% and 12.8% of patients, respectively. Nonhematological toxicity was minimal. Twenty-eight (18%) of 158 cycles required dose modifications and/or delays. Twenty-five patients received a gemcitabine dose intensity of >/=580 mg/m(2)/wk. The received DIs were 601.8 mg/m(2)/wk for gemcitabine and 21.0 for cisplatin, with a relative DIs of 90.3% and 90.1%, respectively. The response rate of 27 evaluable patients with NSCLC was 44% (95% confidence interval [CI], 25.3 to 62.7%).Conclusions: The shorter schedule of gemcitabine on days 1 and 4 plus cisplatin on day 2 produces an effective DI and a toxicity profile comparable to that of weekly regimens.

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Crit Rev Oncol Hematol. 2006 May 10; [Epub ahead of print]
Granulocyte growth factors in the treatment of non-small cell lung cancer (NSCLC).
Grossi F, Tiseo M.
Division of Medical Oncology A, Disease Management Team-Lung Cancer, National Institute for Cancer Research, L. go R. Benzi, 10, 16132 Genova, Italy.

Neutropenia and subsequent infections are common events that limit treatment of non-small cell lung cancer (NSCLC). Granulocyte growth factors (G- and GM-CSF) have been introduced in clinical practice and their use has yielded a reduction of the infection risk related to chemotherapy and a dose increase of drug delivery. Randomized clinical trials have shown that granulocyte colony-stimulating factors and, more recently, the longer-acting pegylated granulocyte colony-stimulating factor (pegfilgrastim) effectively reduce the incidence and severity of neutropenia and of its complications. Recommendations for the use of haematopoietic colony-stimulating factors from the American Society of Clinical Oncology (ASCO) have been published in 1994 and updated in 1996, 1997 and 2000. Recently, moreover, National Comprehensive Cancer Network (NCCN) guidelines for the myeloid growth factors in cancer treatment make available. Chemotherapy-associated myelosuppression is a major limitation of anticancer therapy also in early stage, local advanced and metastatic NSCLC. Recently, dose-dense chemotherapy has been shown to improve the outcome in early stage breast cancer and non-Hodgkin's lymphoma. However, few randomized trials have been reported on chemotherapy with or without granulocyte growth factors as primary prophylaxis in NSCLC. Presently, there is no evidence for a benefit in response rate and survival from the use of granulocyte growth factors as support of chemotherapy, in particular, for locally advanced and metastatic NSCLC. In clinical practice, the role of granulocyte growth factors for NSCLC treatment should be limited following the guidelines. An appropriate use of granulocyte growth factors may reduce the overall cost of treatment and improve the quality of life, important aims in the treatment of patients with local advanced or metastatic NSCLC. In the future, we need to identify patients who can benefit from granulocyte growth factors for optimize the schedule and doses, in advanced disease and also, after the recent positive results of adjuvant chemotherapy, in early stages. This review summarizes the present knowledge on the use of granulocyte growth factors in NSCLC.

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J Clin Oncol. 2006 May 8; [Epub ahead of print]
Phase III Study Comparing Oral Topotecan to Intravenous Docetaxel in Patients With Pretreated Advanced Non-Small-Cell Lung Cancer.
Ramlau R, Gervais R, Krzakowski M, von Pawel J, Kaukel E, Abratt RP, Dharan B, Grotzinger KM, Ross G, Dane G, Shepherd FA.
Regional Lung Disease Centre, Oncology Department, Poznan; Centre of Oncology & Institute, Warsaw, Poland; Centre Francois Baclesse, Caen, France; Asklepios Klinik, Gauting bei Muenchen, Munich; Thoraxzentrum, Hamburg, Germany; University of Cape Town, Cape Town, South Africa; GlaxoSmithKline, Collegeville, PA; GlaxoSmithKline, Harlow, United Kingdom; and Princess Margaret Hospital, Toronto, Ontario, Canada.

PURPOSE: This open-label, randomized, multicenter, phase III study compared oral topotecan versus intravenous (IV) docetaxel in patients with previously treated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage III or IV NSCLC, performance status </= 2, who had received only one prior chemotherapy regimen, were randomly assigned to treatment with oral topotecan 2.3 mg/m(2)/d on days 1 to 5 or IV docetaxel 75 mg/m(2) day 1 every 21 days. RESULTS: A total of 829 patients were randomly assigned. In intent-to-treat analysis, 1-year survival rates were 25.1% with topotecan and 28.7% with docetaxel. The difference of -3.6% (95% CI, -9.59% to 2.48%) met the predefined criteria for noninferiority of topotecan relative to docetaxel because the lower limit of the 95% CI was above -10%. Median survival was 27.9 weeks with topotecan and 30.7 weeks with docetaxel. Although not statistically significant (log-rank P = .057), the higher survival rate with docetaxel was maintained across the entire treatment period. The median time to progression was 11.3 weeks with topotecan versus 13.1 weeks with docetaxel (log-rank P = .02). The overall response rate was 5% in each group. Grade 3/4 neutropenia occurred more frequently with docetaxel (60% v 50%). Grade 3/4 anemia and thrombocytopenia occurred more frequently with topotecan (26% v 10% and 26% v 7%, respectively). CONCLUSION: Oral topotecan provides activity in the treatment of relapsed, locally advanced, unresectable NSCLC. Both regimens were well tolerated with differing safety profiles. Topotecan may provide an option for patients who desire an orally available treatment after relapse.

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Internist (Berl). 2006 May 6; [Epub ahead of print]
[Lung cancer.]
[Article in German]
Huber RM.
Pneumologie, Klinikum der Universitat - Innenstadt, Ziemssenstrasse 1, 80336, Munchen, pneumologie@med.uni-muenchen.de.

Although various benign and malignant tumors can occur in the bronchi and lungs, lung cancer is by far the most common tumor and the leading cause of tumor death worldwide. For therapeutic reasons lung cancer is classified currently as small cell (SCLC) or non small cell lung cancer (NSCLC). The main cause is smoking. There are no specific symptoms that enable early detection. Staging is according to the international TNM-system. As the results of therapy to date are disappointing and many questions remain unsolved, as many patients as possible should be included in further prospective trials. In SCLC polychemotherapy is mandatory; in local tumor stages radiotherapy should be combined early on with chemotherapy, and in cases of complete remission, prophylactic cranial irradiation is indicated. In operable stages of NSCLC adjuvant chemotherapy demonstrates a survival benefit. In locally advanced NSCLC, radiochemotherapy is now the standard of care. Advanced stages require chemotherapy usually with two drugs, second-line chemotherapy is indicated in cases of relapse.

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Treat Respir Med. 2006;5(3):181-91.
Taxanes in the treatment of non-small cell lung cancer.
Fanucchi M, Khuri FR.
Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.

Paclitaxel and docetaxel, drugs that bind tightly to beta-tubulin and disrupt microtubule dynamics, are widely used in the treatment of non-small cell lung cancer (NSCLC), the most common cause of cancer death in men and women living in the US. These well tolerated drugs, alone or in combination with another cytotoxic agent, have been shown to increase the survival of patients with metastatic disease or malignant effusions. Both paclitaxel and docetaxel can be combined with concurrent chest irradiation for patients with locally advanced NSCLC. The combination of carboplatin and paclitaxel, when given postoperatively to patients with stage IB NSCLC, improved survival compared with surgery alone, with little toxicity. Taxane combinations are undergoing study as adjuvant therapy for patients with other stages of operable disease. Except for a recent trial with bevacizumab, efforts to improve the efficacy of taxane/platinum combinations in patients with advanced disease by adding a third 'targeted' drug have thus far been unsuccessful.

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Oncology (Williston Park). 2006 Apr;20(4):373-80; discussion 385-6, 388, 393 passim.
Treatment of stage I-III non-small-cell lung cancer in the elderly.
Gridelli C, Maione P, Rossi A.
Division of Medical Oncology, SG Moscati Hospital, Avellino, Italy. cgridelli@libero.it

Elderly patients with stage I-III non-small-cell lung cancer (NSCLC) constitute a peculiar patient population and need specific therapeutic approaches. Limited resections are an attractive alternative for elderly patients with resectable NSCLC because of the potential reduction in postoperative complications. Curative radiation therapy is an acceptable alternative for elderly patients who are unfit for or refuse surgery. Hypofractionated stereotactic body radiation therapy is of particular interest for this population because of its favorable tolerance. Elderly patients may tolerate chemotherapy poorly because of comorbidity and organ failure. The survival benefit obtained with adjuvant platinum-based chemotherapy in the younger population may vanish or decrease in the elderly because of a potential higher toxic death rate or lower compliance to treatment. The efficacy and feasibility of adjuvant chemotherapy for elderly patients need to be investigated in specific trials. Neoadjuvant chemotherapy remains an experimental approach under investigation in the general patient population, and consequently should not be considered in clinical practice in the elderly. Retrospective analyses on chemoradiation in elderly patients should be considered globally ambiguous and at risk of selection bias. Only specifically designed prospective studies will elucidate the real role and feasibility of this combined approach in the treatment of unselected elderly patients.

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Lung Cancer. 2006 Mar;51(3):335-345. Epub 2006 Feb 14.
Should chemotherapy combinations for advanced non-small cell lung cancer be platinum-based? A meta-analysis of phase III randomized trials.
Pujol JL, Barlesi F, Daures JP.
Departement de Biostatistiques, Epidemiologie et Recherche Clinique, Institut Universitaire de Recherche Clinique, Rue de la Cardonille, 34093 Montpellier, Cedex 5, France; Departement d'Oncologie Thoracique, Centre Hospitalier Universitaire de Montpellier, Hopital Arnaud de Villeneuve, 34295 Montpellier, Cedex, France.

BACKGROUND: Non-platinum regimens have been proposed as an alternative to the platinum-based combinations for treatment of advanced non-small cell lung cancer. However, conflicting results were reported. METHODS: Meta-analysis of phase III trials randomizing platinum-based versus non-platinum combinations as first-line chemotherapy with 1-year survival rate as a primary endpoint. Fourteen trials have been identified. Experimental arms were gemcitabine/vinorelbine (n=4), gemcitabine/taxane (n=7), gemcitabine/epirubicin (n=1), paclitaxel/vinorelbine (n=1), and gemcitabine/ifosfamide (n=1). The comparator was a doublet of a platinum compound plus a third generation agent for all but two studies (triplets). Updated data were available for 13 studies. The Peto and Yusuf method was used to generate odds ratios (OR). All tests are two-sided. RESULTS: A statistical heterogeneity was detected when the 13 studies were analyzed. Considering that current guidelines recommend platinum-based doublets as standard therapy we therefore limited the meta-analysis to the set of 11 phase III studies which used a platinum-based doublet (2298 and 2304 patients in platinum-based and non-platinum arms, respectively). No significant heterogeneity was detected in this consistent group of studies. Patients treated with a platinum-based regimen benefited from a statically significant reduction in the risk of death at 1 year (OR: 0.88, 95% CI 0.78-0.99; p=0.044) and a lower risk of being refractory to chemotherapy (OR: 0.87, 0.73-0.99; p=0.049). Forty-four (1.9%) and 29 (1.3%) toxic-related deaths were reported for platinum-based and non-platinum regimens, respectively (OR: 1.53; 0.96-2.49, p=0.08). An increased risk of grade 3-4 gastro-intestinal and hematological toxicity for patients receiving platinum-based chemotherapy was statistically demonstrated. There was no statically significant increase in risk of febrile neutropenia, OR=1.23 (0.94-1.60, p=0.063). CONCLUSION: A platinum-based doublet induced a statically significant reduction in the risk of death when compared with non-platinum chemotherapy without inducing an unacceptable increase in toxicity.

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Expert Opin Drug Saf. 2006 Mar;5(2):303-312.
Irinotecan in the treatment of small cell lung cancer: a review of patient safety considerations.
Kawahara M.
Director, Department of Medical Services, National Hospital Organization Kinki-chuo Chest Medical Center, 1180 Nagasone, Sakai, Osaka, 591-8555, Japan. kawaharam@kch.hosp.go.jp.

A water soluble derivative of camptothecin, irinotecan (CPT-11) is effective against small-cell lung cancer (SCLC), as well as non-SCLC and gastrointestinal cancers. This extended review of recently concluded and ongoing studies focuses on irinotecan in the treatment of limited (LD) and extensive (ED) SCLC specifically considering the safety of patients. Irinotecan-induced diarrhoea is pervasive, and can be severe and life-threatening especially in combination with neutropenia. It can have a significant impact on patient quality of life, negatively influencing compliance with therapy and dose-intensity. For LD SCLC, irinotecan can be administered with radiotherapy concurrently or sequentially. In a Phase III study for ED SCLC comparing etoposide and cisplatin (EP) and irinotecan and cisplatin (IP) regimens, severe myelosuppression was more frequent in the EP arm than in the IP arm, and conversely severe or life-threatening diarrhoea was more frequent in the IP arm than in the EP arm. IP resulted in significantly higher response rates and overall survival in Japan, and confirmatory Phase III studies are ongoing. Irinotecan should not be administered to patients with any degree of ongoing diarrhoea above their baseline. Irinotecan can be administered with relative safety for patients with SCLC only through careful patient monitoring, especially regarding diarrhoea and myelosuppression.

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Ann Oncol. 2006 Mar;17(3):473-83.
Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): A meta-analysis of individual data from 1764 patients.
Auperin A, Le Pechoux C, Pignon JP, Koning C, Jeremic B, Clamon G, Einhorn L, Ball D, Trovo MG, Groen HJ, Bonner JA, Le Chevalier T, Arriagada R.
Unit of Biostatistics and Epidemiology, Radiation Oncology and Medicine, Institut Gustave-Roussy, Villejuif, France.

BACKGROUND: Despite several randomised trials comparing radiotherapy alone with concomitant radio-chemotherapy in patients with locally advanced non-small cell lung cancer (NSCLC), it is not clear whether the addition of chemotherapy improves survival. PATIENTS AND METHODS: This meta-analysis was based on individual patient data from published and unpublished randomised trials which compared radiotherapy alone with the same radiotherapy combined with concomitant cisplatin- or carboplatin-based chemotherapy. Trials with accrual completed after 2000 were excluded. Trials were sought in electronic databases, clinical trial registries and by additional manual searches. The primary endpoint was overall survival analysed using the log-rank test stratified by trials. RESULTS: There were twelve eligible trials that included a total of 1921 patients. The data from 3 trials were not available. Therefore, the analysis was based on 9 trials including 1764 patients. Median follow-up was 7.2 years. The hazard ratio of death among patients treated with radio-chemotherapy compared to radiotherapy alone was 0.89 (95% confidence interval, 0.81-0.98; P = 0.02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years. There was some evidence of heterogeneity among trials and sensitivity analyses did not lead to consistent results. The combination of platin with etoposide seemed more effective than platin alone. CONCLUSIONS: Concomitant platin-based radio-chemotherapy may improve survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy.

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Ann Thorac Surg. 2006 Mar;81(3):1028-32.
Selective mediastinal lymphadenectomy for clinico-surgical stage I non-small cell lung cancer.
Okada M, Sakamoto T, Yuki T, Mimura T, Miyoshi K, Tsubota N.
Department of Thoracic Surgery, Hyogo Medical Center for Adults, Akashi City, Hyogo, Japan. morihito1217jp@aol.com

BACKGROUND: Improved radiologic imaging provides earlier detection of non-small cell lung cancer, but controversy exists regarding the need for complete lymph node dissection. This study was designed to evaluate the possibility of lesser mediastinal dissection for early-stage lung cancer. METHODS: Selective mediastinal dissection is defined as follows: Dissection of the upper mediastinum for upper-lobe tumors is performed but it is not needed for lower-lobe tumors with intact hilar and lower mediastinal nodes. Also, dissection of the lower mediastinum for an upper-lobe tumor is not routinely required when the nodes in the hilum and upper mediastinum are negative. From 1997 through 2002, 377 patients with clinico-surgical stage I non-small cell lung cancer underwent curative-intent surgery with selective dissection (group S). In addition, 358 patients with the same-stage disease who underwent complete lymphadenectomy by the same surgical team served as historic controls (group C). RESULTS: The characteristics of the two groups were well balanced. There was no significant difference in disease-free survival (p = 0.376) or overall survival (p = 0.060). Multivariate analysis showed that the dissection mode did not significantly influence either disease-free survival (p = 0.636) or overall survival (p = 0.119). The postoperative morbidity rates were 17.3% and 10.1% for group C and group S, respectively (p = 0.005). One operative death occurred in each group (0.3%). The rates of distant metastasis and local recurrence were similar in the two groups. CONCLUSIONS: Selective mediastinal dissection for clinico-surgical stage I non-small cell lung cancer proved to be as effective as complete dissection, and although large multicenter trials are warranted, it might be considered as an alternative for curative surgery in this era of minimally invasive surgery.

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Respiration. 2006;73(1):78-89.
Transbronchial needle injection: a systematic review of a new diagnostic and therapeutic paradigm.
Seymour CW, Krimsky WS, Sager J, Kruklitis RJ, Lund ME, Musani AI, Sterman DH.
Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pa., USA.

Background and Objective: Transbronchial needle catheters are commonly used during flexible and rigid bronchoscopy for needle aspiration. The use of these catheters can be expanded by employing the technique of transbronchial needle injection. Methods and Results: By injecting lesions in the airways, peribronchial structures, mediastinum, or lung parenchyma, transbronchial needle injection has been applied to the treatment of lung cancer, inflammatory disorders of the airways, recurrent respiratory papillomatosis, as well as bronchopleural fistulas. Diagnostic applications have included the localization of peripheral lung nodules as well as sentinel lymph nodes. Conclusions: Our review defines this bronchoscopic technique and summarizes its various reported applications. Copyright (c) 2006 S. Karger AG, Basel.

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Lung Cancer. 2006 Feb 16; [Epub ahead of print]
Gefitinib in patients with chemo-sensitive and chemo-refractory relapsed small cell cancers: A Hoosier Oncology Group phase II trial.
Moore AM, Einhorn LH, Estes D, Govindan R, Axelson J, Vinson J, Breen TE, Yu M, Hanna NH.
Indiana University School of Medicine, 535 Barnhill Drive, Room 473, Indianapolis, IN 46202, USA; The Hoosier Oncology Group, A Subsidiary of the Walther Cancer Institute, Indianapolis, IN, USA.

BACKGROUND: Gefitinib has demonstrated activity in patients with non-small cell lung cancer (NSCLC). Clinical trials have not demonstrated a relationship between response to gefitinib and over-expression of the epidermal growth factor receptor (EGFR). Although, EGFR is not over-expressed in small cell lung cancer (SCLC), we postulated that gefitinib might affect tumor growth through other mechanisms. Agents that are active in NSCLC usually are also effective in SCLC. METHODS: The primary objective was to assess the clinical control rate: complete response (CR) partial response (PR) and stable disease (SD>90 days), of gefitinib in patients with chemo-resistant and chemo-sensitive small cell cancers. Eligibility criteria included pathologic proof of a neuroendocrine tumor, especially small cell cancer, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2, prior treatment with one or two prior chemotherapy regimens and adequate end-organ function. Patients received gefitinib, 250mg p.o. daily until disease progression or intolerable side effects. RESULTS: From April 2003 to March 2004, 19 patients were enrolled. Small cell lung cancer accounted for 18 of the 19 patients and one patient had metastatic Merkel cell carcinoma. Twelve patients (63%) had chemo-sensitive disease, defined as progression greater than three months from completion of prior chemotherapy; 7 (37%) had chemo-refractory disease; 13 (68%) had one prior chemotherapy regimen. Other patient characteristics: mean age 64 years (range 52-79 years); ECOG PS 0/1/2=7/9/3, M:F=9:10. Grade 3 toxicities included: fatigue in three patients (15.8%), pulmonary toxicities in three (15.8%) and one patient (5.3%) each with hyperglycemia or pain. Four patients had grade four toxicities: one patient (5.3%) with fatigue and three patients (15.8%) with dyspnea. There were no patients with grade 3 or 4 rash or diarrhea. Two patients had stable disease (<90 days) and 17 had progressive disease as their best response. This study was a two-stage design and because the continuing criterion for stage one was not met, stage 2 was not performed. Median time to progression (TTP) was 50 days (95% CI=21-58 days). One year overall survival (OS) was 21% (95% CI=6-45.6%). CONCLUSION: Although gefitinib has activity in select patients with NSCLC, this study failed to demonstrate benefit in patients with small cell lung cancer.

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Lung Cancer. 2006 Feb 14; [Epub ahead of print]
Phase II study of irinotecan and docetaxel in patients with previously treated non-small cell lung cancer: An Alpe-Adria Thoracic Oncology Multidisciplinary group study (ATOM 007).
Grossi F, Fasola G, Rossetto C, Spizzo R, Meduri S, Sibau A, Vigevani E, Tumolo S, Adami G, Sacco C, Recchia L, Rizzato S, Ceschia T, Belvedere O.
Medical Oncology A, Disease Management Team-Lung Cancer, National Institute for Cancer Research, L.go R. Benzi 10, 16132 Genoa, Italy.

This study was designed to evaluate the activity and tolerability of irinotecan and docetaxel in patients with previously treated non-small cell lung cancer (NSCLC). Eligibility included recurrent or progressive NSCLC, previous chemotherapy, age >/=18 years, ECOG PS </=2. Treatment consisted of irinotecan (160mg/m(2) i.v.), followed by docetaxel (65mg/m(2) i.v.) on day 1 of a 21-day cycle, for a maximum of 6 cycles. Forty patients were enrolled. Median age was 60 years and median ECOG PS was 1. All patients were evaluable for toxicity and 31 (78%) were evaluable for response. A total of 125 cycles was administered (median, 3; range, 1-6). Most common grade 3-4 toxicities were neutropenia (62%), neutropenic fever (22%), and diarrhea (32%). Response rate was 10%; a further 40% of patients achieved stable disease. All responses were observed in patients with ECOG PS </=1, age <70 years, and who had received only one prior chemotherapy regimen. Median time to progression was 2.8 months and median survival was 7.4 months. Because of significant toxicity and limited activity, further investigation of irinotecan plus docetaxel in second line NSCLC is not recommended.

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Lung Cancer. 2006 Feb 13; [Epub ahead of print]
A phase II study of weekly paclitaxel combined with carboplatin for elderly patients with advanced non-small cell lung cancer.
Inoue A, Usui K, Ishimoto O, Matsubara N, Tanaka M, Kanbe M, Gomi K, Koinumaru S, Saijo Y, Nukiwa T.
Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, 4-1 Seiryomachi, Aoba-ku, Sendai 980-8575, Japan.

We conducted this phase II study to explore the efficacy and safety of weekly paclitaxel combined with carboplatin in elderly patients with advanced non-small cell lung cancer (NSCLC). Elderly patients (>/=70 years old) of stage IIIB, IV, or recurrent NSCLC with PS 0 or 1 were enrolled. Patients received paclitaxel at a dose of 70mg/m(2) on Days 1, 8, 15, and carboplatin at the target dose of the area under the curve (AUC) of six on Day 1 every 28 days for at least two cycles. Forty-two patients were enrolled and 40 patients were treated with a median of three cycles (range, 1-5). The overall response rate (ORR) was 45% (95% confidence interval, 30-60%). The median survival time (MST) was 14 months and the 1-year survival rate was 62%. Twenty-eight patients (70%) had grade 3/4 neutropenia and two patients (5%) experienced grade 3 febrile neutropenia. Non-hematological toxicities were generally mild to moderate and grade 3 peripheral neuropathy was seen in one patient (3%). There was one treatment-related death by infection due to neutropenia. Weekly paclitaxel and carboplatin combination chemotherapy was an effective and safe regimen in elderly patients with advanced NSCLC. A randomized trial comparing this treatment with the conventional tri-weekly regimen of paclitaxel and carboplatin is warranted.

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Eur Respir J. 2006 Feb 15; [Epub ahead of print]
Efficacy of a toxicity-adjusted topotecan therapy in recurrent small-cell lung cancer.
Huber RM, Reck M, Gosse H, von Pawel J, Mezger J, Saal JG, Kleinschmidt R, Steppert C, Steppling H.
Klinikum der Universitat, Innenstadt, Ziemssenstr. 1, 80336 Munchen.

A prospective multi-center trial investigated whether topotecan given at a starting dose of 1.25 mg.m(-2) with individual dose adjustment can improve safety in patients with relapsed/refractory SCLC without loss of efficacy.Patients received topotecan intravenously on days 1-5 every 21 days up to 6 courses. In the absence of relevant hematotoxicities topotecan was escalated to 1.5 mg.m(-2) and reduced to 1.0 mg.m(-2) in case of severe hematotoxicities.Of 170 recruited patients 73.2% had stage IV disease, 63.4% had platinum containing pre-treatment. Patients received a total of 521 courses. In 72.6% of those courses the dose remained at 1.25 mg.m(-2); in 9.1% it was reduced and in 18.3% escalated. Overall response rate was 14.1% including one complete response, 28.8% had stable disease. Median duration of response was 13.6 weeks, median survival 23.4 weeks. Clinical benefit was obvious for sensitive as well as for refractory patients. Hematotoxicity of grade 3 or 4 was clearly lower compared to standard dose of 1.5 mg.m(-2).In conclusion, topotecan in a dose of 1.25 mg.m(-2) appears to be as effective as the dose of 1.5 mg.m(-2) with reduced toxicity. Since patients with recurrent SCLC have a poor prognosis they especially benefit from the good tolerability.

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Lung Cancer. 2006 Feb 13; [Epub ahead of print]
Tracheal sleeve pneumonectomy: Long-term outcome.
Roviaro G, Vergani C, Maciocco M, Varoli F, Francese M, Despini L.
Department of Surgical Sciences, University of Milan and Department of Surgery, Ospedale Maggiore Policlinico IRCCS, Milan, Italy.

Selected primary lung cancers less than 2cm from the carina or invading the tracheo-bronchial angle, formerly considered inoperable, can be amenable to tracheal sleeve pneumonectomy (TSP). Such a delicate technique, can entail remarkable post-operative morbidity and mortality, and only few clinical series are reported. Purpose of this paper is to examine complications and long-term survival of our personal series and those reported in literature. At our academic department from 1983 to December 2004, out of 99 patients with NSCLC less than 2cm from the carina, 35 (35.4%) were deemed inoperable after conventional staging; the remaining 64 underwent surgery. Since 1993 in every patient with lung cancer we perform a thoracoscopic exploration as the first step of the intervention. Unexpected causes of inoperability were found at thoracotomy in nine patients (14.1%) and at thoracoscopy in two other patients. Of the remaining 53 patients, 52 had a right TSP and one a left TSP. Intraoperative mortality was nil. Perioperative mortality was 7.5%. Major complications occurred in 11.3% of the patients. Thirty (56.6) patients are alive and disease-free 23-97 months after surgery; for 18 (33.4%) of these, more than 5 years have elapsed after the operation. TSP is the only concrete option for treating lung cancer originating less than 2cm from the carina. The review of our experience and of other reported series suggests that, with careful selection of patients and meticulous surgical technique, operative mortality and complications are acceptable. Long-term survival and prognosis are encouraging.

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Semin Oncol. 2006 Feb;33(1 Suppl 1):17-24.
Second-line treatment options in non-small cell lung cancer: a comparison of cytotoxic agents and targeted therapies.
de Marinis F, De Santis S, De Petris L.
5th Pneumo-oncology Unit, Department of Oncology, S. Camillo-Forlanini Hospitals, Rome, Italy.

Current options for the second-line treatment of non-small cell lung cancer (NSCLC) include cytotoxic drugs, such as docetaxel and pemetrexed, and targeted therapies. Docetaxel was approved in the United States and Europe in 2000 after two phase III trials showed drug superiority versus best supportive care alone and versus alternative single-agent chemotherapy. Pemetrexed was approved in the United States and Europe in 2004 after a phase III trial showed that, compared with docetaxel, it had comparable activity (median survival time of approximately 8 months in both arms) and a more favorable toxicity profile: grade 3-4 neutropenia was observed in 5.3% versus 40.2% of patients in the pemetrexed and docetaxel arms, respectively, while febrile neutropenia was observed in 1.9% versus 12.7% of patients, respectively. In the United States, gefitinib and erlotinib have also been approved for the treatment of recurrent NSCLC (in 2003 and 2004, respectively), while in Europe the registration of these agents is currently under evaluation. This review focuses on the use of docetaxel and pemetrexed for the second-line treatment of NSCLC and compares these drugs with targeted therapies, highlighting the latest developments in pharmacogenomics that might lead to a more tailored approach to treatment.

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Cancer Biol Ther. 2005 Dec 12;4(12) [Epub ahead of print]
Evaluation of Irinotecan plus Paclitaxel in Patients with Advanced Non-Small Cell Lung Cancer.
Murren JR, Andersen N, Psyrri D, Brandt D, Nadkarni R, Rose M, Davies MJ, Parisot N, Rosenfield AT, Pizzorno G, Zelterman D.
Yale University School of Medicine, New Haven, Connecticut, USA.

Purpose: We conducted a phase II study to evaluate the efficacy and safety of the combination of irinotecan and paclitaxel in patients with advanced stage non-small cell lung cancer (NSCLC). Patients and Methods: Patients were eligible if they had histologically confirmed chemotherapy naive stage IV NSCLC or stage IIIB disease that was not suitable for combined modality therapy. Patients were treated with irinotecan 50 mg/m2 and paclitaxel 75 mg/m2 on days 1 and 8 of a 21-day cycle. If the patient did not experience >grade 1 toxicity during the first cycle, the dose of irinotecan could be escalated to 60 mg/m(2). Patients were evaluated for tumor response rate, time to progression (TTP), overall survival (OS) and toxicity. Results: Twenty-three eligible patients were treated. Two (9%) patients achieved a partial response. Eight patients (35%) had stable disease. The median number of cycles given per patient was four (range 1-29). The major toxicities were grade >/=3 neutropenia (26%) and grade 3 diarrhea (5%). The median time to progression was 2.8 months (range 0.5-21.8 months) for all patients and 4.3 months for the patients who had either stable disease or a partial response. The median overall survival was 9.2 months (range 0.5-40 months). The one- and two-year survival rates were 39% and 13%, respectively. Conclusion: The combination of irinotecan and paclitaxel is safe in advanced NSCLC and affords a survival similar to other non-platinum as well as platinum-based doublets. However, this combination does not have sufficient activity to justify further study in an unselected population. If biomarkers are developed that can guide the selection of chemotherapy in an individual patient, there may be a rationale for further evaluation of this regimen.

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Surg Endosc. 2004 Nov;18(11):1657-62.
Video-assisted thoracoscopic surgery (VATS) segmentectomy for small peripheral lung cancer tumors: intermediate results.
Shiraishi T, Shirakusa T, Iwasaki A, Hiratsuka M, Yamamoto S, Kawahara K.
Second Department of Surgery, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Fukuoka City, Fukuoka 814-0180, Japan. tshiraishi-ths@umin.ac.jp

BACKGROUND: We investigated the feasibility and suitability of video-assisted thoracoscopic surgery (VATS) segmentectomy for curing selected non-small cell lung cancer (NSCLC) with this less invasive technique. METHODS: We performed VATS segmentectomy for small (< 20 mm) peripherally located tumors and pathologically confirmed lobar lymph node-negative disease by frozen-section examination during surgery. Of the 34 patients who underwent this limited resection, 22 were treated with complete hilar and mediastinal lymph node dissection (intentional group), whereas 12 patients who were deemed to be high risk in their toleration for lobectomy underwent VATS segmentectomy with incomplete hilar and mediastinal lymph node dissection (compromised group). The surgical and clinical parameters were evaluated and compared with those of segmentectomy under standard thoracotomy to evaluate the technical feasibility of VATS segmentectomy. RESULTS: We found that VATS segmentectomy could be performed safely with a nil mortality rate and acceptably low morbidity. The mean period of observation was relatively short at 656.7 +/- 572.1 and 783.4 +/- 535.8 days in the intentional and compromised groups, respectively. At the time of writing, all intentional patients remain alive and free of recurrence. There were two cases of non-cancer-related death in the compromised group. Clinical data indicated that VATS segmentectomy caused the same number or fewer surgical insults compared with segmentectomy under standard thoracotomy. CONCLUSIONS: The present results are intermediate only; the rate of long-term survival and the advantages of the less invasive procedure still need further investigation. Nevertheless, we believe that VATS segmentectomy with complete lymph node dissection is a reasonable treatment option for selected patients with small peripheral NSCLC.

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Nat Clin Pract Oncol. 2005 Nov;2(11):554-61.
EGFR inhibitors: what have we learned from the treatment of lung cancer?
Giaccone G, Rodriguez JA.
G Giaccone is the Head of the Department of Medical Oncology, and JA Rodriguez is a member of the Department of Medical Oncology at the Free University Medical Center, Amsterdam, Netherlands.

Tyrosine kinase inhibitors directed against the epidermal growth factor receptor (EGFR) are the first molecular-targeted agents to be approved in the US and other countries for the treatment of advanced non-small-cell lung cancer after failure of chemotherapy. Some patient characteristics, such as never-smoking, female gender, East Asian origin, adenocarcinoma histology, and bronchioloalveolar subtype, are associated with a greater benefit from treatment with EGFR inhibitors. Recently, studies have identified gene mutations targeting the kinase domain of the EGFR that are related to the response to inhibitors. Most EGFR mutations predict a higher benefit from treatment compared with wild-type receptors and are correlated with clinical features related to better outcome; some EGFR mutations, however, confer drug resistance. The analysis of material usually available from lung cancer patients, using techniques such as direct sequencing to determine EGFR mutational status, can be technically challenging. In this regard, high EGFR copy number and EGFR protein detected by immunohistochemistry can also be used to select those patients who would benefit from treatment. Prospective validation of biological and clinical markers of sensitivity needs to be performed.

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Respirology. 2005 Nov;10(5):629-35.
Gemcitabine and carboplatin in the treatment of locally advanced and metastatic non-small cell lung cancer.
Leow CH, Liam CK.
Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

Gemcitabine and carboplatin in the treatment of locally advanced and metastatic non-small cell lung cancer LEOW CH, LIAM CK. Respirology 2005; 10: 629-635Objective: The aim of the study was to evaluate the response, survival advantage and toxicity profile of gemcitabine-carboplatin combination cytotoxic chemotherapy in patients with locally advanced and metastatic non-small cell lung cancer (NSCLC). Methodology: Patients who received gemcitabine-carboplatin combination chemotherapy over a 2.5-years period were analyzed. Carboplatin at a dose of 5 mg/mL/min (area under the concentration-time curve) was given on day 1 and gemcitabine (1000 mg/m(2)) on days 1 and 8, every 3 weeks. Results: Of 49 chemotherapy-naive patients (median age, 62 years) who received this treatment, 57% were males, 12% had stage IIIa, 39% stage IIIb and 49% metastatic disease. The Eastern Cooperative Oncology Group (ECOG) performance status of 70% of the patients was 1 at the time of commencement of chemotherapy and 2 for the remaining 30% of patients. The overall response rate, based on 33 evaluable patients, was 27.3%. The response rate was not affected by age, stage of disease or performance status. The median survival was 9 months. Median survival among patients with an ECOG performance status of 1 was 11 months, as compared with 4 months for patients with an ECOG performance status of 2 (P < 0.001). Toxicity was generally well tolerated and there were no treatment-related deaths. Conclusions: Gemcitabine-carboplatin combination chemotherapy is an effective and well-tolerated cytotoxic regimen among Malaysian patients with advanced NSCLC. A performance status of 1 or less was associated with a better survival.

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Lancet. 2005 Oct 29-Nov 4;366(9496):1527-37.
Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer).
Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, Thongprasert S, Tan EH, Pemberton K, Archer V, Carroll K.
Medical Oncology, Christie Hospital NHS Trust, Manchester M20 4BX, UK. nick.thatcher@christie-tr.nwest.nhs.uk

BACKGROUND: This placebo-controlled phase III study investigated the effect on survival of gefitinib as second-line or third-line treatment for patients with locally advanced or metastatic non-small-cell lung cancer. METHODS: 1692 patients who were refractory to or intolerant of their latest chemotherapy regimen were randomly assigned in a ratio of two to one either gefitinib (250 mg/day) or placebo, plus best supportive care. The primary endpoint was survival in the overall population of patients and those with adenocarcinoma. The primary analysis of the population for survival was by intention to treat. This study has been submitted for registration with ClinicalTrials.gov, number 1839IL/709. FINDINGS: 1129 patients were assigned gefitinib and 563 placebo. At median follow-up of 7.2 months, median survival did not differ significantly between the groups in the overall population (5.6 months for gefitinib and 5.1 months for placebo; hazard ratio 0.89 [95% CI 0.77-1.02], p=0.087) or among the 812 patients with adenocarcinoma (6.3 months vs 5.4 months; 0.84 [0.68-1.03], p=0.089). Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than the placebo group for never-smokers (n=375; 0.67 [0.49-0.92], p=0.012; median survival 8.9 vs 6.1 months) and patients of Asian origin (n=342; 0.66 [0.48-0.91], p=0.01; median survival 9.5 vs 5.5 months). Gefitinib was well tolerated, as in previous studies. INTERPRETATION: Treatment with gefitinib was not associated with significant improvement in survival in either coprimary population. There was pronounced heterogeneity in survival outcomes between groups of patients, with some evidence of benefit among never-smokers and patients of Asian origin.

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Cancer. 2005 Oct 28; [Epub ahead of print]
Phase II study of pemetrexed in combination with carboplatin in the first-line treatment of advanced nonsmall cell lung cancer.
Zinner RG, Fossella FV, Gladish GW, Glisson BS, Blumenschein GR Jr, Papadimitrakopoulou VA, Pisters KM, Kim ES, Oh YW, Peeples BO, Ye Z, Curiel RE, Obasaju CK, Hong WK, Herbst RS.
The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

BACKGROUND: The primary objectives of this study were to determine the efficacy and tolerability of a pemetrexed-carboplatin combination as first-line therapy in patients with advanced nonsmall cell lung cancer. METHODS: Eligibility criteria included Zubrod performance status of 0 or 1, Stage IIIB (malignant effusion) or IV disease, and no prior chemotherapy. Treatment was pemetrexed 500 mg/m(2) given intravenously and carboplatin area under the serum concentration-time curve = 6 given intravenously on Day 1 every 3 weeks for six cycles; patients could receive additional cycles at the discretion of the treating physician and patient. All patients received folic acid, vitamin B(12), and dexamethasone prophylaxis. RESULTS: Fifty patients (31 men and 19 women) were treated. The median age was 62 years. Ninety-six percent of patients had Stage IV disease, and 88% had a performance status of 1. The median number of cycles was 6; 15 patients received 8 or more cycles. There was Grade 3/4 neutropenia in 11 (22%) and 2 (4%) patients, respectively; Grade 3/4 thrombocytopenia in 1 (2%) and 0 patients, respectively. Three patients (6%) experienced Grade 3 nonhematologic side effects (diarrhea, neutropenic pneumonia, and fatigue). No patients had sensory neuropathy or alopecia > Grade 1. The partial response rate was 24%, median time to progression 5.4 months, 1-year survival 56.0%, and median survival 13.5 months. CONCLUSIONS: This is an active, very well-tolerated regimen. Trials focused on how to integrate this doublet with novel agents are warranted. Cancer 2005. (c) 2005 American Cancer Society.

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Semin Thorac Cardiovasc Surg. 2005 Fall;17(3):205-12.
Gene therapy for lung cancer.
Toloza EM.
Department of Surgery, and Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, NC.

Over the past three decades, the molecular biology of lung cancer has been progressively delineated. Concurrently, gene therapy techniques have been developed that allow targeting or replacement of dysfunctional genes in cancer cells, such as activated tumor-promoting oncogenes, inactivated tumor-suppressing, or apoptosis-promoting genes. This article will review the therapeutic implications of molecular changes associated with non-small cell lung cancer and the status of gene therapy.

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Semin Thorac Cardiovasc Surg. 2005 Fall;17(3):186-90.
Surgical strategies and outcomes after induction therapy for non-small cell lung cancer.
Burfeind WR Jr, Harpole DH Jr.
Department of Surgery, Duke University Medical Center, Durham, NC.

Surgery as the sole therapy for locally advanced non-small cell lung cancer (NSCLC) is usually not curative. Adjuvant chemotherapy has been evaluated by several randomized Phase III trials and found to confer a survival benefit over surgery alone for stage IB-IIIA NSCLC. Induction therapy applies a cytoreductive and systemic therapy before definitive locoregional therapy. Theoretical advantages include improved diffusion of chemotherapy agents into the tumor, improved compliance, and a higher complete resection rate. Results from multiple Phase II and III studies have been encouraging, but the role of surgery after induction therapy remains inconclusively defined. Randomized trials are underway to better define the role of induction therapy, and enrollment of patients into such trials should be encouraged.

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Br J Cancer. 2005 Oct 25; [Epub ahead of print]
Front-line paclitaxel and irinotecan combination chemotherapy in advanced non-small-cell lung cancer: a phase I-II trial.
Stathopoulos GP, Dimitroulis J, Antoniou D, Katis C, Tsavdaridis D, Armenaki O, Marosis C, Michalopoulou P, Grigoratou T, Stathopoulos J.
1First Oncology Deptartment, Errikos Dunant Hospital, Athens, Greece.

Our purpose was to determine the efficacy of irinotecan plus paclitaxel administered on day 1, repeated every 2 weeks, in untreated patients with advanced or metastatic non-small-cell lung cancer (NSCLC). In total, 56 patients with inoperable or metastatic stage III and IV NSCLC with a histologically or cytologically confirmed diagnosis were enrolled. None of the patients had undergone prior chemotherapy or radiation therapy. Treatment involved irinotecan 125 mg m(-2) and paclitaxel 135 mg m(-2) administered on day 1 and repeated every 2 weeks for a planned number of nine cycles. With a standard dose of paclitaxel at 135 mg m(-2), the dosage of irinotecan was escalated at four levels: 75, 100, 125 and 150 mg m(-2); 125 mg m(-2) was established as the maximum tolerated dose; this dosage was administered to 46 patients. A total of 52 patients (median age 65 years, range 38-77 years) were assessable for toxicity and survival and 46 for response rate. Out of 46 evaluable patients, 19 achieved partial response (41.3%), 17 had stable disease (37%) and 10 (21.7%) experienced disease progression. The median duration of response was 6 months (range 2-9+ months). The main adverse reactions were myelotoxicity (grades 3 and 4) in 10 (19.2%) patients and diarrhoea (grade 3) in four (7.7%) patients. Irinotecan combined with paclitaxel, administered every 2 weeks, appears to be an effective treatment for advanced-stage NSCLC.British Journal of Cancer advance online publication, 25 October 2005; doi:10.1038/sj.bjc.6602827.

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Oncologist. 2005 Oct;10(9):728-33.
Paclitaxel/Carboplatin/Etoposide Versus Paclitaxel/Topotecan for Extensive-Stage Small Cell Lung Cancer: A Minnie Pearl Cancer Research Network Randomized, Prospective Phase II Trial.
Greco FA, Thompson DS, Morrissey LH, Erland JB, Burris HA 3rd, Spigel DR, Joseph G, Corso SW, Spremulli E, Hainsworth JD.
Sarah Cannon Research Institute, 250 25th Avenue North, Suite 110, Nashville, Tennessee 37203, USA. Telephone: 615-329-7274; Fax: 615-986-0029; e-mail fgreco@tnonc.com.

Purpose. To compare the combination of paclitaxel (Taxol((R)); Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) and topotecan (Hycamtin((R)); Glaxo SmithKline, Philadelphia, http://www.gsk.com) with paclitaxel, carboplatin (Paraplatin((R)); Bristol-Myers Squibb), and etoposide (Etopophos((R)), VePesid((R)); Bristol-Myers Squibb) in patients with previously untreated extensive-stage small cell lung cancer.Patients and Methods. In this phase II trial, 120 patients were randomly allocated to receive either topotecan (1.5 mg/m(2) i.v. days 1, 2, and 3) and paclitaxel (175 mg/m(2) i.v. day 1) every 21 days orpaclitaxe l (200mg/m(2) i.v. day 1), carboplatin (area under the concentration-time curve 6 i.v. day 1), and etoposide (50 mg/100 mg alternating daily by mouth days 1-10) every 21 days, each regimen for a maximum of eight cycles. The primary end points were objective response rate and time to progression.Results. The paclitaxel-carboplatin-etoposide combination produced a significantly higher overall response rate (78% versus 48%), longer median time to progression (7.6 months versus 5.5 months), and greater number of patients free from progression at 1 year (14% versus 8%) compared with paclitaxel plus topotecan. There was no difference in overall survival. Toxicities were similar in the two treatment arms.Conclusions. The paclitaxel-carboplatin-etoposide combination produced a superior overall response rate and time to progression in patients with extensive-stage small cell lung cancer compared with paclitaxel plus topotecan. The platinum compounds continue to be a necessary component of the initial therapy for these patients.

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Ann Oncol. 2005 Oct 25; [Epub ahead of print]
A randomized phase II trial comparing every 3-weeks carboplatin/paclitaxel with every 3-weeks carboplatin and weekly paclitaxel in advanced non-small cell lung cancer.
Socinski MA, Ivanova A, Bakri K, Wall J, Baggstrom MQ, Hensing TA, Mears A, Tynan M, Beaumont J, Peterman AH, Niell HB.
Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.

BACKGROUND: The optimal schedule of taxane administration has been an area of active interest in several recent clinical trials. METHODS: To address a pure schedule question, we randomized 161 patients with advanced stage IIIB or IV non-small-cell lung cancer (NSCLC) to either paclitaxel 225 mg/m(2) every 3 weeks x 4 cycles or 75 mg/m(2)/week x 12 (cumulative dose on each arm = 900 mg/m(2)). Both arms received concurrent carboplatin AUC 6 every 3 weeks x 4 cycles. RESULTS: The two arms were well-balanced in terms of known prognostic factors. The overall response rate and survival outcomes were similar on the two arms. There was significantly more grade 3/4 thrombocytopenia and grade 2-4 anemia on the weekly arm but less severe myalgias/arthralgias and alopecia. No difference in the rates of peripheral neuropathy was observed; however, patients on the every 3 weeks arm reported significantly more taxane therapy-related side-effects on the functional assessment of cancer therapy taxane subscale. CONCLUSIONS: This randomized trial exploring schedule-related issues with carboplatin/paclitaxel confirms the versatility of this regimen.

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J Clin Oncol. 2005 Oct 24; [Epub ahead of print]
Multicenter Phase I/II Study of Cetuximab With Paclitaxel and Carboplatin in Untreated Patients With Stage IV Non-Small-Cell Lung Cancer.
Thienelt CD, Bunn PA Jr, Hanna N, Rosenberg A, Needle MN, Long ME, Gustafson DL, Kelly K.
Division of Medical Oncology and Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Aurora, CO; Indiana University, Indianapolis, IN; Bendheim Cancer Center, Greenwich, CT; and ImClone Systems Incorporated, Branchburg, NJ.

PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have demonstrated antitumor activity in patients with non-small-cell lung cancer (NSCLC). This study examined the safety profile of the monoclonal antibody EGFR inhibitor, cetuximab, when added to paclitaxel and carboplatin in untreated patients with stage IV NSCLC. Secondary objectives included efficacy and paclitaxel and carboplatin pharmacokinetics during cetuximab treatment. PATIENTS AND METHODS: Patients with tumor evidence of EGFR by immunohistochemistry, performance status of 0 to 2, and measurable disease received paclitaxel 225 mg/m(2) with carboplatin area under the curve = 6 on day 1 every 3 weeks. Cetuximab was administered at 400 mg/m(2), 1 week before paclitaxel and carboplatin, then weekly at 250 mg/m(2). The regimen continued until disease progression or intolerable toxicity. RESULTS: Thirty-one of 32 enrolled patients were treated. The most common cetuximab toxicity was rash in 84% of patients (grade 3 in 13%). Pharmacokinetic sampling did not reveal an interaction between carboplatin, paclitaxel, and cetuximab. An objective response was observed in eight patients (26%). With a median follow-up of 19 months, the median time to progression was 5 months, median survival was 11 months, and the 1- and 2-year survival rates were 40% and 16%, respectively. CONCLUSION: The combination of cetuximab, paclitaxel, and carboplatin was safe and well tolerated in this population of stage IV patients. The response rate, time to progression, and median survival were slightly superior to historical controls treated with paclitaxel and carboplatin alone. A randomized phase II trial has completed accrual.

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Ann Thorac Surg. 2005 Sep;80(3):1021-6.
Proper treatment selection may improve survival in patients with clinical early-stage nonsmall cell lung cancer.
Birim O, Kappetein AP, Goorden T, van Klaveren RJ, Bogers AJ.
Department of Cardiothoracic Surgery, Erasmus MC Rotterdam, Rotterdam, The Netherlands.

BACKGROUND: In patients with early-stage nonsmall cell lung cancer treatment selection is rarely assessed. Many surgical papers report only the outcome of patients who underwent surgery although selection may influence the outcome. In this report, treatment selection and the outcome of both surgically and nonsurgically treated patients is evaluated. METHODS: Three hundred sixty patients (269 surgically treated and 91 nonsurgically treated) with clinical stage I and II were included. Risk factors were scaled according to the Charlson comorbidity index (CCI). Hospital morbidity and long-term survival were evaluated. RESULTS: Mean age was 64 years for the surgical and 74 for the nonsurgical patients. Mean CCI score was 1.3 and 2.4, and 5-year survival was 47% and 3%, respectively. Male sex, pneumonectomy, and CCI score of 3 or more were predictive for major postoperative complications. For the nonsurgical patients receiving radiotherapy, the 2-year survival was 40%; for the patients receiving no radiotherapy, 2-year survival was 5%. Male sex, age, treatment, and clinical stage were prognostic for survival. Patients with a CCI score of 3 or more showed a better survival after surgery than after radiotherapy. Patients with a CCI score of 3 or more who were surgically treated had a higher prevalence of forced expiratory volume in 1 second of 70% or more compared with the patients receiving radiotherapy. CONCLUSIONS: Patients with a CCI score of 3 or more have an increased risk of major postoperative complications. Nevertheless, patients with a CCI score of 3 or more show a better survival after surgery than after radiotherapy. For patients with significant comorbidity but with sufficient pulmonary reserve, surgery offers the best outcome. For patients with a high CCI score and insufficient pulmonary reserve or for those who refuse surgery curative, radiotherapy is a good alternative.

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J Surg Oncol. 2005 Aug 24;91(4):237-242 [Epub ahead of print]
Retrospective review of lung cancer patients with pleural dissemination after limited operations combined with parietal pleurectomy.
Ohta Y, Shimizu Y, Matsumoto I, Tamura M, Oda M, Watanabe G.
Department of General and Cardiothoracic Surgery, Kanazawa University School of Medicine, Kanazawa, Japan.

BACKGROUND AND OBJECTIVES: The long-term control of malignant effusion is necessary to achieve long-term survival in lung cancer patients with carcinomatous pleuritis. This report describes our results of limited operations including parietal pleurectomy (pl) on a hypothesis that the most effective target area for controlling malignant pleural effusion is the parietal pleura. METHODS: Forty-two patients with pleural dissemination with/without malignant pleural effusion were analyzed retrospectively. The operative procedures used were partial resection of the primary site with pl in 20 cases, segmentectomy with pl in 2 cases, lobectomy with pl in 19 cases, and pl only in 1 case. Postoperative adjuvant treatment was performed in 31 patients. RESULTS: Adenocarcinoma was the dominant histology, and the pathological stages were IIIB in 34 cases and IV (intrapulmonary metastasis) in 8 cases. The overall 3-, 5-, and 10-year survival rates were 30.1%, 17.2%, and 10.3%, respectively. When stratified by the TNM classification, the overall 3-, 5-, and 10-year survival rates were 56.3%, 32.1%, and 24.1%, respectively, in the T4N0M0 group and 21.1%, 7.0%, and 0%, respectively, in the T4N1-2M0 group (P = 0.0257). Among the 24 patients whose recurrent patterns could be identified, only 2 patients developed recurrent malignant effusion. CONCLUSIONS: With appropriate patient selection, the use of limited surgery combined with pl followed by intrapleural and systemic chemotherapy appears to be effective in management of the disease. J. Surg. Oncol. 2005;91:237-242. (c) 2005 Wiley-Liss, Inc.

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Arch Bronconeumol. 2005 Aug;41(8):430-433.
T2N1M0 Non-Small Cell Lung Cancer: Surgery and Prognostic Factors.
[Article in English, Spanish]
Padilla J, Calvo V, Penalver J, Jorda C, Escriva J, Ceron J, Garcia Zarza A, Pastor J, Blasco E.
Servicio de Cirugia Toracica. Hospital Universitario La Fe. Valencia. Espana.

Objective: To determine the prognostic factors for the survival in a group of patients operated on for a non-small cell lung cancer classified as T2N1M0. Patients and methods: Two hundred sixteen patients treated exclusively with surgery were studied. Kaplan-Meier survival and Cox multivariable regression analyses were used. RESULTS: The overall survival rate was 39.8% at 5 years and 29.9% at 10 years. Sex, age, presence or absence of symptoms, type of resection, number, and location of affected lymph nodes had no effect on survival. Tumor size (P=.04) and histologic type (P=.03) did significantly affect prognosis. Both variables entered into the Cox multivariable regression model. CONCLUSIONS: Patients operated on for non-small cell lung cancer classified as T2N1M0 have an overall probability of 5-year survival of approximately 40%. However, the prognosis for this group of patients is heterogeneous: in our study it was affected by the histologic type (45.5% for squamous cell and 25% for non-squamous cell cancers) and tumor size (53% for tumors with a diameter of </=3 cm, 45% for tumors between 3.1 and 5 cm, and 29% for a tumor diameter >5 cm).

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Int J Radiat Oncol Biol Phys. 2005 Aug 19; [Epub ahead of print]
Stereotactic body radiation therapy of early-stage non-small-cell lung carcinoma: Phase I study.
McGarry RC, Papiez L, Williams M, Whitford T, Timmerman RD.
Department of Radiation Oncology, Indiana University, Indianapolis, IN.

PURPOSE: A Phase I dose escalation study of stereotactic body radiation therapy to assess toxicity and local control rates for patients with medically inoperable Stage I lung cancer. METHODS AND MATERIALS: All patients had non-small-cell lung carcinoma, Stage T1a or T1b N0, M0. Patients were immobilized in a stereotactic body frame and treated in escalating doses of radiotherapy beginning at 24 Gy total (3 x 8 Gy fractions) using 7-10 beams. Cohorts were dose escalated by 6.0 Gy total with appropriate observation periods. RESULTS: The maximum tolerated dose was not achieved in the T1 stratum (maximum dose = 60 Gy), but within the T2 stratum, the maximum tolerated dose was realized at 72 Gy for tumors larger than 5 cm. Dose-limiting toxicity included predominantly bronchitis, pericardial effusion, hypoxia, and pneumonitis. Local failure occurred in 4/19 T1 and 6/28 T2 patients. Nine local failures occurred at doses </=16 Gy and only 1 at higher doses. Local failures occurred between 3 and 31 months from treatment. Within the T1 group, 5 patients had distant or regional recurrence as an isolated event, whereas 3 patients had both distant and regional recurrence. Within the T2 group, 2 patients had solitary regional recurrences, and the 4 patients who failed distantly also failed regionally. CONCLUSIONS: Stereotactic body radiation therapy seems to be a safe, effective means of treating early-stage lung cancer in medically inoperable patients. Excellent local control was achieved at higher dose cohorts with apparent dose-limiting toxicities in patients with larger tumors.

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Expert Rev Anticancer Ther. 2005 Aug;5(4):657-66.
Current role of image-guided ablative therapies in lung cancer.
Simon CJ, Dupuy DE.
Department of Diagnostic Imaging, Brown Medical School, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA. csimon2@lifespan.org

Lung cancer is the leading cause of cancer-related mortality in the USA. Until recently, lung cancer treatment options (dependent upon the tumor grading and staging at presentation, and patient comorbidities) included surgical resection (lobar or sublobar), chemotherapy and external-beam radiation therapy. While these options are still viewed as the primary standard of care, newer minimally invasive percutaneous ablative techniques such as radiofrequency ablation, microwave ablation and cryoablation are currently being examined as treatment alternatives, especially in the setting of the nonsurgical candidate. This review will focus on these three distinct thermoablative techniques in the percutaneous setting of lung cancer treatment.

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J Clin Oncol. 2005 Aug 20;23(24):5774-8.
Phase II Trial of the Novel Retinoid, Bexarotene, and Gemcitabine Plus Carboplatin in Advanced Non-Small-Cell Lung Cancer.
Edelman MJ, Smith R, Hausner P, Doyle LA, Kalra K, Kendall J, Bedor M, Bisaccia S.
University of Maryland Greenebaum Cancer Center, 22 S Greene St, Baltimore, MD 21201-1595; e-mail: Medelman@umm.edu.

PURPOSE Platinum-based chemotherapy is the standard treatment for advanced non-small-cell lung cancer (NSCLC). Unfortunately, a plateau in efficacy with currently available agents has been reached. Previous studies of the retinoid, bexarotene, a retinoid X receptor-specific ligand, have indicated that it may improve outcome in advanced NSCLC. PATIENTS AND METHODS Patients with previously untreated stage IIIB or stage IV disease, a performance status of 0 to 2, and adequate organ status were entered. Treatment consisted of up to six cycles of carboplatin (area under the curve = 5.0 on day 1) and gemcitabine (1,000 mg/m(2) on days 1 and 8) administered every 21 days. Bexarotene 400 mg/m(2) orally was to be administered continuously beginning on day 1 and until progression of disease. All patients received atorvastatin 10 mg orally beginning before bexarotene. The objective was to demonstrate a 1-year survival rate of more than 50%. Results Forty-eight patients were entered; all were assessable for survival, and 47 were assessable for toxicity and response. The therapeutic regimen was well tolerated except for hypertriglyceridemia. The median time to progression was 6.7 months, and overall median survival was 12.7 months. There was a 25% response rate and a 1-year survival rate of 53%. These results were compared with the outcome of 33 patients treated at our institution with two-drug, platinum-based chemotherapy on controlled trials with similar entry criteria in the previous 5 years. CONCLUSION Bexarotene can be safely added to platinum-based chemotherapy provided that there is aggressive prophylaxis of hypertriglyceridemia. The median time to progression and overall survival are promising and warrant further evaluation of bexarotene in advanced NSCLC.

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Cancer Invest. 2005;23(4):296-302.
Gefitinib in patients with advanced non-small cell lung cancer (NSCLC): the expanded access protocol experience at the University of Pennsylvania.
Veronese ML, Algazy K, Bearn L, Eaby B, Alavi J, Evans T, Stevenson JP, Shults J.
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA. luisa.veronese@pharma.novartis.com

Gefitinib (Iressa; AstraZeneca Pharmaceuticals, Wilmington, DE) is an oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) with favorable toxicity and antitumor activity in pretreated patients with non-small cell lung cancer (NSCLC). The purpose of this study was to evaluate the toxicity and efficacy of gefitinib in patients with advanced NSCLC treated at our institution as part of an expanded access protocol; 112 patients with advanced NSCLC were entered. All patients had failed at least one previous chemotherapy regimen, or were not suitable for any systemic chemotherapy because of poor performance status (PS), or were ineligible for other clinical trials. Therapy consisted of gefitinib 250 mg orally once daily; 10.5% (95% CI 5.3-17.9%) of patients achieved partial/minimal response (PR/MR) and 29.5% (95% CI 21.0-39.2%) had stable disease (SD), resulting in a disease control rate (PR/MR+SD) of 40% (95% CI 31-50%). The median duration of treatment for all patients was 12 weeks (range 2-116 weeks) and for patients achieving disease control 28 weeks (range 8-116). Nine patients received gefitinib for more than 1 year. Median survival was 30 weeks. Symptoms were improved in 36% of evaluable patients, and 64% of patients who achieved disease control experienced improvement of their disease related symptoms. Adverse events were generally mild and consisted mostly of skin rash (48%) and diarrhea (38%). A statistically significant association was observed between disease control and skin rash (p = < 0.001), nonsmoking status (p = 0.048), and symptom improvement (p = 0.001). The disease control rate was not statistically associated with histology, PS, gender, or number of prior treatments. In addition, longer survival was significantly associated with skin rash (p = < 0.001) and symptom improvement (p = < 0.001). Gefitinib demonstrated relevant clinical activity and a favorable toxicity profile in pretreated patients with advanced NSCLC. The development of toxicity was associated with a favorable response. In addition, a history of never having smoked seems to predict a higher efficacy of gefitinib.

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Chest. 2005 Aug;128(2):947-57.
Chemotherapy for elderly patients with non-small cell lung cancer: a review of the evidence.
Gridelli C, Shepherd FA.
Division of Medical Oncology, S.G. Moscati Hospital, Via Circumvallazione 68, 83100 Avellino, Italy. cgridelli@libero.it

Chemotherapy for elderly patients with non-small cell lung cancer (NSCLC) has been questioned due to the perceived potential for higher toxicity in this population, possibly attributable to progressive organ failure and comorbidities. This non-systematic review presents the authors' selection of key evidence for the use of chemotherapy for elderly patients with NSCLC. To date, single-agent chemotherapy with agents such as vinorelbine, gemcitabine, docetaxel, and paclitaxel has been a reasonable option. Data on non-platinum-based combinations are limited, but recent investigations of gemcitabine plus vinorelbine failed to show superiority over either agent alone. Retrospective subset analyses from large randomized trials suggest that the efficacy and tolerability of platinum-based combination chemotherapy are similar in both the elderly and their younger counterparts. Further phase III trials that specifically examine platinum-based combinations in selected elderly NSCLC patients are therefore warranted. The potential impact of new targeted therapies-alone or in combination with chemotherapy-is being investigated.

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Clin Oncol (R Coll Radiol). 2005 Aug;17(5):332-6.
A phase I study of moderate-dose radiation therapy and weekly gemcitabine in patients with locally advanced non-small cell lung cancer not suitable for radical chemoradiation therapy.
Burmeister BH, Fielding DI, Ramsay JR, Baumann KC, Dauth M, Walpole ET.
University of Queensland, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia. bryan_burmeister@health.qld.gov.au

AIMS: To describe the toxicity and response seen in patients receiving moderate-dose radiation therapy with concurrent weekly low-dose gemcitabine in the management of locally advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Eighteen patients with confirmed NSCLC were enrolled over a 17-month period from August 2000 until January 2002. All had localised disease but were considered unsuitable for curative therapy. Radiation therapy was given to a dose of 30 Gy in 15 fractions over 3 weeks. Gemcitabine was given weekly before and within 3 h of fractions 1, 6 and 11. The study was designed as a dose-escalation study, commencing at 100 mg/m2 and increasing at levels of 50 mg/m2, until the maximum tolerated dose (MTD) was reached. RESULTS: The MTD was regarded as being 150 mg/m2. The major acute toxicity observed was oesophagitis. Skin reactions were also reported. The overall response rate in all patients was 88%, with 44% achieving a complete response. CONCLUSION: The combination of gemcitabine and moderate-dose radiation therapy is feasible, and offers low toxicity and excellent response rates in patients with localised NSCLC not suitable for high-dose therapy.

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Invest New Drugs. 2005 Aug 2; [Epub ahead of print]
Gemcitabine and vinorelbine (GV) versus cisplatin, gemcitabine and vinorelbine (CGV) as first-line treatment in advanced non small cell lung cancer: Results of a prospective randomized phase II study.
Esteban E, Fra J, Fernandez Y, Corral N, Vieitez JM, Palacio I, de Sande JL, Fernandez JL, Muniz I, Villanueva N, Estrada E, Mareque B, Una E, Buesa JM, Lacave AJ; on behalf of the Grupo Oncologico del Norte de Espana ("GON").
Clinical Oncology Services, Hospital de Ponferrada, Asturias, Spain, eestebang@seom.org.

The objective of this study was to assess whether adding cisplatin to gemcitabine/vinorelbine combination improves the clinical outcome in patients with non-small-cell lung cancer (NSCLC). Chemotherapy-naive patients with advanced NSCLC; age </=75 years: Karnofsky performance status >/=60%, and with adequate hematological, renal and hepatic function, were randomized into 2 treatment groups to receive Gemcitabine 1250 mg/m(2) + vinorelbine 30 mg/m(2) (GV group), or cisplatin 50 mg/m(2) + gemcitabine 1000 mg/m(2) + vinorelbine 25 mg/m(2) (CGV group). All drugs were administered on days 1 and 8 every three weeks: From September 1999 to March 2003, 114 patients were enrolled. No statistically significant difference was observed in GV vs CGV group in objective response (37 versus 47%, respectively; P = 0.5), median time to progression (5 versus 5.8 months; P = 0.6), overall survival (9 versus 10 months; P = 0.9) and 1-year survival (26 versus 28%; P = 0.9). Conversely, toxicities were significantly higher for CGV, including grade 3-4 neutropenia (24 versus 45%); neutropenic fever (4 versus 14%, including one toxic death); grade 3-4 thrombocytopenia (2 versus 14%); and grade 3-4 emesis (2 versus 14%). Our results suggest that the combination of gemcitabine and vinorelbine is less toxic than three-drug combination with cisplatin while showing similar efficacy.

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Lung Cancer. 2005 Jun;48(3):399-407. Epub 2005 Jan 23.
Phase II trial of karenitecin in patients with relapsed or refractory non-small cell lung cancer (CALGB 30004).
Miller AA, Herndon JE 2nd, Gu L, Green MR; The Cancer and Leukemia Group B.
Comprehensive Cancer Center of Wake Forest University, Medical Center Blvd., Winston-Salem, NC 27157, USA.

PURPOSE:: This Phase II trial was designed to determine the response rate, survival, failure-free survival, and toxicity of second-line therapy with karenitecin in patients with relapsed or refractory non-small cell lung cancer (NSCLC). METHODS:: Eligibility criteria included: only one prior chemotherapy program, measurable disease, performance status 0-1, adequate hematologic, renal, and hepatic function. Cases were stratified as relapsed or refractory. RESULTS:: Fifty-five patients were accrued and 52 were eligible of whom 28 had relapsed and 24 had refractory disease. Overall patient characteristics were: median age 63 years (range, 45-79 years), 52% males, 63% performance status 1, 50% adenocarcinoma, 21% squamous, 15% large cell, and 12% undifferentiated NSCLC. In both strata, one patient each (4%) had a partial response and 12 patients each (43% for relapsed, 50% for refractory) had stable disease. Median survival was 10.4 months (95% CI, 8.5-17.0) for relapsed NSCLC and 6.0 months (95% CI, 3.7-9.7) for refractory NSCLC. One-year survival was 36% (95% CI, 14-58%) and 21% (95% CI, 5-37%) for relapsed and refractory NSCLC, respectively. Frequent toxicities were neutropenia (grade 3/4 in 15/15%) and thrombocytopenia (grade 3/4 in 17/8%). No patient had lethal toxicity. CONCLUSION:: Second-line treatment with karenitecin was tolerable with reversible bone marrow suppression as the major toxicity. The partial response rates, median survival times, and 1-year survival rates in the relapsed and refractory subgroups are comparable to overall second-line outcomes for other agents considered active in this clinical setting.

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Intern Med J. 2005 Jun;35(6):336-42.
Cisplatin and gemcitabine induction chemotherapy followed by concurrent chemoradiotherapy or surgery for locally advanced non-small cell lung cancer.
Byrne MJ, Phillips M, Powell A, Cameron F, Joseph D, Spry N, Dewar J, Van Hazel G, Buck M, Lund H, De Melker Y, Newman M.
Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.

Abstract Background: We report a study of induction chemotherapy followed by concurrent chemoradiotherapy for stage IIIA/IIIB non-small cell lung cancer. Methods: Patients received two cycles of induction chemotherapy with cisplatin 100 mg/m(2) on day 1 and gemcitabine 1000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. If the disease was unresectable, surgery was followed with two further cycles. If unresectable, patients received cisplatin 100 mg/m(2) day 1, 29 with 5-fluorouracil 1000 mg/m(2) per 24 h continuous infusion for 96 h on days 2-5 and days 30-33 of the radiotherapy administration. Radiation therapy consisted of 63 Gy, 35 fractions, 7 weeks. Results: Of 48 patients, 40% had a partial response to induction chemotherapy. Four of eleven patients with stage IIIA tumours had resectable disease. The remaining seven patients plus 37 with stage IIIB disease had chemoradiotherapy. Response at the completion of all therapy was 62% (IIIA 73%, IIIB 59%). For all patients the median survival was 15.3 months: 1 year and 3 years, 58% and 25%, respectively. Those with IIIB disease responding to induction chemotherapy had significantly superior survival to those that did not respond (37 months vs 11 months; P = 0.005). This remained significant from a landmark at 8 weeks after the start of treatment (P = 0.01). Conclusion: These results are equivalent to other studies using induction chemotherapy prior to concurrent chemoradiotherapy. Response to induction chemotherapy may have major prognostic significance. (Intern Med J 2005; 35: 336-342).

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Int J Radiat Oncol Biol Phys. 2005 Jun 1;62(2):342-50.
Phase I study of thoracic radiation dose escalation with concurrent chemotherapy for patients with limited small-cell lung cancer: Report of Radiation Therapy Oncology Group (RTOG) protocol 97-12.
Komaki R, Swann RS, Ettinger DS, Glisson BS, Sandler AB, Movsas B, Suh J, Byhardt RW.
Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX USA.

Purpose: The purpose of RTOG 97-12 was to determine the maximum tolerated dose (MTD) of thoracic radiation therapy (RT) with concurrent chemotherapy for patients with limited-stage small-cell lung cancer. Patients and Methods: Sixty-four patients received four cycles of cisplatin (60 mg/m(2) i.v.) and etoposide (120 mg/m(2) i.v. Days 1-3) (PE), with concurrent thoracic RT starting on Day 1. Thoracic RT was given during the first two cycles with 1.8 Gy/fraction daily to the clinical target volume, followed by thoracic RT to the gross tumor volume b.i.d. for the last 3, 5, 7, 9, or 11 treatment days (total dose 50.4, 54.0, 57.6, 61.2, or 64.8 Gy, respectively). The MTD was based on the dose that produced Grades 3-4 nonhematologic toxicity (mainly esophagitis and pneumonitis) in greater than 50% of patients. Results: After the first 8 patients were enrolled in Arm 1, administration of etoposide was changed from 120 mg/m(2) i.v. on Days 2 and 3 of each cycle to 240 mg/m(2) p.o. for patient convenience as outpatients. Total thoracic RT doses from 50.4 Gy to 61.2 Gy over 5 weeks given with PE were well tolerated. Three of the first 5 patients in the 64.8 Gy arm developed Grade 3 acute esophagitis; the MTD was determined to be 61.2 Gy. Fifty-four (87%) of the 62 evaluable patients achieved a complete (68%) or partial (19%) tumor response. The 18-month survival was 25% for patients receiving 50.4 Gy and 82% for those receiving 61.2 Gy. Conclusions: The MTD for this accelerated thoracic RT regimen with concurrent PE was 61.2 Gy over 5 weeks.

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Eur J Cardiothorac Surg. 2005 Jun;27(6):1099-105. Epub 2005 Mar 2.
Early and long-term results of lung resection for non-small-cell lung cancer in patients with severe ventilatory impairment.
Magdeleinat P, Seguin A, Alifano M, Boubia S, Regnard JF.
Hopital Hotel-Dieu, Unite de Chirurgie Thoracique, 1 Place du Parvis Notre-Dame, 75004 Paris, France.

Objective: To study clinical characteristics, surgical treatment modalities, early and long-term outcome of patients with severe ventilatory impairment undergoing lung resection for NSCLC. Methods: We performed a retrospective review of clinical records of all patients with severe chronic ventilatory impairment (FEV1 and/or FVC</=50% of predicted values) operated on for NSCLC in a 21-year period (1983-2003). Results: One hundred and six patients were operated on. Mean FEV1 and FVC were 40% (range 23-50%) and 69% (17-117%), respectively. An obstructive pattern was observed in 87 cases (82%). Extent of maximal exeresis was based on the assessment of predicted post-operative FEV1 (ppoFEV1). Major resections were contraindicated if ppoFEV1 was lower than 30%. Sixteen pneumonectomies, 73 lobectomies and 17 sublobar resections were carried out. Pathologic stages were I, II, IIIA and IIIB in 58, 26, 18 and 4 cases, respectively. Resection was complete in 104 patients. Operative mortality and morbidity were 8.5% (n=9) and 70% (n=74), respectively. Twenty-two patients needed prolonged (>48h) mechanical ventilation. Overall mean ppoFEV1 loss was 9.1% (0-34%). If ppoFEV1 loss was >15%, the morbidity rate was 100%. Mean PaCO2 and ppoFEV1 loss were higher among patients who died (41mmHg versus 37mmHg, P=0.02 and 13.2% versus 8.5%, P=0.025, respectively) as compared with operative survivors. Among patients with PaCO2>39mmHg and ppoFEV1 loss>15% (n=9), mortality rate was 33%. Overall 1-year and 5-year survival rates were 82 and 33%, respectively. Respiratory failure was the cause of late death in 2 patients. Among patients available at follow-up (n=85), respiratory function was considered subjectively improved, stable and worsened in 6 (7%), 62 (73%) and 17 (20%) cases, respectively. Eleven patients needed continuous oxygen therapy. Conclusions: Lung resection should not be denied a priori in patients with severe ventilatory impairment. Evaluation of predicted post-operative function often allows major resections, which are functionally economic, at the price of a high operative morbidity. Operative mortality, long-term survival and respiratory function are acceptable in the absence of a valid therapeutic alternative.

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Eur J Cardiothorac Surg. 2005 Jun;27(6):1092-8. Epub 2005 Apr 18.
Comparison of neoadjuvant cisplatin-based chemotherapy versus radiochemotherapy followed by resection for stage III (N2) NSCLC.
Pezzetta E, Stupp R, Zouhair A, Guillou L, Taffe P, von Briel C, Krueger T, Ris HB.
Department of Thoracic Surgery, Centre Hospitalier Universitaire Vaudois, University of Lausanne, CH-1011 Lausanne, Switzerland.

Objective: Comparison of prospectively treated patients with neoadjuvant cisplatin-based chemotherapy vs radiochemotherapy followed by resection for mediastinoscopically proven stage III N2 non-small cell lung cancer with respect to postoperative morbidity, pathological nodal downstaging, overall and disease-free survival, and site of recurrence. Methods: Eighty-two patients were enrolled between January 1994 to June 2003, 36 had cisplatin and doxetacel-based chemotherapy (group I) and 46 cisplatin-based radiochemotherapy up to 44Gy (group II), either as sequential (25 patients) or concomitant (21 patients) treatment. All patients had evaluation of absence of distant metastases by bone scintigraphy, thoracoabdominal CT scan or PET scan, and brain MRI, and all underwent pre-induction mediastinoscopy, resection and mediastinal lymph node dissection by the same surgeon. Results: Group I and II comprised T1/2 tumors in 47 and 28%, T3 tumors in 45 and 41%, and T4 tumors in 8 and 31% of the patients, respectively (P=0.03). There was a similar distribution of the extent of resection (lobectomy, sleeve lobectomy, left and right pneumonectomy) in both groups (P=0.9). Group I and II revealed a postoperative 90-d mortality of 3 and 4% (P=0.6), a R0-resection rate of 92 and 94% (P=0.9), and a pathological mediastinal downstaging in 61 and 78% of the patients (P<0.01), respectively. 5y-overall survival and disease-free survival of all patients were 40 and 36%, respectively, without significant difference between T1-3 and T4 tumors. There was no significant difference in overall survival rate in either induction regimens, however, radiochemotherapy was associated with a longer disease-free survival than chemotherapy (P=0.04). There was no significant difference between concurrent vs sequential radiochemotherapy with respect to postoperative morbidity, resectability, pathological nodal downstaging, survival and disease-free survival. Conclusions: Neoadjuvant cisplatin-based radiochemotherapy was associated with a similar postoperative mortality, an increased pathological nodal downstaging and a better disease-free survival as compared to cisplatin doxetacel-based chemotherapy in patients with stage III (N2) NSCLC although a higher number of T4 tumors were admitted to radiochemotherapy.

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Eur J Cardiothorac Surg. 2005 Jun;27(6):1086-91. Epub 2005 Mar 2.
Postoperative adjuvant chemotherapy for stage I non-small cell lung cancer.
Park JH, Lee CT, Lee HW, Baek HJ, Zo JI, Shim YM.
Department of Thoracic Surgery, Korea Cancer Center Hospital, Nowon-Ku Gongneung-Dong 215-4, Seoul 139-706, South Korea.

Objective: Surgery constitutes the mainstay of treatment in stage I non-small cell lung cancer (NSCLC). However, a significant fraction of patients after surgical resection die mainly due to systemic relapse. Nonetheless, the best adjuvant treatment to improve survival and decrease relapse rate remains as an ever controversial issue. Therefore, we conducted a randomized trial to determine whether postoperative adjuvant chemotherapy is beneficial in prolonging survival and decreasing recurrence in patients with completely resected stage I NSCLC. Methods: It was designed as a randomized, prospective two-armed study with surgery only (control group, 59 patients) versus surgery plus adjuvant MVP (mitomycin C, vinblastin and cisplatin) chemotherapy (study group, 59 patients). Results: Data for all the patients were complete. Twenty-four patients in the control group and nine patients in the study group experienced tumor recurrence during the follow-up. Neither histological type nor surgical extent correlated with recurrence. However, the addition of adjuvant MVP chemotherapy could decrease the rate of recurrence and the incidence of cancer-related death after surgery in the patients of stage I NSCLC (P<0.05). We followed up at least 5 years, and the duration of mean follow-up was 7.3 years. The rates of the loco-regional and distant metastases were 3.4 and 40.7% in the control group, and 3.4 and 11.9% in the study group, respectively. The 5- and 10-year survival rates were 74.6 and 56.3% in the control group, and 81.4 and 65.0% in the study group, respectively (P=0.19, log-rank test). The 5- and 10-year disease-free survival rates were 64.8 and 54.8% in the control group, and 88.8 and 76.8% in the study group, respectively (P=0.002, log-rank test). Conclusions: Our results suggest that the addition of adjuvant MVP chemotherapy may reduce the incidence of distant metastasis and prolong the disease-free survival of the patients with stage I NSCLC after surgery.

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Lung Cancer. 2005 May 20; [Epub ahead of print]
Combination of chemotherapy without platinum compounds in the treatment of advanced non-small cell lung cancer: A systematic review of phase III trials.
Barlesi F, Pujol JL.
Montpellier Academic Hospital, Unite d'Oncologie Thoracique, Hopital Arnaud de Villeneuve, Avenue du Doyen Giraud, 34295 Montpellier Cedex 5, France; Faculty of Medicine (Universite de la Mediterranee), Assistance Publique Hopitaux de Marseille, Thoracic Oncology, Federation des Maladies Respiratoires, Sainte-Marguerite Hospital, 13274 Marseille Cedex 09, France.

Hitherto, platinum-based combinations are world-wide accepted regimens in the treatment of advanced non-small cell lung cancer (NSCLC) due to a clear survival improvement using various platinum-based doublets in comparison with best supportive care only. However, treatment-allocated time and period with high grade toxicity could be considered as wasted from the patient point of view and the high toxicity induced by platinum-based doublets urges the research of alternate treatments. Newest cytotoxic compounds as so-called third generation drugs (i.e. vinorelbine, docetaxel, paclitaxel and gemcitabine) yield a better efficacy/toxicity ratio. Platinum-free doublet regimens based on these new drugs are expected to offer the patients an improved survival without decreasing his quality of life. Recent update of ASCO guidelines recommended that "for stage IV NSCLC, [...] non-platinum-containing chemotherapy regimens may be used as alternatives to platinum-based regimens in the first line." In spite of this recommendation, the case of non-platinum containing regimen is still debatable and this review deals with methodological statements highlighted by the reports of 14 recently reported randomised studies comparing non-platinum with platinum-based doublets. (174 words)

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Eur J Cancer. 2005 May;41(8):1117-26.
Docetaxel administration schedule: From fever to tears? A review of randomised studies.
Engels FK, Verweij J.
Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands.

The anti-cancer agent docetaxel is approved for the treatment of patients with locally advanced or metastatic breast cancer, non-small cell lung cancer (NSCLC) and for the treatment of androgen-independent prostate cancer. At the recommended dose of 60-100mg/m(2) given every 3 weeks, severe neutropenia is the dose-limiting toxicity and a major concern especially when treating patients at high-risk from myelotoxic complications. A less toxic schedule, involving weekly docetaxel administration was developed for patients with poor performance status, multiple comorbidities, poor haematological reserves or those who were heavily pre-treated, elderly or patients for whom palliation is the focus of treatment. Recent randomised trials allow a comparison of efficacy and toxicity between weekly and 3-weekly treatments. Efficacy appears to be similar for the two schedules regardless of the disease while weekly docetaxel is significantly less myelotoxic. However, this benefit comes at the cost of cumulative increases in hyperlacrimation, skin- and nail-toxicity and negatively affects quality of life. Currently, 3-weekly docetaxel remains the standard schedule for treatment, whereas the weekly schedule offers a possibility of treatment individualisation for those patients where the risk of myelosuppression is considered unacceptable.

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J Clin Oncol. 2005 May 10;23(14):3270-8.
Adjuvant chemotherapy in completely resected non-small-cell lung cancer.
Pisters KM, Le Chevalier T.
UT M. D. Anderson Cancer Center, Unit 432, PO Box 301402, Houston, TX 77230-1402, USA. kpisters@mdanderson.org

Surgery alone has long been the standard treatment for patients with operable non-small-cell lung cancer (NSCLC). However, despite complete resection, 5-year survival rates have been disappointing, with about 50% of patients eventually suffering relapse and death from disease. Randomized trials conducted in the 1980s hinted at a survival benefit for postoperative cisplatin-based regimens, but they were underpowered. A meta-analysis published in 1995 found a nonsignificant 13% reduction in the risk of death associated with cisplatin-based chemotherapy, with an increase of survival of 5% at 5 years. This led to renewed interest in adjuvant chemotherapy in resected NSCLC. Thousands of patients have been included in a new generation of randomized trials in the last 10 years. Most of these recent studies have now been reported and several have demonstrated a clear survival advantage for patients treated with platin-based adjuvant therapy. These results also suggest a greater benefit with modern two-drug regimens. In view of the most recent data, postoperative platin-based chemotherapy can now be considered the standard of care for completely resected NSCLC patients with good performance status.

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J Clin Oncol. 2005 May 10;23(14):3257-69.
Multimodality therapy for stage III non-small-cell lung cancer.
Farray D, Mirkovic N, Albain KS.
Loyola University Medical Center, Cardinal Bernardin Cancer Center, 2160 South First Avenue, Maywood, IL 60153-5589, USA.

The treatment of stage III non-small-cell lung cancer has evolved over the last two decades, with combined-modality therapy the current standard of care. As a result, intermediate and long-term survival has improved for patients in this common stage category, compared to the poor outcomes achieved with the historical standard of once-daily radiation therapy alone. This review summarizes two decades of clinical research regarding bimodality and trimodality approaches for the heterogenous stage subsets within the stage III designation, discusses the rationale and status of prophylactic brain irradiation, and concludes with perspectives on progress and future directions. Chemotherapy plus radiotherapy given concurrently is the optimal treatment for the group of patients with advanced stage III disease. The potential role of a surgical resection following chemotherapy (with or without radiation) in this setting is still controversial. The only subsets for which trimodality treatments are clearly preferred include T4N0-1 disease and superior sulcus tumors. The other major stage III subgroup has a minimal disease burden with low tumor volume and/or microscopic N2 disease, thus technically could undergo a surgical resection upfront. Induction chemotherapy before surgery may yield a survival advantage, although the phase III trials in this area are not conclusive. Given the marked survival benefit from adjuvant chemotherapy after surgery in even earlier stages of non-small-cell lung cancer, the proper sequence of surgery and chemotherapy (before v after surgery) remains an important unresolved question in this subgroup. Furthermore, how to incorporate radiation therapy, as well as whether it should be given at all in this subset of patients, are other important issues actively under study in ongoing trials.

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Intern Med J. 2005 Feb;35(2):77-82.
Gefitinib in advanced non-small cell lung cancer.
Sharma R, Boyer M, Clarke S, Millward M.
Sydney Cancer Centre, Australia.

Abstract Background: Gefitinib is an oral, selective epidermal growth factor receptor (EGFR) inhibitor that has activity in non-small cell lung cancer (NSCLC). Aim: To evaluate the tolerability, safety-profile and response of single agent gefitinib in patients with advanced stage NSCLC. Methods: Twenty-seven patients of good performance status with stage IIIB or IV NSCLC were entered on the study at the Sydney Cancer Centre. Gefitinib was prescribed at an oral dose of 250 mg daily, as a continuous dose. Radiological evaluation of indicator lesions occurred at baseline and were repeated every 2-3 months until disease progression. Toxicity was graded using standard measures at baseline and at every month. Results: The response rate was 17% in the patients eligible for evaluation. Symptom improvement was observed in 75% of patients. No patients withdrew because of adverse events. Toxicity was observed in 15 patients and consisted mainly of rash (59%), which was usually mild in severity. Conclusion: Gefitinib is active in NSCLC. It is well tolerated with minimal side-effects. Symptomatic improvement was found in the majority of patients treated with gefitinib. There may be a role for gefitinib in the palliation of symptoms in patients with advanced NSCLC. (Intern Med J 2005; 35: 77-82).

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J Clin Oncol. 2005 Feb 7; [Epub ahead of print]
Clinically Meaningful Improvement in Symptoms and Quality of Life for Patients With Non-Small-Cell Lung Cancer Receiving Gefitinib in a Randomized Controlled Trial.
Cella D, Herbst RS, Lynch TJ, Prager D, Belani CP, Schiller JH, Heyes A, Ochs JS, Wolf MK, Kay AC, Kris MG, Natale RB.
Evanston Northwestern Healthcare and Northwestern University Feinberg School of Medicine, Evanston, IL; University of Texas M.D. Anderson Cancer Center, Houston, TX; Massachusetts General Hospital Cancer Center, Boston, MA; University of California, Los Angeles Medical Center, Los Angeles; Cedars-Sinai Comprehensive Cancer Center, Beverly Hills, CA; University of Pittsburgh Cancer Institute, Pittsburgh, PA; University of Wisconsin Hospital, Madison, WI; AstraZeneca, Wilmington, DE; Memorial Sloan-Kettering Cancer Center, New York, NY; and AstraZeneca, Macclesfield, United Kingdom.

PURPOSE: Evaluation of disease-related symptom improvement rate by the Lung Cancer Subscale (LCS) of the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire was a coprimary end point of the pivotal phase II trial of gefitinib (Iressa; AstraZeneca, Wilmington, DE) conducted in the United States. This report includes the results of analyses exploring the relationship between weekly LCS scores and radiographic response and survival, as well as detailed protocol-specified analysis of symptom and quality-of-life data. PATIENTS AND METHODS: In this trial, 216 symptomatic patients with advanced non-small-cell lung cancer (NSCLC) who had at least two prior chemotherapy regimens received gefitinib 250 or 500 mg/d. Disease-related symptoms were assessed weekly and quality of life was assessed monthly by LCS and FACT-L, respectively. RESULTS: Symptom improvement was rapid and correlated with tumor response and survival. At the recommended gefitinib dose of 250 mg/d, median overall survival times were 13.6 and 4.6 months for patients with and without symptom improvement, respectively, and 9.7 months for patients with symptom improvement without tumor response. Among patients with stable disease or disease progression, those with symptom improvement had significantly better overall survival than those without improvement. At 250 mg/d, 30% of patients showed a quality-of-life improvement that was correlated with tumor response. CONCLUSION: This triadic analysis of response, survival, and symptom data supports the hypothesis that tumor response and symptom response are related and that each predicts survival. Among these NSCLC patients treated with gefitinib, symptom improvement was complementary to and, for most patients, preceded evidence of radiographic regression.

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Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):690-6.
Pemetrexed Combined with Oxaliplatin or Carboplatin as First-Line Treatment in Advanced Non-Small Cell Lung Cancer: A Multicenter, Randomized, Phase II Trial.
Scagliotti GV, Kortsik C, Dark GG, Price A, Manegold C, Rosell R, O'brien M, Peterson PM, Castellano D, Selvaggi G, Novello S, Blatter J, Kayitalire L, Crino L, Paz-Ares L.
Department of Clinical and Biological Sciences, S. Luigi Gonzaga Hospital, University of Torino, Turin, Italy.

PURPOSE: To determine efficacy and toxicity of two pemetrexed-based regimens in chemonaive patients with locally advanced or metastatic non-small cell lung cancer.EXPERIMENTAL DESIGN: Patients were randomly assigned to receive pemetrexed 500 mg/m(2) plus oxaliplatin 120 mg/m(2) (PemOx) or pemetrexed plus carboplatin AUC6 (PemCb). All drugs were given on day 1 of a 21-day cycle for up to six cycles. Folic acid and vitamin B(12) were given to all patients to minimize pemetrexed-related toxicities.RESULTS: Forty-one patients received PemOx and 39 received PemCb. Objective tumor response rates were 26.8% for PemOx patients (95% confidence interval, 14.2-42.9) and 31.6% for PemCb patients (95% confidence interval, 17.5-48.7). Median time to progression was 5.5 and 5.7 months, respectively, for PemOx and PemCb. Median overall survival times were 10.5 months for both treatment groups (range, <1 to >20 months). The 1-year survival rate was 49.9% for PemOx patients and 43.9% for PemCb patients. Common toxicity criteria grade 3 or 4 hematologic toxicities among PemOx patients were grade 3 or 4 neutropenia (7.3%), grade 3 thrombocytopenia (2.4%), and grade 3 anemia (2.4%). PemCb patients experienced grade 3 or 4 neutropenia (25.6%), grade 3 or 4 thrombocytopenia (17.9%), and grade 3 anemia (7.7%). Grade 3 vomiting occurred in three PemOx patients and grade 3 fatigue occurred in three PemCb patients. One grade 3 neurosensory toxicity occurred in the PemOx group. Three patients (PemOx 1 and PemCb 2) experienced febrile neutropenia.CONCLUSIONS: Efficacy measures for both regimens seem similar to the most effective chemotherapies for advanced non-small cell lung cancer (platinum combinations) with less hematologic and nonhematologic toxicity. Comparing either of these two regimens to platinum-based therapies in a large randomized trial is warranted.

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Clin Lung Cancer. 2005 Jan;6(4):245-9.
Results of a Phase II Trial of Gemcitabine in Patients with Non-Small-Cell Lung Cancer and a Performance Status of 2.
Neubauer MA, Reynolds CH, Joppert MG, Whitaker T, Ghaddar H, Marsland TA, Asmar L.
US Oncology Research, Inc., Houston, TX; e-mail: marcus.neubauer@usoncology.com.

This trial was designed to determine the 1-year survival rate, efficacy, progression-free survival (PFS), and toxicity with gemcitabine in patients with stage IIIB (with pleural effusion) or stage IV non-small-cell lung cancer (NSCLC) with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2. Gemcitabine 1250 mg/m2 was administered intravenously on days 1 and 8 of each 21-day cycle. Treatment consisted of 6 cycles; patients who responded with complete response or partial response received </= 2 additional cycles. Forty-two patients were enrolled at 31 community-based centers between March and November 2002. Most patients had stage IV disease (74%). The median age was 73 years (range, 58-84 years), and 19% had received prior palliative radiation therapy. Patients received a median of 3 cycles (range, 1-8 cycles). The median survival was 4.8 months (range, < 1 to 19.2 months), and the estimated 1-year survival was 20%. Median PFS was 2.5 months (range, < 1 to 19.2 months), and PFS at 1 year was 11.1%. Thirty-one patients died of disease progression, and 1 each died of myocardial infarction, brain herniation, pneumonia, and respiratory failure. Seven patients were not evaluable for response; 4 refused or received no treatment, treatment in 2 failed (myocardial infarction and pneumonia), and 1 was lost to follow-up. Among 35 evaluable patients, there were 5 partial responses (14%), 10 with stable disease (29%), and 20 with disease progression (57%). Drug-related grade >/= 3 toxicities included neutropenia (18%), anemia (8%), and dyspnea (2.6%). These results suggest that patients with NSCLC with an ECOG PS of 2 may benefit from single-agent chemotherapy gemcitabine. General toxicity, including myelotoxicity, was relatively low. Further studies comparing single-agent chemotherapy with combination chemotherapy for patients with a PS of 2 are warranted.

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Lung Cancer. 2004 Dec;46 Suppl 2:S23-32.
Neoadjuvant treatment of early-stage resectable non-small-cell lung cancer.
Betticher DC, Rosell R.
Institute of Medical Oncology, University of Bern, 3010 Bern, Switzerland. Daniel.betticher@insel.ch

New approaches to the treatment of locally advanced non-small-cell lung cancer (NSCLC) include a focus on improving survival for patients with stage-III disease, which has traditionally implied regionally advanced, yet potentially surgically resectable, disease. Neoadjuvant, or induction, therapy has been one such focus in order to improve control of systemic disease. The use of neoadjuvant chemotherapy with surgery appears to increase median survival and, perhaps more importantly, may enhance long-term survival, indicating cure. Clinical trials assessing the feasibility and efficacy of docetaxel, a taxane with considerable activity in NSCLC, alone or in combination with a platinum analog, have yielded promising results. Current research focuses on optimal integration of neoadjuvant chemotherapy into treatment strategies for patients with early-stage and locally advanced NSCLC.

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Lung Cancer. 2004 Dec;46 Suppl 2:S33-9.
Adjuvant treatment of lung cancer: current status and potential applications of new regimens.
Le Chevalier T, Lynch T.
Department of Medicine, Institut Gustave Roussy, Villejuif, France. tle-che@igr.fr

Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of lung cancers diagnosed worldwide. Surgical resection offers the best chance for cure for those patients diagnosed with early-stage disease; however, the vast majority of patients will eventually relapse. Despite complete surgical resection, recurrences are likely due to undetectable microscopic disease at diagnosis, making these patients potential candidates for effective adjuvant therapy. Postoperative radiation therapy may actually have a detrimental effect in patients with NO-N1 disease and has been shown to possibly prevent local recurrences in patients with N2 disease. Although results from a large meta-analysis of data on adjuvant chemotherapy suggested an absolute benefit of 5% at 5 years from cisplatin-based chemotherapy, a rate similar to that seen in breast and colon cancers where adjuvant chemotherapy is a standard of care, the use of adjuvant therapy in NSCLC remained controversial. In addition, results of the International Adjuvant Lung Cancer Trial (IALT), which compared adjuvant cisplatin-based chemotherapy to observation in patients with resected stage-I-IIIA NSCLC, suggested that adjuvant therapy had the potential to prevent a substantial number of deaths each year. Two recently reported landmark studies have demonstrated the survival advantages of adjuvant therapy for patients with early-stage NSCLC. Docetaxel, one of the most active agents for advanced NSCLC, is also regularly used for locally advanced disease as part of neoadjuvant or combined-modality regimens. As recent findings have established the value of adjuvant chemotherapy for early-stage NSCLC, agents such as docetaxel warrant rigorous evaluation in this setting.

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Lung Cancer. 2004 Dec;46 Suppl 2:S13-21.
Docetaxel in combined-modality treatment of inoperable locally or regionally advanced lung cancer.
Scagliotti GV, Douillard JY.
University of Turin, Department of Clinical & Biological Sciences, S. Luigi Hospital - Thoracic Oncology Unit, Orbassano (Torino), Italy. giorgio.scagliotti@unito.it

Although most clinicians use a combination of a platinum-containing regimen and radiation therapy to treat non-small-cell lung cancer (NSCLC), there is no reference regimen for inoperable stage-III NSCLC. Limited phase-III data suggest concurrent chemoradiotherapy is preferable to sequential therapy. Combined-modality chemoradiotherapy with cisplatin plus agents such as vindesine, mitomycin C, vinblastine, etoposide, vinorelbine, or paclitaxel yield a median survival of only 15-17 months, with distant metastases being the most common reason for failure. The need for new therapeutic approaches to target distant metastases is a critical issue. In addition to its proven antitumor properties in NSCLC, docetaxel has radiosensitizing activity, making it well-suited for use in combined-modality regimens. Several phase-I/II studies have demonstrated that concurrent docetaxel, cisplatin, and radiation therapy is a feasible regimen, yielding objective response rates of 70-90%. A regimen of cisplatin plus docetaxel induction followed by thoracic radiotherapy plus docetaxel resulted in an objective response of 58% in a phase-II trial. A second phase-II trial evaluating a unique regimen of chemoradiotherapy using cisplatin and etoposide followed by consolidation docetaxel yielded a median survival of 26 months. This compares favorably to historical data demonstrating a median survival of 15 months using cisplatin, etoposide, and radiation therapy without consolidation docetaxel. Phase-III research is currently underway to confirm the favorable phase-II results with docetaxel.

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Cancer J. 2004 Nov-Dec;10(6):368-73.
High-dose-rate brachytherapy in combination with stenting offers a rapid and statistically significant improvement in quality of life for patients with endobronchial recurrence.
Allison R, Sibata C, Sarma K, Childs CJ, Downie GH.
Department of Radiation Oncology, The Brody School of Medicine, Greenville, North Carolina 27858, USA. ALLISONR@mail.ecu.edu

Symptomatic endobronchial recurrence after treatment failure is common in advanced non-small cell lung cancer. Optimal palliation has yet to be defined. We examined the combination of near-simultaneous, high-dose-rate (HDR) brachytherapy with stenting in this cohort of patients. Informed consent for intervention was obtained for 10 patients experiencing severely symptomatic (hemoptysis and oxygen-dependent shortness of breath), biopsy-proven endobronchial recurrence. All patients (eight men, two women, aged 52-77 years) had failed to respond to chemoradiotherapy for stage IIIB non-small cell lung cancer. Intervention consisted of placement of a self-expanding metallic stent (Nitinol/Ultraflex stent, Boston Scientific Co., Natick, MA) into the obstructing region. During that same bronchoscopy, HDR catheters were introduced. A dose of 6 Gy at 0.5 cm from the catheter was then delivered via an HDR unit. Two additional HDR sessions followed at weekly intervals for a total dose of 18 Gy. Patients under went follow-up bronchoscopes 1 month after the last HDR and when clinically indicated. All patients completed the prescribed therapy. No morbidity was noted from bronchoscopy, HDR, or stenting. All patients had rapid relief of signs and symptoms. At 1 week after stenting/first HDR, a statistically significant improvement in Karnofsky status was noted. Pulmonary palliation was maintained for the duration of their survival. The radio-opaque stent also offered significant advantages for catheter placement and verification during the HDR procedure. Although this series is small, the beneficial outcome obtained deserves further evaluation.

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J Chemother. 2004 Nov;16 Suppl 4:104-7.
Second-line chemotherapy in the treatment of advanced non-small cell lung cancer (NSCLC).
Ardizzoni A, Tiseo M.
Azienda Ospedaliera-Universitaria, Parma, Italy. aardizzoni@ao.pr.it

An increasing number of patients with advanced non-small cell lung cancer (NSCLC) progressing after front-line chemotherapy are still in good performance status and willing to receive further treatment. Several drugs have been tested in this setting of treatment, but the only agent registered world-wide for second-line chemotherapy of advanced NSCLC is docetaxel. This drug, at dose of 75 mg/m2 every three weeks, has been the standard of care as second-line chemotherapy since 2000, based on two trials that reported improved survival times and quality of life when comparing with best supportive care (TAX 317) and with ifosfamide or vinorelbine (TAX 320). Docetaxel, given at this dose and schedule, resulted in significant haematological toxicity, with many patients at risk for neutropenic fever. Pemetrexed is a novel multitargeted antifolate agent with single-agent activity in first- and second-line treatment of NSCLC. In a phase III study in 571 patients pemetrexed, comparing with docetaxel in second-line chemotherapy, demonstrated clinically equivalent therapeutic outcomes, but a more favourable haematological toxicity profile, with fewer episodes of neutropenia, neutropenic fever, and infections and less use of granulocyte colony-stimulating factor support. Others several agents have been evaluated for the second-line treatment of patients with non-small cell lung cancer, but no comparative phase III studies with docetaxel has been carried out. The epidermal growth factor receptor-tyrosine kinase inhibitors gefitinib (ZD1839, Iressa) and erlotinib (OSI 774, Tarceva) have been evaluated in the second- and third-line setting. Both drugs have demonstrated interesting response rates and toxicity profile and, in particular, erlotinib evidenced a survival advantage of 2 months respect placebo in recent phase III trial. Future developments are likely to value poli-chemotherapy or combination chemotherapy with EGFR tyrosine kinase inhibitors in second-line treatment of advanced NSCLC.

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Clin Lung Cancer. 2004 Nov;6(3):162-9.
Adjuvant therapy of resected non-small-cell lung cancer.
Socinski MA.
Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill ; e-mail: socinski@med.unc.edu.

Surgical resection of early-stage non-small-cell lung cancer (NSCLC) remains the standard of care in patients fit for surgery. Careful preoperative staging is imperative, as is pathologic documentation of the mediastinal nodal contents. Adjuvant postoperative thoracic radiation therapy (RT) clearly has an impact in reducing locoregional recurrence but has no clear impact on survival. The Postoperative RT (PORT) metaanalysis raised concerns about PORT, particularly in stage I/II NSCLC, suggesting it may negatively impact survival. This was not a concern in stage III NSCLC, in which the risk of locoregional recurrence is higher. However, distant recurrence remains the dominant pattern in resected NSCLC, suggesting that the majority of patients with early-stage resected NSCLC harbor occult micrometastatic disease. Historically, the role of adjuvant chemotherapy has been controversial, and its routine use was not supported by the published data, which consisted of a small number of underpowered trials using inadequately delivered, antiquated chemotherapy. More recently, larger trials have been reported with conflicting results. Like adjuvant PORT, chemotherapy combined with RT has not improved survival over PORT alone. The use of adjuvant cisplatin-based therapy did not show a survival advantage in the Adjuvant Lung Project Italy study but did in the International Adjuvant Lung Trial, creating controversy in the routine implementation of adjuvant therapy in all patients. Recently completed randomized trials by the Cancer and Leukemia Group B and the National Cancer Institute of Canada provide convincing evidence of a substantial benefit from adjuvant therapy in well-staged and completely resected stage I/II NSCLC. Currently, the totality of the data supports a discussion with patients with resected NSCLC regarding the potential benefits of adjuvant therapy.

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Clin Lung Cancer. 2004 Nov;6(3):154-61.
Therapeutic advances in second-line treatment of advanced non-small-cell lung cancer.
Bonomi PD.
Rush University Medical Center, Section of Medical Oncology, Chicago, IL ; e-mail: philip_bonomi@rsh.net.

A majority of patients with lung cancer present with advanced disease: approximately 30% with locally advanced disease and 45% with metastatic disease. The prognosis for these patients is poor, with 5-year survival rates ranging from 5% to 15% for stage IIIB disease and < 5% for stage IV disease. For patients confronting advanced disease, chemotherapy is an essential option for disease control and palliation. Although a number of effective first-line regimens exist, virtually all patients with advanced non-small-cell lung cancer (NSCLC) will have disease relapse. For these patients, identifying the optimal treatment course remains a challenge. This article reviews approved and investigational second-line therapeutic options in patients with relapsed advanced NSCLC. Recently, docetaxel has been shown to improve survival in patients with advanced NSCLC who had progressive disease following treatment with platinum-containing chemotherapy. Subsequently, permetrexed was compared with docetaxel in a second-line treatment study that showed survival for both patient groups was virtually identical. Recently, erlotinib was associated with significantly longer survival compared with best supportive care in the second- or third-line treatment settings. Salvage treatment for NSCLC is reviewed, and the relative merits of the currently available treatments as well as agents that are pending Food and Drug Administration approval as second-line treatments are discussed.

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Br J Cancer. 2004 Nov 23; [Epub ahead of print]
A randomised clinical trial of two docetaxel regimens (weekly vs 3 week) in the second-line treatment of non-small-cell lung cancer. The DISTAL 01 study.
Gridelli C, Gallo C, Di Maio M, Barletta E, Illiano A, Maione P, Salvagni S, Piantedosi FV, Palazzolo G, Caffo O, Ceribelli A, Falcone A, Mazzanti P, Brancaccio L, Capuano MA, Isa L, Barbera S, Perrone F.
1Oncologia Medica, Azienda Ospedaliera S Giuseppe Moscati, Avellino.

Docetaxel (75 mg m(-2) 3-weekly) is standard second-line treatment in advanced non-small-cell lung cancer (NSCLC) with significant toxicity. To verify whether a weekly schedule (33.3 mg m(-2) for 6 weeks) improved quality of life (QoL), a phase III study was performed with 220 advanced NSCLC patients, </=75 years, ECOG PS </=2. QoL was assessed by EORTC questionnaires and the Daily Diary Card (DDC). No difference was found in global QoL scores at 3 weeks. Pain, cough and hair loss significantly favoured the weekly schedule, while diarrhoea was worse. DDC analysis showed that loss of appetite and overall condition were significantly worse in the 3-week arm in the first week, while nausea and loss of appetite were more severe in the weekly arm in the third week. Response rate and survival were similar, hazard ratio of death in the weekly arm being 1.04 (95% CI 0.77-1.39). A 3-weekly docetaxel was more toxic for leukopenia, neutropenia, febrile neutropenia and hair loss; any grade 3-4 haematologic toxicity was significantly more frequent in the standard arm (25 vs 6%). The weekly schedule could be preferred for patients candidate to receive docetaxel as second-line treatment for advanced NSCLC, because of some QoL advantages, lower toxicity and no evidence of strikingly different effect on survival.British Journal of Cancer advance online publication, 23 November 2004; doi:10.1038/sj.bjc.6602241 www.bjcancer.com.

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Clin Lung Cancer. 2004 Nov;6(3):175-83.
Prospective Randomized Phase III Trial of Etoposide/ Cisplatin Versus High-Dose Epirubicin/Cisplatin in Small-Cell Lung Cancer.
Artel-Cortes A, Gomez-Codina J, Gonzalez-Larriba JL, Barneto I, Carrato A, Isla D, Camps C, Garcia-Giron C, Font A, Meana A, Lomas M, Vadell C, Arrivi A, Alonso C, Maestu I, Campbell J, Rosell R.
Hospital Universitario Miguel Servet, Zaragosa, Madrid Spain ; e-mail: aartalc@salud.aragob.es.

High-dose epirubicin plus cisplatin was compared with the reference regimen of etoposide/cisplatin in small-cell lung cancer (SCLC). Four hundred two previously untreated patients with SCLC were randomized to receive etoposide 100 mg/m(2) on days 1-3 and cisplatin 100 mg/m(2) on day 1 or epirubicin 100 mg/m(2) and cisplatin 100 mg/m(2) on day 1 every 21 days for a total of 6 cycles. Patients were stratified according to treatment center and extent of disease (limited disease, n = 207; extensive disease, n = 195). Patients with limited disease were treated with thoracic radiation therapy after completion of chemotherapy, and those who exhibited a complete response were advised to receive prophylactic cranial irradiation. The primary endpoint was survival, and secondary endpoints were time to progression (TTP), response, toxicity, and costs. Patient characteristics were generally well balanced in the 2 arms, even though more patients in the epirubicin/cisplatin arm had > 5% weight loss and poor Karnofsky performance index compared with the etoposide/cisplatin arm. One hundred thirty-four patients (66.3%) in the etoposide/cisplatin arm and 126 (63.0%) in the epirubicin/cisplatin arm received all 6 planned cycles of chemotherapy. Response rate, TTP, and survival did not differ significantly between the 2 arms. Grade 3/4 neutropenia and toxic deaths occurred more frequently in the etoposide/cisplatin arm. Epirubicin/cisplatin showed a similar activity with a slightly lower toxicity profile than the reference regimen of etoposide/cisplatin. The epirubicin/cisplatin regimen may be recommended in the treatment of SCLC.

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Semin Radiat Oncol. 2004 Oct;14(4):326-34.
Management of unresectable stage III non-small cell lung cancer: The role of combined chemoradiation.
Penland SK, Socinski MA.

Until the late 1980s, thoracic radiation therapy (TRT) was considered the standard of care for patients with stage III disease despite extremely poor 5-year survival rates. Several studies evaluating TRT combined with chemotherapy showed a survival advantage. Based on these data, combined modality therapy became accepted as the standard of care in this group of patients with good performance status and made the treatment of locally advanced non-small cell lung cancer (NSCLC) a multidisciplinary endeavor. Recent studies have shown that concurrent chemoradiotherapy offers a significantly greater survival advantage than sequential chemoradiotherapy and should be considered standard of care in stage III inoperable NSCLC. Although numerous Phase III trials have clearly demonstrated a survival benefit in those patients who receive combined modality therapy, many questions remain. The most effective combination of drugs, their optimal mode of administration, the use of either induction or consolidation therapy in addition to a backbone of concurrent therapy, and the details of TRT, including total dose, fractionation, acceleration, treatment volumes, and tumor targeting remain important issues to define. Although progress has been made in treatment for locally advanced NSCLC, the majority of patients still die within 5 years either from locoregional or distant progression of disease. This article will review the current data regarding treatment of this heterogeneous group of patients. In addition, a brief summary of new molecular therapies and chemotherapeutics will be presented.

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Semin Radiat Oncol. 2004 Oct;14(4):315-21.
Adjuvant chemotherapy and radiotherapy in non-small cell lung cancer.
Erman M, Moretti L, Soria JC, Le Chevalier T, Van Houtte P.

Although surgical resection remains the best potentially curative treatment for non-small cell lung cancer (NSCLC), more than half the patients undergoing resection will eventually die of recurrent disease. Approximately two thirds of relapses occur outside the chest, indicating a potential role for adjuvant chemotherapy. Indeed, a meta-analysis has suggested an absolute survival benefit of 5% at 5 years with adjuvant cisplatin-based regimens. This finding has incited several large-scale randomized trials, the largest of which, the International Adjuvant Lung Trial, has confirmed a similar survival advantage. Conversely, a meta-analysis on postoperative radiotherapy has suggested a detrimental effect, especially for stage I and II patients, that is related most probably to a poor radiation technique. Its value for stage III remains controversial: the observed reduction in local failure did not translate into a survival benefit. In this article, the current status of adjuvant chemotherapy and radiotherapy are reviewed, and future prospects are discussed.

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Drug Saf. 2004;27(14):1081-92.
Overview of the Tolerability of Gefitinib (IRESSA(trade mark)) Monotherapy : Clinical Experience in Non-Small-Cell Lung Cancer.
Forsythe B, Faulkner K.
Drug Safety, AstraZeneca, Macclesfield, UK.

Cytotoxic chemotherapy treatment options for patients with non-small-cell lung cancer (NSCLC) have limited efficacy and are often associated with significant toxicity. Therefore, there is an unmet need for novel drugs that are not only effective in treating this disease but are also well tolerated. Gefitinib is an orally active epidermal growth factor receptor tyrosine kinase inhibitor that blocks the signal transduction pathways implicated in cancer cell growth and survival. It has recently been approved for the treatment of advanced/refractory NSCLC. This review presents the tolerability data from phase I and II gefitinib monotherapy trials, along with data from the worldwide 'Expanded Access Programme' and post-marketing use of gefitinib.Gefitinib was found to be generally well tolerated at the approved dosage of 250 mg/day; the most commonly reported adverse drug reactions (ADRs) were mild to moderate skin rash and diarrhoea, which were manageable and non-cumulative. Other ADRs observed with the use of gefitinib included: dry skin, pruritus, acne, nausea, vomiting, anorexia, asthenia and asymptomatic elevations in liver transaminase levels. Well recognised adverse effects seen with cytotoxic chemotherapy (such as bone marrow depression, neurotoxicity and nephrotoxicity) were not observed. Although the frequency and severity of ADRs increased with the dosage across the range studied (50-1000 mg/day), few patients required dosage reductions or the withdrawal of treatment, and those who did usually received gefitinib >/=600 mg/day.Thus, the available data indicate that gefitinib is well tolerated in patients with a range of solid tumours, including locally advanced or metastatic NSCLC.

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Lung Cancer. 2004 Aug;45 Suppl 2:S139-41.
Combined-modality treatment of non-small-cell lung cancer stages I-III (take home messages).
Rube C, Fleckenstein J.
Department of Radiotherapy and Radiation Oncology, Saarland Medical University, Kirrberger Strasse, D-66421 Homburg/Saar, Germany. ruebe@uniklinik-saarland.de

Combined-modality approaches including surgery, radiotherapy and chemotherapy have led to a clear improvement of treatment results in localised NSCLC. For stages I and II, postoperative adjuvant chemotherapy may lead to an improved progression-free survival. In stage IIIA, preoperative chemotherapy, respectively radio-chemotherapy, increases the incidence of complete resections. Compared to radio-chemotherapy alone the implementation of surgery in stage IIIA(N2)-patients leads to a better progression-free survival. For stage IIIB simultaneous radio-chemotherapy with or without additional sequential chemotherapy has become the new standard of treatment for patients in sufficient clinical condition. In the future, the implementation of further individual selection and prognostic parameters including tumour volume, location of the tumour, response to induction treatment, co-morbidities and molecular tumour analysis may contribute to further individualise the treatment approach.

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Lung Cancer. 2004 Aug;45 Suppl 2:S107-12.
Surgery after multimodality treatment for non-small-cell lung cancer.
Stamatis G, Eberhard W, Pottgen C.
Department of Thoracic Surgery and Endoscopy, Ruhrlandklinik, Tuschener Weg 40, D-45239 Essen, Germany. g.stamatis-ruhrlandklinik@t-online.de

Neoadjuvant treatment for Locally advanced non-small-cell lung cancer (NSCLC) stage IIIA and IIIB promises higher resection rates because of a reduction of the primary tumour and sterilisation of mediastinal nodes ("downstaging"). In this study we analyse the perioperative course and the long-term survival of patients with trimodality treatment. Between 03/1991 and 12/2002, 392 patients with NSCLC underwent resection after induction treatment. Included were 266 males and 126 females, age 55.8 +/- 9 (28-74), of whom 218 were stage-IIIA patients, 174 were stage-IIIB patients. Induction treatment included 3 courses of chemotherapy with cisplatin/etoposide or cisplatin/paclitaxel, followed by one course of chemotherapy with cisplatin/etoposide as well as hyperfractionated accelerated radiotherapy of the primary tumour and the mediastinal nodes with 45 Gy, followed by surgery. Before induction treatment all patients underwent mediastinoscopy. In patients with N3 disease mediastinoscopy was repeated before surgery. Resections included 133 pneumonectomies (34%), 15 bilobectomies (4%), 55 sleeve lobectomies (14%), 168 lobectomies (42.5%), 6 segmentectomies (1,5%), and 15 explorative thoracotomies (4%). In-hospital mortality rates amounted to 4.6% (18 patients) while postoperative morbidity ran up to 46% (180 patients). Morbidity and mortality rates were significantly higher in patients with Karnofsky status lower than 80% and patients older than 65 years. Bronchopleural fistulas occurred in 16 patients (3.2%). The protection of the bronchial stump or anastomosis with viable tissue, like pericardial fat, proves to be a significant factor for the reduction of septic complications. For NSCLC, the 5- and 7-year survival rates were 36% and 31%, respectively, for stage IIIA, and 26% for stage IIIB. This intensive trimodality treatment proves to be feasible. Treatment-related toxicities are overall moderate and acceptable. Accurate cardiopulmonary evaluation before surgery and reinforcement of bronchial stump or anastomosis can contribute to reducing complications. Induction treatment demonstrated a "downstaging effect", so that a clear trend for organ-sparing resection was observed. Long-term survival rates for selected groups look very promising when compared to historical controls.

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J Clin Oncol. 2004 Aug 15;22(16):3238-47.
Determinants of tumor response and survival with erlotinib in patients with non--small-cell lung cancer.
Perez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, Karp D, Rigas J, Clark GM, Santabarbara P, Bonomi P.
Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, 111 E 210th St, Bronx, NY 10467, USA. rperezso@montefiore.org

PURPOSE: Erlotinib is a highly specific epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. This phase II study of erlotinib in patients with HER1/EGFR-expressing non-small-cell lung cancer previously treated with platinum-based chemotherapy evaluated tumor response, survival, and symptom improvement. PATIENTS AND METHODS: Fifty-seven patients received an oral, continuous daily dose of 150 mg of erlotinib. Assessments of objective response used WHO and Response Evaluation Criteria in Solid Tumors criteria. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, supplemented with a lung cancer module, Quality of Life Questionnaire LC13, was used to measure health-related quality of life. Additional analyses were performed to identify predictors of response and survival. RESULTS: The objective response rate was 12.3% (95% CI, 5.1% to 23.7%). Responses were observed regardless of type or number of prior chemotherapy regimens. Median survival time was 8.4 months (95% CI, 4.8 to 13.9 months), and the 1-year survival rate was 40% (95% CI, 28% to 54%). Erlotinib therapy was associated with tumor-related symptom improvement. The drug was well tolerated; drug-related cutaneous rash and diarrhea were observed in 75% and 56% of patients, respectively. One patient experienced toxicity consisting of severe grade 3 rash and diarrhea. Time since diagnosis and good performance status were significant predictors of survival in a multivariate Cox proportional hazards model, whereas HER1/EGFR staining intensity was not. Additionally, survival correlated with the occurrence and severity of rash. CONCLUSION: Erlotinib was active and well tolerated in this patient population, and further clinical development is clearly warranted. Cutaneous rash seems to be a surrogate marker of clinical benefit, but this finding should be confirmed in ongoing and future studies.

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Cancer Chemother Pharmacol. 2004 Aug 7 [Epub ahead of print]
Phase I study of green tea extract in patients with advanced lung cancer.
Laurie SA, Miller VA, Grant SC, Kris MG, Ng KK.
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, 1275 York Avenue, 10126, New York, NY, USA.

PURPOSE. Epidemiologic studies suggest that consumption of green tea may have a protective effect against the development of several cancers. Preclinical studies of green tea and its polyphenolic components have demonstrated antimutagenic and anticarcinogenic activity, and inhibition of growth of tumor cell lines and animal tumor models, including lung cancer. Green tea may also have chemopreventive properties, and enhancement of cytotoxicity of chemotherapeutic agents has been demonstrated. This trial was designed to determine the maximum tolerated dose (MTD) of green tea extract (GTE) in patients with advanced lung cancer. METHODS. A total of 17 patients with advanced lung cancer were registered to receive once-daily oral dosing of GTE at a starting dose of 0.5 g/m(2) per day, with an accelerated dose-escalation scheme. RESULTS. On this schedule, the MTD of GTE was 3 g/m(2) per day, and at this dose, GTE was well tolerated with no grade 3 or 4 toxicity seen. Dose-limiting toxicities were diarrhea, nausea and hypertension. No objective responses were seen in this trial. Seven patients had stable disease ranging from 4 to 16 weeks; no patient remained on therapy longer than 16 weeks due to the development of progressive disease. CONCLUSIONS. This study suggests that while relatively nontoxic at a dose of 3 g/m(2) per day, GTE likely has limited activity as a cytotoxic agent, and further study of GTE as a single-agent in established malignancies may not be warranted. Further studies should focus on the potential chemopreventive and chemotherapy-enhancing properties of GTE.

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J Thromb Haemost. 2004 Aug;2(8):1266-71.
A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer.
Altinbas M, Coskun HS, Er O, Ozkan M, Eser B, Unal A, Cetin M, Soyuer S.
Department of Oncology, Erciyes University Medical Faculty, MK Dedeman Oncology Hospital, Kayseri, Turkey.

Summary. Background Small cell lung cancer (SCLC) is a chemotherapy-responsive tumor type but most patients ultimately experience disease progression. SCLC is associated with alterations in the coagulation system. The present randomized clinical trial (RCT) was designed to determine whether addition of low-molecular-weight heparin (LMWH) to combination chemotherapy (CT) would improve SCLC outcome compared with CT alone. Methods Combination CT consisted of cyclophosphamide, epirubicine and vincristine (CEV) given at 3-weekly intervals for six cycles. Eighty-four patients were randomized to receive either CT alone (n = 42) or CT plus LMWH (n = 42). LMWH consisted of dalteparin given at a dose of 5000 U once daily during the 18 weeks of CT. Results Overall tumor response rates were 42.5% with CT alone and 69.2% with CT plus LMWH (P = 0.07). Median progression-free survival was 6.0 months with CT alone and 10.0 months with CT plus LMWH (P = 0.01). Median overall survival was 8.0 months with CT alone and 13.0 months with CT plus LMWH (P = 0.01). Similar improvement in survival with LMWH treatment occurred in patients with both limited and extensive disease stages. The risk of death in the CT + LMWH group relative to that in the CT group was 0.56 (95% confidence interval 0.30, 0.86) (P = 0.012 by log rank test). Toxicity from the experimental treatment was minimal and there were no treatment-related deaths. Conclusions These results support the concept that anticoagulants, and particularly LMWH, may improve clinical outcomes in SCLC. Further clinical trials of this relatively non-toxic treatment approach are indicated.

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J Int Med Res. 2004 Jul-Aug;32(4):375-83.
Randomized phase 2 study of radiotherapy alone versus radiotherapy with paclitaxel in non-small cell lung cancer.
Sarihan S, Kayisogullari U, Ercan I, Engin K.
Department of Radiation Oncology, Uludag University, Medical College, Bursa, Turkey. sureyya@uludag.edu.tr

This randomized phase 2 study aimed to assess and compare the toxicity and response rates in patients with unresectable non-small cell lung cancer treated with radiotherapy (1.8-2 Gray [Gy] daily, five fractions a week, total 63 Gy) or radiotherapy + paclitaxel administered weekly (1.8 Gy daily, five fractions a week, total 59.4 Gy). Twelve patients in the latter arm received 30 mg/m2 paclitaxel (median six cycles) over a 3-h infusion once weekly. After assessing toxicity, the remaining nine patients received 60 mg/m2 paclitaxel weekly (median six cycles). Response was evaluated radiologically 1 month after treatment. Grade 3 toxicity was 20% and 38% in the radiotherapy and chemoradiotherapy groups, respectively. Overall survival rates in complete and objective (complete plus partial) responders and progression-free survival rate of the objective responders were significantly better in the chemoradiotherapy arm. We believe that using paclitaxel in concurrent chemoradiotherapy regimens may be effective in patients with unresectable, locoregionally advanced non-small cell lung cancer.

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Clin Lung Cancer. 2004 Jul;6(1):33-42.
A Phase II Trial of Preoperative Concurrent Radiation Therapy and Weekly Paclitaxel/Carboplatin for Patients with Locally Advanced Non-Small-Cell Lung Cancer.
Hainsworth JD, Gray JR, Litchy S, Bearden JD, Shaffer DW, Houston GA, Greco FA.
The Sarah Cannon Cancer Center and Tennessee Oncology, Nashville, TN; e-mail: jhainsworth@tnonc.com

This study was designed to evaluate the efficacy and toxicity of a novel preoperative combined-modality regimen in patients with locally advanced non-small-cell lung cancer (NSCLC). Patients with clinical stage IIB, IIIA, or IIIB NSCLC received preoperative combined-modality therapy with concurrent radiation therapy (RT) and weekly paclitaxel/carboplatin for 5 consecutive weeks. After this treatment, patients believed to have resectable disease by standard surgical criteria underwent thoracotomy. Patients whose disease remained unresectable after initial therapy received further RT with concurrent paclitaxel/carboplatin. Of 107 patients entered into this clinical trial, only 20 patients (19%) were considered to have surgically resectable disease at the time of study entry. Ninety-eight patients (92%) completed preoperative combined-modality therapy. Forty-nine patients (46%) underwent thoracotomy and 34 patients had definitive resection. Fourteen patients (13%) had pathologic complete response (pCR). Thirteen of 18 patients (72%) with clinical stage T3 N0 (IIB) tumors had definitive resections, and 33% had pCR. After a median follow-up of 32 months, the 1- and 2-year actuarial survival rates for the entire group are 64% and 42%, respectively. Favorable-prognosis subgroups included patients who had definitive resection and patients with clinical stage T3 N0 tumors (2-year survival rates of 67% for both subgroups). Preoperative therapy with RT and weekly paclitaxel/carboplatin showed activity in this patient population; however, disease in the majority of patients with extensive involvement of mediastinal nodes remained unresectable after this treatment. Results in patients who initially had unresectable disease do not appear different than results achieved with concurrent RT/chemotherapy approaches. Postoperative complications associated with this preoperative combined-modality regimen were more frequent than expected with resection alone.

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Nippon Geka Gakkai Zasshi. 2004 Jul;105(7):412-6.
[Evidence-based practice guideline for unresectable advanced lung cancer in 2003]
[Article in Japanese]
Fukuoka M, Kurata T, Yamamoto N.
Department of Medical Oncology, Kinki University School of Medicine.

Recently evidence-based practice guideline for lung cancer in 2003 has been published. Recommendations for the treatment of unresectable non-small cell and small cell lung cancer are described here. Cisplatin-based chemotherapy combined with thoracic radiotherapy is recommended for the treatment for unresectable stage III non-small cell lung cancer. New chemotherapy agents, including paclitaxel, docetaxel, gemcitabine, vinorelbine, and irinotecan have been incorporated into combination regimens with carboplatin or cisplatin have become the standard therapy for advanced/metastatic NSCLC. Docetaxel is recommended as second-line therapy for patients with locally advanced or metastatic NSCLC who have progressed on first-line therapy. Etopside and cisplatin concurrently combined with twice-daily thoracic radiotherapy (TRT) is the standard care of limited -disease small cell lung cancer (SCLC). Recent randomized controlled trial demonstrated that irinotecan and cisplatin is superior to etoposide and cisplatin, a standard treatment of extensive-disease SCLC. This practice guideline should be updated periodically.

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Nippon Geka Gakkai Zasshi. 2004 Jul;105(7):404-7.
[Guidelines for the treatment of lung cancer with lymph node involvement]
[Article in Japanese]
Ikeda N, Tsuboi M, Ohira T, Hirano T, Kato H.
Department of Surgery, Tokyo Medical University, Japan.

Lung cancer with mediastinal lymph node involvement has a poor prognosis, especially when treated with surgery alone. Such cases are considered to be managed best by multimodality treatment. Some randomized trials showed positive results of induction chemotherapy and adjuvant chemotherapy in locally advanced lung cancer, but more evidence is needed to create the standard treatment for stage III lung cancer. A combination of chemotherapy and radiotherapy remain the standard of care for patients with obvious N2 disease, and the role of surgery following induction chemotherapy or chemo-radiotherapy in advanced stage III patients will be evaluated in phase III trials. Enrollment of patients in prospective clinical trials is strongly recommended to clarify unresolved issues in this clinical setting.

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Nippon Geka Gakkai Zasshi. 2004 Jul;105(7):392-403.
[Guide line for the treatment of stage I and stage II non small cell lung cancer]
[Article in Japanese]
Kobayashi K.
Department of Surgery, School of Medicine, Keio University, Tokyo, Japan.

Evidence based treatment modalities should be established as more than 55,000 patients die of lung cancer every year and its number is increasing. For stage I and stage II non small cell lung cancer (NSCLC), surgery is strongly recommended if there are no contraindications such as impaired pulmonary function and other medical disorders. Although lobectomy (bilobectomy or pneumonectomy) with mediastinal lymphnode dissection is standard operation for stage I and stage II NSCLC, limited operation (segmentectomy or extended segmentectomy) for peripherally located small sized cancer (less than 2 to 3) is now being performed to assess if there is survival difference between standard operation. Also numbers of patients undergoing video-assisted thoracoscopic surgery (VATS) is increasing and studies to compare postoperative survival rate and postoperative quality of life with standard operation is performed. To improve postoperative survival, pre and postoperative treatment such as chemotherapy, radiotherapy or combination of these treatments have been undertaken. Very recently usefulness of postoperative adjuvant chemotherapy with Uracil-Tegafur for stage I adenocecinoma was reported from Japan. For patients with stage I and stage II NSCLS in whom operation is not feasible for medical reasons, radical radiation therapy is recommended.

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Nippon Geka Gakkai Zasshi. 2004 Jul;105(7):388-91.
[Management of central-type early lung cancer: an evidence-based clinical guideline]
[Article in Japanese]
Sakurada A, Endo C, Sato M, Kondo T.
Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University.

With the support of the Japan Ministry of Health, Labour and Welfare, clinical guidelines for the management of lung cancer have been completed according to evidence-based methods. In this article, we focus on the guidelines for central-type early lung cancer. Reviewing a total of 3,196 reports that include key words related to central-type early lung cancer, 41 were selected and applied to determine recommendations for diagnostic or therapeutic methods. Among diagnostic methods, sputum cytology for the high-risk group and bronchoscopy for patients with positive sputum cytology were evaluated as recommendable. Among therapeutic methods, surgery and photodynamic therapy were evaluated as recommendable. For some methods, including fluorescence bronchoscopy and endobronchial ultrasonography brachitherapy, there was insufficient evidence to conclude that they are efficacious. At present, efforts to clarify the efficacy of these methods should be continued.

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Lung Cancer. 2004 May;44(2):241-9.
Phase II study of alternating chemotherapy regimens for advanced non-small cell lung cancer.
Stewart DJ, Tomiak E, Shamji FM, Maziak DE, MacLeod P.
Faculty of Medicine, University of Ottawa, Ottawa, Canada.

Purpose: We assessed the use of alternating drugs with differing mechanisms of action as treatment for advanced non-small cell lung cancer. Background: We hypothesized that the shape of a dose-response curve would be determined by the major mechanisms of resistance of a cancer to the drug being studied. Assessment of data from published clinical trials suggested that if our hypothesis were correct resistance of non-small cell lung cancer to most agents is due to "saturable passive" resistance mechanisms (non-competitive inhibition of drug effect due to deficiency of a factor required for drug effect) rather than to "active" resistance mechanisms (competitive inhibition of drug effect due to excess of a factor) or to "non-saturable passive resistance (due to factor alteration or mutation). Using drugs with differing mechanisms of action is a strategy that might be of value against passive resistance. Method: In patients with advanced non-small cell lung cancer, we used four alternating cisplatin-based regimens. In each regimen, cisplatin 80mg/m(2) was given iv on day 1 of each course. The regimens were: [Formula: see text] 25mg/m(2) days 1, 8 and 15, [Formula: see text] 1000mg/m(2) days 1, 8 and 15, [Formula: see text] 200mg/m(2) day 1 iv over 1h, and [Formula: see text] 100mg/m(2) po days 1-6. Patients were assigned randomly to different regimen sequences. Patients first received 1 course of each of these 4 regimens, then received 1 further course of each of single agent vinorelbine, gemcitabine, paclitaxel and etoposide (at the same doses as in courses 1-4), without cisplatin. (Cisplatin was omitted from courses 5-8 to limit cumulative toxicity.) Change in tumor size was measured after each course. Results: Thirty-six patients were entered. One patient achieved complete remission and nine achieved partial remissions, for an objective response rate of 28% (95% confidence intervals, 13-43%). Nineteen patients (53%) (95% confidence intervals, 37-69%) had stable disease. Eleven patients had growth of >10% on one regimen followed by tumor shrinkage of >10% on a later one. Median survival was 8.1 months, 1-year survival was 28% and 2-year survival was 6%. No unexpected toxicity was seen. Conclusions: The use of four alternating regimens is feasible in advanced non-small cell lung cancer. Response rates and survival times were comparable to those observed for standard chemotherapy approaches, suggesting that this strategy does not offer any major advantage. We plan to explore the hypothesis that this approach failed since tumor cells surviving first exposure to chemotherapy rapidly down-regulate their ability to undergo apoptosis.

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Lung Cancer. 2004 May;44(2):231-9.
Phase II study of weekly paclitaxel as second-line therapy in patients with advanced non-small
cell lung cancer.
Ceresoli GL, Gregorc V, Cordio S, Bencardino KB, Schipani S, Cozzarini C, Bordonaro R, Villa E.
Department of Oncology, Scientific Institute San Raffaele, Via Olgettina, 60-20132 Milan, Italy.

A growing number of patients, mainly cisplatin-pretreated, require second-line therapy for non-small cell lung cancer (NSCLC) but the optimal treatment and appropriate criteria for patient selection have not been defined yet. A second-line phase II study was conducted in cisplatin-pretreated patients with advanced NSCLC to evaluate the activity and toxicity of weekly paclitaxel. Fifty-three consecutive NSCLC patients (9 stage IIIA-B, 44 stage IV) progressing after one front line cisplatin-based chemotherapy were enrolled. Previous treatment with taxanes was not allowed. Patients with stage III were also pretreated with thoracic radiotherapy. Weekly paclitaxel was administered as 1-h infusion at a dose of 80mg/m(2) for three weeks with one week off, for a maximum of four courses. All patients were assessable for response, toxicity and survival. A complete response was observed in one case, partial response in 7, for an overall response rate (RR) of 15%, (95% [Formula: see text] -25%). Stable disease (SD) was registered in 11 patients, for an overall clinical benefit ( [Formula: see text] ) of 36% (95% [Formula: see text] -49%). Toxicity was mild, with G3-4 neutropenia and thrombocytopenia in 6 and 2% of patients, respectively. Non-hematological toxicities were negligible. No significant correlation between patient or treatment-related variable and RR was observed. CB was significantly higher in patients with non-squamous histology ( [Formula: see text] ) and no progression within 4 months of first line cisplatin-based chemotherapy ( [Formula: see text] ). Median progression-free survival (PFS) was 7 months in responders and 4 months in pts with SD. PFS was significantly related to good performance status (PS) ( [Formula: see text] ) and non-squamous histology ( [Formula: see text] ). In conclusion, weekly paclitaxel has acceptable palliative activity and excellent tolerance in cisplatin-pretreated patients. Patients with PS 0-1, non-squamous histology and with no progression within 4 months of first line cisplatin-based chemotherapy seem more likely to benefit from this treatment.

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Lung Cancer. 2004 May;44(2):221-30.
Outcomes of patients with advanced non-small cell lung cancer treated with gefitinib (ZD1839, 'Iressa') on an expanded access study.
Janne PA, Gurubhagavatula S, Yeap BY, Lucca J, Ostler P, Skarin AT, Fidias P, Lynch TJ, Johnson BE.
Massachusetts General Hospital, 55 Fruit St., Boston, MA 02115, USA.

Purpose: To investigate the anti-tumor activity and toxicity of the epidermal growth factor receptor (EGFR) inhibitor gefitinib (ZD1839 or Iressa trade mark; AstraZeneca Pharmaceuticals, Wilmington, DE), in patients with advanced non-small cell lung cancer (NSCLC). Methods: This was an open label, expanded access program (EAP) of oral gefitinib administered at 250mg per day continuously until evidence of undue toxicity or disease progression. Results: Two hundred consecutive patients with advanced NSCLC were enrolled in this study. The median number of prior chemotherapy regimens was 2 (range 0-6). One hundred seventy-two patients were treated with gefitinib; 23 expired from disease progression prior to treatment and 5 withdrew their consent. One hundred fifty-four patients are evaluable for toxicity; 8 (5.2%) experienced grade 3/4 toxicity; 2 patients discontinued therapy for grade 3 rash and one for grade 3 nausea. Of 172 patients evaluable for efficacy, 7 (4.1%; 95% CI; 1.7-8.2%) experienced a partial response (PR); 60 patients (34.9%) had stable disease (SD) as their best response. Median survival for all patients was 4.5 months (95% CI; 4.1-4.9 months). One-year survival was 29%. Significant independent prognostic factors associated with improved survival were female gender, good performance status (0/1), and adenocarcinoma histology. Conclusion: Gefitinib has anti-tumor activity, in a heterogeneous population of NSCLC patients treated on the EAP study. Treatment with gefitinib in this population is associated with a longer survival in women, those with good performance status and in patients with adenocarcinomas. These findings need to be further validated in additional clinical studies.

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JAMA. 2004 Apr 14;291(14):1763-8.
Lung cancer in US women: a contemporary epidemic.
Patel JD, Bach PB, Kris MG.
Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, and the Robert H. Lurie Comprehensive Cancer Center, Chicago, Ill 60611, USA. jd-patel@northwestern.edu

Lung cancer is the leading cause of cancer death in US women and is responsible for as many deaths as breast cancer and all gynecological cancers combined. Most lung cancer is caused by cigarette smoke. Despite all that is known about the devastating effects of cigarettes, one quarter of women in the United States continue to smoke. Women are targeted in tobacco advertising, and teenage girls are often drawn to cigarette smoking under a variety of social pressures.Following the increase in smoking, the death rate from lung cancer in US women rose 600% from 1930 to 1997. Women may be more susceptible than men to the carcinogenic properties of cigarette smoke. In addition, differences in the biology of lung cancer exist between the 2 sexes with higher levels of DNA adduct formation, increased CYP1A1 expression, decreased DNA repair capacity, and increased incidence of K-ras gene mutations in women. The novel estrogen receptor beta has also been detected in lung tumors and suggests that estrogen signaling may have a biological role in tumorigenesis. Given these differences and given the enormous toll this disease has on US women, undertaking sex-specific research in lung cancer is crucial. Finally, disseminating information about this epidemic may prevent a similar epidemic in other parts of the world where women are just now becoming addicted to tobacco.

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Curr Opin Oncol. 2004 Mar;16(2):136-40.
Chemotherapy of small cell lung cancer: state of the art.
Chrystal K, Cheong K, Harper P.
Department of Medical Oncology, Guy's Hospital, St Thomas Street, London SE1 9RT, UK. kathryn.chrystal@gstt.sthames.nhs.uk

PURPOSE OF REVIEW: Small cell lung cancer was termed chemosensitive with the introduction of combination chemotherapy in the 1970s. However, two decades of trials have seen little significant progress in achieving its "curable" potential. This paper presents an update of data recently published from phase 2 and phase 3 trials. RECENT FINDINGS: Platinum and etoposide combination chemotherapy remains the standard of care in small cell lung cancer. New agents, including irinotecan, may improve outcomes, but confirmatory trials are awaited. Triplet therapy, dose intensification, and maintenance therapy have not demonstrated meaningful survival improvements given the increased associated toxicity. Outcomes in limited-stage disease are optimized with the use of concurrent and early chemoradiation. New agents offering an improved toxicity profile for second-line therapy are emerging. SUMMARY: Small cell lung cancer remains an aggressive disease. Recent advances have yielded, at best, only modest gains. New strategies are required, including incorporation of novel targeted agents.

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Indian J Chest Dis Allied Sci. 2004 Jan-Mar;46(1):9-15.
Ifosfamide containing regimen for non-small cell lung cancer.
Behera D, Aggarwal AN, Sharma SC, Gupta D, Jindal SK.
Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India. dbehera@glide.net.in

BACKGROUND: Combination chemotherapy has been demonstrated as one of the best active regimens in patients with non-small cell lung cancer (NSCLC). METHODS: A total of 206 patients with advanced unresectable NSCLC stage III B or stage IV were enrolled to receive combination chemotherapy with mitomycin, ifosfamide and cisplatin. About a third of them (n=63) did not continue therapy after the first course either because of toxicity, lack of affordability, or death. The remaining 143 patients (121 males) received two or more cycles of chemotherapy. RESULTS: Nearly half of all followed-up patients showed a partial or complete radiological response. Overall performance status (Karnofsky scale) worsened in 28 (19.6%) and improved in 44 (30.8%). While 50 patients (35%) gained weight, 65 (45.5%) lost weight during follow-up. Overall median survival was 20 weeks [95% confidence interval (CI), 16 to 24 weeks]. However, overall survival improved progressively with the number of chemotherapy cycles administered. Median survival in patients receiving at least three, four and five chemotherapy cycles was 23 (95% CI, 19-27); 27 (95% CI, 24-30) and 35 (95% CI, 28-42) weeks respectively. Survival at the end of three, six, nine and 12 months was 64.3%, 29.4%, 14.7% and 9.8%) respectively. Survival had no association with age of the patient, but was significantly correlated with baseline performance status (Pearson's correlation coefficient 0.29 p<0.01). The cost of each course of chemotherapy was a little over 100 US dollars. The side effects were minimal and acceptable, and the regimen was tolerated well by all the patients. CONCLUSION: Ifosfamide regimen containing mitomycin and cisplatin is a chemotherapeutic combination for treating patients with advanced NSCLC.

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Am J Clin Oncol. 2004 Feb;27(1):89-95.
Phase I study with dose escalation of gemcitabine and cisplatin in combination with ifosfamide (GIP) in patients with non-small-cell lung carcinoma.
Bourgeois H, Billiart I, Chabrun V, Chieze S, Lemerre D, Germain T, Ferrand V, Meurice JC, Daban A, Tourani JM.
Federation de Cancerologie et d'Hematologie, University Hospital, Poitiers, France.

Gemcitabine (G) and cisplatin (P) are active reference agents in patients with non-small-cell lung cancer (NSCLC). Ifosfamide (I) has also been approved for NSCLC treatment. This phase I trial aimed to determine the dose-limiting toxicity (DLT), maximum tolerated dose [maximum tolerated dosage (MTD)], and recommended dose (RD) of a GIP combination in patients with advanced/metastatic NSCLC. In this study, one cycle of chemotherapy combined the following: ifosfamide: 3 g/m2 fixed dose (24-hour intravenous infusion) combined with mesna, day 1; gemcitabine: starting dose 1,000 mg/m2/d, escalating by 250 mg/m2 increments, days 1 and 15; cisplatin: starting dose 80 mg/m2, subsequently 100 mg/m2, day 15; in cohorts of at least 3 patients. Cycles were repeated every 28 days and no hematopoietic growth factors were administered. DLT was evaluated after the first chemotherapy cycle. Thirty-three patients (30 men, 3 women) with stage III (14 patients)/IV (19 patients) NSCLC were treated at eight dose levels, receiving 109 cycles of chemotherapy. Neutropenia was the only DLT reported. Although the MTD was not reached at the highest tested dose level, the RD chosen corresponds to the full doses of the GP3000 doublet standard (G: 3,000 mg/m2; P: 100 mg/m2 per cycle) every 28 days. Nonhematologic toxicities were mainly grade I-II. Relative dose intensities of G, I, and P at the RD were 96%, 98%, and 96%, respectively. Sixteen of 33 patients with measurable/evaluable disease had an objective response including two complete responses. In conclusion, GIP chemotherapy is safe and appears to be active in patients with NSCLC. The RD is gemcitabine: 1,500 mg/m2 days 1 and 15; ifosfamide: 3 g/m2 day 1; cisplatin: 100 mg/m2 day 15. A confirmatory phase II study is currently under way, before a phase III trial of GIP versus GP.

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Br J Surg. 2004 Feb;91(2):217-23.
Percutaneous radiofrequency ablation of pulmonary metastases in patients with colorectal cancer.
King J, Glenn D, Clark W, Zhao J, Steinke K, Clingan P, Morris DL.
University of New South Wales Department of Surgery, St George Public Hospital, Sydney, Australia.

INTRODUCTION: This study aimed to assess the safety and efficacy of imaging-guided percutaneous radiofrequency ablation (RFA) for local control of lung metastases from colorectal cancer (CRC). METHODS: Twenty patients with lung metastases from CRC were treated with a RITA Starburst XL electrode and RITA 1500 generator using temperature control and impedance monitoring. Patients received intravenous sedation and analgesia, or local anaesthetic, and stayed in hospital for at least 24 h after treatment. RFA was assessed with computed tomography (CT) at 1 week and 1 month, and then every 3 months. RESULTS: Forty-four CRC lung metastases in 19 patients were treated successfully at 25 treatment sessions. Five of 19 patients were retreated for new lesions. There were 13 pneumothoraces following the 25 treatments, and six patients required drainage. The median length of follow-up was 730 (range 148-924) days. Six months after treatment CT demonstrated that three lesions had progressed, 25 metastases were stable or smaller, and 11 were no longer visible. At 12 months five metastases had progressed, 11 were smaller or stable, and nine were not visible. CONCLUSION: Percutaneous imaging-guided RFA was associated with modest morbidity. RFA can achieve local control of CRC lung metastases: nine of 25 metastases were not visible on CT at 12 months after treatment. Copyright 2003 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

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J Thorac Cardiovasc Surg. 2004 Jan;127(1):108-13.
Two commonly used neoadjuvant chemoradiotherapy regimens for locally advanced stage III non-small cell lung carcinoma: long-term results and associations with pathologic response.
Machtay M, Lee JH, Stevenson JP, Shrager JB, Algazy KM, Treat J, Kaiser LR.
Department of Radiation Oncology, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA. machtay@xrt.upenn.edu

BACKGROUND: We performed this study to determine the outcomes (pathologic response, survival, local-regional control, and toxicity) in patients treated with neoadjuvant chemoradiotherapy and planned operation for stage IIIA non-small cell lung carcinoma. METHODS: Patients treated from 1993 to 2000 with neoadjuvant chemoradiotherapy and a predetermined plan for subsequent surgical resection for stage III non-small cell lung carcinoma were analyzed. All patients underwent pretreatment evaluation at the university's Multidisciplinary Lung Cancer Center. Most patients (87%) had complete mediastinoscopy staging, and all were believed to be poor candidates for up-front operation because of bulky extent of disease. The radiotherapy program used conventional, 2-dimensionally planned treatment to 45 to 54 Gy in 1.8- to 2-Gy fraction size. Concurrent chemotherapy consisted of etoposide/cisplatin or carboplatin/paclitaxel. Study end points included resectability, pathologic response, local-regional control, survival, and toxicity. An exploratory comparison between pathologic response and long-term survival was performed. An exploratory comparison between older chemotherapy (etoposide/cisplatin) and third-generation chemotherapy (carboplatin/paclitaxel) was also performed. RESULTS: Of 53 patients, 45 (85%) were deemed surgical candidates after induction therapy. Twenty-two (42% of the initial cohort) patients had a major pathologic response to stage 0, I, or II disease. The 5-year actuarial survival was 31%. Major pathologic response was associated with improved survival (48% vs 24%; P =.027). The overall rate of early death potentially related to therapy in this series was 9%; this mostly occurred in patients who underwent right pneumonectomy. There was no difference in efficacy or mortality between etoposide/cisplatin and radiotherapy versus carboplatin/paclitaxel and radiotherapy, although the latter regimen was associated with less grade 3 or higher acute toxicity necessitating interruption or hospitalization during neoadjuvant treatment (P =.02). In-field local control was achieved in 83% of all patients (90% of the patients who underwent resection). Brain metastases as the first site of treatment failure occurred in 23% of all patients. CONCLUSIONS: Neoadjuvant concurrent chemoradiation delivers high resectability, major pathologic response rate, and excellent local-regional control, with encouraging long-term survival considering the patient population studied. Major pathologic response correlates with long-term survival. Neoadjuvant carboplatin/paclitaxel and radiotherapy is an appropriate framework on which to add new therapies.

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N Engl J Med. 2004 Jan 22;350(4):351-60.
Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer.
Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J; International Adjuvant Lung Cancer Trial Collaborative Group.
Instituto de Radiomedicina, Santiago, Chile.

BACKGROUND: On the basis of a previous meta-analysis, the International Adjuvant Lung Cancer Trial was designed to evaluate the effect of cisplatin-based adjuvant chemotherapy on survival after complete resection of non-small-cell lung cancer. METHODS: We randomly assigned patients either to three or four cycles of cisplatin-based chemotherapy or to observation. Before randomization, each center determined the pathological stages to include, its policy for chemotherapy (the dose of cisplatin and the drug to be combined with cisplatin), and its postoperative radiotherapy policy. The main end point was overall survival. RESULTS: A total of 1867 patients underwent randomization; 36.5 percent had pathological stage I disease, 24.2 percent stage II, and 39.3 percent stage III. The drug allocated with cisplatin was etoposide in 56.5 percent of patients, vinorelbine in 26.8 percent, vinblastine in 11.0 percent, and vindesine in 5.8 percent. Of the 932 patients assigned to chemotherapy, 73.8 percent received at least 240 mg of cisplatin per square meter of body-surface area. The median duration of follow-up was 56 months. Patients assigned to chemotherapy had a significantly higher survival rate than those assigned to observation (44.5 percent vs. 40.4 percent at five years [469 deaths vs. 504]; hazard ratio for death, 0.86; 95 percent confidence interval, 0.76 to 0.98; P<0.03). Patients assigned to chemotherapy also had a significantly higher disease-free survival rate than those assigned to observation (39.4 percent vs. 34.3 percent at five years [518 events vs. 577]; hazard ratio, 0.83; 95 percent confidence interval, 0.74 to 0.94; P<0.003). There were no significant interactions with prespecified factors. Seven patients (0.8 percent) died of chemotherapy-induced toxic effects. CONCLUSIONS: Cisplatin-based adjuvant chemotherapy improves survival among patients with completely resected non-small-cell lung cancer. Copyright 2004 Massachusetts Medical Society

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Br J Cancer. 2004 Jan 26;90(2):359-65.
A randomised phase II study of weekly paclitaxel or vinorelbine in combination with cisplatin against inoperable non-small-cell lung cancer previously untreated.
Chen YM, Perng RP, Shih JF, Lee YC, Lee CS, Tsai CM, Whang-Peng J.
Chest Department, Taipei Veterans General Hospital, Taipei, Taiwan. ymchen@vghtpe.gov.tw

Phase II studies have suggested that weekly paclitaxel has a higher response rate and better toxicity profile than the conventional schedule of once every 3 or 4 weeks. Our aim was to evaluate the efficacy of weekly paclitaxel plus cisplatin (PC) vs vinorelbine plus cisplatin (VC) in chemonaive non-small-cell lung cancer (NSCLC) patients. From October 2000 to May 2002, 140 patients were enrolled. The treatment dose was P 66 mg m(-2) intravenous infusion (i.v.) on days 1, 8, and 15, and C 60 mg m(-2) i.v. on day 15, or V 23 mg m(-2) i.v. on days 1, 8, and 15, and C 60 mg m(-2) i.v. on day 15, every 4 weeks. In all, 281 cycles of PC and 307 cycles of VC were given to the patients in the PC and VC arms, respectively. There were 26 partial responses and one complete response (overall 38.6%) in the PC arm, and no complete responses, but 27 partial responses (overall 38.6%) in the VC arm. Myelosuppression was more common in the VC arm (P<0.001). Peripheral neuropathy and myalgia were significantly more common in the PC arm (P<0.001). The median time to disease progression was 6 months in the PC arm and 8.4 months in the VC arm (P=0.0344). The median survival time was 11.7 months in the PC arm and 15.4 months in the VC arm (P=0.297). We concluded that weekly PC is not suggested for NSCLC patients due to the relatively shorter progression-free survival and more common nonhaematological toxicities.British Journal of Cancer (2004) 90, 359-365. doi:10.1038/sj.bjc.6601526 www.bjcancer.com

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Kyobu Geka. 2004 Jan;57(1):51-5.
[Clinical study on video-assisted thoracic surgical simultaneously stapled subsegmentectomy for peripheral lung tumors]
[Article in Japanese]
Ikeda T, Kanzaki M, Kuwata H, Isaka T, Miyano Y, Oyama K, Mae M, Murasugi M, Onuki T.
Department of First Surgery, Tokyo Women's Medical University, Tokyo, Japan.

BACKGROUND: The purpose of this study is to confirm the safety and validity of video-assisted thoracic surgical simultaneously stapled subsegmentectomy (simultaneously stapling of all subsegmental bronchi and vessels in their natural construction). METHODS: The clinicopathologic information of the 10 patients who underwent video-assisted thoracic surgical simultaneously stapled subsegmentectomy for primary lung cancer (6) and metastatic lung tumor (4) were reviewed retrospectively. The patient population consisted of 7 men and 3 women with a mean age of 70.2 years. RESULTS: Median operative time was 201 minutes. Average blood loss was 76 ml. Mean duration of thoracic drainage was 3 days. There was no surgical mortality. Recurrence was diagnosed in 2 of 6 lung cancer patients (each of contralateral lung metastasis and brain metastasis), and 1 of 2 died 26 months after the operation. All patients have been followed for a mean period of 30.4 months with no local recurrence. CONCLUSIONS: Video-assisted thoracic surgical simultaneously stapled subsegmentectomy is safe and may be an acceptable alternative to segmentectomy, and wedge resection for strictly selective patients with peripheral lung tumors.

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Kyobu Geka. 2004 Jan;57(1):31-7.
[New surgical technique of pulmonary segmentectomy by ultrasonic scalpel and absorbable sealing materials]
[Article in Japanese]
Matsumura Y, Okada Y, Shimada K, Endo C, Chida M, Sakurada A, Sato M, Kondo T.
Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.

We developed new surgical technique of pulmonary segmentectomy by ultrasonic scalpel to sever intersegmental pulmonary tissue and absorbable sealing materials to cover the cut surface of lung. This method is expected to preserve more anatomical lung volume than the segmentectomy with surgical stapler. Two cases of post surgical recurrent lung cancer, 3 cases of pulmonary metastasis and 4 cases of primary lung cancer were applied this technique to preserve function. Among 3 materials examined, best result was obtained with polyglycolic acid felt (PGAF:Neoveil). PGAF is a very soft and thin (0.15 mm depth) new absorbable material that is able to closely adhere to irregular sections of the lung with fibrin glue and effectively seals air leakage. Mean chest drainage period after surgery in 6 cases with PGAF was 3.3 days. Excellent lung expansion was obtained immediately after the surgery and PGAF was disappeared completely on chest CT within 1 year. Although the possible superiority of this method is suggested in the present study, further comparative study is necessary to clarify the advantage of this new technique.

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Kyobu Geka. 2004 Jan;57(1):25-9.
[Limited resection for small peripheral lung cancer using intraoperative pathologic examination]
[Article in Japanese]
Watanabe T, Okada A, Imakiire N, Hirono T.
Division of Chest Surgery, Nishiniigata-Central Hospital, Niigata, Japan.

From 1996 to 2002, we performed intentional limited resection for small peripheral lung cancer using intraoperative pathologic examination. Wedge resection was performed in patients who had small peripheral adenocarcinoma (< or = 20 mm), suspected of being Noguchi type A or B, and confirmed by intraoperative pathologic examination. Extended segmentectomy was performed in the rest of patients (tumor diameter < or = 20 mm), and not suspected of being Noguchi type A or B. Hilar and mediastinal lymph nodes sampling was performed in this group. If lymph node metastasis was detected by the intraoperative pathologic examination, the surgical procedures was converted into a lobectomy with lymph node dissection. Limited resection was performed in 27 patients, wedge resection in 8, and extended segmentectomy in 19. All patients received wedge resection are alive without sign of recurrence. In extended segmentectomy, 17 patients are alive with no evidence of disease, 1 patient died of non-pulmonary disease, and 1 patient is alive with recurrent disease. The overall survival rate at 5 years was 100% in wedge resection, 91% in extended segmentectomy, and 79% in standard lobectomy. We conclude that limited resection for small peripheral lung cancer using intraoperative pathologic examination may be safe and effective procedure.

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Kyobu Geka. 2004 Jan;57(1):4-8.
[Diagnosis and surgical treatment for small-sized peripheral lung cancer]
[Article in Japanese]
Iyoda A, Fujisawa T, Moriya Y.
Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Small-sized peripheral lung cancers have been detected more frequently as a result of recent developments in diagnostic imaging including high-resolution computed tomography (HRCT). Although the diagnosis of small-sized peripheral lung cancers is difficult, it makes an adequate diagnosis possible using transbronchial fine needle aspiration cytology or a new thin-type bronchoscope. Surgical treatment using mini-thoracotomy or video-assisted thoracic surgery is effective for early stage small-sized peripheral lung cancers. Lesser resection of lung cancer may provide many benefits to patients, such as preserving vital lung tissue and providing the chance for further resection if a second primary lung cancer develops, however, lobectomy with systematic hilar and mediastinal lymph node dissection should remain the standard surgical treatment, and an intentional limited resection should be adopted for very limited patients with a definitive early stage because of recurrence rates.

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Br J Cancer. 2004 Jan 12;90(1):82-6.
Efficacy and tolerability of gefitinib in pretreated elderly patients with advanced non-small-cell
lung cancer (NSCLC).
Cappuzzo F, Bartolini S, Ceresoli GL, Tamberi S, Spreafico A, Lombardo L, Gregorc V, Toschi L, Calandri C, Villa E, Crino L.
Bellaria Hospital, Division of Medical Oncology, Via Altura 3, Bologna 40139, Italy. federico.cappuzzo@ausl.bo.it

The activity and toxicity profile of gefitinib in non-small cell lung cancer (NSCLC) patients aged 70 years or older has been only partially evaluated. The aim of this study was to evaluate the response rate and safety of gefitinib in elderly NSCLC patients. Elderly NSCLC patients pretreated with chemotherapy and with at least one measurable lesion received gefitinib at the daily dose of 250 mg until disease progression, unacceptable toxicity or refusal. From August 2001 to May 2003, 40 consecutive elderly patients have been enrolled onto the study in three Italian institutions. We observed one complete (2.5%) and one partial response (2.5%), 18 disease stabilisations (NC: 45%) lasting at least 2 months, including six patients (15%) who had disease stabilisation of 6 months or longer, for an overall disease control rate of 50% (95% CI: 34.5-65.5%). The median duration of response was 4.4 months (range 1.7-9.2). The side effects were generally mild and consisted of diarrhoea and skin toxicity. Grade 1-2 diarrhoea occurred in 23.6%, and one patient experienced grade 4 diarrhoea, requiring hospitalisation. Grade 1-2 skin toxicity, including rash, pruritus, dry skin, and acne, occurred in 20 patients (52.6%). Gefitinib is safe and well tolerated in elderly pretreated NSCLC patients. The disease-control rate achieved suggests that this drug could represent a valid option in the management of this unfavourable subgroup of patients.

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J Clin Oncol. 2004 Jan 1;22(1):127-32.
Phase II trial of cisplatin/etoposide and concurrent radiotherapy followed by paclitaxel/carboplatin consolidation for limited small-cell lung cancer: Southwest Oncology Group 9713.
Edelman MJ, Chansky K, Gaspar LE, Leigh B, Weiss GR, Taylor SA, Crowley J, Livingston R, Gandara DR.
Southwest Oncology Group (S9713), Operations Office, 14980 Omicron Drive, San Antonio, TX 78245-3217, USA.

PURPOSE: Limited small-cell lung cancer (LSCLC) is characterized by a high initial response rate to chemoradiotherapy, but local or systemic relapse occurs in the majority of patients. Previous Southwest Oncology Group trials in LSCLC have utilized cisplatin and etoposide (PE) delivered concurrently with thoracic radiotherapy followed by two consolidation cycles. Newer chemotherapy regimens such as paclitaxel and carboplatin are active in small-cell lung cancer and hold the promise of improving both local and systemic control. S9713 evaluated the substitution of paclitaxel and carboplatin for PE consolidation in LSCLC. PATIENTS AND METHODS: Between July 1998 and August 1999, 96 patients were accrued from 43 institutions. Eighty-nine patients were eligible; 87 were assessable for survival and response. Treatment consisted of cisplatin 50 mg/m(2) on days 1, 8, 29, and 36, and etoposide 50 mg/m(2) on days 1 to 5 and days 29 to 33, with concurrent radiotherapy of 61 Gy beginning on day 1. Consolidation therapy was carboplatin (area under the curve = 6) and paclitaxel 200 mg/m(2), both drugs administered on day 1 of a 21 day cycle for three cycles. RESULTS: The response rate was 86% (complete response, 33%; partial response, 53%). Median overall survival was 17 months (95% CI, 12.7 to 19.0). One- and 2-year overall survivals were 61% and 33%, respectively. Median progression-free survival (PFS) was 9 months, 1-year PFS was 40%, and 2-year PFS was 21%. CONCLUSION: Consolidation therapy with paclitaxel and carboplatin in LSCLC resulted in an outcome similar to that seen in prior Southwest Oncology Group trials. This study and others which have tested paclitaxel in small-cell lung cancer dampens enthusiasm for this agent in the primary management of LSCLC.

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Am J Respir Med. 2003;2(6):477-90.
Combined modality treatment of non-small-cell lung cancer.
Westeel V, Depierre A.
Chest Disease Department, Jean Minjoz University Hospital, Besancon Cedex, France. virginie.westeel@ufc-chu.univ-fcomte.fr

Among all nonmetastatic non-small-cell lung cancer (NSCLC) patients, the best survival rates are observed in patients who undergo surgery. Nevertheless, 5-year survival rates vary between 20% and 60% depending on the stage of the disease. Several combined modality treatments have been investigated to improve outcome in localized NSCLC. These include local treatment, systemic before local treatment, concomitant systemic and local treatments, and systemic after local treatment. Preoperative irradiation was shown to be of no benefit on local recurrence rates or overall survival. Even doses of radiation >/=40 grays (Gy) were associated with lower survival rates. Postoperative irradiation did not influence survival in stage III disease and seemed to be deleterious in stages I and II disease. Modern radiotherapy techniques might be of interest in this setting but have been insufficiently tested. The early phase III studies of preoperative chemotherapy versus primary surgery in stage III NSCLC showed a tremendous difference in favor of chemotherapy. A larger study did not confirm these results but suggested that preoperative chemotherapy might have a greater effect in stages I and II of the disease. In locally advanced disease, chemotherapy followed by radiotherapy was shown to increase survival when compared with radiotherapy alone. Studies comparing concurrent chemoradiation with radiotherapy only were in favor of the concomitant schedule, which improved local control. Promising results have been reported with chemoradiation followed by surgery in stage IIIa and even stage IIIb disease. Randomized studies of postoperative chemotherapy demonstrated a 5% improvement in 5-year survival over adjuvant-free treatment. Postoperative chemoradiation showed no advantage over postoperative radiotherapy. Several trials that are ongoing or whose accrual was recently completed should further define the role of perioperative chemotherapy in resectable NSCLC and of trimodality treatments in advanced disease. Targeted agents are being developed in the postoperative setting. New schedules of chemoradiation with higher therapeutic indexes are also being investigated in nonresectable stage III NSCLC.

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Jpn J Thorac Cardiovasc Surg. 2003 Dec;51(12):646-50.
Video-assisted thoracic surgery for lung cancer: is it a feasible operation for stage I lung cancer?
Tatsumi A, Ueda Y.
Department of General Thoracic Surgery, Kochi Municipal Hospital, Kochi, Japan.

OBJECTIVE: The objective of this study was to confirm the safety and feasibility of video-assisted thoracic surgery (VATS) for primary lung cancer and to compare prognoses with that of conventional procedures, and then to examine whether VATS would supplant a conventional thoracotomy for stage I lung cancer. METHODS: From September 1995 through March 2002, 144 patients with primary lung cancer, included 118 patients with postoperative stage I, underwent VATS lobectomy. We reviewed the previous cases whether they could be candidates for VATS lobectomy according to present indications. 166 cases were supposed to be candidates for VATS, and 121 cases of postoperative stage I disease were recruited into the "conventional thoracotomy" group. RESULTS: There was no mortality or major complication except one case, and mean follow-up was 31.8 months in VATS. The number of removed lymph nodes was not significantly less than the number by conventional thoracotomy (p=0.061). Five-year survival for patients with pathological stage IA adenocarcinoma was 92.4% (n=66) in VATS and 86.9% (n=50) in conventional thoracotomy, and a statistical significance could not be recognized (p=0.980). The length of hospital stay was significantly short in VATS lobectomy (p<0.0001). CONCLUSIONS: VATS lobectomy for stage I lung cancer can be performed safely with minimal morbidity, satisfying survival comparable with that of lobectomy through conventional thoracotomy. VATS approach is a feasible surgical technique for patients with stage I lung cancer.

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Ann Thorac Surg. 2003 Dec;76(6):1821-7.
Quality of life after tailored combined surgery for stage I non-small-cell lung cancer and severe emphysema.
Pompeo E, De Dominicis E, Ambrogi V, Mineo D, Elia S, Mineo TC.
Division of Thoracic Surgery, Policlinico Tor Vergata University, Rome, Italy. pompeo@med.uniroma2.it

BACKGROUND: We analyzed the early and long-term quality of life changes occurring in 16 patients undergoing tailored combined surgery for stage I non-small-cell lung cancer (NSCLC) and severe emphysema. METHODS: Mean age was 65 +/- 5 years. All patients had severe emphysema with severely impaired respiratory function and quality of life. Tumor resection was performed with sole lung volume reduction (LVR) in 5 patients, separate wedge resection in 3 patients, segmentectomy in 2 patients, and lobectomy in 6 patients. A bilateral LVR was performed in 5 patients. Quality of life was assessed at baseline and every 6 months postoperatively by the Short-form 36 (SF-36) item questionnaire. RESULTS: Mean follow-up was 44 +/- 21 months. All tumors were pathologic stage I. There was no hospital mortality nor major morbidity. Significant improvements occurred for up to 36 months in the general health (p = 0.02) domain and for up to 24 months in physical functioning (p = 0.02), role physical (p = 0.005), and general health (p = 0.01) SF-36 domains. Associated improvements regarded dyspnea index (-1.3 +/- 0.6) forced expiratory volume in one second (+0.28 +/- 0.2L), residual volume (-1.18 +/- 0.5L) and 6-minute-walking test distance (+86 +/- 67 m). Actuarial 5-year survival was similar to that of patients with no cancer undergoing LVRS during the same period (68% vs 82%, p = not significant). CONCLUSIONS: Our study suggests that selected patients with stage I NSCLC and severe emphysema may significantly benefit from tailored combined surgery in terms of long-term quality of life and survival.

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Ann Thorac Surg. 2003 Dec;76(6):1810-4; discussion 1815.
Induction chemoradiotherapy and surgical resection for selected stage IIIB non-small-cell lung cancer.
Ichinose Y, Fukuyama Y, Asoh H, Ushijima C, Okamoto T, Ikeda J, Okamoto J, Sakai M.
Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan. yichinos@nk-cc.go.jp

BACKGROUND: Combination chemotherapy using an oral combination of uracil and tegafur (UFT) plus cisplatin and concurrent thoracic radiotherapy is reported to have a high response rate and less toxicity for locally advanced non-small-cell lung cancer (NSCLC) patients. We performed a phase II trial using this chemoradiotherapy as an induction treatment. METHODS: Patients with marginally resectable stage IIIB NSCLC, an age younger than 70 years, a performance status of 0 or 1, and good organ function were eligible. The UFT (400 mg/m(2)) was administered orally on days 1 through 14 and 22 through 35 and cisplatin (80 mg/m(2)) was injected intravenously on days 8 and 29. Radiotherapy with a total dose of 40 Gy was delivered in 20 fractions from day 1. A surgical resection was performed from 3 to 6 weeks after completing the induction treatment. RESULTS: Twenty-seven patients, 18 male and 9 female with a median age of 56 years and ranging from 36 to 69 years, were entered into the phase II trial. Clinical T4 and N3 cancers were observed in 22 and 7 patients, respectively. Twenty-five (93%) achieved a partial response. The most frequently observed adverse event was grade 3 leukopenia in 26%. Of 25 patients who underwent a thoracotomy, 22 had a tumor resection. In all 22 patients a complex resection including a resection of the superior vena cava, carina, and vertebrae was required. Operative morbidity and mortality rates were 36% and 4% respectively. The calculated 1-year and 3-year survival rates of all 27 patients were 73% and 56% respectively. CONCLUSIONS: Chemotherapy using UFT plus cisplatin and concurrent radiotherapy as induction treatment and a surgical resection for patients with marginally resectable stage IIIB NSCLC is feasible and promising. However it is difficult to conduct multi-institutional trials even for selected stage IIIB disease as a complex resection in almost all patients is necessary.

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Ann Thorac Surg. 2003 Dec;76(6):1782-8.
Sleeve lobectomy or pneumonectomy: optimal management strategy using decision analysis techniques.
Ferguson MK, Lehman AG.
Department of Surgery, The University of Chicago, Chicago, Illinois 60637, USA. mferguso@surgery.bsd.uchicago.edu

BACKGROUND: The choice between sleeve lobectomy and pneumonectomy is controversial for patients with early-stage lung cancer and who have acceptable lung function. METHODS: We performed a meta-analysis of results of sleeve lobectomy and pneumonectomy published in English from 1990 to 2003. A decision model was developed with 5-year survival, quality-adjusted life years (QALY), and cost effectiveness as the outcomes, and sensitivity analyses were performed. RESULTS: The model favored sleeve lobectomy (3.5 percentage point survival advantage) when the reward was 5-year survival; the results were influenced primarily by the 5-year survival rates for patients who did not develop recurrent cancer. Sleeve lobectomy was strongly favored when the reward was QALY (1.53 QALY advantage). Sleeve lobectomy was more cost effective than pneumonectomy, and had an incremental cost effectiveness ratio of $1,300/QALY. CONCLUSIONS: In patients with anatomically appropriate early-stage lung cancer, sleeve lobectomy offers better long-term survival and quality of life than does pneumonectomy and is more cost effective.

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Ann Thorac Surg. 2003 Dec;76(6):1796-801.
Lung resection for non-small-cell lung cancer in patients older than 70: mortality, morbidity, and late survival compared with the general population.
Birim O, Zuydendorp HM, Maat AP, Kappetein AP, Eijkemans MJ, Bogers AJ.
Department of Cardiothoracic Surgery, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands.

BACKGROUND: Operative mortality and morbidity in elderly patients operated on for non-small-cell lung cancer are acceptable. However, risk factors for hospital mortality and the benefits for the patients in the long term are insufficiently defined, and survival compared with the general population is not known. METHODS: From January 1989 to October 2001, 126 consecutive patients older than 70 years of age underwent resection for non-small-cell lung cancer. Each patient was scaled according to the Charlson Comorbidity Index. Postoperative events were divided into minor and major complications. Risk factors for complications and long-term survival were assessed by univariate and multivariate logistic regression analysis. Survival was compared with the yearly expected survival rates of the general population. RESULTS: The hospital mortality was 3.2%. Minor complications occurred in 71 (57%) patients, major complications, in 16 (13%) patients. No risk factor was predictive for major complications. However, a Charlson comorbidity grade of 3 to 4 was predictive for major complications (odds ratio, 12.6; 95% confidence interval, 1.5 to 108.6). Our study showed a 5- and 10-year survival rate of 37% (95% confidence interval, 23 to 51) and 15% (95% confidence interval, 8 to 22). Smoking (odds ratio, 2.3), chronic obstructive pulmonary disease (odds ratio, 2.1), and pathologic stage IIIA (odds ratio, 2.2) or IIIB (odds ratio, 11.9) were risk factors for long-term survival. The observed survival was lower than the expected survival, but the difference decreased with increasing time after pulmonary resection. CONCLUSIONS: Pulmonary resection for non-small-cell lung cancer in patients older than 70 years shows acceptable morbidity and mortality. The Charlson index is a better predictor of complications than individual risk factors. In time survival is no longer correlated with the disease but follows the same pattern as the general population.

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

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

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Semin Oncol Nurs. 2003 Nov;19(4):244-9.
Tobacco-related diseases.
Burns DM.
University of California-San Diego School of Medicine, 1545 Hotel Circle So, Suite 310, San Diego, CA 92108, USA.

OBJECTIVE: To provide an overview of the disease risks associated with cigarette smoking and the benefits of smoking cessation. DATA SOURCES: Government reports and monographs, and research articles. CONCLUSION: Cigarette smoking causes over 400,000 deaths per year and is a major cause of coronary heart disease, chronic obstructive pulmonary disease, and lung cancer. The disease risks associated with cigarette smoking are proportional to the intensity and duration of smoking. Cessation of cigarette smoking results in a decline in risk in relation to the risks of continuing smokers. IMPLICATIONS FOR NURSING PRACTICE: Clinicians must be aware of the magnitude of smoking-related risks and the benefits of smoking cessation as a critical intervention.

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Clin Lung Cancer. 2003 Nov;5(3):169-73.
Management of advanced non-small-cell lung cancer in elderly populations.
Lilenbaum R.
Thoracic Oncology Program, The Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida 33140-2840, USA. rlilenba@salick.com

Elderly patients, defined as those >or= 70 years of age, represent approximately 40% of all patients diagnosed with non-small-cell lung cancer in the United States. Nonetheless, elderly patients have been underrepresented in national cooperative group trials, and many do not receive appropriate treatment. Whereas the benefit of systemic chemotherapy in younger patients is accepted by most clinicians, there remains a great deal of skepticism with respect to older patients, who are often labeled unfit for chemotherapy. More recent studies with a special focus on elderly patients demonstrate that these patients indeed benefit from chemotherapy. The landmark Elderly Lung Cancer Vinorelbine Italian Study Group trial and the Multicentre Italian Lung Cancer in the Elderly Study clarified the role of vinorelbine in the treatment of elderly patients. Retrospective and prospective subgroup analyses from selected North American trials suggested that elderly patients also benefit from platinum-based combinations. Whether elderly patients should be treated with single-agent versus combination chemotherapy is discussed in this review. The available data suggest that patients should be evaluated for chemotherapy based on their performance status and comorbidities rather than age alone. For elderly patients judged fit to receive combination chemotherapy, carboplatin-based regimens are a reasonable option. In elderly patients with less than optimal performance status or significant comorbid conditions, single-agent therapy may be more appropriate.

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Bull Cancer. 2003 Oct;90(10):917-8.
[Advanced nonsmall cell lung cancer: importance of chemotherapy in the control of symptoms]
[Article in French]
Margery J, Le Moulec S, Grassin F, Bauduceau O, Dot JM, Vedrine L, Natali F, Guigay J.

Chemotherapy in advanced non-small-cell lung cancer may be a controversy because it is only palliative and costly. Benefit of chemotherapy is nevertheless clear in survival and particularly life quality. Beside this technical criteria, two other factors have an impact on the therapeutic decision: symptom control and patient's personal expectations. The aim of the strategy is to determine an acceptable compromise in each situation.

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Vopr Onkol. 2003;49(5):647-51.
[Accelerated fractionation regimens in radiotherapy of inoperable non-small-cell lung cancer]
[Article in Russian]
Val'kov MIu, Zolotkov AG, Mardynskii IuS, Asakhin SM, Kudriavtsev LV, Akishin VA.
Northern State Medical University, Arkhangelsk.

The results of definitive radiation treatment (1988-2000) for 375 patients with inoperable non-small cell lung cancer were analyzed. Three regimens of fractionation were used: (1) accelerated fractionation (AF)--(133), 2.5 Gy, 3 days a week, to a total of 47.5--55 Gy; (2) accelerated hyperfractionation (AHF)--(93), 1.25 Gy, daily, to a total of 60-72.5 Gy and standard fractionation (SF)--(149), 2 Gy, daily, to a total of 58-68 Gy. The advantages of AHF were established as regards complete regression rate (54.9% vs. 18.6%--SF and 18.1%--AF; p(0.001), median survival (30.5(2.4 months vs. 18.9 (1%--SF (p = 0.004) and 20.4 (2.4--AF (p = 0.004)), and 3-year survival (36.6% vs. 16.7%--SF (p = 0.005) and 15.5%--AF (p = 0.005). 17.9%, 9.0% (p = 0.11) and 8.1% (p = 0.08) have survived, respectively. Overall survival in the AHF group was superior in stages IIB--III; in stage I, the results were identical. Immediate response to radical radiotherapy appeared the only statistically significant factor of survival (p = 0.005-0.008) in all the groups.

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Cancer. 2003 Nov 1;98(9):1918-24.
A phase II study of weekly docetaxel plus capecitabine for patients with advanced nonsmall cell
lung carcinoma.
Han JY, Lee DH, Kim HY, Hong EK, Yoon SM, Chun JH, Lee HG, Lee SY, Shin EH, Lee JS.
Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Republic of Korea.

BACKGROUND: Docetaxel is an active agent in advanced nonsmall-cell lung carcinoma (NSCLC) and demonstrates preclinical and clinical synergism with capecitabine. We conducted the current Phase II study to evaluate the efficacy and safety of the docetaxel/capecitabine combination in chemotherapy-naive patients with advanced NSCLC. METHODS: Eligibility required Stage IIIB or IV NSCLC, bidimensionally measurable disease, and an Eastern Cooperative Oncology Group performance score of 2 or lower. Treatment consisted of docetaxel 36 mg/m(2) intravenously on Days 1 and 8 plus capecitabine 1000 mg/m(2) orally twice per day on Days 1-14 of a 21-day cycle, for a maximum of 6 cycles. RESULTS: Of 39 patients enrolled, 39 and 36 patients were evaluated for toxicity and response, respectively. The overall response rate was 53% (95% confidence interval [CI], 37-69%) with 19 partial responses (no complete response). The median duration of response was 6.2 months (range, 2.1-15.7 months). At a median follow-up of 14.2 months, 19 patients died. The median overall survival time was 17.8 months, with a 1-year survival rate of 56.4% (95% CI, 40.9-72.0%). There were two treatment-related deaths (one death due to pneumonia and one due to sepsis). Hematologic toxicity was mild to moderate. Thirteen percent of the patients had Grade 3 or 4 neutropenia. However, Grade 2 or 3 nonhematologic toxicities were frequent, which included asthenia (51%), stomatitis (33%), hand-foot syndrome (33%), and diarrhea (29%). CONCLUSIONS: The docetaxel/capecitabine combination showed promising antitumor activity for chemotherapy-naive patients with advanced NSCLC, However, it was frequently associated with moderate-to-severe nonhematologic toxicities, suggesting clinical synergism in both efficacy and toxicity. Further adjustment of the dose schedule is recommended to maximize the therapeutic index. Copyright 2003 American Cancer Society.

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Kyobu Geka. 2003 Oct;56(11):943-8.
[Complications of major lung resections by video-assisted thoracoscopic surgery]
[Article in Japanese]
Watanabe A, Osawa H, Watanabe T, Mawatari T, Ichimiya Y, Takahashi N, Abe T.
Department of Second Surgery, School of Medicine, Sapporo Medical University, Sapporo, Japan.

Lobectomy by video-assisted thoracoscopic surgery (VATS) is gradually being performed more frequently because of advantages regarding pain and pulmonary function. Complications sometimes occur during or after VATS lobectomy. The purpose of this study was to analyze the incidence and the causes of the complications. From 1997 to 2003, 185 patients underwent VATS lobectomies. Selected diseases for this approach included primary lung cancer (n = 172), metastatic lung cancer (n = 7), benign lung tumors (n = 3) and lung sequestration (n = 3). The VATS approach was converted to open thoracotomy in 15 (8.1%) of 185 patients because of bleeding (n = 8), dense hilar adenopathy (DHA, n = 3), local extent of disease (n = 3) of intraoperative cardiac trouble (n = 1). Intraoperative complications involved injury to a blood vessel (n = 21), stapling failure (n = 15), lung injury (n = 7), nerve injury (n = 3), and others. Predictive factors for injury to pulmonary arteries was DHA (OR 37.0, p < 0.0001). Postoperative surgical death occurred in 2 patients due to pneumonia. Postoperative morbidity was 22.9%. A surgical operation without any good direct or thoracoscopic view or the use of a thoracoscopic tool without knowledge of the directions on its use should be avoided. The VATS approach should be replaced by open thoracotomy if there are DHA.

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JAMA. 2003 Oct 22;290(16):2149-58.
Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial.
Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, Albain KS, Cella D, Wolf MK, Averbuch SD, Ochs JJ, Kay AC.Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center and the Weill Medical College of Cornell University, New York, NY 10021, USA.

CONTEXT: More persons in the United States die from non-small cell lung cancer (NSCLC) than from breast, colorectal, and prostate cancer combined. In preclinical testing, oral gefitinib inhibited the growth of NSCLC tumors that express the epidermal growth factor receptor (EGFR), a mediator of cell signaling, and phase 1 trials have demonstrated that a fraction of patients with NSCLC progressing after chemotherapy experience both a decrease in lung cancer symptoms and radiographic tumor shrinkages with gefitinib. OBJECTIVE: To assess differences in symptomatic and radiographic response among patients with NSCLC receiving 250-mg and 500-mg daily doses of gefitinib. DESIGN, SETTING, AND PATIENTS: Double-blind, randomized phase 2 trial conducted from November 2000 to April 2001 in 30 US academic and community oncology centers. Patients (N = 221) had either stage IIIB or IV NSCLC for which they had received at least 2 chemotherapy regimens. INTERVENTION: Daily oral gefitinib, either 500 mg (administered as two 250-mg gefitinib tablets) or 250 mg (administered as one 250-mg gefitinib tablet and 1 matching placebo). MAIN OUTCOME MEASURES: Improvement of NSCLC symptoms (2-point or greater increase in score on the summed lung cancer subscale of the Functional Assessment of Cancer Therapy-Lung [FACT-L] instrument) and tumor regression (>50% decrease in lesion size on imaging studies). RESULTS: Of 221 patients enrolled, 216 received gefitinib as randomized. Symptoms of NSCLC improved in 43% (95% confidence interval [CI], 33%-53%) of patients receiving 250 mg of gefitinib and in 35% (95% CI, 26%-45%) of patients receiving 500 mg. These benefits were observed within 3 weeks in 75% of patients. Partial radiographic responses occurred in 12% (95% CI, 6%-20%) of individuals receiving 250 mg of gefitinib and in 9% (95% CI, 4%-16%) of those receiving 500 mg. Symptoms improved in 96% of patients with partial radiographic responses. The overall survival at 1 year was 25%. There were no significant differences between the 250-mg and 500-mg doses in rates of symptom improvement (P =.26), radiographic tumor regression (P =.51), and projected 1-year survival (P =.54). The 500-mg dose was associated more frequently with transient acne-like rash (P =.04) and diarrhea (P =.006). CONCLUSIONS: Gefitinib, a well-tolerated oral EGFR-tyrosine kinase inhibitor, improved disease-related symptoms and induced radiographic tumor regressions in patients with NSCLC persisting after chemotherapy.

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Int J Radiat Oncol Biol Phys. 2003 Oct 1;57(2):402-8.
Effect of amifostine on toxicities associated with radiochemotherapy in patients with locally advanced non-small-cell lung cancer.
Antonadou D, Throuvalas N, Petridis A, Bolanos N, Sagriotis A, Synodinou M.
Department of Radiation Oncology, Metaxa Cancer Hospital, Piraeus, Greece. d_antona@hol.gr

PURPOSE: Radiochemotherapy (RCT) is an effective treatment for locally advanced non-small-cell lung cancer (NSCLC), but can be limited by acute and late toxicities (esophagitis, pneumonitis, and myelosuppression). This trial investigated whether pretreatment with amifostine, a radioprotector, could reduce the incidence of radiochemotherapy-induced acute and late toxicities. METHODS AND MATERIALS: Between October 1997 and August 1999, 73 patients with previously untreated Stage IIIa-IIIb NSCLC were randomized to treatment with RCT alone (n = 36) or RCT plus amifostine (300 mg/m(2) daily i.v. infusion, n = 37). RCT consisted of either paclitaxel (60 mg/m(2)) or carboplatin (AUC 2) once weekly during a 5- to 6-week course of conventional radiotherapy given as 2 Gy/5 days/week to a total dose of 55 to 60 Gy. Blood cell counts were measured weekly; esophagitis and acute lung toxicity were evaluated during the treatment course. Treatment efficacy was assessed following World Health Organization criteria for response. Late lung toxicity was assessed at 3 and 6 months after RCT and was graded from 0 to 4 according to the Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer criteria. RESULTS: A total of 68 patients were evaluable for toxicity analysis (RCT group, n = 32; RCT + amifostine, n = 36). There was no significant difference between treatment arms in patient baseline characteristics. The incidence of Grade >or=3 esophagitis during RCT was significantly lower for patients receiving amifostine than for patients receiving RCT alone (38.9% vs. 84.4%%, p < 0.001). Furthermore, the incidence of Grade >or=3 acute pulmonary toxicity was significantly reduced in patients treated with RCT plus amifostine compared to patients who received RCT alone (19.4% vs. 56.3%, p = 0.002). At 3 months after RCT, patients treated with amifostine had a significantly lower incidence of pneumonitis than patients who received RCT alone (p = 0.009). Combined response rates (complete plus partial responses) were 82.2% in the RCT group and 88.8% in the RCT plus amifostine group (p = 0.498).Amifostine is effective in reducing the incidence of both acute and late toxicities associated with RCT in patients with locally advanced NSCLC without compromising antitumor efficacy.

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Cancer. 2003 Oct 15;98(8):1707-15.
Gemcitabine, paclitaxel, and cisplatin as induction chemotherapy for patients with biopsy-proven Stage IIIA(N2) nonsmall cell lung carcinoma: a Phase II multicenter study.
De Marinis F, Nelli F, Migliorino MR, Martelli O, Cortesi E, Treggiari S, Portalone L, Crispino C, Brancaccio L, Gridelli C.
Fifth Operative Unit of Pulmonary Oncology, Carlo Forlanini Hospital, Rome, Italy. f.demarinis@oncpneumo.it

BACKGROUND: The objective of the current study was to define the activity and tolerability, as well as the influence on resectability, of the combination of gemcitabine, paclitaxel, and cisplatin (GTP) as induction chemotherapy for patients with Stage IIIA(N2) nonsmall cell lung carcinoma (NSCLC). METHODS: Forty-nine chemotherapy-naive patients (median age, 61 years; World Health Organization performance status, 0-1) with biopsy-proven Stage IIIA(N2) disease received 1000 mg/m(2) gemcitabine, 125 mg/m(2) paclitaxel, and 50 mg/m(2) cisplatin on Days 1 and 8 of every 3 weeks until reevaluation for surgery or definitive radiotherapy. RESULTS: Grade 3-4 neutropenia was the most common hematologic toxicity, occurring in 32.7% of patients; however, only 1 case of febrile neutropenia was reported. Grade 3-4 thrombocytopenia occurred in 12.2% of patients but was not associated with bleeding. Severe nonhematologic toxicities were uncommon; the only Grade 4 nonhematologic toxicity was diarrhea, which occurred in 4% of patients. One patient died after the first course of therapy, but this event was found to be unrelated to treatment. Thirty-six patients (73.5%) achieved an objective response, and an additional 4 patients had stable disease with clearance of mediastinal lymph nodes. Overall, 29 patients underwent thoracotomy and 27 (55%) underwent complete resection. Mediastinal nodes were free of tumor in 35% of all cases, and 8 pathologic complete responses (16%) were reported. Median survival was 23 months, with a 1-year survival rate of 85%. CONCLUSIONS: GTP is highly active as an induction chemotherapy regimen for Stage IIIA(N2) NSCLC and yields good toxicity results. The use of GTP in combination with radiotherapy and new biologic drugs should be explored. Copyright 2003 American Cancer Society.

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Cancer Invest. 2003;21(4):517-25.
Combined therapy with topotecan and gemcitabine in patients with inoperable or metastatic non-small cell lung cancer.
Dabrow MB, Francesco MR, Gilman PB, Cantor R, Rose L, Meyer TJ.
Thomas Jefferson University, Philadelphia, Pennsylvania, USA. dabrowmb@pearl.umdnj.edu

PURPOSE: We conducted a phase I/II trial of topotecan combined with gemcitabine in patients with metastatic or unresectable non-small cell lung cancer (NSCLC) based on preclinical data showing in vitro synergy against an established lung adenocarcinoma cell line. The aim was to determine the maximally tolerated dose (MTD) of topotecan when the gemcitabine dose is held constant, as well the dose limiting toxicity (DLTs) of this combination in NSCLC patients. PATIENTS AND METHODS: Twenty-four patients with stage IIIB or IV NSCLC were treated weekly times 3 with a week break with gemcitabine (1250 mg/m2 over 30 minutes) and topotecan (30 minutes) at varying doses. The starting dose of topotecan was 1.0 mg/m2 and doses were escalated in 0.25-mg/m2 increments until the MTD was achieved. RESULTS: The MTD of gemcitabine/topotecan was 1250 mg/m2 of gemcitabine and 2.00 mg/m2 of topotecan (level 5). Neutropenia was the DLT. Few nonhematologic toxicities were observed. There were 5 (21%) partial responses among 24 patients. The median survival was 22 weeks. Two patients have had prolonged (> 2 year) survival. CONCLUSION: The combination of gemcitabine and topotecan seems to be active against NSCLC with acceptable hematologic toxicity and minimal nonhematologic toxicity. The recommended dose for further study is 1250 mg/m2 of gemcitabine (days 1, 8, 15) and 2.0 mg/m2 of topotecan (days 1, 8, 15) administered every 28 days.

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Br J Cancer. 2003 Sep 1;89(5):803-7.
Phase I/II study of daily carboplatin, 5-fluorouracil and concurrent radiation therapy for locally advanced non-small-cell lung cancer.
Yoshizawa H, Tanaka J, Kagamu H, Maruyama Y, Miyao H, Ito K, Sato T, Iwashima A, Suzuki E, Gejyo F.
Division of Respiratory Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. nnys@med.niigata-u.ac.jp

A study was undertaken to determine the maximum tolerated dose, the dose-limiting toxicities and the response rate of carboplatin and 5-fluorouracil administered daily with concurrent thoracic radiation therapy in patients with locally advanced non-small-cell lung cancer. In a phase I/II clinical trial, patients with histologically documented, unresectable stage IIIA or IIIB non-small-cell lung cancer (NSCLC) were enrolled. Carboplatin (20-40 mg m(-2) 2-h infusion, daily) and 5-fluorouracil (200 mg m(-2) 24-h continuous infusion, daily) were administered concurrently with radiotherapy on days 1-33. Radiotherapy, with a total dose of 60 Gy, was delivered in 30 fractions on days 1-40. In the phase I portion, the daily dose of carboplatin was escalated from 20 to 40 mg m(-2). Once the maximum tolerated dose (MTD) and recommended dose (RD) of carboplatin was determined, the study entered the phase II portion. In the phase I portion, the daily MTD and RD of carboplatin were 40 and 35 mg m(-2), respectively. The dose-limiting toxicity was neutropenia. In the following phase II study, 30 patients were entered and the objective response rate was 76.7% (95% CI, 62-92%) and the local control rate was 85.7%. The median survival time was 19.8 months, with a survival rate of 70% at 1 year, 36.7% at 2 years. The major toxicities of treatment were neutropenia (>or=grade 3, 87.9%) and thrombocytopenia (>or=grade 3, 23.3%). This combined therapy for locally advanced non-small-cell lung cancer is promising and shows acceptable toxicity.

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Br J Cancer. 2003 Sep 1;89(5):795-802.
Phase I/II study of docetaxel and cisplatin with concurrent thoracic radiation therapy for locally advanced non-small-cell lung cancer.
Kiura K, Ueoka H, Segawa Y, Tabata M, Kamei H, Takigawa N, Hiraki S, Watanabe Y, Bessho A, Eguchi K, Okimoto N, Harita S, Takemoto M, Hiraki Y, Harada M, Tanimoto M; Okayama Lung Cancer Study Group.
Second Department of Internal Medicine, Okayama University Medical School, Okayama, Japan. kkiura@md.okayama-u.ac.jp

Recent studies have suggested the superiority of concomitant over sequential administration of chemotherapy and radiotherapy. Docetaxel and cisplatin have demonstrated efficacy in advanced non-small-cell lung cancer (NSCLC). This study evaluated the safety, toxicity, and antitumour activity of docetaxel/cisplatin with concurrent thoracic radiotherapy for patients with locally advanced NSCLC. Patients with locally advanced NSCLC (stage IIIA or IIIB), good performance status, age <or=75 years, and adequate organ function were eligible. Both docetaxel and cisplatin were given on days 1, 8, 29, and 36. Doses of docetaxel/cisplatin (mg m(-2)) in the phase I study portion were escalated as follows: 20/30, 25/30, 30/30, 30/35, 30/40, 35/40, 40/40, and 45/40. Beginning on day 1 of chemotherapy, thoracic radiotherapy was given at a total dose of 60 Gy with 2 Gy per fraction over 6 weeks. In the phase I portion, the maximum tolerated doses (MTD) among 33 patients were docetaxel 45 mg m(-2) and cisplatin 40 mg m(-2). The major dose-limiting toxicity (DLT) was radiation oesophagitis. The recommended doses (RDs) for the phase II study were docetaxel 40 mg m(-2) and cisplatin 40 mg m(-2). A total of 42 patients were entered in the phase II portion. Common toxicities were leukopenia, granulocytopenia, anaemia, and radiation oesophagitis, with frequencies of grade >or=3 toxicities of 71, 60, 24, and 19%, respectively. Toxicity was significant, but manageable according to the dose and schedule modifications. Dose intensities of docetaxel and cisplatin were 86 and 87%, respectively. Radiotherapy was completed without a delay in 67% of 42 patients. The overall response rate was 79% (95% confidence interval (CI), 66-91%). The median survival time was 23.4+ months with an overall survival rate of 76% at 1 year and 54% at 2 years. In conclusion, chemotherapy with cisplatin plus docetaxel given on days 1, 8, 29, and 36 and concurrent thoracic radiotherapy is efficacious and tolerated in patients with locally advanced NSCLC and should be evaluated in a phase III study.

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J Clin Oncol. 2003 Sep 1;21(17):3207-13.
Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial.
Alberola V, Camps C, Provencio M, Isla D, Rosell R, Vadell C, Bover I, Ruiz-Casado A, Azagra P, Jimenez U, Gonzalez-Larriba JL, Diz P, Cardenal F, Artal A, Carrato A, Morales S, Sanchez JJ, de las Penas R, Felip E, Lopez-Vivanco G; Spanish Lung Cancer Group.
Hospital Arnau de Vilanova, San Clemente 12, 46015 Valencia, Spain. alberola_vicara@gva.es

PURPOSE: To compare the survival benefit obtained with cisplatin plus gemcitabine, a cisplatin-based triplet, and nonplatinum sequential doublets in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Stage IIIB to IV NSCLC patients were randomly assigned to receive cisplatin 100 mg/m2 day 1 plus gemcitabine 1,250 mg/m2 days 1 and 8, every 3 weeks for six cycles (CG); cisplatin 100 mg/m2 day 1 plus gemcitabine 1,000 mg/m2 and vinorelbine 25 mg/m2 days 1 and 8, every 3 weeks for six cycles (CGV); or gemcitabine 1,000 mg/m2 plus vinorelbine 30 mg/m2 days 1 and 8, every 3 weeks for three cycles, followed by vinorelbine 30 mg/m2 days 1 and 8 plus ifosfamide 3 g/m2 day 1, every 3 weeks for three cycles (GV-VI). RESULTS: Five hundred fifty-seven patients were assigned to treatment (182 CG, 188 CGV, 187 GV-VI). Response rates were significantly inferior for the nonplatinum sequential doublet (CG, 42%; CGV, 41%; GV-VI, 27%; CG v GV-VI, P =.003). No differences in median survival or time to progression were observed. Toxicity was higher for the triplet: grade 3 to 4 neutropenia (GC, 32%; CGV, 57%; GV-VI, 27%; P <.05); neutropenic fever (CG, 4%; CGV, 19%; GV-VI, 5%; P <.0001); grade 3 to 4 thrombocytopenia (CG, 19%; CGV, 23%; GV-VI, 3%; P =.0001); and grade 3 to 4 emesis (GC, 22%; GCV, 32%; GV-VI, 6%; P <.0001). CONCLUSION: On the basis of these results, CG remains a standard regimen for first-line treatment of advanced NSCLC.

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J Natl Cancer Inst. 2003 Oct 1;95(19):1453-61.
Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer.
Scagliotti GV, Fossati R, Torri V, Crino L, Giaccone G, Silvano G, Martelli M, Clerici M, Cognetti F, Tonato M; Adjuvant Lung Project Italy/European Organisation for Research Treatment of Cancer-Lung Cancer Cooperative Group Investigators.
University of Torino, Department of Clinical and Biological Sciences, S. Luigi Hospital, Thoracic Oncology Unit, Orbassano, Torino, Italy. giorgio.scagliotti@unito.it

BACKGROUND: Surgery is the primary treatment for patients with stage I, II, or IIIA non-small-cell lung cancer (NSCLC). However, long-term survival of NSCLC patients after surgery alone is largely unsatisfactory, and the role of adjuvant chemotherapy in patient survival has not yet been established. METHODS: Between January 1994 and January 1999, 1209 patients with stage I, II, or IIIA NSCLC were randomly assigned to receive mitomycin C (8 mg/m2 on day 1), vindesine (3 mg/m2 on days 1 and 8), and cisplatin (100 mg/m2 on day 1) every 3 weeks for three cycles (MVP group; n = 606) or no treatment (control group; n = 603) after complete resection. Randomization was stratified by investigational center, tumor size, lymph-node involvement, and the intention to perform radiotherapy. The primary endpoint was overall survival and secondary endpoints were progression-free survival and toxicity associated with adjuvant treatment. Survival curves were analyzed using the log-rank test. All statistical tests were two-sided. RESULTS: After a median follow-up time of 64.5 months, there was no statistically significant difference between the two patient groups in overall survival (hazard ratio = 0.96, 95% confidence interval = 0.81 to 1.13; P =.589) or progression-free survival (hazard ratio = 0.89, 95% confidence interval = 0.76 to 1.03; P =.128). Only 69% of patients received the three planned cycles of MVP. Grades 3 and 4 neutropenia occurred in 16% and 12%, respectively, of patients in the MVP arm. Radiotherapy was completed by 65% of patients in the MVP arm and by 82% of patients in the control group. In the multivariable analysis, only disease stage and sex were associated with survival. CONCLUSION: This randomized trial failed to prospectively confirm a statistically significant role for adjuvant chemotherapy in completely resected NSCLC. Given the poor compliance with the MVP regimen used in this study, future studies should explore more effective treatments.

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Gan To Kagaku Ryoho. 2003 Sep;30(9):1283-7.
[Daily low-dose cisplatin plus concurrent high-dose thoracic radiotherapy in elderly patients with locally advanced unresectable non-small-cell lung cancer]
[Article in Japanese]
Nakano K, Yamamoto M, Iwamoto H, Hiramoto T.
Dept. of Respiratory Medicine, National Medical Center of Kure.

There are few prospective studies of concurrent chemoradiotherapy in elderly patients with locally advanced unresectable non-small-cell lung cancer (NSCLC), although the therapy has proved superior to radiotherapy alone for the treatment of younger patients. We conducted a pilot study to assess the tolerance and efficacy of concurrent cisplatin and thoracic radiation in elderly patients with locally advanced unresectable NSCLC. Eligible patients were more than 71 years old and had unresectable Stage I, II, or III NSCLC. Cisplatin was administered at 6 mg/m2 daily intravenously on days 1 through 5, days 8 through 12, days 29 through 33 and days 36 through 40. Beginning day on 1, thoracic radiation was delivered at 2.0 Gy daily to a total dose of 60 Gy. Twelve patients were registered and 11 were eligible. Patient characteristics were ages of 73 to 80 years, and stage III A (18%) and stage III B (73%) NSCLC. The most common grade 3 toxicities included leukopenia (20%) and thrombocytopenia (9%). Grades 3/4 elevation of serum creatinin, esophagitis and pneumonitis did not occur. The overall confirmed response rate was 82%, and median overall survival was 23 months. The 2-year survival rate was 53%. This chemoradiotherapy regimen is well tolerated with promising response and survival in elderly patients with unresectable NSCLC.

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Br J Cancer. 2003 Sep 15;89(6):1013-21.
Supportive care in patients with advanced non-small-cell lung cancer.
Di Maio M, Perrone F, Gallo C, Iaffaioli RV, Manzione L, Piantedosi FV, et al.
National Cancer Institute: Clinical Trials Unit, Naples

The present study describes supportive care (SC) in patients with advanced non-small-cell lung cancer (NSCLC), evaluating whether it is affected by concomitant chemotherapy, patient's performance status (PS) and age. Data of patients enrolled in three randomised trials of first-line chemotherapy, conducted between 1996 and 2001, were pooled. The analysis was limited to the first three cycles of treatment. Supportive care data were available for 1185 out of 1312 (90%) enrolled patients. Gastrointestinal drugs (45.7%), corticosteroids (33.4%) and analgesics (23.8%) were the most frequently observed categories. The mean number of drugs per patient was 2.43; 538 patients (45.4%) assumed three or more supportive drugs. Vinorelbine does not produce substantial variations in the SC pattern, while cisplatin-based treatment requires an overall higher number of supportive drugs, with higher use of antiemetics (41 vs 27%) and antianaemics (10 vs 4%). Patients with worse PS are more exposed to corticosteroids (42 vs 30%). Elderly patients require drugs against concomitant diseases significantly more than adults (20 vs 7%) and are less frequently exposed to antiemetics (12 vs 27%). In conclusion, polypharmacotherapy is a relevant issue in patients with advanced NSCLC. Chemotherapy does not remarkably affect the pattern of SC, except for some drugs against side effects. Elderly patients assume more drugs for concomitant diseases and receive less antiemetics than adults.

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AJR Am J Roentgenol. 2003 Sep;181(3):711-5.
Percutaneous radiofrequency ablation of pulmonary malignancies: combined treatment with brachytherapy.
Jain SK, Dupuy DE, Cardarelli GA, Zheng Z, DiPetrillo TA.
Department of Diagnostic Imaging, Rhode Island Hospital, Brown Medical School, 593 Eddy St., Providence, RI 02903, USA.

OBJECTIVE: The purpose of this article is to report the clinical experience and technical feasibility of percutaneous radiofrequency ablation in conjunction with brachytherapy, a novel approach in the treatment of lung neoplasms. Data from three patients with lung malignancies illustrate the expanding therapeutic indications of this minimally invasive intervention. CONCLUSION: Percutaneous radiofrequency ablation in conjunction with brachytherapy is a promising minimally invasive combination modality. It may be a treatment option for patients with primary, recurrent, or metastatic malignancies of the lung that are not amenable to surgery or further external beam radiation therapy.

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J Control Release. 2003 Aug 28;91(1-2):225-31.
GVAX (GMCSF gene modified tumor vaccine) in advanced stage non small cell lung cancer.
Nemunaitis J.
US Oncology, Dallas, TX, USA. john.nemunaitis@usoncology.com

Treatment for advanced stage non-small cell lung cancer is limited. In an attempt to determine whether immune stimulating activity can be induced with a GMCSF gene transduced autologous tumor vaccine (GVAX), 83 patients were entered into trial (20 with stage 1B/IIB disease and 63 with stage IIIB/IV disease). Patients fulfilling eligibility criteria underwent surgical harvest of autologous lung tumor tissue. The tissue was then processed, transfected with an E1 deleted, E3 deleted adenoviral GMCSF gene vector irradiated prior to injection. Patients received a series of six vaccinations (1 every two weeks). Forty-three of the 83 patients were eligible for treatment (10 in cohort A and 33 in cohort B). These results have previously been reported. GVAX was well tolerated. Three of 33 patients with advanced disease achieved complete response. Evidence of immunologic activity following vaccination in a subset of patients was suggested, based on antibody response to either autologous SV40 transformed tumor cells or allogeneic non-small cell lung cancer tumor cells. These results supported further clinical investigation with GVAX in non-small cell lung cancer.

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Br J Cancer. 2003 Sep 15;89(6):1008-12.
Phase II study of cisplatin, ifosfamide, and irinotecan with rhG-CSF support in patients with stage IIIb and IV non-small-cell lung cancer.
Fujita A, Ohkubo T, Hoshino H, Takabatake H, Tagaki S, Sekine K, Abe S.
Division of Respiratory Disease, Minami-ichijo Hospital, South-1 West-13, Chuo-ku, Sapporo 060-0061, Japan. afujita@sa2.so-net.ne.jp

A phase II study of cisplatin, ifosfamide, and irinotecan with recombinant human granulocyte colony stimulating factor (rhG-CSF) support was conducted in previously untreated patients with stage IIIB or IV non-small-cell lung cancer (NSCLC). Between June 1998 and August 2001, 50 patients were registered in this phase II study. Cisplatin (20 mg m(-2)) and ifosfamide (1.5 g m(-2)) were administered on days 1-4 and irinotecan (60 mg m(-2)) was given on days 1, 8, and 15, respectively. This regimen was repeated every 4 weeks. rhG-CSF was administered subcutaneously at a dose of 50 microg m(-2) on days 5-18 except on the days of irinotecan treatment. In total, 49 patients were assessable for toxicity and response and 50 for survival. In all, 33, patients (67.3%; 95% confidence interval 57.4-77.2%) achieved an objective response. The median response duration was 192 days and the median time to progression for 49 patients was 170 days. The median survival time was 540 days with 1- and 2-year survival rates of 63.5 and 30.7%, respectively. Grade 3 or 4 neutropenia and thrombocytopenia developed in 63.3 and 38.8% of the patients, respectively. In conclusion, the combination of cisplatin, ifosfamide, and irinotecan with rhG-CSF support was highly effective for the treatment of stage IIIB or IV NSCLC with acceptable toxicities.

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Gan To Kagaku Ryoho. 2003 Aug;30(8):1079-84.
[Iressa (gefitinib)]
[Article in Japanese]
Kudoh S, Yoshimura A, Gemma A.
Fourth Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.

Gefitinib is an epidermal growth factor receptor (EGFR) inhibitor that is reported to be well tolerated and active in patients with chemotherapy-resistant non small cell lung cancer. On the other hand, gefitinib was also reported to produce a severe adverse event, interstitial lung disease, in less than 2% of treated patients. Given these circumstances, it is important to evaluate this drug and to establish its use clinically. We do not have sufficient data to evaluate gefitinib at this time. Phase III study of second/third line or maintenance therapy using gefitinib is required for such an evaluation. The development of individualized therapy with gefitinib might be also be required.

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Semin Oncol. 2003 Aug;30(4 Suppl 10):37-44.
The emerging role of pemetrexed (Alimta) and gemcitabine in non-small cell lung cancer.
Le Chevalier T.
Department of Medicine, Instutut Gustave-Roussy, Villejuif, France.

In recent years, several new cytotoxic agents have been investigated for the management of non-small cell lung cancer (NSCLC), including the antimetabolic gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and the new multitargeted antifolate pemetrexed (Alimta, Eli Lilly and Company), which are both among the most active agents in advanced NSCLC. Gemcitabine has become one of the key drugs in the management of NSCLC, alone or in association with platin compounds. Promising results have also been reported with pemetrexed used as a single-agent or in combination with cisplatin or gemcitabine. These results indicate that pemetrexed may also play a vital role in the treatment of NSCLC, malignant mesothelioma, and other solid tumors. Ongoing (and planned) trials are investigating the use of single-agent pemetrexed, or combinations with cisplatin, gemcitabine, and other cytotoxic agents in various malignancies.

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Ugeskr Laeger. 2003 Aug 18;165(34):3234-7.
[Diet and lung cancer]
[Article in Danish]
Fabricius PG, Lange P.
Lungemedicinsk Klinik, Afsnit 222, H:S Hvidovre Hospital, Kettegard Alle 30, DK-2650 Hvidovre.

Lung cancer is the leading cause of cancer-related deaths worldwide. While cigarette smoking is of key importance, factors such as diet also play a role in the development of lung cancer. MedLine and Embase were searched with diet and lung cancer as the key words. Recently published reviews and large well-designed original articles were preferred to form the basis of the present article. A diet rich in fruit and vegetables reduces the incidence of lung cancer by approximately 25%. The reduction is of the same magnitude in current smokers, ex-smokers and in persons who have never smoked. Vitamin A, C and E supplements and beta-carotene offer no protection against the development of lung cancer. On the contrary, in two major randomised intervention trials beta-carotene supplement has resulted in increased mortality. Smoking remains by far the leading cause of lung cancer and the adverse effects can only be slightly alleviated by a healthy diet.

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Neoplasma. 2003;50(3):204-9.
Weekly paclitaxel for advanced non-small cell lung cancer patients not suitable for
platinum-based therapy.
Juan O, Albert A, Villarroya T, Sanchez R, Casan R, Caranana V, Campos JM, Alberola V.
Department of Medical Oncology, Hospital Arnau de Vilanova, 46015 Valencia, Spain. juan_osc@gva.es

Platinum-based combinations are efficacious in the treatment of advanced non-small cell lung cancer (NSCLC) but their toxicity makes them unsuitable for elderly and for patients with co-morbidities. We assessed the efficacy and toxicity of low-dose of paclitaxel in patients who were elderly or who had contraindications against cisplatin therapy. Seventy-one patients (median age 68; range 42-82 years) with unresectable NSCLC were treated with weekly paclitaxel (80 mg/m2) infusion (1 h) for several cycles without intervening rest periods. Thirty-seven patients had PS 1 and 34 had PS 2 status. A total of 614 courses were administered (median 9, range 2-20). There were no episodes of grade 4 toxicities and only 1 patient had grade 3 thrombopenia. Grade 3 anemia or neutropenia were not observed and severe non-hematological toxicity was uncommon: grade 1-2 fatigue in 52%; grade 1-2 motor neuropathy in 42% and grade 3 in 5.5%; grade 1-2 sensory neuropathy in 46.3% of patients. Twenty-seven of the 67 evaluable patients (40.3%) had an objective response, whereas 26 patients (38.8%) had stable disease. The median overall survival for the entire group was 8.4 months (95% CI = 5.6 to 11.2) and the 1-year and 2-year survival was 37.4% and 12.1%, respectively. The median time-to-progression was 5.4 months (95% CI = 3.3 to 7.4). Our data show that low-dose weekly paclitaxel is active and well tolerated in this group of patients with NSCLC and poor prognosis and, as such, is useful for patients in whom platinum-based combinations are not suitable.

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Expert Rev Anticancer Ther. 2003 Aug;3(4):435-42.
Second-line chemotherapy for non-small cell lung cancer.
Shepherd FA.
Princess Margaret Hospital, Toronto, Ontario, Canada. frances.shepherd@uhn.on.ca

Several agents have been evaluated for the second-line treatment of patients with non-small cell lung cancer. The TAX 317 trial found that patients treated with docetaxel (Taxotere) 75 mg/m2 had significantly longer survival than those treated with best supportive care alone. In addition, symptom control was better for patients who received chemotherapy. The TAX 320 trial found that treatment with docetaxel 75 or 100 mg/m2 resulted in significantly higher response rates than treatment with vinorelbine (Navelbine) or ifosfamide (Mitoxana), and the 1-year survival rate was also significantly better for patients treated with docetaxel 75 mg/m2. A large randomized trial compared pemetrexed (LY-231514 or Alimta) 500 mg/m2 with docetaxel 75 mg/m2. Response and survival rates were similar in the two treatment arms, however, the toxicity profile of pemetrexed was superior to that of docetaxel with significantly less Grade 3/4 neutropenia and febrile neutropenia. Fewer patients in the pemetrexed arm required hospitalization. Topotecan (Hycamtin) 2.3 mg/m2/day orally for 5 days has been compared with docetaxel 75 mg/m2 in a large 800-patient study. The results of this trial are awaited. Gemcitabine (Gemzar) and irinotecan (Campto) have been evaluated both as single agents and in combination with each other and study results do not suggest that either of these drugs is superior to docetaxel or pemetrexed. The vinca alkaloid vinorelbine has proved to be inferior to docetaxel in a randomized trial. The epidermal growth factor receptor inhibitors gefitinib (ZD1839, Iressa) and erlotinib (CP-358774, OSI 774, Tarceva) have been evaluated in Phase II trials in the second- and third-line setting. Both drugs have demonstrated interesting response rates ranging from 10 to almost 20%. The results of placebo-controlled randomized trials of this family of drugs are awaited. In summary, several studies have now found a definite role for the second-line treatment of patients with non-small cell lung cancer.

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Semin Oncol. 2003 Aug;30(4 Suppl 10):2-12.
Update on gemcitabine/carboplatin in patients with advanced non-small cell lung cancer.
Harper P.
Medical Oncology, Guy's and St. Thomas Hospital, London, United Kingdom.

Platinum-based chemotherapy regimens comprise a standard treatment approach for patients with advanced and metastatic non-small cell lung cancer (NSCLC). Based on results from randomized studies and meta-analyses, it has been established that such therapy significantly improves survival and maintains or improves quality of life relative to best supportive care. Combinations of cisplatin or carboplatin with gemcitabine, a newer-generation nucleoside antimetabolite with single-agent activity of 20% to 26% in advanced NSCLC, have shown antitumor activity and are well tolerated. In many studies in the advanced-disease setting, carboplatin has replaced cisplatin because of its improved nonhematologic toxicity profile and greater ease of administration. Encouraging results in the phase II setting have led to the design and implementation of several phase III studies of gemcitabine/carboplatin in the treatment of patients with advanced NSCLC. Results of three phase III trials involving more than 900 patients not previously treated with chemotherapy are discussed herein. These studies compared gemcitabine/carboplatin versus gemcitabine alone, gemcitabine/carboplatin versus gemcitabine/cisplatin, and gemcitabine/carboplatin versus mitomycin/ifosfamide/cisplatin (MIP), a regimen commonly used in Europe. Results show that gemcitabine/carboplatin efficacy was equivalent or superior to that achieved with single-agent gemcitabine or other platinum-based treatments. The regimen was well tolerated overall, and available data from one study show a significant improvement in quality of life. Thus, gemcitabine/carboplatin appears to be a viable option in the first-line treatment of advanced NSCLC. The results of one study reviewed suggest that gemcitabine/carboplatin can be considered for the treatment of patients over 70 years old.

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Semin Oncol. 2003 Aug;30(4 Suppl 9):56-70.
Combined treatment for limited small cell lung cancer.
Komaki R.
Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 97, Houston, TX 77030, USA.

Radiation therapy is an important component for the management of limited small cell lung cancer (SCLC) in addition to systemic treatment. The role of surgery is limited for SCLC because of the nature of the disease, which often spreads to regional lymph nodes or spreads distantly. There have been major advances in the treatment of limited-stage SCLC during the past decade because of early application of thoracic radiation therapy (TRT) with concurrent chemotherapy, accelerated TRT, the application of prophylactic cranial irradiation for patients who achieved complete response to concurrent chemotherapy and TRT, and the improvement in supportive care such as discontinuation of tobacco smoking after the diagnosis of SCLC, nutritional support, pain control, granulocyte colony-stimulating factor, erythropoietin, and adequate antibiotics. It is important to select patients with limited SCLC who are able to tolerate concurrent chemotherapy and accelerated TRT.

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J Natl Cancer Inst. 2003 Aug 6;95(15):1118-27.
Randomized phase III trial of paclitaxel, etoposide, and carboplatin versus carboplatin, etoposide, and vincristine in patients with small-cell lung cancer.
Reck M, von Pawel J, Macha HN, Kaukel E, Deppermann KM, Bonnet R, Ulm K, Hessler S, Gatzemeier U.
Department of Thoracic Oncology, Hospital Grosshansdorf, Hamburg, Germany.

BACKGROUND: Paclitaxel administered in combination with a topoisomerase-II inhibitor (such as etoposide) and carboplatin is an effective and safe first-line treatment for patients with small-cell lung cancer (SCLC). We conducted a randomized phase III multicenter trial to determine whether paclitaxel plus etoposide plus carboplatin improves the outcome of patients with primary SCLC relative to standard chemotherapy (carboplatin, etoposide, and vincristine). METHODS: Between January 1998 and December 1999, 614 patients with SCLC stages I-IV were randomly assigned to the standard arm (309 patients) or the experimental arm (305 patients). Treatment courses were repeated every 21 days for a maximum of six courses. All patients were evaluated for response rate, survival, and toxicities every two courses. The primary endpoint was survival. Survival curves were estimated with the Kaplan-Meier method and compared using the log-rank test. All statistical tests were two-sided. RESULTS: A total of 608 patients were evaluable for all endpoints (standard arm 307 patients, experimental arm 301 patients). The hazard ratio [HR] of death for patients receiving the standard treatment was statistically significantly higher than that for patients receiving the experimental treatment (HR = 1.22, 95% confidence interval [CI] = 1.03 to 1.45; P =.024). Progression-free survival was also statistically significantly shorter for patients in the standard arm relative to that of patients in the experimental arm (HR = 1.21, 95% CI = 1.03 to 1.42). There were no differences in the response rates (complete and partial combined) to the treatments (standard arm: 69.4%, 95% CI = 63.9% to 74.5%; experimental arm: 72.1%, 95% CI = 66.7% to 77.1%; difference = 2.7%, 95% CI = 4.5% to 9.9%). Rates of severe grade of anemia, leukocytopenia, neutropenia, and thrombocytopenia were lower in the experimental arm than in the standard arm. CONCLUSION: Patients with previously untreated SCLC who received paclitaxel, etoposide, and carboplatin showed improved overall and progression-free survival and less frequent hematologic toxicities than those who received the standard therapy.

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Anticancer Res. 2003 Jul-Aug;23(4):3479-84.
Paclitaxel and vinorelbine combination in advanced inoperable adenocarcinoma of the lung:
a phase II study.
Stathopoulos GP, Veslemes M, Georgatou N, Antoniou D, Tsavdaridis D, Katis K, Giaboudakis P, Rigatos SK, Marosis K.
First Department of Medical Oncology, Errikos Dynan Hospital, Athens, Greece. dr-gps@ath.forthnet.gr

BACKGROUND: The purpose of this study was to determine the efficacy of paclitaxel (PCT) combined with vinorelbine (VRL) in adenocarcinoma of the lung. PATIENTS AND METHODS: Untreated inoperable patients with metastatic disease were enrolled and underwent front-line treatment with a new combination as follows: a 30-minute infusion of VRL at a dose of 25 mg/m2 followed by a 3-hour infusion of PCT 135 mg/m2. Chemotherapy was repeated every 2 weeks with the intention of administering 9 cycles. RESULTS: Fifty-four out of 58 enrolled patients were assessable; the median age was 63 years (range 48-81). All patients were chemotherapy-naive and all had histologically- or cytologically- confirmed adenocarcinoma. Twenty-seven patients (50%) responded: 5 with complete response (9.3%) and 22 with partial response (40.7%); 17 patients had stable disease (31.5%) and 10 showed disease progression (18.5%). Median response duration was 6 months (range 2-14.5) and median survival was 10 months (range 2-35+). The main adverse reaction was myelotoxicity in 87% of the patients, of whom only 8 (14.8%) had grade 4 neutropenia which in 4 cases (7.4%) was febrile. No patient required dose reduction, but treatment was postponed by one week in 4 patients a total of nine times. Patients received 98.6% of the planned dose. CONCLUSION: The PCT and VRL combination is an active first-line treatment for lung adenocarcinoma. These two cytotoxic drugs produce acceptable toxicity when repeated every 2 weeks.

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Cas Lek Cesk. 2003;142 Suppl 1:40-3.
[Chemoradiotherapy of non-small-cell bronchogenic carcinoma]
[Article in Czech]
Coupek P, Seneklova Z, Perkova H, Kebedeova D.
Klinika komplexni onkologicke pece-oddeleni radiacni inkologie, Masarykuv onkologicky ustav, Brno. couplek@mou.cz

Lung cancer is the worldwide most widespread tumor disease with very poor prognosis. It is the most frequent cause of death on a malignancy. Surgery remains the treatment of choice, however, it can be applied to a small number of patients who are at the time of diagnosis in the operable stage. Chemoradiotherapy can be used either as an exclusive or as a neoadjuvant treatment. This paper reviews chemoradiotherapy regiments in those two clinical situations. With exclusive chemoradiotherapy, the concomitant scheme seems to be the most favourable.

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Respir Care Clin N Am. 2003 Jun;9(2):207-36.
The role of chemotherapy in the treatment of unresectable stage III and IV nonsmall cell lung cancer.
Socinski MA.
Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, CB #7305, 3009 Old Clinic Building, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7305, USA. socinski@med.unc.edu

Modern platinum-based combination chemotherapy has played a major role in the therapeutic approach to unresectable stage III and IV NSCLC. Randomized phase III trials clearly documented a survival as well as palliative benefit to treatment in patients with stage IV NSCLC who have a good PS (PS 0-1). The optimal therapeutic approach in patients with poor PS (PS 2) has not yet been defined. Recent trials that focused on the elderly suggested that they receive benefits from chemotherapy that are similar to their younger counterparts. The benefit from chemotherapy seems to occur early (initial 3 to 4 cycles) and prolonged therapy is not indicated. Second-line therapy that is administered upon progression was shown to provide survival and palliative benefits. In unresectable stage III NSCLC, the addition of chemotherapy to TRT improves long-term survival and has the potential to cure a minority of patients. Although sequential and concurrent chemoradiotherapy approaches have improved survival in phase III trials, concurrent strategies seem superior in comparative trials. New techniques in radiation therapy, such as three-dimensional treatment planning, may allow safer administration of both modalities concurrently and allow higher doses of TRT to be delivered. In unresectable stage III and stage IV NSCLC, the role of the new "targeted" therapies is currently being defined in several randomized, phase III trials. It is imperative that physicians who care for patients with advanced NSCLC be aware of these trials and attempt to enroll their patients, if possible. It is only through the successful and timely completion of well-designed clinical trials that we will advance our knowledge of improved treatment options for our patients with this disease.

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Respir Care Clin N Am. 2003 Jun;9(2):191-205.
Combined modality therapy of early stage nonsmall cell lung cancer.
Pisters KM.
Department of Thoracic/Head & Neck Medical Oncology, University of Texas, M. D. Anderson Cancer Center, Box 432, Houston, TX 77030, USA. kpisters@mdanderson.org

Therapy for locally advanced NSCLC has evolved into a multidisciplinary effort. Patients who are considered for this approach should undergo rigorous testing to accurately stage their disease. Patients with pleural effusions (with rare exception) are not candidates for intensive combined modality therapy. Appropriate patients for combined modality therapy should have a good performance status (generally Zubrod 0 or 1), adequate pulmonary function, absence of significant heart, lung, or other medical diseases, and be appropriate candidates for combination chemotherapy and thoracic surgery or thoracic radiotherapy. Several lessons can be learned from looking broadly at the phase II and phase III combined modality experience. The available data do not support the routine use of postoperative therapy in patients with completely resected disease. Treatment with chemotherapy before surgery or radiation has demonstrated survival benefit in patients with stage III disease. The French phase III trial of induction chemotherapy in patients with early stage disease found an 11-month improvement in overall survival (P = 0.15) and a significant increase in the risk of death for patients with stage I and II disease. The ongoing U.S. intergroup trial (SWOG 9900) and European trials will help to further define the role of chemotherapy in patients with clinical stage IB, II and IIIA NSCLC. Clinical trials should be conducted to compare preoperative chemoradiotherapy with preoperative chemotherapy. The recently completed intergroup 0139 trial (chemoradiation followed by surgery or not) should help to define whether surgery and radiation are required in the management of stage IIIA NSCLC. Finally, further improvement in survival with the use of "newer" cytotoxic agents seems unlikely as phase III trials in metastatic NSCLC have not demonstrated marked superiority over cispiatin-based regimens. Ongoing trials are assessing the incorporation of newer, biologic-based "targeted" therapies. Despite the dismal findings of trials of postoperative therapy, many patients continue to have surgery as their initial treatment followed by postoperative therapy. In contrast, trials with induction treatment seem to offer improved survival. It is time for a true multidisciplinary approach to the treatment of locally advanced NSCLC. Pulmonary physicians, thoracic surgeons, medical oncologists, and radiation oncologists should meet before the initiation of treatment to plan the most appropriate therapy for the individual patient.

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Respir Care Clin N Am. 2003 Jun;9(2):163-90.
The role of radiotherapy and chemotherapy for curative management of medically inoperable and stage III nonsmall cell lung cancer, and radiotherapy for palliation of symptomatic disease.
Turrisi AT 3rd, Bogart J, Sherman C, Silvestri G.
Department of Radiation Oncology, Medical University of South Carolina, P.O. Box 250318, Charleston, SC 29425, USA. turrisi@radonc.musc.edu

Radiotherapy has an expanding role in all phases of treatment of nonsmall cell lung cancer. Evolutions in technique, such as three-dimensional conformal radiotherapy, hold the promise for more effective treatment of patients with early stage disease who are not candidates for surgical intervention. Multimodality therapy for patients with locally advanced disease is evolving rapidly, with evidence accruing as to the optimal schedules and doses of radiotherapy and combination chemotherapy. Palliative dose schedules are being refined that maximize patient comfort while providing substantial symptom relief.

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Respir Care Clin N Am. 2003 Jun;9(2):141-62.
Surgical viewpoints for the definitive treatment of lung cancer.
Bilfinger TV.
Division of Cardiothoracic Surgery, Department of Surgery, State University of New York-Stony Brook, Health Sciences Center T19, Stony Brook, NY 11794-8191, USA. bilfinge@surg.som.sunysb.edu

Surgery remains a central pillar in the treatment of lung cancer. To optimize surgical interventions, careful preoperative assessment is necessary. Pulmonary status and cardiac status are the main risks to be considered. After operability has been established, resectability is assessed by staging the lung cancer. Surgery offers a variety of tools to accomplish complete staging before resection. Successful resection is defined as the complete removal of the cancer. To accomplish this goal, a multidisciplinary approach is evolving rapidly. For patients with nonoperable cancer, surgical techniques have been developed to manage airway obstructions and to drain effusions.

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Rozhl Chir. 2003 May;82(5):273-7.
[ Sentinel node detection and its importance in the surgical treatment of non-small cell lung carcinoma—review]
[Article in Czech]
Jedlicka V, Capov I, Pestal A, Stasek T, Wechsler J.
Chirurgicka klinika LF MU a FN u sv. Anny v Brne.

The optimal type of treatment of the non-small lung cancer has not been found, yet. Systematical mediastinal lymphadenectomy, which is the method of choice in the surgical resection of the lung cancer, is potentially risky and its role is still unclear. The sentinel lymph node technique represents a promising alternative to the standard treatment. The hitherto reached results have to be evaluated with care and greater studies are necessary. According to our opinion, the best results can be expected in stage Ia NSCLC. The combination of the intraoperative scintigraphy and blue dye technique will be probably necessary in the next studies. The review gives the current state-of-art and some suggestions to the future.

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Cancer Gene Ther 2003 Apr;10(4):287-93
Inhibitory effect of adenovirus-uteroglobin transduction on the growth of lung cancer cell lines.
Lee JC, Park KH, Han SJ, Yoo CG, Lee CT, Han SK, Shim YS, Kim YW.

Uteroglobin is a secretory protein synthesized by most epithelia, including the respiratory tract. It has strong anti-inflammatory properties that appear to be related to the inhibition of phospholipase A2. Recent experimental evidence indicates that uteroglobin has an inhibitory effect on the proliferation and invasion of cancer cells. We investigated the effects of the adenovirus-uteroglobin (ad-UG) transduction on the growth of lung cancer cell lines, which did not express the uteroglobin gene. Upon transduction of ad-UG, the rate of cell growth and the ability to produce colonies in soft agar were evaluated. Cell cycle analysis, Western blot for cell cycle-related proteins and annexin V staining for apoptosis were carried out to see if they were associated with the changes in cell growth. All the tested lung cancer cell lines did not express the uteroglobin gene. The growth rates, and colony-forming ability of transformed cells, were significantly inhibited by the induction of uteroglobin gene expression. The DNA histogram showed that the cell fraction of the G2/M phase was increased, and this G2/M phase arrest was related to a decrease of cdk1 and cyclin A. However, a fraction of apoptotic cells were same as the control. From these results, uteroglobin is thought to have an inhibitory effect on the growth of lung cancer cells. This suggests a potential role for uteroglobin in gene therapy for lung cancer.

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Acta Pol Pharm 2002 Nov-Dec;59(6):473-8
Current strategies for anticancer chemoprevention and chemoprotection.
Krzystyniak KL.
Department of Biological Sciences, University of Quebec-Montreal, Montreal, Canada H3C 3P8.

Relatively new targets in drug design projects in cancer pharmacology include cytostatic agents, immune system modulators, and angiogenesis inhibitors. Preventive oncology applies pharmacological agents to reverse, retard, or halt progression of neoplastic cells to invasive malignancy. Prevention of cancer, however, can be accomplished through many strategies, including changes in diet and lifestyle. For example, the vast majority of lung cancers (80-90%) can be attributed to cigarette smoking and therefore, the most effective primary preventive strategy for lung cancer is to quit smoking. Chemoprevention through interruption of multistage careinogenesis include different molecular targets. Selective estrogen receptor modulators (SERMs) act as estrogen receptor (ER) agonists. Ligands for the peroxisome proliferator-activated receptor gamma (PPAR-gamma) suppress breast carcinogenesis in experimental models and induce differentiation of human liposarcoma cells. Selective PPAR modulators (SPARMs), by analogy to the SERM concept, are designed to have desired effects on specific genes relevant to carcinogenesis. Enzymatic approach in endocrine-related tumors involve inhibition of aromatase to prevent breast cancer and inhibition of 5-alpha-reductase to prevent prostate cancer. Down-regulation of inflammatory prostaglandin synthesis by inhibition of cyclooxygenase-2 (COX-2). inhibition of the inducible nitric oxide synthase (iNOS), and stimulation of phase II detoxication system, are currently examined in experimental models and clinical trials. Overall, potential targets in preventive strategies to reduce the risk of cancer involve agonists of endocrine receptors, factors down-regulating inflammation, factors inducing programmed cell death (PCD)/apoptosis, enzymatic inhibitors and gene therapy.

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Clin Exp Immunol 2003 Apr;132(1):1-8
Immunological hurdles to lung gene therapy.
Ferrari S, Griesenbach U, Geddes DM, Alton E.
UK Cystic Fibrosis Gene Therapy Consortium, Department of Gene Therapy, National Heart and Lung Institute, Imperial College Faculty of Medicine, London, UK.

Gene delivery has the potential to offer effective treatment to patients with life-threatening lung diseases such as cystic fibrosis, alpha1-antitrypsin deficiency and lung cancer. Phase I/II clinical trials have shown that, in principle, gene transfer to the lung is feasible and safe. However, gene expression from both viral and non-viral gene delivery systems has been inefficient. In addition to extra- and intracellular barriers, the host innate and acquired immune system represents a major barrier to successful gene transfer to the lung. Results from studies in experimental animals and clinical trials have shown that inflammatory, antibody and T cell responses can limit transgene expression duration and readministration of the gene transfer vector. We will review here how the development of pharmacological and/or immunological agents can modulate the host immune system and the limitations of these strategies. A better understanding of the immunological barriers which exist in the lung might allow for a more sustained expression of the transgene and importantly help overcome the problem of readministration of viral vectors.

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Mol Biotechnol 2003 Jan;23(1):51-60
Aerosol gene therapy.
Gautam A, Waldrep JC, Densmore CL.
Department of Molecular Physiology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.

Gene therapy is a novel field of medicine that holds tremendous therapeutic potential for a variety of human diseases. Targeting of therapeutic gene delivery vectors to the lungs can be beneficial for treatment of various pulmonary diseases such as lung cancer, cystic fibrosis, pulmonary hypertension, alpha-1 antitrypsin deficiency, and asthma. Inhalation therapy using formulations delivered as aerosols targets the lungs through the pulmonary airways. The instant access and the high ratio of the drug deposited within the lungs noninvasively are the major advantages of aerosol delivery over other routes of administration. Delivery of gene formulations via aerosols is a relatively new field, which is less than a decade old. However, in this short period of time significant developments in aerosol delivery systems and vectors have resulted in major advances toward potential applications for various pulmonary diseases. This article will review these advances and the potential future applications of aerosol gene therapy technology.

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Gan To Kagaku Ryoho 2003 Feb;30(2):193-7
[Clinical study of adenoviral mediated p53 gene therapy for non-small cell lung cancer in Japan]
[Article in Japanese]
Kagawa S, Fujiwara T, Tanaka N.
Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan.

The prognosis in case of non-small cell lung cancer (NSCLC) remains poor, and novel treatment modalities are urgently needed for advanced NSCLC. Backed by advances in the understanding of cancer biology, gene therapy has been developed in recent years. The p53 gene is altered in over 50% of cancers and has been extensively studied as a tumor suppressor gene. Adenoviral-mediated p53 gene transfer is currently under clinical evaluation worldwide for the treatment of cancer. We are now conducting a phase I study of Ad-p53 for advanced NSCLC patients in Japan. As an interim report, we provide a brief summary of the current status of this study, highlighting the safety and clinical efficacy of Ad-p53. As of September 2002, 13 patients were enrolled to this study, and safety and antitumor effects have been noted.

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Gene Ther 2003 Mar;10(5):386-95
Recombinant adenovirus shedding after intratumoral gene transfer in lung cancer patients.
Griscelli F, Opolon P, Saulnier P, Mami-Chouaib F, Gautier E, Echchakir H, Angevin E, Le Chevalier T, Bataille V, Squiban P, Tursz T, Escudier B.
Department of Biology, Institut Gustave Roussy, Villejuif, France.

We conducted two phase 1 trials of direct intratumoral injection of a recombinant E1E3-deleted adenovirus (AdR) encoding either the bacterial enzyme beta-galactosidase (Ad.RSVbetagal) or interleukin 2 (IL2, AdTG5327) into primary nonsmall-cell lung cancers of 21 patients. We report here virus shedding and the duration of virus expression in the tumor after intrabronchial injection of 10(7), 10(8) or 10(9) PFU of adenovirus. The infectious AdR and the viral DNA were detected in PBL, plasma, stool and aerodigestive samples in a dose-dependent manner, since cell cultures and PCRs were found to be positive mainly for samples from patients who received the highest AdR dose (10(9) PFU). We detected beta-galactosidase activity in the tumor biopsy samples of 66% of the patients, seemingly dose related, and only low levels of IL2 mRNA could be detected in tumor biopsy samples. E1 sequences were not detected by PCR in any of the PBL and bronchial samples collected after virus delivery, except in one patient. In this patient, E1 sequences were detected in PBL as well as in tumor biopsy samples collected at days 8, 30 and 60 and were correlated with longer beta-galactosidase expression in tumor samples. PBL tested before and after virus delivery contained both E1 sequences indicating that they did not result from replication-competent adenovirus (RCA) E1 sequences present in the inoculum. In addition, only on the day of the injection was Ad.RSVbetagal also detected in E1-positive PBL, indicating that virus replication in blood was very unlikely.

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Clin Cancer Res 2003 Jan;9(1):93-101
Induction of p53-regulated genes and tumor regression in lung cancer patients after intratumoral delivery of adenoviral p53 (INGN 201) and radiation therapy.
Swisher SG, Roth JA, Komaki R, Gu J, Lee JJ, Hicks M, Ro JY, Hong WK, Merritt JA, Ahrar K, Atkinson NE, Correa AM, Dolormente M, Dreiling L, El-Naggar AK, Fossella F, Francisco R, Glisson B, Grammer S, Herbst R, Huaringa A, Kemp B, Khuri FR, Kurie JM, Liao Z, McDonnell TJ, Morice R, Morello F, Munden R, Papadimitrakopoulou V, Pisters KM, Putnam JB Jr, Sarabia AJ, Shelton T, Stevens C, Shin DM, Smythe WR, Vaporciyan AA, Walsh GL, Yin M.
Department of Thoracic and Cardiovascular Surgery, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA. sswisher@mdanderson.org

PURPOSE: We designed a prospective single arm Phase II study to evaluate the feasibility and mechanisms of apoptosis induction after Ad-p53 (INGN 201) gene transfer and radiation therapy in patients with non-small cell lung cancer. EXPERIMENTAL DESIGN: Nineteen patients with nonmetastatic non-small cell lung cancer who were not eligible for chemoradiation or surgery were treated as outpatients with radiation therapy to 60 Gy over 6 weeks in conjunction with three intratumoral injections of Ad-p53 (INGN 201) on days 1, 18, and 32. RESULTS: Seventeen of 19 patients completed all planned radiation and Ad-p53 (INGN 201) gene therapy as outpatients. The most common adverse events were grade 1 or 2 fevers (79%) and chills (53%). Three months after completion of therapy, pathologic biopsies of the primary tumor revealed no viable tumor (12 of 19 patients, 63%), viable tumor (3 of 19 patients, 16%), and not assessed (4 of 19 patients, 21%). Computed tomography and bronchoscopic findings at the primary injected tumor revealed complete response (1 of 19 patients, 5%), partial response (11 of 19 patients, 58%), stable disease (3 of 19 patients, 16%), progressive disease (2 of 19 patients, 11%), and not evaluable (2 of 19 patients, 11%). Quantitative reverse transcription-PCR analysis of the four p53 related genes [p21 (CDKN1A), FAS, BAK, and MDM2] revealed that Bak expression was increased significantly 24 h after Ad-p53 (INGN 201) injection and levels of CDKN1A and MDM2 expression were increased over the course of treatment. CONCLUSIONS: Intratumoral injection of Ad-p53 (INGN 201) in combination with radiation therapy is well tolerated and demonstrates evidence of tumor regression at the primary injected tumor. Serial biopsies of the tumor suggest that BAK gene expression is most closely related to Ad-p53 (INGN 201) gene transfer.

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Cancer Gene Ther 2003 Jan;10(1):57-63
Recombinant adenoviruses expressing dominant negative insulin-like growth factor-I receptor demonstrate antitumor effects on lung cancer.
Lee CT, Park KH, Adachi Y, Seol JY, Yoo CG, Kim YW, Han SK, Shim YS, Coffee K, Dikov MM, Carbone DP.
Department of Internal Medicine, Seoul National University College of Medicine, South Korea.

The continuous growth of tumors depends on the altered regulation of the cell cycle, which is in turn modulated by signals from growth factors and their receptors. Blockade of insulin-like growth factor (IGF)-I and IGF-IR by antisense or dominant negative plasmid transfection can suppress tumorigenicity and induce regression of established tumors. We have constructed two recombinant adenoviruses: an adenovirus expressing truncated IGF-IR (ad-IGF-IR/950) with an engineered stop codon at amino acid residue 950, and an adenovirus expressing the soluble extracellular domain of IGF-IR (ad-IGF-IR/482) with an engineered stop codon at amino acid residue 482. Ad-IGF-IR/950 produces a defective receptor with an intact alpha subunit and a defective beta subunit lacking the tyrosine kinase domain. Dominant negative inhibition results from competition of the defective receptor with normal IGF-IR subunits, or the competition with normal IGF-IR for ligand by the soluble receptor. We were able to show here that ad-IGF-IR/950 induced the increased expression of IGF-IR on the cell surface and ad-IGF-IR/482 induced the secretion of the soluble fragment of IGF-IR. The transduction of both ad-IGF-IR/950 and ad-IGF-IR/482 could blunt the growth-stimulatory effect of IGF-I on human lung cancer cell lines. Both ad-IGF-IR/950 and ad-IGF-IR/482 effectively blocked IGF-I-induced Akt kinase activation. Intratumoral injection of ad-IGF-IR/482 virus showed significant growth suppression in established lung cancer xenografts. These findings suggest that these ad-IGF-IR/dn (950, 482) have the potential to be effective and practical cancer gene therapy strategies.

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Ai Zheng 2002 Dec;21(12):1328-31
[Treatment of spontaneous metastatic lung cancer with interleukin-12 gene-modified
dendritic cells vaccine]
[Article in Chinese]
Chen JQ, Xiu QY, Shen C, Yan ZM.
Department of Respiratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, P. R. China. erinyin@81890.net

BACKGROUND & OBJECTIVE: Although many works have been done in treatment of metastatic lung cancer, effective method is lacked. This study was designed to investigate the treatment of spontaneous metastatic lung cancer by interleukin-12 (IL-12) gene-modified dendritic cells (DC) vaccine. METHODS: The spontaneous metastatic lung cancer model, prepared by injection of the 3LL Lewis lung cancer cells into the footpads of C57BL/6 mice, were treated by subcutaneous vaccination with tumor antigen peptide Mut1-pulsed, IL-12 gene-modified dendritic cells (DC-IL-12/Mut1) derived from the normal bone marrow. After treatment, the lung weight, the number of lung metastatic nodes, the survival time of the tumor-bearing mice were observed, and the NK and CTL activities were respectively determined. RESULTS: Compared with mice treated with Mut1-pulsed, control LacZ gene modified DC and untreated DC, tumor-bearing mice treated with DC-IL-12/Mut1 had the lightest lung weights (P < 0.01), the least lung metastatic node numbers (P < 0.01), the longest survival time (P < 0.01), also with the induction of potent CTL activity (P < 0.01) and NK activity (P < 0.01). CONCLUSION: Tumor antigen-pulsed, IL-12 gene-modified dendritic cells have significant therapeutic effects on the spontaneous metastatic lung cancer, the possible mechanism involved with induction of CTL activity and enhancement of NK activity.

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Clin Cancer Res 2003 Mar;9(3):961-8
Tumor Cyclooxygenase 2-dependent Suppression of Dendritic Cell Function.
Sharma S, Stolina M, Yang SC, Baratelli F, Lin JF, Atianzar K, Luo J, Zhu L, Lin Y, Huang M, Dohadwala M, Batra RK, Dubinett SM.
University of California Los Angeles School of Medicine-Wadsworth Pulmonary Immunology Laboratory, Veterans Administration Greater Los Angeles Healthcare System [S. S., M. S., S-C. Y., F. B., J. F. L., K. A., J. L., L. Z., Y. L., M. H., M. D., R. K. B.].

Dendritic cells (DCs) serve as professional antigen-presenting cells and are pivotal in the host immune response to tumor antigens. To define the pathways limiting DC function in the tumor microenvironment, we assessed the impact of tumor cyclooxygenase (COX)-2 expression on DC activities. Bone marrow-derived DCs were cultured in either tumor supernatant (TSN) or TSN from COX-2-inhibited tumors. After culture, DCs were pulsed with tumor-specific peptides, and their ability to generate antitumor immune responses was assessed following injection into established murine lung cancer. In vitro, DC phenotype, alloreactivity, antigen processing and presentation, and interleukin (IL)-10 and IL-12 secretion were evaluated. DCs cultured in TSN failed to generate antitumor immune responses and caused immunosuppressive effects that correlated with enhanced tumor growth. However, genetic or pharmacological inhibition of tumor COX-2 expression restored DC function and effective antitumor immune responses. Functional analyses indicated that TSN causes a decrement in DC capacity to (a) process and present antigens, (b) induce alloreactivity, and (c) secrete IL-12. Whereas TSN DCs showed a significant reduction in cell surface expression of CD11c, DEC-205, MHC class I antigen, MHC class II antigen, CD80, and CD86 as well as a reduction in the transporter-associated proteins, transporter associated with antigen processing 1 and 2, the changes in phenotype and function were not evident when DCs were cultured in supernatant from COX-2-inhibited tumors. We conclude that inhibition of tumor COX-2 expression or activity can prevent tumor-induced suppression of DC activities.

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Expert Opin Biol Ther 2002 Mar;2(3):265-78
The development of immunotherapies for non-small cell lung cancer.
Salgaller ML.
Northwest Biotherapeutics, Inc., Suite 100, 21720 23rd Drive SE, Bothell, WA 98021, USA. mls@nwbio.com

Standard of care for non-small cell lung cancer (NSCLC) (surgery, chemotherapy and radiation) may enhance patient survival but the enhancement is typically transient and quite uncommon with advanced disease. Researchers and medical professionals are using new approaches to improve patient mortality and morbidity. One of these approaches, immunotherapy, seeks to stimulate antitumour immunity above a threshold level needed for tumour regression or to induce stability in the face of progression. Among the most established approaches are vaccines involving monoclonal antibodies (mAbs) or immune effector cells. These approaches stimulate the humoral and cell-mediated arms of the immune system, respectively. As the development of humanised or fully human antibodies has spurred exploration of radioimmunoconjugates and immunotoxins, mAbs have enjoyed a revival of sorts. Cell-based therapies using the tumour cell itself as a vaccine component has resulted in disease stabilisation or regression. In addition, immune cells (e.g., T-lymphocytes and dendritic cells [DCs]) are the focal point of numerous patient trials in which meaningful clinical impact was achieved. In general, there are many tactics under development for the treatment of NSCLC. This review primarily concerns immunotherapeutic cancer treatments that are either already in clinical trial or well progressed into preclinical studies.

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Zhonghua Yi Xue Za Zhi 2001 Jul 10;81(13):779-82
[Treatment of spontaneous metastatic lung cancer with tumor antigen-pulsed, interleukin-18 gene-modified dendritic cells]
[Article in Chinese]
Chen J, Cao X, Xiu Q.
Department of Respiratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.

OBJECTIVE: To investigate the effect of tumor antigen-pulsed, interleukin-18 (IL-18) gene-modified dendritic cells in treatment of spontaneous metastatic lung cancer. METHODS: 3LL Lewis lung cancer cells were injected into the footpads of C57BL/6 mice to establish a spontaneous metastatic lung cancer model. Ninety-six mice with lung cancer were divided into 8 groups, 12 in each. treated differently. One group was treated by subcutaneous vaccination for two times of tumor antigen peptide Mut1-pulsed, IL-18 gene-modified dendritic cells (DC-IL-18/Mut1) that were derived from normal bone marrow. The other groups were treated with other measures. After treatment, the lung weight, number of metastatic nodes on the lung surface, survival time, and NK and CTL activities were examined. RESULTS: Compared with the mice treated with Mut1-pulsed control LacZ gene-modified DC and those treated with untreated DC, the tumor-bearing mice treated with DC-IL-18/Mut1 had the lightest lung weight (215 mg +/- 20 mg Vs 398 mg +/- 23 mg and 987 mg +/- 45 mg, t = 14.7 and 38.4, P < 0.01), the least lung metastatic nodes (0 Vs 7.8 +/- 2.7 and 49, P < 0.01), the longest survival time (chi(2) = 6.78 and 10.49 respectively, P < 0.01), the strongest cytotoxic T cell activity (53.4 +/- 3.1 Vs 41.3 +/- 2.6 and 9.8 +/- 2.1, t = 13.4 and 15, 7 respectively, P < 0.01), and increased proportions of CD4 + Tcells, CD8 + Tcells, and NK cells. CONCLUSION: Tumor antigen-pulsed, IL-18 gene-modified dendritic cells have a significant therapeutic effect on spontaneous netastatic lung cancer through induction of anti-tumor immunological responses.

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Br J Cancer 2003 Mar 24;88(6):887-94
L523S, an RNA-binding protein as a potential therapeutic target for lung cancer.
Wang T, Fan L, Watanabe Y, McNeill PD, Moulton GG, Bangur C, Fanger GR, Okada M, Inoue Y, Persing DH, Reed SG.

Approaches to vaccine-based immunotherapy of human cancer may ultimately require targets that are both tumour-specific and immunogenic. In order to generate specific antitumour immune responses to lung cancer, we have sought lung cancer-specific proteins that can be targeted for adjuvant vaccine therapy. By using a combination of cDNA subtraction and microarray analysis, we previously reported the identification of an RNA-binding protein within the KOC family, L523S, to be overexpressed in squamous cell cancers of the lung. We show here that L523S exhibits significant potential for vaccine immunotherapy of lung cancer. As an oncofetal protein, L523S is normally expressed in early embryonic tissues, yet it is re-expressed in a high percentage of nonsmall cell lung carcinoma. The specificity of L523S expression in lung cancer was demonstrated by both mRNA and protein measurements using real-time PCR, Western blot, and immunohistochemistry analyses. Furthermore, we show that immunological tolerance of L523S is naturally broken in lung cancer patients, as evidenced by detectable antibody responses to recombinant L523S protein in eight of 17 lung pleural effusions from lung cancer patients. Collectively, our studies suggest that L523S may be an important marker of malignant progression in human lung cancer, and further suggest that treatment approaches based on L523S as an immunogenic target are worthy of pursuit.British Journal of Cancer (2003) 88, 887-894. doi:10.1038/sj.bjc.6600806 www.bjcancer.com

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Ann Oncol 2003 Mar;14(3):461-6
Epidermal growth factor-based cancer vaccine for non-small-cell lung cancer therapy.
Gonzalez G, Crombet T, Torres F, Catala M, Alfonso L, Osorio M, Neninger E, Garcia B, Mulet A, Perez R, Lage R.
Center of Molecular Immunology.

BACKGROUND: The role that growth factors and their receptors play in human cancer growth and progression makes them interesting targets for novel treatment modalities. Our approach consisted of active immunotherapy with the epidermal growth factor (EGF). Two pilot clinical trials were conducted to examine the safety and immunogenicity of a five-dose immunization protocol and to compare different adjuvants and treatment designs. PATIENTS AND METHODS: Forty patients with advanced non-small-cell lung cancer were enrolled in both trials. They were randomized to be treated with aluminum hydroxide or montanide ISA 51 as adjuvants in the EGF vaccine preparation. The use of cyclophosphamide prevaccination treatment was evaluated in the second trial. RESULTS: Pooled data from both trials showed that the use of montanide as adjuvant increased the percentage of good antibody responders (GAR). Cyclophosphamide prevaccination treatment did not provoke improvements in antibody response. GAR had a significant increase in survival as compared with poor antibody responders. Response duration was also related to a significant improvement in survival rates. CONCLUSIONS: Vaccination with five doses of EGF vaccine is safe and immunogenic. Montanide ISA 51 increased the percentage of GAR. There is a direct relationship between anti-EGF antibody titers and immune response duration with survival time.

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Gan To Kagaku Ryoho 2003 Mar;30(3):371-5
[Efficacy of docetaxel (TXT) combined with cisplatin (CDDP) in non-small cell lung cancer]
[Article in Japanese]
Kuroki S, Iwanaga K, Kato O, Takahashi K, Haruta Y, Soejima Y, Koyanagi K, Furukawa T, Soejima Y, Nagata M, Naitoh K, Aoki Y, Hayashi S.
Dept. of Internal Medicine, Saga Social Insurance Hospital.

A multicenter cooperative study of docetaxel (60 mg/m2) combined with cisplatin (60 mg/m2) was performed in stage III and IV patients with inoperable non-small cell lung cancer from March 1998 to September 1999. Of 37 patients enrolled, 36 patients were eligible. One patient obtained a complete response (CR) and nine patients had a partial response (PR). The overall response rate in 36 patients was 28.6%. The median survival time was 360 days. The response rates of stage III and stage IV patients were 36.8% and 18.7%, respectively. The median survival times of stage III and stage IV patients were 502 days and 286 days, respectively. The major toxicities were grade 3 leukopenia (16.2%), grade 3 neutropenia (32.4%), and grade 4 neutropenia (10.8%).

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Gan To Kagaku Ryoho 2003 Mar;30(3):365-70
[Cost-effectiveness of weekly paclitaxel for patients with advanced non-small cell lung cancer]
[Article in Japanese]
Suyama H, Hitsuda Y, Matsumoto S, Nakamoto M, Shigeoka Y, Nakanishi H, Igishi T, Burioka N, Yasuda K, Sako T, Miyata M, Endo M, Shimizu E.
Third Dept. of Internal Medicine, Faculty of Medicine, Tottori University.

Paclitaxel is known to be efficacious in treating non-small cell lung cancer (NSCLC). We initiated a phase II trial of weekly paclitaxel (W-PTX) therapy in advanced NSCLC, and found that W-PTX was feasible for advanced NSCLC patients. We evaluated the cost of W-PTX from receipts and compared it with a standard cisplatin-vinorelbine (VC) regimen. The aim of this study was to assess the cost of W-PTX therapy. Previously untreated patients with stage IV NSCLC and patients with stage III B/IV NSCLC after at least one previous cisplatin based regimen were eligible if they had preserved organ function for treatment. Paclitaxel was administered at a dose of 80 mg/m2 for 3 consecutive weeks on a 4-week cycle. Patients received at least 1 course of W-PTX in our hospital and then, if possible, were treated on outpatients basis. All patients receiving the VC regimen were treated in the hospital. The mean cost of W-PTX for one month was approximately 699,000 yen per inpatient and 236,000 yen per outpatient. On the other hand, the mean cost of VC for one month was approximately 816,000 yen per patient. Although the cost of W-PTX for inpatient did not differ greatly from the cost of VC, the cost of W-PTX for outpatients was significantly lower than that of VC. The findings of this study suggest that W-PTX is feasible as a cost-effective chemotherapy for patients with advanced NSCLC.

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