Lung Cancer Highlights from ASCO Ornella Belvedere, Francesco Grossi

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1 This material is protected by U.S. Copyright law. Unauthorized reproduction is prohibited. For reprints contact: Lung Cancer Lung Cancer Highlights from ASCO 2005 Ornella Belvedere, Francesco Grossi Department of Medical Oncology, University Hospital, Udine, Italy; Medical Oncology A, Disease Management Team - Lung Cancer, National Institute for Cancer Research, Genoa, Italy Learning Objectives Key Words. Non-small cell lung cancer Advanced disease Locally advanced disease Adjuvant chemotherapy Neoadjuvant chemotherapy Elderly After completing this course, the reader will be able to: 1. Discuss the results of recent trials on the addition of a molecularly targeted agent to standard first-line chemotherapy in NSCLC. 2. Explain the role of surgery in the treatment of stage III NSCLC. 3. Discuss the current status of adjuvant chemotherapy in NSCLC. CME Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com Abstract Exciting news regarding lung cancer was presented at the American Society of Clinical Oncology (ASCO) 2005 Annual Meeting held in Orlando, FL. Last but not least among the big killers, after breast cancer and colorectal cancer, non-small cell lung cancer (NSCLC) can now benefit from the addition of a molecularly targeted agent to standard first-line chemotherapy. The Eastern Cooperative Oncology Group 4599 phase III trial showed superior survival in patients with advanced nonsquamous NSCLC when the angiogenesis inhibitor bevacizumab was added to standard firstline chemotherapy with carboplatin and paclitaxel, compared with the same chemotherapy alone. Careful patient selection is mandatory to avoid fatal bleeding following bevacizumab administration. The role of surgery in the multimodality treatment of stage III NSCLC was further defined by the North American Intergroup 0139 trial and the European Organization for the Research and Treatment of Cancer Lung Cancer group trial. The final results of the Adjuvant Navelbine International Trialist Association trial add further support to adjuvant platinum-based chemotherapy following radical surgery in early-stage NSCLC. Interesting studies further addressed the correlation between molecular tumor profiling and clinical outcome with molecularly targeted agents in NSCLC, in particular gefitinib and erlotinib. Still, the Southwest Oncology Group 0023 randomized trial of maintenance gefitinib after definitive chemoradiation in unresectable NSCLC failed to demonstrate an advantage for maintenance gefitinib over placebo. Unfortunately, no striking results have been reported for small cell lung cancer and pleural malignant mesothelioma. The results of the studies in this report are updated with the data presented at the 2005 ASCO Annual Meeting. The Oncologist 2006;11:39 50 Correspondence: Francesco Grossi, M.D., Medical Oncology A, Disease Management Team Lung Cancer, National Institute for Cancer Research, Largo Rosanna Benzi 10, Genoa, Italy. Telephone: ; Fax: ; francesco. grossi@istge.it Received July 21, 2005; accepted for publication October 12, AlphaMed press /2006/$12.00/0 The Oncologist 2006;11:

2 40 Lung Cancer Highlights Advanced Non-Small Cell Lung Cancer Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC #704865) in patients with advanced nonsquamous nonsmall cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial - E4599 A.B. Sandler, R. Gray, J. Brahmer, A. Dowlati, J.H. Schiller, M.C. Perry, D.H. Johnson The Eastern Cooperative Oncology Group (ECOG) trial 4599 evaluated the effectiveness of the addition of bevacizumab (Avastin ; Genentech, Inc., South San Francisco, CA, a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF), to a standard platinum-based chemotherapy in chemotherapy-naive patients with advanced nonsquamous non-small cell lung cancer (NSCLC) [1]. This trial was conducted to confirm the encouraging activity and survival observed in a small randomized phase II trial with the addition of bevacizumab to carboplatin (Paraplatin ; Bristol-Myers Squibb, Princeton, NJ, plus paclitaxel (Taxol ; Bristol-Myers Squibb) chemotherapy in untreated advanced NSCLC [2, 3]. In that trial, a higher incidence of severe tumorrelated bleeding episodes was observed in patients with squamous histology and centrally located tumors treated with bevacizumab. Accordingly, in the ECOG trial 4599, patients with squamous cell NSCLC, brain metastasis, or gross hemoptysis were excluded. From July 2001 to April 2004, 878 patients were randomized to receive either paclitaxel (200 mg/m 2 ) plus carboplatin (to an area under the concentration time curve [AUC] of 6), or the same chemotherapy plus bevacizumab (15 mg/kg) on day 1 every 3 weeks. Chemotherapy was continued up to six cycles; patients in the experimental arm received single-agent bevacizumab after the six cycles of chemotherapy until progressive disease or intolerable toxicity. Patients in the chemotherapy arm alone were not allowed to cross over to bevacizumab. The primary end point was overall survival; secondary end points were response rate, time to progression, and toxicity. The study was designed to have an 80% power to detect a 25% longer median survival time (from 8 months in the control arm to 10 months in the experimental arm), with an overall onesided 2.5% type I error. At the 2005 Annual Meeting of the American Society of Clinical Oncology (ASCO), Dr. Sandler reported the results of the second interim analysis, performed after 469 (72.2%) of the 650 deaths required for final analysis. Patient characteristics and study results are summarized in Table 1. There was a significant advantage for patients in the bevacizumab arm in terms of median survival (12.5 months vs months; p =.0075). In addition, patients treated with bevacizumab had a significantly greater response rate (27% vs. 10%; p <.0001) and a significantly longer progression-free survival time (6.4 months vs. 4.5 months; p <.0001). Both regimens were well tolerated; a higher incidence of bleeding was associated with bevacizumab administration (4.5% vs. 0.7%). There were 10 treatment-related deaths: five were a result of hemoptysis, all in the experimental arm. No retrospective analysis correlating biomarkers such as VEGF, fibroblast growth factor, and cell-adhesion molecules with survival and response outcomes has been reported so far. In conclusion, the addition of bevacizumab to carboplatin plus paclitaxel in patients with nonsquamous NSCLC provides a statistically and clinically significant survival advantage with tolerable toxicity. Based on these results, Table 1. Summary of the Eastern Cooperative Oncology Group 4599 trial CBDCA+PTX CBDCA+PTX+bevacizumab p value No. of patients Overall response rate (%) <.0001 Median survival (months) year survival (%) year survival (%) Median TTP (months) <.0001 Grade 4 neutropenia (%) Grade 3 4 hemorrhage (%) <.001 Grade 3 4 hypertension (%) <.001 Abbreviations: CBDCA, carboplatin; PTX, paclitaxel; TTP, time to progression. The Oncologist

3 Belvedere, Grossi 41 the carboplatin paclitaxel bevacizumab regimen is the new standard regimen in first-line advanced nonsquamous NSCLC for future ECOG trials. A randomized phase III trial comparing bexarotene/ cisplatin/vinorelbine versus cisplatin/vinorelbine in chemotherapy-naive patients with advanced or metastatic nonsmall cell lung cancer (NSCLC) J. Jassem, P. Zatloukal, R. Ramlau, P. Schwarzenberger, S. Orlov, J. Rodrigues-Pereira, G. Temperley, M. Mabry, A. Negro-Vilar, Z. Dziewanowska, SPIRIT I Lung Cancer Study Group Randomized phase III trial comparing bexarotene/ carboplatin/paclitaxel versus carboplatin/paclitaxel in chemotherapy-naive patients with advanced or metastatic nonsmall cell lung cancer (NSCLC) G.R. Blumenschein, F. Khuri, U. Gatzemeier, W.H. Miller, J. von Pawel, J.R. Rigas, R.S. Herbst, Z. Dziewanowska, A. Negro-Vilar, M. Mabry, SPIRIT II Lung Cancer Study Group Study Designs and Results Dr. Jassem and Dr. Blumenschein presented the results of the SPIRIT (Studies Providing Investigational Research in Targretin) 1 and SPIRIT 2 trials, respectively [4, 5]. These trials were conducted to assess the role of bexarotene (Targretin ; Ligand Pharmaceuticals, San Diego, ligand.com) in combination with chemotherapy as first-line treatment in advanced NSCLC. Bexarotene is a novel, oral, multitargeted synthetic agent that binds specifically to retinoid X receptors. It belongs to a family of drugs called rexinoids and is currently approved by the U.S. Food and Drug Administration for the treatment of cutaneous manifestations of T-cell lymphoma in patients who are refractory to at least one prior line of systemic therapy [6]. In the SPIRIT trials, 1,225 previously untreated advanced NSCLC patients were randomized to receive chemotherapy either with or without bexarotene (400 mg/ m 2 daily). In the SPIRIT 1 trial, chemotherapy consisted of cisplatin (Platinol ; Bristol-Myers Squibb) (100 mg/m 2 ) on day 1 plus vinorelbine (Navelbine ; GlaxoSmithKline, Philadelphia, (25 mg/m 2 ) on days 1, 8, 15, and 22 i.v. every 4 weeks [4]; in the SPIRIT 2 trial, chemotherapy consisted of carboplatin (AUC, 6) plus paclitaxel (200 mg/m 2 ) on day 1 i.v. every 3 weeks [5]. Patients in the experimental arm were offered the option to continue bexarotene as maintenance therapy until progression. Overall survival was the primary end point in both studies. Results were consistent between the SPIRIT trials: the combination of bexarotene and chemotherapy provided no better efficacy than chemotherapy alone. Drug-related adverse events were generally rare, and comparable toxicity profiles were reported for the bexarotene and control arms, with the exceptions of neutropenia, febrile neutropenia, hypertriglyceridemia, and hypercholesterolemia. A retrospective subset analysis suggests that the elevation in triglyceride levels in patients treated with bexarotene in both studies correlates with longer survival (Table 2). As these two studies were well designed and conducted, it can be concluded that there is no role for bexarotene in combination with chemotherapy in unselected advanced NSCLC. Table 2. Summary of the SPIRIT trials SPIRIT 1 (n = 613) SPIRIT 2 (n = 612) CDDP+VNB CDDP+VNB+BEX CBDCA+PTX CBDCA+PTX+BEX PFS (months) MS (months) year survival (%) MS BEX high TG (months) a d MS BEX low TG (months) 7.5 b 6.6 e Neutropenia (%) c Febrile neutropenia (%) NR NR Dyspnea 4 10 NR NR Hypertryglyceridemia (%) Hypercholesterolemia (%) 0 6 NR NR a p =.08; b p =.009; c p.05; d p =.014; e p =.001. Abbreviations: BEX, bexarotene; CBDCA, carboplatin; CDDP, cisplatin; MS: median survival; NR, not reported; PFS, progression-free survival; PTX, paclitaxel; SPIRIT, Studies Providing Investigational Research in Targretin; TG, triglycerides; VN, vinorelbine.

4 42 Lung Cancer Highlights Commentary Until ASCO 2005, the only standard first-line treatment for patients with advanced NSCLC and good performance status was a two-drug, platinum-based regimen, with either cisplatin or carboplatin combined with a third-generation agent (paclitaxel, gemcitabine [Gemzar ; Eli Lilly and Company, Indianapolis, docetaxel [Taxotere ; Aventis Pharmaceuticals Inc., Bridgewater, NJ, aventispharma-us.com], or vinorelbine). A recent randomized trial comparing four commonly used regimens failed to demonstrate a superior treatment, with a response rate of 19%, median survival duration of 7.9 months, and 1-year survival rate of 33% [7]. Attempts to improve the efficacy of first-line chemotherapy with either nonplatinum regimens [8], three-drug regimens [9, 10], or the addition of a molecularly targeted agent to standard chemotherapy [11 14] failed to demonstrate a benefit over a two-drug, platinum-based regimen. After ASCO 2005, based on the randomized phase III ECOG trial 4599, a two-drug, platinum-based regimen plus bevacizumab is the new standard of care for selected nonsquamous NSCLC patients. That study is a milestone in the history of lung cancer treatment. It is the first randomized trial in the past decade to show a survival advantage in first-line NSCLC, the first randomized trial to show a survival advantage adding a third drug, and the first randomized trial to show a survival advantage with the addition of a molecularly targeted agent to standard chemotherapy in this setting. Although bevacizumab is a molecularly targeted agent, no biologic biomarker of efficacy has been used to identify patients likely to respond. However, patient selection was required, to reduce the risk for fatal bleeding following the administration of bevacizumab. Patients with squamous cell carcinoma, and also patients with a history of hemoptysis, brain metastasis, or uncontrolled hypertension, are not good candidates for bevacizumab-containing regimens. In daily practice, these precautions will significantly limit the portion of advanced NSCLC patients eligible for this treatment. Of note, the response rate in the control arm was only 10%; no clear explanation for such a low activity compared with previous trials is available, although it might be related to the use of the Response Evaluation Criteria in Solid Tumors for the assessment of response in this study. In a preliminary subset analysis, survival benefit was observed across all treatment subgroups except for gender. In spite of a significant difference in terms of response rate and time to progression for women in the bevacizumab arm versus women in the chemotherapy alone arm, no survival benefit was observed between the two groups. A possible explanation is that the survival advantage for women in the bevacizumab arm was covered by the subsequent administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as second- or third-line therapy, which have shown efficacy in women with adenocarcinoma histology. To assess the safety and efficacy of bevacizumab with other chemotherapy regimens, a similar randomized phase III trial evaluating the addition of bevacizumab to standard chemotherapy with cisplatin and gemcitabine in previously untreated advanced NSCLC patients is currently ongoing (BO17704 trial). There was bad news from the SPIRIT trials: the addition of bexarotene to standard two-drug, platinum-based chemotherapy did not improve survival in first-line NSCLC. Despite different chemotherapy regimens and geographical sites, negative results were consistent between the two studies. However, an important consistent observation raised from the retrospective subset analysis was that a substantial elevation in triglyceride levels ( five times the upper limit of normal) within the first 3 4 weeks of treatment with bexarotene correlates with longer survival. There is no univocal interpretation at this time. Ongoing biochemical and pharmacogenomic studies will confirm whether hypertriglyceridemia is an optimal, early biomarker of bexarotene survival benefit in NSCLC. The role of statins must also be addressed. It was recently reported that statins may have antitumor activity [15]. In the SPIRIT trials, antilipid therapy was started on day 1 in the bexarotene arm. Locally Advanced NSCLC A randomized trial of radical surgery (S) versus thoracic radiotherapy (TRT) in patients (pts) with stage IIIA-N2 nonsmall cell lung cancer (NSCLC) after response to induction chemotherapy (ICT) (EORTC 08941) J.P. van Meerbeeck, G. Kramer, P.E. Van Schil, C. Legrand, E.F. Smit, F.M. Schramel, B. Biesma, V.C. Tjan- Heijnen, N. van Zandwijk, G. Giaccone, EORTC-Lung Cancer Group On behalf of the European Organization for Research and Treatment of Cancer (EORTC) Lung Cancer Group, Dr. van Meerbeeck presented the results of the EORTC trial. In this randomized phase III trial, patients with histologically or cytologically proven stage IIIA-N2 NSCLC who achieved at least a minor response after three cycles of platinum-based induction chemotherapy were randomized to receive either radical surgery or thoracic radiation therapy [16]. Postoperative thoracic radiation therapy was recommended in cases of incomplete resection only. The primary end point was overall survival; secondary end points were time to progression and treatment-related toxicities. To observe an increase in the 5-year overall survival rate The Oncologist

5 Belvedere, Grossi 43 from 15% with consolidation thoracic radiation therapy to 25% with surgery, 292 events of the 358 planned randomized patients had to be observed (log-rank test, power 80%, type I error 5%). Overall, 579 patients were registered in the study, and 332 patients (57%) responding to induction chemotherapy were randomized. The response rate to induction chemotherapy was 62% (95% confidence interval [CI], 58% 66%) among the 570 patients who received at least one cycle of chemotherapy. Among the 154 patients who underwent surgery, radical resection was achieved in 50% of cases, while exploratory thoracotomy was performed in 14% of cases. Pathological downstaging was recorded in 42% of patients. Operative mortality was 4%: five of the six postoperative deaths followed a pneumonectomy. Postoperative radiation therapy was delivered in 39% of the patients. Among the 155 patients randomized to thoracic radiation therapy and actually irradiated, 86% received at least 60 Gy. The median total treatment time was 43 days (range, days). Late grade 3 4 pulmonary and esophageal toxicities occurred in 9% of patients in the radiation therapy arm. There was a 1% death rate due to consolidation radiation therapy. There was no significant difference between the two arms in terms of survival or progression-free survival (Table 3). Median survival times were 16.4 months and 17.5 months (hazard ratio [HR], 1.06; 95% CI, ; p =.60) and median progression-free survival times were 9.0 months and 11.3 months (HR, 1.06; 95% CI, ; p =.61) in the surgery and radiation therapy arms, respectively. Based on these results, chemoradiotherapy is the standard treatment for future EORTC trials in stage IIIA-N2 NSCLC. Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) versus CT/RT followed by surgical resection for stage IIIA(pN2) nonsmall cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 9309) K.S. Albain, R.S. Swann, V.R. Rusch, A.T. Turrisi, F.A. Shepherd, C.J. Smith, D.R. Gandara, D.H. Johnson, M.R. Green, R.C. Miller, North American Lung Cancer Intergroup Dr. Albain presented the updated results of the Intergroup 0139 (Radiation Therapy Oncology Group [RTOG] 9309) trial [17]. The objective of this trial was to determine the role of surgery after chemoradiation in patients with stage IIIA (pn2) NSCLC compared with chemotherapy plus fullcourse radiation therapy. Patients with ECOG performance status scores of 0 1 and technically resectable T1-3, pn2, M0 NSCLC were randomized to receive induction chemoradiotherapy (cisplatin, 50 mg/m 2 on days 1, 8, 29, and 36, and etoposide [Etopophos, VePesid ; Bristol-Myers Squibb], 50 mg/m 2 on days 1 5 and 29 33, plus concomitant thoracic radiation therapy with 45 Gy starting on day 1 followed by either resection or further radiation therapy to 61 Gy if no progression was observed at the end of the induction chemoradiation phase. In both arms, two additional cycles of consolidation chemotherapy with cisplatin and etoposide were given after surgery and definitive radiation therapy. From March 1994 to November 2001, 429 patients were enrolled and 396 were eligible (93%). The first analysis, presented in 2003, reported better progression-free survival, which did not translate in a longer overall survival, in the surgery arm. The updated analysis presented by Dr. Albain at ASCO 2005 was performed after a median follow-up of 81 months and after all patients were followed for at least 2.5 years. There were 16 (7.9%) treatment-related deaths in the surgery arm and four (2.1%) in the definitive radiation therapy arm. The previously reported advantage in favor of the surgery arm in terms of progression-free survival was confirmed, with a median of 12.8 months versus 10.5 months (p =.017; HR, 0.77 [95% CI, ) and 5-year progression-free survival rates of 22.4% versus 11.1% (Table 4). Table 3. Summary of the European Organization for Research and Treatment of Cancer trial CT/S CT/TRT p value No. of patients Median PFS (months) year PFS (%) MS (months) year survival (%) Abbreviations: CT, chemotherapy; MS, median survival; PFS, progression-free survival; S, surgery; TRT, thoracic radiation therapy. Table 4. Summary of the North American Intergroup 0139 (Radiation Therapy Oncology Group 9309) trial CT/RT/S CT/TRT p value No. of patients Median PFS (months) year PFS (%) MS (months) year survival (%) Abbreviations: CT, chemotherapy; MS, median survival; PFS, progression-free survival; RT, radiation therapy; S, surgery; TRT, thoracic radiation therapy.

6 44 Lung Cancer Highlights The survival curves by treatment arm superimpose through year 2, then separate: there was an absolute 5-year survival benefit of 7% for the surgery arm (27.2% vs. 20.3%; p =.10; odds ratio, 0.63 [95% CI, ]). Independent favorable survival predictors were gender (female) and no weight loss. Fourteen of the 15 postoperative deaths followed a pneumonectomy, suggesting that trimodality is not optimal when pneumonectomy is needed, due to a high mortality rate. Low incidence of pneumonitis on SWOG 0023: A preliminary analysis of an ongoing phase III trial of concurrent chemoradiotherapy followed by consolidation docetaxel and gefitinib/placebo maintenance in patients with inoperable stage III nonsmall cell lung cancer K. Kelly, L.E. Gaspar, K. Chansky, K.S. Albain, J. Crowley, D.R. Gandara, Southwest Oncology Group In the Southwest Oncology Group (SWOG) 9504 phase II trial of cisplatin plus etoposide with concurrent thoracic radiation therapy followed by consolidation docetaxel in stage IIIB patients, a median survival time of 26 months and a 29% 5-year survival rate were reported [18]. This was the core regimen for the SWOG 0023 randomized phase III trial evaluating the incorporation of gefitinib (Iressa ; Astra- Zeneca Pharmaceuticals, Wilmington, DE, astrazeneca-us.com) as a maintenance therapy in unresectable stage III NSCLC after definitive therapy [19]. Patients received cisplatin (50 mg/m 2 on days 1,8, 29, and 33) and etoposide (50 mg/m 2 on days 1 5 and 29 33) with concurrent thoracic radiation (total dose of 61 Gy), followed by docetaxel (75 mg/m 2 on day 1, every 3 weeks) for three cycles. Nonprogressing patients after docetaxel were randomized to receive either gefitinib or placebo. Gefitinib could be continued for up to 5 years, or progressive disease or unacceptable toxicity. The study was designed to demonstrate a 33% improvement in the median survival time in the gefitinib arm over the estimated 21-month survival duration in the control arm. The primary end point was overall survival. Following the disclosure of the negative results of the Iressa Survival Evaluation in Lung cancer trial that failed to demonstrate a survival benefit with gefitinib in second- and third-line therapy in advanced NSCLC over placebo, an unplanned interim analysis was performed and the SWOG 0023 study was closed on April 15, The median overall survival time for all 575 eligible patients was 19 months. Two-hundred sixty-three patients nonprogressing after docetaxel administration were randomized. There were no significant differences in terms of progression-free survival or overall survival between the two arms (Table 5). Grade 3 4 pneumonitis was more frequent during docetaxel treatment (8% of patients), while during gefitinib maintenance, 3% of patients reported grade 3 4 pneumonitis, compared with 0% in the placebo arm. Other toxicities were within expected ranges. Although not statistically significant, more deaths were reported in the gefitinib arm than in the placebo arm. The study was closed to accrual because, statistically, there was no chance that the study would turn out to be positive. Commentary Despite its being clear that a multimodality approach is superior to surgery alone for patients with stage IIIA-N2 NSCLC, it remains a challenge to determine the best strategy in terms of treatment modalities to be used and treatment sequence. The EORTC trial is the first trial to compare consolidation thoracic radiation therapy with radical surgery in patients with stage IIIA-N2 NSCLC achieving a partial response to induction chemotherapy. No significant difference was observed between the two arms in terms of overall survival and progression-free survival. Interestingly, there was an initial advantage in terms of survival for patients in the radiation therapy arm (median survival time, 17.5 months vs months), likely related to perioperative mortality; however, the 5-year survival rate was slightly superior in the surgery arm (15.7% vs. 14%). Subset analyses show a significantly longer median survival time for lobectomy than for pneumonectomy (25.4 months vs months) and for patients achieving a tumor downstaging with a pn1-n0 at surgery versus radiation therapy (22.7 months vs months; p =.0009) (Table 6). These results of the EORTC trial are consistent with the results of the RTOG 9309 trial, first presented at the ASCO 2003 Annual Meeting [20] and updated this year. This study shows that the addition of surgical resection to chemoradiation results in longer progression-free survival, which does not translate into overall survival advantage. In the subset analysis, chemoradiation therapy was superior when pneumonectomy was required (19 months vs. 29 months), although this was not significant. However, when surgery can be limited to a lobectomy, this approach Table 5. Summary of the Southwest Oncology Group 0023 trial Gefitinib Placebo p value No. of patients Median progression-free survival (months) a Median survival (months) a a Number of months after randomization to gefitinib or placebo. The Oncologist

7 Belvedere, Grossi 45 Table 6. European Organization for Research and Treatment of Cancer trial: subset analysis of patients in the surgery arm (n = 154) No. of patients Median survival (months) 5-year survival (%) p value (Bi)-lobectomy Pneumonectomy ypn0/n ypn Abbreviation: yp, classification performed at surgery following induction chemotherapy. is significantly superior to definitive radiation therapy (34 months vs. 22 months; p =.002). Based on these two trials, following induction therapy, patients who are candidates for pneumonectomy are likely to benefit more from consolidation radiation therapy instead, as well as patients who do not achieve mediastinal lymph node downstaging. Selected patients with a good performance status and minimal or microscopic N2 disease after induction therapy could be offered surgical resection as long as planned surgery is limited to a lobectomy. Hence, accurate restaging at completion of induction chemotherapy is critical, including remediastinoscopy and/or positron emission tomography/computerized tomography scan. Regarding unresectable stage III NSCLC, according to the preliminary analysis of the prematurely closed SWOG 0023 trial, there is no survival benefit for maintenance gefitinib following definitive chemoradiation therapy (p =.09). The continuation of the study to the planned accrual would not show a survival benefit for gefitinib (p =.0015). The reasons for the higher number of deaths in the gefitinib arm are unclear, and molecular analyses for EGFR mutations and evaluations of K-ras mutations are currently ongoing. Interestingly, consolidation docetaxel following concurrent cisplatin plus etoposide with thoracic radiation therapy is very promising. However, the results of the ongoing randomized phase III trial of cisplatin etoposide thoracic radiation therapy followed by maintenance docetaxel versus observation (LUN01-24 trial) by the Hoosier Oncology Group should be awaited before this regimen can be considered a standard option for patients with unresectable stage III NSCLC. Early-Stage NSCLC S9900: A phase III trial of surgery alone or surgery plus preoperative (preop) paclitaxel/carboplatin (PC) chemotherapy in early stage nonsmall cell lung cancer (NSCLC): Preliminary results K. Pisters, E. Vallieres, P. Bunn, J. Crowley, R. Ginsberg, P. Ellis, B. Meyers, R. Marks, J. Treat, D. Gandara, Southwest Oncology Group On behalf of the SWOG and the other cooperative groups that contributed, Dr. Pisters presented the results of the SWOG 9900 trial [21]. The aim of that study was to evaluate whether neoadjuvant chemotherapy improves survival over surgery alone in clinical stage IB, II, and IIIA NSCLC patients. At the time the study was designed, a randomized phase III trial supported the use of neoadjuvant chemotherapy [22], while results of adjuvant chemotherapy trials were disappointing or inconclusive. The trial was designed to demonstrate a 33% higher median survival in the neoadjuvant chemotherapy arm over the expected median survival of 2.7 years in the surgery alone arm, and the accrual of 600 patients was planned. Because of the recent positive results of adjuvant chemotherapy trials in this setting, patient accrual was closed early in July From October 1999 to July 2004, 354 patients with clinical stage T2N0, T1-2N1, and T3N0-1 NSCLC (excluding superior sulcus tumors) were randomized to receive either three cycles of chemotherapy with paclitaxel (225 mg/m 2 ) and carboplatin (AUC, 6) on day 1 every 3 weeks followed by surgery or surgery alone. Seventy percent of the patients were stage IB/IIA and were equally distributed between the two arms. Overall, 77% of the patients in the neoadjuvant arm completed the three cycles planned: a 3% complete response rate and a 38% partial response rate were observed in the induction chemotherapy arm, for an overall response rate of 41%. Eighty-four percent of patients in both arms underwent complete resection. Although data favored the neoadjuvant arm, no statistically significant differences were observed in terms of median progression-free survival and overall survival (Table 7). ANITA: Phase III adjuvant vinorelbine (N) and cisplatin (P) versus observation (OBS) in completely resected (stage I-III) nonsmall-cell lung cancer (NSCLC) patients (pts): Final results after 70-month median follow-up. On behalf of the Adjuvant Navelbine International Trialist Association J. Douillard, R. Rosell, M. Delena, A. Legroumellec, A. Torres, F. Carpagnano

8 46 Lung Cancer Highlights Table 7. Summary of the Southwest Oncology Group 9900 trial Preoperative CT Surgery p value No. of patients Response rate (%) 41 N/A PFS (months) Median survival (months) year survival (%) year survival (%) Abbreviations: CT, chemotherapy; PFS, progression-free survival; N/A, not applicable. Table 8. Summary of the Adjuvant Navelbine International Trialist Association trial OBS NVB+CDDP p value No. of patients RFS (months) MS (months) year survival (%) year survival (%) year survival (%) year survival (%) Abbreviations: CDDP, cisplatin; MS, median survival; NVB, vinorelbine; OBS, observation; RFS, relapse-free survival. Dr. Douillard presented the final results of the prospective randomized phase III trial of adjuvant chemotherapy versus observation following radical surgery in early stage NSCLC, also known as the Adjuvant Navelbine International Trialist Association (ANITA) trial [23]. Adjuvant chemotherapy consisted of cisplatin (100 mg/m 2 ) on day 1 and vinorelbine (30 mg/m 2 ) on days 1, 8, 15, and 22 every 4 weeks for four cycles. Postoperative radiation therapy was left up to the investigator. The primary end point was overall survival. Assuming a 5% alpha error, 10% beta error, and 90% power to demonstrate a 10% improvement in survival at 2 years, between December 1994 and December 2000, 840 patients with completely resected stage IB (T2N0), II, or IIIA NSCLC were accrued. Stage IIIA patients were 35% of the total and were well balanced between the two arms. At the time of final analysis, the median follow-up was >70 months. Adjuvant chemotherapy provided a significant benefit over observation in terms of relapse-free survival and overall survival (Table 8). Median survival times were 65.8 months in the adjuvant chemotherapy arm and 43.8 months in the observation arm (p =.013; HR, 0.79 [95% CI, ]). One percent of the patients in the treatment arm died of drug-related toxicity. The most frequently observed grade 3 4 toxicity in the chemotherapy arm was neutropenia (84.6%), with febrile neutropenia in 12.5% of the patients. In a subanalysis, no significant advantage was observed in stage IB (pt2n0) patients, while there was a significant advantage for the N1 and N2 patients. Commentary In recent years, several trials were conducted to address the role of adjuvant and neoadjuvant chemotherapy in early stage NSCLC. Trials of neoadjuvant chemotherapy have always experienced slow accrual. In a small randomized pilot feasi- The Oncologist bility trial of neoadjuvant chemotherapy in this setting, only 55% of the eligible patients agreed to participate [24]. In addition, the accrual of patients in trials comparing neoadjuvant chemotherapy followed by surgery with surgery alone has become even slower, as a result of the recent disclosure of positive results in favor of adjuvant chemotherapy. In the S9900 trial that closed early, progression-free survival and overall survival trends favored neoadjuvant chemotherapy, although the difference was not statistically significant. The survival in the surgery alone arm was better than anticipated, maybe reflecting the improvement in staging over the past few years. The S9900 trial results are consistent with data reported from a similar trial by Depierre et al. [22] (Table 9). To clarify the role of neoadjuvant chemotherapy in early stage NSCLC, other randomized trials are currently ongoing and a metaanalysis is also planned. Regarding adjuvant chemotherapy, the ANITA trial showed a survival benefit for postoperative chemotherapy with vinorelbine and cisplatin in completely resected NSCLC patients. However, the combination of cisplatin and weekly vinorelbine does not seem feasible: the median relative dose intensity of vinorelbine was 58.6%, and 85% of the patients experienced grade 3 4 neutropenia. Interestingly, an updated subanalysis presented by Dr. Rosell at the World Conference on Lung Cancer in Barcelona, Spain, in July 2005, suggests a benefit from postoperative radiation therapy in N2 patients [25]. This observation deserves further prospective trials to address whether postoperative radiation therapy improves the outcome in stage IIIA-N2 patients. This positive study is consistent with adjuvant trials reported since the ASCO 2003 meeting, that is, the International Adjuvant Lung Cancer (IALT) trial, the Japan Lung Cancer Research Group (JLCRG) trial, the Cancer and Leukemia Group B (CALGB) 9633 trial, and the Intergroup JBR.10 trial (Table 10). In addi-

9 Belvedere, Grossi 47 tion, two recently published meta-analyses also support adjuvant chemotherapy, with an 11% relative reduction in mortality associated with cisplatin, and a 17% relative reduction associated with uracil-tegafur [27]. The 11% relative reduction in mortality with cisplatin-based adjuvant chemotherapy translates into an approximately 4% absolute improvement in survival. Thus, it would be necessary to treat approximately 25 patients to prevent one additional death at 5 years. To optimize the administration of adjuvant chemotherapy and the use of molecularly targeted agents in this setting, biological markers and molecular prognostic indicators should be identified to select patients more likely to benefit from adjuvant therapy. In this regard, Petersen et al. reported a predictive model based on an oncogenic signaling pathway gene-expression profile that accurately distinguishes patients with good prognosis from those with poor prognosis [28]. In conclusion, it is clear that chemotherapy added to radical surgery improves the outcome in operable NSCLC. While there is growing evidence to support adjuvant chemotherapy following radical surgery compared with surgery alone, it is still unclear whether neoadjuvant chemotherapy is equally effective: randomized trials comparing preoperative with postoperative chemotherapy in resectable NSCLC are warranted. As of now, neoadjuvant chemotherapy should be considered investigational in this setting and adjuvant chemotherapy with a two-drug, platinum-based regimen should be considered as a standard of care after radical resection of stage II and IIIA NSCLC in patients with good performance status. NSCLC in the Elderly Randomized phase III study of docetaxel (D) versus vinorelbine (V) for elderly patients (pts) with advanced Table 9. Comparison of Southwest Oncology Group 9900 trial and the Depierre et al. neoadjuvant trial S9900 trial Depierre et al. [22] trial Preoperative CT Control Preoperative CT Control PFS/DFS (months) a 13 Median survival (months) b 26 1-year survival (%) year survival (%) a p =.033. b stage I II: risk for death, 0.68 (95% confidence interval, ; p =.027). Abbreviations: CT, chemotherapy; PFS/DFS, progression-free survival/disease-free survival. Table 10. Adjuvant trials in non-small cell lung cancer [26] Trial Chemotherapy regimen n of patients OS advantage for CT arm ECOG PE for 4 cycles (RT) 488 No ALPI-EORTC MVP for 3 cycles 1,197 No BLT Pva for 3 cycles 381 No JCOG 9304 PV for 3 cycles 119 No IALT PE or PVa for 3 4 cycles 1,867 4% at 5 yrs NCIC-JBR.10 PN for 4 cycles % at 5 yrs CALGB 9633 CT for 3 cycles % at 4 yrs UFT meta-analysis UFT for 1 2 yrs 2, % at 5 yrs 7% at 7 yrs ANITA 01 PN for 4 cycles % at 2 yrs 8.6% at 5 yrs Abbreviations: ALPI-EORTC, Adjuant Lung Project Italy-European Organization for Research and Treatment of Cancer; ANITA, Adjuvant Navelbine International Trialist Association; BLT, Big Lung Trial; CALGB, Cancer and Leukemia Group B; CT, carboplatin plus paclitaxel; ECOG, Eastern Cooperative Oncology Group; IALT, International Adjuvant Lung Cancer; JCOG, Japanese Clinical Oncology Group; MVP, mitomycin, vindesine, and cisplatin; N, vinorelbine; NCIC-JBR.10, National Cancer Institute of Canada Clinical Trials Group-JBR.1O; OS, overall survival; PE, cisplatin plus etoposide; PN, cisplatin plus vinorelbine; PV, cisplatin plus vindesine; Pva, cisplatin plus a vinca alkaloid; RT, radiation therapy; UFT, uracil-tegafur.

10 48 Lung Cancer Highlights nonsmall cell lung cancer (NSCLC): Results of a West Japan Thoracic Oncology Group trial (WJTOG9904) K. Takeda, S. Kudoh, K. Nakagawa, M. Takada, N. Katakami, K. Matsui, M. Andoh, T. Satoh, S. Negoro, M. Fukuoka On behalf of the West Japan Thoracic Oncology Group (WJTOG), Dr. Takeda presented the results of the WJTOG trial 9904 [29]. That randomized phase III trial was conducted to evaluate whether docetaxel provides better overall survival than vinorelbine in elderly patients (age 70 years) with previously untreated advanced NSCLC and ECOG performance status (PS) scores of 0 2. The primary end point was overall survival; secondary end points were adverse events, progression-free survival, response, and quality of life. The study was designed to have an 80% power to detect an improvement in median survival from 6.4 months, observed in the Elderly Lung Cancer Vinorelbine Italian Study (ELVIS) trial [30], in the vinorelbine arm, to 10.3 months in the docetaxel arm. From May 2000 to September 2003, 182 patients were randomized to receive either docetaxel (60 mg/m 2 ) on day 1 every 3 weeks or vinorelbine (25 mg/m 2 ) on days 1 and 8 every 3 weeks. Patient characteristics and study results are summarized in Table 11. Despite a significant difference in terms of response rate and progression-free survival in favor of docetaxel, there was no significant difference between the two arms in terms of overall survival. The quality of life analysis favored docetaxel. Chemotherapy in patients 80 with advanced nonsmall cell lung cancer: combined results from SWOG 0027 and LUN 6. P.J. Hesketh, R. Lilenbaum, K. Chansky, A. Dowlati, P. Graham, J. Crowley, D.R. Gandara A poster presented by Dr. Hesketh [31] reported treatment outcome in the combined cohort of patients 80 years from the previously reported SWOG 0027 trial [32] and the investigator-initiated multicenter trial LUN 6 [33]. The SWOG 0027 and the LUN 6 were both phase II trials evaluating chemotherapy in previously untreated patients, stratified into two cohorts: age 70 years and/or impaired performance status (ECOG PS score, 2). Overall, 49 octogenarian patients were considered from these two trials; treatment outcome in the 80 cohort was compared with the outcome of patients <80 in the SWOG 0027 trial. In the SWOG 0027 trial, patients received three courses of vinorelbine immediately followed by three courses of docetaxel. In the LUN 6 trial, patients were randomized to receive docetaxel either every 3 weeks or weekly. These chemotherapy regimens were well tolerated and resulted in a disease control rate of 54% in the 80 cohort. In patients with ECOG PS scores of 0 1, there was a longer median survival time in the <80 group compared with the 80 group (11 months vs. 7 months, respectively; p =.20), while in patients with ECOG PS scores of 2, median survival was comparable (5 months vs. 4 months, respectively; p =.52). Commentary Despite the high incidence of advanced NSCLC in the elderly, the likelihood of receiving chemotherapy decreases with increasing age. Factors influencing the decision to treat or not to treat elderly patients include reduced organ function, presence of comorbidities, and impaired performance status [34]. The randomized ELVIS study demonstrated that single-agent vinorelbine is superior to best supportive care in previously untreated elderly patients (>70 years of age) in terms of survival and quality of life [30]. Other single agents, that is, gemcitabine, paclitaxel, and docetaxel, have demonstrated promising activity and acceptable toxicity in this setting. Although the WJTOG randomized phase III trial failed to demonstrate its ambitious hypothesis of docetaxel improving the median survival time from 6.4 months reported for vinorelbine to 10.3 months, singleagent docetaxel is a good option in elderly patients. The analysis of the combined cohorts of patients aged 80 years from the SWOG 0027 and the LUN 6 trials provides further support to the use of chemotherapy in elderly patients with advanced NSCLC. Table 11. Summary of the West Japan Thoracic Oncology Group trial DOC VNB p value No. of patients Age (years) Median Range Completed four cycles (%) Overall response rate (%) Median survival (months) < year survival (%) Median PFS (months) <.001 Grade 3 4 neutropenia (%) Abbreviations: DOC, docetaxel; PFS: progression-free survival; VNB, vinorelbine. The Oncologist

11 Belvedere, Grossi 49 There is a need for clinical trials specifically designed for elderly patients. Important issues need to be addressed in this setting, such as the use of platinum-based and nonplatinumbased combination chemotherapy and the role of targeted therapies, in particular erlotinib (Tarceva ; OSI Pharmaceuticals, Inc., Melville, NY, and gefitinib. Disclosure of Potential Conflicts of Interest The authors indicate no potential conflicts of interest. References 1 Sandler AB, Gray R, Brahmer J et al. Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC #704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) Trial - E4599. Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, Herbst RS, Sandler AB. Non-small cell lung cancer and antiangiogenic therapy: what can be expected of bevacizumab? 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