The Oncologist ASCO 2000: Critical Commentaries Lung Cancer Highlights THOMAS J. LYNCH, JR. Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA Key Words. Small cell lung cancer Non-small cell lung cancer Treatment Metastatic disease ABSTRACT Have we made any progress in the treatment of advanced non-small cell lung cancer (NSCLC) over the past 15 years? After hearing the Eastern Cooperative Oncology Group (ECOG) 1594 presented by Dr. Joan Schiller at the plenary session of the 36th Annual Meeting of ASCO, it is hard to be certain. Schiller reported the results of one of the world s largest randomized trials in metastatic lung cancer comparing four platinum-based doublets. There were no differences in survival (primary endpoint) or response between these four regimens, although the cisplatin/gemcitabine arm had a superior time to progression. In her commentary METASTATIC NON-SMALL CELL LUNG CANCER A Randomized Phase III Trial of Four Chemotherapy Regimens in Advanced Non-Small Cell Lung Cancer (NSCLC). JH Schiller, D Harrington, A Sandler, C Belani, C Langer, J Krook, DH Johnson (ABSTRACT 2). Study Design and Results Eastern Cooperative Oncology Group (ECOG 1594) was a randomized trial of four chemotherapy regimens for patients with advanced NSCLC [1]. Eligible patients had either stage IV NSCLC or wet stage 3B (malignant pleural effusion). Patients were stratified by performance status, weight loss, stage and presence of brain metastases. The primary endpoint of this trial was survival, with response rate, time to progression and toxicity assessment on this study, Dr. Francis Shepherd concluded that progress in the treatment of metastatic lung cancer has occurred at a snail s pace. Despite the disappointing results of ECOG 1594, there were notable trials describing new agents with novel mechanisms of action reported at this year s ASCO meeting. In small-cell lung cancer, the combination of cisplatin/ irinotecan was found to be superior to cisplatin/etoposide. For NSCLC, novel agents Iressa anti-epidermal growth factor receptor tyrosine kinase and anti-vascular endothelial growth factor monoclonal antibody appear promising. The Oncologist 2000;5:274-279 being secondary endpoints. There were no formal cost comparisons or quality-of-life evaluations. From October 1996 until May 1999, 1,207 patients were randomized into one of the four following arms shown in Table 1. The characteristics of the 1,207 patients are shown in Table 2. Initially patients were eligible with performance status (PS) 0, 1, or 2. However, the poor outcome in the PS- 2 patients resulted in restricting the eligibility to those with PS-0, 1. The groups were well balanced for known prognostic factors. The number of patients who were ineligible was similar across all four arms. The efficacy results of this study are shown in Table 3. All tests for significance were comparisons between a study arm and the cisplatin/24-h paclitaxel control arm. There were no significant differences in terms of response, median survival or one-year survival. Cisplatin/gemcitabine (Arm B) Downloaded from http://theoncologist.alphamedpress.org/ by guest on October 14, 2018 Correspondence: Thomas J. Lynch, Jr., M.D., Massachusetts General Hospital Cancer Center, Hematology-Oncology Department, Room 201 Cox Building, 100 Blossom Street, Boston, Massachusetts 02114-2617, USA. Telephone: 617-724-1136; Fax: 617-724- 3166; e-mail: lynch.thomas@mbh.harvard.edu Received June 29, 2000; accepted for publication June 29, 2000. AlphaMed Press 1083-7159/2000/$5.00/0 The Oncologist 2000;5:274-279 www.theoncologist.com
Lynch 275 Table 1. Design of ECOG 1594 Arm A Cisplatin 75 mg/m 2 day 2 Paclitaxel 135 mg/m 2 /24 h day 1 q 3 weeks Arm B Cisplatin 100 mg/m 2 day 1 Gemcitabine 1,000 mg/m 2 day 1, 8, 15 q 4 weeks Arm C Cisplatin 75 mg/m 2 day 1 Docetaxel 75 mg/m 2 day 1 q 3 weeks Arm D Carboplatin area under the concentration time curve 6 day 1 Paclitaxel 225 mg/m 2 /3 h day 1 q 3 weeks Table 2. Patient characteristics for ECOG 1594 A B C D Cis/Pac24 Cis/Gem Cis/Doc Carb/Pac3 n of patients 292% 288% 293% 290% Age 62% 64% 63% 62% Sex (% male) 64% 61% 62% 62% PS = 0, 1 94% 95% 94% 95% Brain mets 12% 14% 13% 12% Weight loss 34% 33% 32% 34% Table 3. Results of ECOG 1594 A B C D Cis/Pac24 Cis/Gem Cis/Doc Carb/Pac3 n of patients 292 288 293 290 Response rate (%) 21.3% 21.0% 17.3% 15.3% Time to progression (mo.) 3.5 4.5** 3.6 3.3 Median survival (mo.) 7.8 8.8 7.4 8.2 One-year survival (%) 31.0% 36.0% 31.0% 35.0% Table 4. Selected toxicities from ECOG 1594 A B C D Cis/Pac24 Cis/Gem Cis/Doc Carb/Pac3 n of patients 292 288 293 290 Grade 3/4 F/N 2/14 1/3** 1/9 0/4** Grade 3/4/5 renal 3/0/0 5/3/1** 3/0/0 1/0/0 Grade 3 nausea 25 37 24 8** Grade 3/4 vomiting 3/21 7/29 3/18 2/7** Grade 3/4 hypersensitivity 1/1 0/0 5/2** 1/1 Grade 3 neuropathy 5 9 5 10 F/N=Fever/Neutropenia was superior in terms of time to progression compared to the control arm of cisplatin/paclitaxel 24-h. As expected there were significant differences in toxicity between the treatment arms. Overall there were significantly fewer grade 4 toxicities in the carboplatin/paclitaxel arm than in the cisplatin/paclitaxel arm. Significantly more patients stopped therapy because of progressive disease in the carboplatin/paclitaxel arm compared with cisplatin/ paclitaxel, and significantly more patients stopped for toxicity in the cisplatin/gemcitabine arm compared to cisplatin/ paclitaxel. Selected grade 3, 4, and 5 adverse events are shown in Table 4. Commentary ECOG 1594 was chosen as a plenary session presentation because it is an important trial that reflects the state of care in 2000 of metastatic NSCLC the leading cause of cancer-related death in North America. The results of this ECOG study are compared to the Southwest Oncology Group (SWOG) 9508 [2] reported at ASCO in 1999 in Table 5. The carboplatin/paclitaxel arms are identical in design between the two studies. These are important studies to compare because they were conducted at nearly the same time and in very similar (though not identical) patient populations. The median and one-year survival is similar for both carboplatin/paclitaxel arms. However, the response rate seen in the carboplatin/paclitaxel arm of ECOG 1594 is lower than that reported in the SWOG study from last year. This trend of the response rates being lower in ECOG 1594 is followed for both the gemcitabine and 24-h paclitaxel arms. The response rates for cisplatin/gemcitabine (21%) are lower than the (30%) response rate observed in Dr. Sandler s large North American trial reported in the Journal of Clinical Oncology this year [3] and shown in Table 6. Finally, as seen in Table 7, the cisplatin/paclitaxel response rate is lower than that reported in the prior ECOG study by Bonomi et al. (30%) [4]. There are several possible reasons for the lower response rates seen in all four Table 5. Comparison between ECOG 1594 and SWOG 9508 ECOG 1594 SWOG 9508 Carb/Pac3 Carb/Pac3 n of patients 290 208 Response rate 15.3% 25% Median survival (mo.) 8.2 8 One-year survival 35% 38% Grade 4 ANC 43% 36% Grade 3 nausea 8% 7%
276 Lung Cancer Highlights Table 6. Comparison between ECOG 1594 and Sandler study ECOG 1594 Sandler Cis/Gem Cis/Gem n of patients 288 260 Response rate 21% 30.4% Median survival (mo.) 8.8 9.1 One-year survival 36% 39% Grade 4 ANC 39% 35% Grade 3 nausea 37% 36% Table 7. Comparison between ECOG 1594 and ECOG 5592 ECOG 5592 ECOG 1594 Cis/Pac24 Cis/Pac24 n of patients 198 292 Response rate 25.3% 21.3% Median survival (mo.) 9.5 7.8 One-year survival 37.4% 31% Grade 4 ANC 74% 57% Grade 3 nausea 10% 25% arms of this study. First, the current study allowed patients with brain metastases to participate. Second, the stage IIIB patients on the ECOG study were those with malignant effusions rather than N3 adenopathy. Also, with the growing acceptance and momentum favoring treatment of patients with metastatic NSCLC, investigators are placing patients on trial that are more reflective of the general population of lung cancer patients. How important is response rate? Survival in the ECOG, SWOG, and Sandler trials is remarkably similar. While response rate is a useful surrogate marker, survival is ultimately the best indicator of the success or failure of a treatment. The median and one-year survivals have clearly improved over the past 20 years. While some of this is likely due to better drugs, much of the gain is from stage migration. As we aggressively scan patients for stage III treatment protocols, we are discovering a better class of stage IV patient to enter into stage IV trials and thus improve overall survival of this group. Overall survival will continue to be the most reliable measure of treatment efficacy in NSCLC trials. The current ECOG trial is the first to be done since the acceptance and growing use of second-line chemotherapy for NSCLC. The study by Shepherd et al. [5] clearly demonstrates that docetaxel is able to significantly prolong survival in previously treated patients. This raises the question of whether time to progression will ultimately become the most important measure in NSCLC trials rather than survival. One explanation for the failure to see a difference in overall survival between the four arms of the current ECOG trial is that second-line therapy obscured any benefits seen. Unfortunately data on second-line therapy were not gathered for this study. Clearly we have reached our limit in developing doublet platinum-based combinations for advanced NSCLC. It is highly unlikely that further trials of platinum doublets are going to produce results much different from those reported by ECOG. Triplet combinations will be pursued, as they should, but they too are unlikely to produce clinically meaningful advances for patients with lung cancer. The future of chemotherapy for NSCLC may rest with sequential use of single agents. The Cancer and Leukemia Group B (CALGB) is testing single-agent paclitaxel versus carboplatin/paclitaxel, and this study will be an important step in answering this question. The finding that second-line therapy of metastatic lung cancer benefits patients with NSCLC adds to the case for sequential single-agent therapy. Ultimately new drugs against new targets are the future of lung cancer therapy. Cooperative groups in the United States will now move forward and test novel agents and combinations of novel agents and established chemotherapy in future trials. A Randomized Phase II Trial Comparing Recombinant Humanized Monoclonal Antibody to Vascular Endothelial Cell Growth Factor (rhumab VEGF) Plus Carboplatin/Paclitaxel (CP) to CP Alone in Patients with Stage IIIB/IV NSCLC. RF DeVore, L Fehrenbacher, RS Herbst, CJ Langer, K Kelly, J Gaudreault, E Holmgren, WF Novotny, F Kabbinavar (ABSTRACT 1896). Study Design and Results A consortium of centers led by Dr. Russell DeVore conducted a randomized phase II trial of carboplatin/paclitaxel with recombinant humanized monoclonal anti-vegf antibody [6]. All patients had stage IIIB (pleural effusion), stage IV or recurrent disease. Patients were eligible only if they had received no prior chemotherapy. The primary endpoints were time to progression, response rate and safety. Overall survival was a secondary endpoint. Ninety-nine patients were randomized to either carboplatin (AUC6)/paclitaxel 200 mg/m 2 (Arm 1), same chemo + 7.5 mg/kg anti-vegf (Arm 2) or same chemo + 15 mg/kg anti-vegf (arm 3). Time to progression was chosen as an endpoint because this was a randomized phase II study and patients on the chemoalone arm were allowed to cross over to anti-vegf upon progression. Patient characteristics were reflective of the standard population of patients in advanced lung cancer trials. There was an imbalance by sex with more men being in the CP-alone arm.
Lynch 277 When responses were analyzed, the response rate to CP with 15 mg/kg of anti-vegf was 40%. Furthermore, when patients with large masses that had become cavitated (but did not change their overall size) were factored in, the response rate was 51% in this arm. There was also a trend (not statistically significant) favoring time to progression in the chemotherapy + 15 mg/kg arm. Toxicity was a major concern in this trial. Six patients treated with chemotherapy plus antibody had life-threatening hemoptysis and four died. The deaths were all in patients with squamous cell cancer. The remainder of toxicity was well balanced between all three groups, with the exception of more diarrhea in the antibody arms. Commentary This study is one of the first to randomly compare a novel agent with chemotherapy versus chemotherapy alone. VEGF is an intriguing target for lung cancer since it is overexpressed in pulmonary neoplasms and has been associated with a poor prognosis. The trial by DeVore et al. demonstrated that the anti-vegf antibody has both potentially exciting activity and potentially devastating toxicity. The median survival of the chemo + 15 mg/kg anti-vegf arm of 17 months is among the highest ever reported for advanced lung cancer. This undoubtedly is due in a large part to patient selection. However, the impressive response rate and the unusual cavitation seen in these lesions is supportive of this drug having activity. The major question is whether toxicity will prohibit further development of this agent. Are there ways to predict who will develop toxicity? Would prophylactic irradiation to the mediastinum prevent fatal hemoptysis? The next step in the development of this agent will be a randomized ECOG phase III study comparing CP alone to CP with 15 mg/kg of anti-vegf. The principle endpoint of the ECOG study will be overall survival, and there will be no cross over between the two arms of the study. In one respect the occurrence of hemoptysis actually supports the activity of this agent from a mechanistic standpoint. SMALL CELL LUNG CANCER Randomized Phase III Study of Irinotecan (CPT-11) and Cisplatin Versus Etoposide and Cisplatin in Extensive- Disease Small-Cell Lung Cancer: Japan Clinical Oncology Group Study (JCOG9511). K Noda, Y Nishiwaki, M Kawahara, S Negoro, T Sugiura, A Yokoyama, M Fukuoka, K Mori, K Watanabe, T Tamura, N Saijo, K Yoshimura (ABSTRACT 1887). Study Design and Results The study by Noda et al. [7] was a randomized phase III trial comparing irinotecan and cisplatin with etoposide and cisplatin. Etoposide and cisplatin were chosen as the reference arm in this trial. Eligible patients included patients with extensive stage small-cell lung cancer (SCLC) with a good PS. Overall survival was the primary endpoint of this study. One hundred fifty-four patients were randomized between two arms. The control arm was cisplatin 80 mg/m 2 /day 1 with VP-16 (etoposide) 100 mg/m 2 /day 1, 2, 3 given every three weeks for four courses. The study arm was cisplatin 60 mg/m 2 /day 1 with CPT-11 (irinotecan) 60 mg/m 2 /day 1, 8, 15 every four weeks for four cycles. The use of G-CSF was allowed for recovery of counts. The original sample size was significantly larger, but the trial was stopped early when the interim analysis showed a significant benefit to the experimental arm in terms of improved overall survival. Patient characteristics and outcome data are shown in Table 8. Nonhematologic toxicities were generally similar between the two groups with the exception of more diarrhea in the irinotecan arm. There were three deaths on study on the irinotecan arm and one death on the etoposide arm. This rate of toxicity is similar to that seen in other trials in extensive SCLC. Study Design and Results 1886 Topotecan (T) versus Observation (OB) Following Cisplatin (P) Plus Etoposide (E) in Extensive Stage Small Cell Lung Cancer (ES SCLC) (E7593): A Phase III Trial of the Eastern Cooperative Oncology Group (ECOG). DH Johnson, S Adak, DF Cella, RF DeVore, A Marcus, JH Schiller (ABSTRACT 1886). ECOG presented a randomized trial of four cycles of topotecan following standard doses of cisplatin/etoposide in extensive stage SCLC [8]. Eligible patients had measurable disease with a good PS. Patients were allowed to have clinically stable central nervous system metastases. All Table 8. Results of randomized trial of cisplatin/etoposide versus cisplatin/irinotecan in extensive SCLC CPT-11/Cisplatin VP-16/Cisplatin n of patients 77 77 Median age 63 63 PS 0, 1 (%) 92% 87% Weight loss <5% 71% 73% Grade 4 neutropenia 25.7% 64.9% Grade 4 thrombocytopenia 4% 0% Overall response rate 83.1% 67.5% Median survival 12.8** 9.4 One-year survival 58.4%** 37.7% Two-year survival 18.9%** 6.5%
278 Lung Cancer Highlights Table 9. Results of ECOG 7593 Observation Topotecan n of patients 112 115 Disease-free survival 2.3 months 3.6 months** Median survival 8.9 months 9.3 months** One-year survival 27% 25% patients received four cycles of cisplatin 60 mg/m 2 /day 1 and etoposide 120 mg/m 2 /day 1, 2, 3. Patients who progressed were taken off the study. All others were randomized to either observation or topotecan 1.5 mg/m 2 /day 5 days, q three weeks for four cycles. ECOG registered 405 patients into the initial therapy with etoposide and cisplatin. Two hundred twenty-seven patients were randomized to either observation or topotecan. Patient characteristics and study results are shown in Table 9. The median survival of all 405 patients was 9.6 months with 35% of patients living one year. The complete and partial response rate was 33% to the induction therapy. The observation arm was not associated with any grade 4 hematologic toxicity, while the topotecan arm had 60% grade 4 neutropenia and 13% grade 4 thrombocytopenia. Nonhematologic toxicity was unusual. Commentary on Abstracts 1886 and 1887 For patients with extensive stage SCLC, there has been little progress over the past 20 years since the establishment of etoposide and cisplatin as the standard of care. At this year s ASCO meeting, two studies tried to improve upon the results found with etoposide and cisplatin. In the ECOG study, four cycles of topotecan added toxicity but did not REFERENCES 1 Schiller J, Harrington D, Sandler A et al. A Randomized Phase III Trial of Four Chemotherapy Regimens in Advanced Non-Small Cell Lung Cancer (NSCLC). [Abstract 2] 36th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, 2000. 2 Kelly K, Crowley J, Bunn P et al. A Randomized Phase III Trial of Paclitaxel Plus Carboplatin Versus Vinorelbine Plus Cisplatin in Untreated Advanced NSCLC: A Southwest Oncology Group Trial. [Abstract 1777] 35th Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, 1999. 3 Sandler A, Nemunaitis J, Denham C et al. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2000;18:122-130. 4 Bonomi P, Kim K, Fairclough D et al. Comparison of survival and quality of life in advanced non-small-cell lung enhance overall survival. Disease-free survival was prolonged by 1.3 months (five weeks). It is not likely that a five-week prolongation of disease-free survival is significant enough to change the standard of practice, particularly when there was no change in overall survival and toxicity was present. Topotecan is one of most active new agents for SCLC. It is particularly disappointing that it has been so hard to bring this agent to front-line therapy. In the poster session on Tuesday, the CALGB reported [9] a trial in extensive SCLC that combined topotecan with paclitaxel and achieved a 9.4- month median survival, similar to the ECOG data with cisplatin/etoposide. Dr. James Jett from the Mayo Clinic [10] presented data with etoposide/cisplatin alternating with topotecan/paclitaxel and found a median survival of 10.5 months. In none of these trials has topotecan produced an overall survival rate superior to that seen with etoposide/cisplatin alone. An alternative may be found in the use of irinotecan. Like topotecan, irinotecan is a topoisomerase I inhibitor with good activity in patients with lung cancer. The JCOG data show a prolongation of survival using irinotecan compared to etoposide when combined with cisplatin. The Japanese study showed an impressive survival advantage to the newer combination. If this is confirmed, this may become the new standard of care for SCLC. The toxicity associated with this regimen was acceptable. In both of these trials, the number of cycles of etoposide/cisplatin used in the control arm was four. For many this will represent a departure from the previous standard of six cycles. The data with four cycles in these two most recently completed studies are remarkably similar to data using six cycles of therapy, leading Dr. David Johnson from ECOG to conclude that four cycles should be the standard duration of therapy for extensive stage SCLC. This is a very reasonable recommendation. cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 2000;18:623-631. 5 Shepherd F, Dancey J, Ramlau R et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18:2095-2103. 6 DeVore R, Fehrenbacher L, Herbst R et al. A Randomized Phase II Trial Comparing Rhumab VEGF (Recombinant Humanized Monoclonal Antibody to Vascular Endothelial Cell Growth Factor) Plus Carboplatin/Paclitaxel (CP) to CP Alone in Patients with Stage IIIB/IV NSCLC. [Abstract 1896] 36th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, 2000.
Lynch 279 7 Noda K, Nishiwaki Y, Kawahara M et al. Randomized Phase III Study of Irinotecan (CPT-11) and Cisplatin Versus Etoposide and Cisplatin in Extensive-Disease Small-Cell Lung Cancer: Japan Clinical Oncology Group Study (JCOG9511). [Abstract 1887] 36th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, 2000. 8 Johnson D, Adak S, Cella D et al. Topotecan (T) vs. Observation (OB) Following Cisplatin (P) Plus Etoposide (E) in Extensive Stage Small Cell Lung Cancer (ES SCLC) (E7593): a Phase III Trial of the Eastern Cooperative Oncology Group (ECOG). [Abstract 1886] 36th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, 2000. 9 Lynch T, Herndon J, Lyss A et al. Paclitaxel (P) + Topotecan (T) + GCSF for Previously Untreated Extensive Small Cell Lung Cancer (E-SCLC): Preliminary Analysis of Cancer and Leukemia Group B (CALGB) 9430. [Abstract 1922] 36th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, 2000. 10 Jett J, Hatfield A, Bauman M et al. Phase II Trial of Topotecan and Paclitaxel (TP) with G-CSF Support Alternating with Etoposide and Cisplatin (EC) in Previously Untreated Extensive Stage Small Cell Lung Cancer (ED-SCLC). [Abstract 1921] 36th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, 2000.
Errata BURNOUT: CARING FOR THE CAREGIVERS Richard T. Penson, Fiona L. Dignan, George P. Canellos, Carol L. Picard, Thomas J. Lynch, Jr. The Oncologist 2000;5:425-434 In the Acknowledgment section on page 434, Lisa Kreuderberger should read Lisa Freuderberger. LUNG CANCER HIGHLIGHTS Thomas J. Lynch, Jr. The Oncologist 2000;5:274-279 In Tables 3 and 6, the median survival time in the Gem/Cis arm of the study should be 8.1 months rather than 8.8 months.