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© 2002 American Society for Clinical Oncology Randomized Phase II Study of Cisplatin With Gemcitabine or Paclitaxel or Vinorelbine as Induction Chemotherapy Followed by Concomitant Chemoradiotherapy for Stage IIIB Non–Small-Cell Lung Cancer: Cancer and Leukemia Group B Study 9431ByFrom the University of Chicago Medical Center and Cancer and Leukemia Group B, Chicago, IL; Dartmouth-Hitchcock Medical Center, Lebanon, NH; Duke Medical Center, Durham, NC; University of Missouri, Columbia, MO; University of Tennessee, Memphis, TN; and Medical University of South Carolina, Charleston, SC. Address reprint requests to Everett E. Vokes, MD, University of Chicago, 5841 S Maryland Ave, MC 2115, Chicago, IL 60637-1470; email: evokes{at}medicine.bsd.uchicago.edu
PURPOSE: To evaluate new drugs in combination with cisplatin in unresectable stage III non–small-cell lung cancer, Cancer and Leukemia Group B (CALGB) conducted a randomized phase II study of two cycles of induction chemotherapy followed by two additional cycles of the same drugs with concomitant radiotherapy. PATIENTS AND METHODS: Eligible patients received four cycles of cisplatin at 80 mg/m2 on days 1, 22, 43, and 64 with arm 1: gemcitabine 1,250 mg/m2 on days 1, 8, 22, and 29 and 600 mg/m2 on days 43, 50, 64, and 71; arm 2: paclitaxel 225 mg/m2 for 3 hours on days 1 and 22 and 135 mg/m2 on days 43 and 64; and arm 3: vinorelbine 25 mg/m2 on days 1, 8, 15, 22, and 29 and 15 mg/m2 on days 43, 50, 64, and 71. Radiotherapy was initiated on day 43 at 2 Gy/d (total dose, 66 Gy). RESULTS: One hundred seventy-five eligible patients were analyzed. Toxicities during induction chemotherapy consisted primarily of grade 3 or 4 granulocytopenia. Grade 3 or 4 toxicities during concomitant chemoradiotherapy consisted of thrombocytopenia, granulo-cytopenia, and esophagitis. Response rates after completion of radiotherapy were 74%, 67%, and 73% for arms 1, 2, and 3, respectively. Median survival for all patients was 17 months. One-, 2-, and 3-year survival rates for the patients on the three arms were 68%/37%/28%, 62%/29%/19%, and 65%/40%/23%. CONCLUSION: Four cycles of gemcitabine, vinorelbine, or paclitaxel in combination with cisplatin can be administered at these doses and schedules. The observed survival rates exceed those of previous CALGB trials and may be attributable to the use of concomitant chemoradiotherapy. Induction chemotherapy added to concomitant chemoradiotherapy is being evaluated in a phase III randomized trial.
DURING THE LAST decade, several new agents with single-agent activity in advanced non–small-cell lung cancer (NSCLC) have been identified.1-4 When tested in the stage IV setting, usually in combination with cisplatin or carboplatin, these agents have been shown to increase the median survival time compared with single-agent cisplatin and chemotherapy regimens of the 1980s.1-12 In addition, their use has led to improved quality of life. For patients with locoregionally advanced unresectable disease (stage IIIB and some stage IIIa), the role of chemotherapy as a component of curative intent therapy has expanded in recent years.1,13 Both sequential and concomitant bimodality strategies have been investigated. The Cancer and Leukemia Group B (CALGB) and others have established that two cycles of induction chemotherapy with cisplatin and vinblastine followed by chest radiotherapy lead to an approximately 4-month increase in median survival time when compared with radiotherapy alone.14-17 The effects of induction chemotherapy seem to be due primarily to a reduction of systemic failure rates without affecting local control.17 Concomitant chemoradiotherapy has also been shown to lead to superior survival when compared with radiotherapy.13,18,19 The combination of cisplatin and etoposide administered with concurrent radiotherapy has lead to encouraging data in the phase II setting when tested by the Southwest Oncology Group (SWOG), although a direct comparison with radiotherapy alone was not pursued.20-22 The improved survival after concomitant chemoradiotherapy seems to be mediated primarily through increased local and regional control.18 Thus, through complimentary mechanisms, both sequential and concomitant combined-modality therapy strategies lead to improved survival. In direct comparison, concomitant therapy is statistically superior to induction chemotherapy, although it is also associated with more severe acute toxicity.23,24 Given the encouraging activity of paclitaxel, gemcitabine, and vinorelbine in the advanced stage setting, we postulated that their further investigation in the stage III setting might lead to further prolongation of survival times. In addition, all three agents have been demonstrated to act as radiation sensitizers in preclinical models.25-30 Therefore, their use with concurrent radiotherapy might lead to radiation sensitization and improved locoregional control. CALGB designed this randomized phase II trial in which patients were randomized to receive one of these three agents in combination with cisplatin for two cycles as induction chemotherapy followed by two additional cycles of these drugs with concurrent standard chest radiotherapy. Our goals were to test the activity of the new agents when administered in combination with cisplatin as induction and concomitant chemoradiotherapy and to establish response rates to each of the two components of therapy, differential toxicities, patterns of failure, and survival times. These end points were evaluated for each of the three study arms with the goal of establishing one or several feasible treatment arms for possible future comparison in a randomized phase III setting against a standard approach. In choosing the specific chemotherapy schedules and doses for induction chemotherapy (Fig 1), we used regimens that had already been administered in the stage IV setting.1-4,6-10 For concomitant chemoradiotherapy, phase I data were available for the combinations including paclitaxel and vinorelbine.30,31 No phase I data were available for the gemcitabine-based arm. It was known that administration of the drug at full systemic doses with radiotherapy had led to severe toxicities.32 Therefore, we opted to test a dose of 600 mg/m2 given on 2 of every 3 weeks during radiotherapy (analogous to the vinorelbine arm).
CALGB 9431 opened in January 1996 and was closed to accrual in June 1998. Eligible patients had histologic or cytologic documentation of NSCLC, including squamous cell carcinoma, adenocarcinoma (including bronchoalveolar cell carcinoma), and large-cell and anaplastic carcinoma (including giant and clear-cell carcinomas). Patients included those who had unresectable or inoperable stage III disease, including N2 to N3 disease and any T stage, or those with T4 disease and any nodal stage. Patients with stage T3N0 or N1 were not eligible. Patients with N3 disease were eligible if all gross disease could be encompassed in the radiation boost field. Patients with scalene, supraclavicular, or contralateral hilar lymph node involvement or direct invasion of the vertebral body or with a pleural effusion that was exudative, bloody, or cytologically proven to contain malignant cells were ineligible. All patients had measurable or assessable disease as measured by chest x-ray, computed tomography (CT), or magnetic resonance (MR) scan performed within 28 days of registration. Assessable lesions included ill-defined masses associated with postobstructive changes or mediastinal or hilar lymphadenopathy measurable only in one dimension. Patients with completely resected tumors were ineligible. All patients were seen by a radiation oncologist before registration onto the study. Additional eligibility criteria included a CALGB performance status of 0 to 1, weight loss of less than 5% in the 3 months before diagnosis, a life expectancy exceeding 2 months, age of 18 years or older, and absence of pregnancy. Patients had not previously received chemotherapy or radiation therapy. Required initial laboratory tests included an absolute granulocyte count of  1,800/µL, hemoglobin 10 gm/dL, platelet count of 100,000/µL, serum creatinine  1.5 times the upper limit of normal, or a 24-hour creatinine clearance of at least 60 mL/min. In addition, liver function tests had to be 1.5 times the upper limit of normal, and the forced expiratory volume in 1 second had to be more than 800 mL. All patients provided written informed consent. Patients were randomized by the CALGB Statistical Center. Pretreatment evaluation included a history and physical examination and routine laboratory studies. Radiological studies included a CT or MR scan of the chest and upper abdomen including adrenals and liver, a chest x-ray, bone scan, bronchoscopy, radiotherapy consult, and pulmonary function tests including forced expiratory volume of 1 second, forced vital capacity, and arterial blood gases.
Treatment Plan On arm 1, cisplatin was given with gemcitabine administered during induction chemotherapy (cycles 1 and 2) at 1,250 mg/m2 IV for 30 minutes on days 1, 8, 22, and 29. During concomitant chemoradiotherapy (cycles 3 and 4), gemcitabine was given at 600 mg/m2 IV for 30 minutes on days 43, 50, 64, and 71. On arm 2, paclitaxel was given at 225 mg/m2 IV for 3 hours on days 1 and 22 during induction chemotherapy (before cisplatin) and at 135 mg/m2 IV for 3 hours on days 43 and 64 during concomitant chemoradiotherapy. Premedications for paclitaxel included dexamethasone at 20 mg orally or IV 12 hours and 6 hours before paclitaxel, diphenhydramine at 50 mg IV 30 minutes before paclitaxel, and cimetidine at 300 mg or ranitidine at 50 mg IV 30 minutes before paclitaxel. On arm 3, vinorelbine was administered at 25 mg/m2 IV for 12 minutes on days 1, 8, 15, 22, and 29 (induction chemotherapy) and at 15 mg/m2 IV for 12 minutes on days 43, 50, 64, and 71 (concomitant chemoradiotherapy).
Radiation Therapy Radiation therapy was given with photon beams from either cobalt-60 or an accelerator with energy between 4 to 25 MV. The target volume consisted of an original and boost volume. The original volume was based on conventional chest x-rays and CT scans taken after two cycles of chemotherapy and included the primary lesion, the ipsilateral hilum and mediastinum with a margin of 2 cm, and any grossly involved nodal sites (ie, biopsy positive, CT/MR scan nodes > 1.5 cm, or any size node with a necrotic center). Even if the primary tumor was in the lung periphery, only one radiation field was used to cover it and the mediastinum. The contralateral hilum was not treated. The boost volume included all sites of gross disease identified after two cycles of chemotherapy, the ipsilateral hilum, the ipsilateral mediastinum, and the subcarinal region from the level of the aortic arch superiorly to 4 cm below the carina inferiorly. The boost volume (ie, +7% and -5% of the prescribed dose) was limited to less than 50% of ipsilateral lung volume.
The spinal cord was 1 cm
Dose Modifications and Induction Chemotherapy For a serum creatinine of 1.5 to 2.0 mg/dL, cisplatin was reduced by 50%. For a serum creatinine greater than 2.0 mg/dL, cisplatin was held and gemcitabine reduced by 50%. For grade 2 neurotoxicity, cisplatin and vinorelbine were administered at 50%, whereas paclitaxel was held until resolution of toxicity to grade 1. All three agents were held for grade 3 neurotoxicity. For documented grade 3 hypersensitivity reactions to paclitaxel or vinorelbine or pulmonary toxicity with gemcitabine, the respective drug was discontinued. For chest pain, hypotension, or arrhythmia other than asymptomatic sinus brachycardia, the paclitaxel infusion was stopped, and patients received no further paclitaxel.
Dose Modifications and Concomitant Chemoradiotherapy
Statistical Assumptions Kaplan-Meier curves were used to describe overall survival and failure-free survival in each treatment group.35 Survival time is defined as the time beginning at randomization until death or last known follow-up. Failure-free survival is computed as the time between randomization and disease progression, death, or last known follow-up.
A total of 187 patients were accrued to this study. Median follow-up time was 43 months. Twelve patients were excluded from this final analysis, including six patients who never received protocol therapy and six that were not eligible (stage II disease, two patients; performance status of 2, three patients; and presence of supraclavicular lymph nodes, one patient). Weight loss was not used as a criterion for excluding patients from analyses given the inconsistencies between the specified eligibility criteria (ie, weight loss < 5% within 3 months as specified by protocol versus 6 months as requested on the on-study data collection form). The baseline patient characteristics are listed in Table 1. Overall, 69% of patients were male with a median age of 61 years (range, 30 to 81 years), adenocarcinoma was the most common histology at 37%, and the overwhelming majority had measurable disease. While all patients were considered unresectable, 52% had stage IIIA disease, and 48% had stage IIIB.
Toxicities Toxicities to induction chemotherapy are listed in Table 2. On all three arms, grade 3 or 4 granulocytopenia was observed in approximately 50% of patients. Notably, on the gemcitabine arm, 25% of patients also had a grade 3 or 4 thrombocytopenia. Two patients on the paclitaxel arm died of treatment-related causes. Most other toxicities were mild to moderate.
Toxicities during concomitant chemoradiotherapy are summarized in Table 3. There were notable differences between the three study arms. Grade 3 or 4 granulocytopenia was seen in 51% of patients treated with gemcitabine and 53% of patients treated with paclitaxel, which contrasts with 27% of patients treated with vinorelbine. In addition, thrombocytopenia was seen in 56% of patients on the gemcitabine arm. Grade 3 or 4 esophagitis was observed on all study arms. However, it was most pronounced on the gemcitabine arm where 35% of patients had grade 3 esophagitis and 17% of patients had grade 4 esophagitis. This contrasted with grade 3 or 4 esophagitis of 35% and 4% for paclitaxel and 13% and 12% for vinorelbine, respectively. Grade 3 or 4 dyspnea as a possible measure of radiation pneumonitis (but also of disease progression) was seen in 14% to 20% of patients. Radiation therapy interruptions were more common on arm 1 (22 of 62 patients) versus arm 2 (nine of 58 patients) and arm 3 (seven of 55 patients).
Response Response to induction chemotherapy and best (final) overall response are listed in Tables 4 and 5. Total response rates to induction chemotherapy on the three study arms were 40%, 33%, and 44%, with overlapping 95% confidence intervals (CIs). Similarly, best overall response rates were 74%, 67%, and 73% for arms 1, 2, and 3, respectively, with overlapping 95% CIs.
Survival Overall median survival time for all patients was 17 months (95% CI, 14.1 to 19.4 months). For the three study arms (gemcitabine, paclitaxel, and vinorelbine), median survival times were 18.3 (95% CI, 13.8 to 23.6), 14.8 (95% CI, 12 to 19.5), and 17.7 (95% CI, 12.4 to 24.7) months, respectively. One-year survival rates were 68% (95% CI, 56% to 79%), 62% (95% CI, 50% to 75%), and 65% (95% CI, 53% to 78%), and 3-year survival rates were 28% (95% CI, 16% to 39%), 19% (95% CI, 19% to 29%), and 23% (95% CI, 12% to 34%). Median failure-free survival times were 8.4, 9.1, and 11.5 months, with 3-year failure-free survival rates ranging from 16% to 18%. Sites of initial failure are listed in Table 6. Combined locoregional and distant failure represented the most common pattern (Figs 2 to 5).
This is the first large mature study to investigate the use of the new drugs of the last decade in the curative intent therapy setting of stage III NSCLC in the cooperative group setting. Our data indicate that all three new agents can be safely combined with cisplatin and radiotherapy and have similar activity but different patterns of toxicities. The overall median survival time of 17 months exceeds that of previous CALGB studies in this patient population.14,15,34 The increased median and long-term survival data compared with those reported in previous CALGB studies could reflect the potential benefit of the novel drugs studied here, the administration of more chemotherapy (four cycles of chemotherapy instead of two), the use of concomitant chemoradiotherapy, or the use of both an induction and concurrent combined modality treatment approach. Induction chemotherapy used alone or followed by radiotherapy and concurrent single-agent carboplatin resulted in a median survival time of 13 and 14 months, respectively.14,34 Two-year survival rates were 26% and 29%, respectively. Other groups have reported similar data with induction chemo-therapy.16,17 Concomitant chemoradiotherapy has been compared directly with induction chemotherapy in several randomized trials.23,24,36,37 Both the Japanese trial evaluating the mitomycin, vinblastine, and cisplatin regimen and the similarly designed United States Intergroup trial (with cisplatin and vinblastine) showed an advantage for the concomitant approach. Of interest, median survival times on the induction chemotherapy arms of the two studies were 13 and 14 months, respectively; median survival on the concomitant chemoradiotherapy arms were 16 and 17 months, respectively. In view of these data, the 17-month median survival time reported here is compatible with the hypothesis that the observed improvement over previous CALGB studies testing induction chemotherapy alone is due to the concomitant chemoradiotherapy portion of the three tested regimens. Alternatively, it could be argued that the increased median survival time is due to the introduction of new drugs in this trial. All three new agents have been shown to be modestly superior in the stage IV setting compared with regimens used in the 1980s1-4,6-10 and have significant radiation enhancing potential as well.25-29 Because a large randomized trial comparing the new drugs versus older regimens in the stage III setting has not been conducted, this interpretation may apply. However, this interpretation seems unlikely in view of the median survival times reported here being similar to data reported for older concomitant chemoradiotherapy regimens.20-24 The randomized phase II trial design does not allow for a statistical comparison of the three arms. Clinically, they seem to have similar response activity and survival times, with the gemcitabine arm resulting in a numerically higher 3-year survival rate. It is possible that this reflects a small advantage for that arm, but this modest potential benefit has to be balanced with its higher toxicity. The toxicities observed during induction therapy were identical to those reported for the same regimens in the stage IV setting. Of greater interest is the differential toxicity profile of the three arms during concomitant chemoradiotherapy. Although all three new agents are known radiation enhancers, the limited available clinical experience with gemcitabine suggested that this drug, in particular, would lead to significant toxicity within the irradiated field.32 Our data show that esophagitis was indeed most common with gemcitabine; however, radiation pneumonitis was not, and all three arms were feasible in the cooperative group setting. Given the higher overall median survival time observed in CALGB 9431 compared with previous trials, we have concluded that the administration of two cycles of induction chemotherapy followed by concomitant chemoradiotherapy should represent the control arm in a follow-up randomized trial. Because differences between the specific study arms are likely to be small, we have elected not to pursue the identification of the "best" of these three regimens. Instead, we are currently comparing the 9431 treatment sequence with concomitant chemoradiotherapy alone using a paclitaxel and carboplatin combination. Thus, we are testing the role of induction chemotherapy in the context of concomitant chemoradiotherapy. An alternative approach that combines concomitant and sequential therapy has been pursued by SWOG.20-22 In that study, patients have been treated with radiotherapy and concomitant cisplatin/etoposide followed by adjuvant cisplatin/etoposide or, more recently, adjuvant docetaxel. Promising survival data have been presented for the latter patients using adjuvant docetaxel. Verification of this approach in a randomized trial that tests the role of adjuvant docetaxel has been initiated by the Hoosier Oncology Group. Thus, concomitant chemoradiotherapy is common to both the CALGB and SWOG approach; in each instance, the added contribution of the sequential chemotherapy component, whether induction or adjuvant, remains to be established. There are additional current concepts of interest in stage III NSCLC. Socinski et al38 have presented intriguing data using the carboplatin/paclitaxel induction and concomitant treatment approach with escalated radiotherapy (74 Gy) using three-dimensional treatment planning to minimize toxicities. They reported a median survival of 26 months and a 2-year survival rate of 52%. The feasibility of dose-escalated radiotherapy with chemotherapy in the cooperative group setting is currently being tested in the CALGB. Another current focus of interest is the addition of targeted therapies to chemotherapy and radiation. In particular, inhibitors of the epidermal growth factor receptor seem promising and are currently being integrated into CALGB protocols in stage III disease. It is our hope that the addition of these novel principles will lead to a further increase in long-term survival rates for future patients.
The appendix listing CALGB institutions and investigators is available online at www.jco.org.
Research for Cancer and Leukemia Group B (CALGB) 9431 was supported in part by grant no. CA31946 from the National Cancer Institute to the CALGB (Richard L. Schilsky, MD, Chairman). We thank Michelle Scheuer for assistance with the preparation of the manuscript and Karen Zhang for help with statistical analysis.
Presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology (ASCO), Atlanta, GA, May 15-18, 1999, and the Thirty-Third Annual Meeting of ASCO, Denver, CO, May 17-20, 1997. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
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23. Furuse K, Fukuoka M, Kawahara M, et al: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 17: 2692-2699, 1999 24. Curran W, Scott C, Langer C: Phase III comparison of sequential versus concurrent chemoradiation for patients with unresected stage III non-small cell lung cancer: Report of Radiation Therapy Oncology Group 9410, 9th World Conference on Lung Cancer. Lung Cancer 29: 93, 2000 25. Edelstein MP, Wolfe LA 3rd, Duch DS: Potentiation of radiation therapy by vinorelbine (Navelbine) in non-small cell lung cancer. Semin Oncol 23: 41-47, 1996[Medline] 26. Choy H, Rodriguez FF, Koester S, et al: Investigation of Taxol as a potential radiation sensitizer. Cancer 71: 3774-3778, 1993[CrossRef][Medline]
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34. Clamon G, Herndon J, Cooper R, et al: Radiosensitization with carboplatin for patients with unresectable stage III non-small-cell lung cancer: A phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group. J Clin Oncol 17: 4-11, 1999 35. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef] 36. Pierre F, Maurice P, Gilles R, et al: A randomized phase III trial of sequential chemo-radiotherapy versus concurrent chemoradiotherapy in locally advanced non-small cell lung cancer (NSCLC) (GLOT-GFPC NPC 95-01 study). Proc Am Soc Clin Oncol 20: 312a, 2001 (abstr 1246) 37. Zatloukal PV, Petruzelka L, Zemanova M, et al: Concurrent versus sequential radiochemotherapy with vinorelbine plus cisplatin (v-p) in locally advanced non-small cell lung cancer: A randomized phase II study. Proc Am Soc Clin Oncol 21: 290a, 2002 (abstr 1159) 38. Socinski MA, Rosenman JG, Schell MJ, et al: Induction carboplatin/paclitaxel followed by concurrent carboplatin/paclitaxel and dose-escalating conformal thoracic radiation therapy in unresectable stage IIIA/B nonsmall cell lung carcinoma: A modified phase I trial. Cancer 89: 534-542, 2000[CrossRef][Medline] Submitted March 12, 2002; accepted July 9, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
