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© 1999 American Society for Clinical Oncology Phase III Study of Concurrent Versus Sequential Thoracic Radiotherapy in Combination With Mitomycin, Vindesine, and Cisplatin in Unresectable Stage III Non–Small-Cell Lung CancerFrom the Department of Internal Medicine, National Kinki Central Hospital for Chest Diseases; Department 2 of Internal Medicine, Osaka Prefectural Habikino Hospital; Department of Internal Medicine, National Toneyama Hospital for Chest Diseases; Department 1 of Internal Medicine, Osaka City University; and Department of Respiratory Disease, Osaka Medical Center Cancer and Cardiovascular Diseases, Osaka; Department of Radiology, Hyogo Medical Center for Adults, Hyogo; Department of Respiratory Disease, Kobe City General Hospital, Kobe; and Department of Respiratory Disease, Aichi Cancer Center, Nagoya, Japan. Address reprint requests to Kiyoyuki Furuse, MD, Office of the Consultant, Division of Respiratory Diseases, Health Insurance Union, Osaka Central Hospital, 3-3-17, Niwashirodai, Sakai, Osaka 590-0133 Japan.
PURPOSE: A phase III study was performed to determine whether concurrent or sequential treatment with radiotherapy (RT) and chemotherapy (CT) improves survival in unresectable stage III non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were assigned to the two treatment arms. In the concurrent arm, chemotherapy consisted of cisplatin (80 mg/m2 on days 1 and 29), vindesine (3 mg/m2 on days 1, 8, 29, and 36), and mitomycin (8 mg/m2 on days 1 and 29). RT began on day 2 at a dose of 28 Gy (2 Gy per fraction and 5 fractions per week for a total of 14 fractions) followed by a rest period of 10 days, and then repeated. In the sequential arm, the same CT was given, but RT was initiated after completing CT and consisted of 56 Gy (2 Gy per fraction and 5 fractions per week for a total of 28 fractions). RESULTS: Three hundred twenty patients were entered onto the study. Pretreatment characteristics were well balanced between the treatment arms. The response rate for the concurrent arm was significantly higher (84.0%) than that of the sequential arm (66%) (P = .0002). The median survival duration was significantly superior in patients receiving concurrent therapy (16.5 months), as compared with those receiving sequential therapy (13.3 months) (P = .03998). Two-, 3-, 4-, and 5-year survival rates in the concurrent group (34.6%, 22.3%, 16.9%, and 15.8%, respectively) were better than those in the sequential group (27.4%, 14.7%, 10.1%, and 8.9%, respectively). Myelosuppression was significantly greater among patients on the concurrent arm than on the sequential arm (P = .0001). CONCLUSION: In selected patients with unresectable stage III NSCLC, the concurrent approach yields a significantly increased response rate and enhanced median survival duration when compared with the sequential approach.
IN THE LAST DECADE, several randomized trials have evaluated the use of chemotherapy with radiotherapy in the treatment of patients with unresectable stage III non–small-cell lung cancer (NSCLC).1 Some trials that used cisplatin-based chemotherapy showed small but definite improvements in survival compared with trials that used radiotherapy.2-4 A patient-based meta-analysis of 3,033 patients in 22 randomized clinical trials was recently reported.5 This analysis indicated a 9% reduction in the annual risk of death, with a consequent improvement in 2-year survival from approximately 16% to approximately 19%. For the trials that used cisplatin-based chemotherapy, the chemotherapy produced a 13% reduction in the risk of death. The most convincing evidence is derived from induction chemotherapy with vinblastine and cisplatin followed by radiotherapy, and this treatment strategy is now an appropriate option for selected patients with unresectable stage III NSCLC. These data together suggest that sequential cisplatin-based chemotherapy followed by radiotherapy is the current standard therapy for unresectable stage III NSCLC. In our prior trial, patients with locally advanced NSCLC were randomized to chemotherapy with or without radiotherapy.6 Median survival was similar in the two cohorts of patients, but long-term survival was clearly superior in the patients who received both cisplatin-based chemotherapy and radiotherapy. Local relapse was greater in the patients who were given chemotherapy alone. This trial provided evidence that chemotherapy has an inadequate effect on local tumor control. Radiotherapy to bulky disease in the thorax was thus an important part of combined-modality treatment. We concluded that both chemotherapy and radiotherapy are essential in the treatment of locally advanced NSCLC. Despite the superiority of combined treatments over chemotherapy alone, the response rate for chemotherapy followed by radiotherapy was still only 50%. In contrast, our phase II study of concurrent radiotherapy and chemotherapy with mitomycin (MMC), vindesine (VDS) and cisplatin for unresectable stage III NSCLC showed a response rate of 87%, a median survival of 16 months, and a 2-year survival rate of 37%.7 These results encouraged us to proceed with further study. We thus initiated a randomized trial to evaluate the therapeutic significance of concurrent radiotherapy and chemotherapy in combination with MMC, VDS, and cisplatin (MVP regimen) compared with sequential therapy for patients with unresectable stage III NSCLC.
Patients We entered 320 patients with histologically or cytologically confirmed unresectable stage III NSCLC. Staging for entry criteria was performed according to the lung cancer staging system of the International Union Against Cancer.8 Patients with T3N0 or T3N1 disease and pleural effusion were excluded. Eligibility criteria included age of younger than 75 years; measurable or assessable lesions; Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2; a required radiation field of less than one half of one lung; no prior chemotherapy, thoracic radiotherapy, or thoracic surgery; and no active concomitant malignancies. Patients with prior malignancies who had been disease-free for more than 5 years were eligible. Patients also were required to have no abnormal hematologic (leukocyte count  4,000/µL, platelet count [PLT] 100,000/µL), hepatic (bilirubin < 1.5 mg/dL, AST/ALT < twice the upper limit of normal), renal (serum creatinine < 1.5 mg/dL), pulmonary (partial pressure of arterial oxygen 70 mm Hg), and cardiac functions. All patients gave informed consent to participate in the study. Patients were staged with routine chest roentgenography, conventional chest tomography; chest computed tomography scan (CT), CT scan of the brain and abdomen, bone scintigraphy, and bronchoscopy.
Treatment Schedule In the concurrent schedule, chemotherapy consisted of VDS (3 mg/m2 on days 1 and 8), cisplatin (80 mg/m2 on days 1), and MMC (8 mg/m2 on days 1). This chemotherapy was repeated every 4 weeks and was administered in two courses. The dose was modified on the basis of blood cell counts and renal function on the day of therapy. VDS was administered at the full calculated dose unless the leukocyte count was less than 2,000/µL or the PLT count was less than 50,000/µL on day 8 or 36 of therapy. If either the leukocyte count or PLT count were below these levels, VDS administration was withheld until counts recovered, at which time it was reinstituted at the full dosage. If the leukocyte count was less than 3,000/µL or the PLT count was less than 75,000/µL on day 29, then chemotherapy was withheld until counts recovered. If grade 4 hematologic toxicity, according to World Health Organization (WHO) criteria,9 occurred during the first course, then doses of VDS and MMC were reduced to 75%. Cisplatin was permanently discontinued at any time when the serum creatinine level was greater than 2 mg/dL.
On day 2 of chemotherapy, radiation was begun using a linear accelerator ( Patients in the sequential therapy group received the same chemotherapy as patients in the concurrent therapy group. After completing two courses of chemotherapy, patients received radiotherapy that consisted of 56 Gy in 28 fractions of 2 Gy each (5 days each week, given over a period of 5 weeks). Radiation fields and criteria of exclusion of spinal cord were the same as in patients receiving the concurrent schedule. If patients responded to chemotherapy (sequential) or chemoradiotherapy (concurrent), then one or more cycles of chemotherapy were given to patients after radiotherapy on both arms, if possible. If grade 4 radiation-induced esophagitis occurred (according to ECOG criteria), then radiotherapy was withheld until esophagitis recovered to grade 3. If leukocyte count was grade 4, then radiotherapy was withheld until it recovered to grade 3. Partial pressure of arterial oxygen was measured every week, and if it worsened to 10 mm Hg or greater, then radiotherapy was withheld until recovery; likewise, if body temperature was greater than 38°C, then radiotherapy was withheld until body temperature returned to normal.
Evaluation Response and toxicity were evaluated according to WHO criteria,9 but grading of esophageal toxicity caused by radiation was defined according to the ECOG criteria.10 Extramural reviewers evaluated the eligibility, assessability, and response in each patient. A complete response (CR) was defined as the disappearance of all measurable lesions for at least 4 weeks. A partial response (PR) was defined as a more than 50% decrease in the sum of the products of the greatest perpendicular diameters of all measurable lesions for at least 4 weeks without the development of new lesions. No change (NC) was defined as a less than 50% reduction or less than 25% increase in the products of the greatest perpendicular of all the lesions without any evidence of new lesions for at least 4 weeks. Progression of disease (PD) was defined as an increase of more than 25% or the appearance of new lesions. Response in both arms was generally evaluated 1 month after completing radiotherapy, except for PD.
Study Design and Statistical Analysis A sample size of 320 patients was planned to provide a power of 80% to detect an improvement in the 2-year survival rate (from 20% to 30%) at a significance level for two-sided test with alpha of 0.05 and beta of 0.20. Survival was calculated from the date of randomization to death or last follow-up evaluation. Actuarial survival curves were calculated by the Kaplan-Meier method11 and were compared for statistical significance using the log-rank test.12
To assess differences between proportions, P values were calculated with the
Patient Characteristics Between August 1992 and December 1994, 320 patients were enrolled at the 27 institutions participating in this study. Five patients were later found to be ineligible: two patients had distant metastasis, one had severe anemia and required blood transfusion, and one enrolled twice. Of the 315 eligible patients, one patient withdrew informed consent after enrollment. Thus 314 patients were assessable for survival, response, and toxicity. The clinical characteristics of the patients are listed in Table 1. Four patients were evaluated as T3N0M0 or T3N1M0 disease by extramural review. All prognostic factors were distributed equally between the two treatment arms.
Response
Treatment Toxicity
Survival
Five patients who had an apparent response after completion of radiotherapy and chemotherapy received surgery. Of these five patients, two in the sequential group had a complete resection and are alive 3 years and 4 years after therapy. However, the remaining two patients in the concurrent group and one patient in the sequential group had incomplete resection and died of recurrence 15, 16, and 33 months after therapy.
Multivariate analysis for each pretreatment variable was performed. PS (0 + 1 v 2, P = .00097) and arm (concurrent v sequential, P = .03998) were most significantly related to survival. Age (< 65 v
Relapse Sites
For these patients with measurable lesions, there was no difference in failure-free survival between the two groups (8.3 v 8.0 months, P = .1518; Fig 2).
Treatment Delivery
On the other hand, 136 (87.2%) of 156 patients on the concurrent arm and 129 (81.6%) of 158 patients on the sequential arm received
Accordingly, 128 (82.1%) of 156 patients on the concurrent arm and 131 (82.9%) of 158 on the sequential arm received chemotherapy (
The combination of radiotherapy and chemotherapy using cisplatin-based regimens has been extensively investigated for application in locally advanced NSCLC. Recent trials conducted by Le Chevalier et al,2,17 Dillman et al,3 and Sause et al18 demonstrated a benefit in the sequential approach. The median survival time (13.4 months) and 2- and 3-year survival rates (27.2% and 13.7%, respectively) in the sequential group from our study seem similar to the results observed in the trials of Dillman et al (median survival time, 13.7 months; 2- and 3-year survival rates, 26% and 24%, respectively),3 Sause et al (median survival time, 13.8 months),18 and Le Chevalier et al (median survival time, 12 months; 2- and 3-year survival rates, 21% and 1%).2 The results of our trial further demonstrate a significant survival advantage for the concurrent approach compared with the sequential approach. The median survival duration in the concurrent approach demonstrated an improvement of 3 months over that of the sequential approach (16.5 v 13.3 months), but the improvement in long-term (2 to 5 years) survival rates in the concurrent approach was slightly better (< 10%) when compared with the sequential approach. The Radiation Therapy Oncology Group14 (73-01) previously reported a randomized study of various irradiation doses and fractionation schedules in radiotherapy for NSCLC.19 The 60-Gy continuous schedule was superior to the same dose given in a split-course fashion. However, we often experienced irregular interruption of radiotherapy in a pilot study of concurrent continuous radiotherapy and the MVP regimen. The main cause of this interruption in radiotherapy was neutropenic fever. Thus in our phase II and current study, we chose regularly scheduled interruption (ie, split-course radiotherapy). In the current study, the incidence of esophagitis was identical for the concurrent and the sequential groups. However, Radiation Therapy Oncology Group 92-04, using a continuous schedule in the concurrent arm in a randomized phase II study comparing concurrent with sequential chemotherapy/radiation for advanced NSCLC, demonstrated that patients on the concurrent arm experienced significantly more acute and chronic esophagitis, although a twice-a-day fractionation schedule was used.20 The low incidence of esophagitis in our study may be due to use of the split-course schedule in radiotherapy (grade 3 esophagitis in concurrent v sequential therapy, four of 156 patients v three of 158 patients). We believe that this schedule might help lessen the toxicity associated with concurrent radiotherapy and intensive chemotherapy and make treatment more acceptable to patients. The timing of chemotherapy relative to radiotherapy may be important. Recently, we compared concurrent versus sequential radiotherapy and chemotherapy for limited-stage small-cell lung cancer (SCLC) in a randomized trial of 228 patients,21 and our results suggested improved outcome for patients who receive concurrent therapy. The data supported a policy of administering thoracic radiation soon after initiation of chemotherapy for limited-stage SCLC.22 Thus these trials for SCLC and NSCLC may support the general concept that early destruction of as many cancer cells as possible by combined-modality treatment is a therapeutic principle that may also apply to treatment of cancers other than lung cancers22; these trials may also support the concept that direct enhancement of local control by simultaneous chemotherapy and radiotherapy may improve both local and long-term outcome. In the delivery of chemotherapy in our current study, patients who were treated with concurrent therapy received significantly more chemotherapy courses (mean, 2.55 courses) when compared with patients treated with sequential therapy (mean, 2.18 courses). In a randomized trial by Le Chevalier et al,2 patients who received chemotherapy followed by radiotherapy and who responded to chemotherapy were given three additional chemotherapy courses after radiotherapy. On the other hand, in the studies of Dillman et al3 and Sause et al18 with the same sequential approach, only two chemotherapy courses were administered before radiotherapy. Although no randomized study comparing the administration of additional chemotherapy versus no administration of additional chemotherapy after radiotherapy has been conducted, the survival results were identical among the three trials (median survival time, 12 to 13.8 months). No randomized trial has addressed the optimal duration of chemotherapy in combined radiotherapy and chemotherapy for locally advanced NSCLC. The incidence of myelosuppression was higher among patients on the concurrent therapy arm than among patients on the sequential therapy arm. Further studies with this approach are warranted to improve toxicity. However, we experienced three treatment-related deaths in the sequential group and one in the concurrent group. This finding suggests that the concurrent approach is acceptable for selected patients with unresectable stage III NSCLC. A 3-month improvement in median survival and better 2- and 3-year survival rates observed in the concurrent radiotherapy and MVP group are encouraging. At the same time, because approximately 70% of the patients in this series relapsed within 3 years, further improvements in the treatment are still needed. More effective chemotherapy must be developed and exploration of improved radiation therapy must be conducted to increase the benefit of this approach.
Additional participating institutions and specialists from the West Japan Lung Cancer Group include the following: National Kinki Central Hospital for Chest Diseases (M. Akira), Osaka Prefectural Habikino Hospital (T. Tada), Osaka City University (T. Nakazima), Kobe City General Hospital (H. Fukuda), Osaka Medical Center Cancer and Cardiovascular Diseases (M. Chatani), Aichi Cancer Center (S. Fuwa), Gifu Municipal Hospital (T. Sawa), Gifu University (K. Goto), National Kyoto Hospital (H. Asamoto), Kinki University (S. Nakajima), Osaka Teishin Hospital (K. Komuta), Osaka General Hospital (S. Negoro), Hyogo Medical College (T. Igarashi), Wakayama Rosai Hospital (T. Hoso), Hiroshima University (M. Yamakido), Kagawa Medical School (J. Takahara), Kagawa Prefectural Central Hospital (M. Kamei), Aso Izka Hospital (H. Yamamoto), Kumamoto Chuo Hospital (E. Kinuwaki), National Minamikyushu Hospital (F. Iwami), Nagasaki Municipal Citizens Hospital (M. Nakano), Saseho City General Hospital (J. Araki), Kumamoto Regional Medical Center (H. Senda), and Kyushu University (K. Nobutomo).
Supported in part by a Grant-in-Aid for Cancer Research no. 2S-1, 5S-1, 8H-1 (principle investigator, M. Shimoyama of the Japan Clinical Oncology Group) from the Ministry of Health and Welfare, Tokyo, Japan. We thank Kinuko Tazima for data collection and statistical analysis, Dr. Kaoru Kubota for making the protocol and reviewing the trial, and Dr. Joseph Aisner for critical review of the manuscript.
1. Pritchard RS, Anthony SP: Chemotherapy plus radiotherapy compared with radiotherapy alone in the treatment of locally advanced, unresectable, non-small cell lung cancer. Ann Intern Med 125:723-729, 1996
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Le Chevalier T, Arriagada R, Quoix E, et al: Radiotherapy alone versus combined chemotherapy and radiotherapy in unresectable non-small cell lung cancer: First analysis of a randomized trial in 353 patients. J Natl Cancer Inst 83:417-423, 1991 3. Dillman RO, Seagren SL, Propert KJ, et al: A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small cell lung cancer. N Engl J Med 323:940-945, 1990[Abstract] 4. Schaake-Koning C, Van den Bogaert W, Dalesio O, et al: Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 326:524-630, 1992[Abstract]
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Kubota K, Furuse K, Kawahara M, et al: Role of radiotherapy in combined modality treatment of locally advanced non-small cell lung cancer. J Clin Oncol 12:1547-1552, 1994 7. Furuse K, Kubota K, Kawahara M, et al: Phase II study of concurrent radiotherapy and chemotherapy for unresectable stage III non-small-cell lung cancer: Southern Osaka Lung Cancer Study Group. J Clin Oncol 13:869-875, 1995[Abstract] 8. Mountain C: A new international classification system for lung cancer. Chest 89:225S-233S, 1986 (suppl) 9. World Health Organization: WHO Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, WHO offset publication no. 48, 1979 10. Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982[Medline] 11. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 12. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother 50:163-170, 1966
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Cochran WG: Some methods for strengthening the common 14. Mehta CR, Patel NR: A network algorithm for performing Fisher's exact test in r x c contingency tables. J Am Stat 78:427-434, 1983 15. Mann HB, Whitney DR: On a test of whether one of two random variables is stochastically larger than the other. Ann Math Stat 18:50-60, 1947 16. Truett J, Cornfield J, Kannel W: A multivariate analysis of the risk of coronary heart disease in Framingham. J Chronic Dis 20:511-524, 1967[Medline]
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Sause WT, Scott C, Taylor S, et al: Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: Preliminary results of a phase III trial in regionally advanced, unresectable non-small cell lung cancer. J Natl Cancer Inst 87:198-205, 1995 19. Perez CA, Bauer M, Edelstein S, et al: Impact of tumor control on survival in carcinoma of the lung treated with irradiation. Int J Radiat Oncol Biol Phys 12:539-547, 1994 20. Komaki R, Scott C, Ettinger D, et al: Randomized phase II study of chemotherapy/radiation therapy combination for favorable patients with locally advanced inoperable non-small cell lung cancer: Radiation Therapy Oncology Group 92-04. Proc Am Soc Clin Oncol 15:514, 1996 (abstr) 21. Takada M, Fukuoka M, Furuse K, et al: Phase III study of concurrent versus sequential thoracic radiotherapy (TRT) in combination with cisplatin (C) and etoposide (E) for limited-stage (LS) small cell lung cancer (SCLC): Preliminary result of the Japan Clinical Oncology Group. Proc Am Soc Clin Oncol 15:372, 1996 (abstr)
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Murray N, Coy P, Pater JL, et al: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer: The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11:336-44, 1993 Submitted August 11, 1998; accepted May 14, 1999. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
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