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© 2002 American Society for Clinical Oncology Phase II Study of Twice-Daily High-Dose Thoracic Radiotherapy Alternating With Cisplatin and Vindesine for Unresectable Stage III Non–Small-Cell Lung Cancer: Japan Clinical Oncology Group Study 9306ByFrom the Department of Internal Medicine, National Cancer Center Hospital, Tokyo; Division of Thoracic Oncology and Radiotherapy, National Cancer Center Hospital East, Kashiwa; Division of Internal Medicine and Radiotherapy, Niigata Cancer Center Hospital, Niigata; Division of Internal Medicine and Radiotherapy, Tochigi Prefectural Cancer Center, Utsunomiya; Division of Internal Medicine and Radiotherapy, National Nishigunma Hospital, Shibukawa; and Japan Clinical Oncology Group Data Center, Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo, Japan. Address reprint requests to Ikuo Sekine, MD, PhD, Department of Internal Medicine, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan; email: isekine{at}gan2.ncc.go.jp
PURPOSE: To evaluate the efficacy and toxicity of high-dose thoracic radiotherapy (TRT) alternating with chemotherapy (CH) for unresectable stage III non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-one patients received TRT with 1.5 Gy twice daily, 5 days a week, on weeks 1, 2, 5, 6, and 9, up to a total dose of 66 to 72 Gy, alternating with cisplatin 80 mg/m2 on day 1 and vindesine 3 mg/m2 on days 1 and 8, repeated every 4 weeks, for two or three courses beginning on week 3.
RESULTS: The median (range) total dose of TRT and number of CH courses were 72 Gy (16.5 to 72 Gy) and three (zero to three), respectively. Delay in TRT CONCLUSION: Alternating high-dose TRT and CH for stage III NSCLC produced a high response rate with median and long-term survival comparable to prior trials utilizing standard approaches in this population. Acute and late esophageal toxicity was observed and interruption of TRT was required in most of the patients.
LUNG CANCER CURRENTLY represents the leading cause of death from malignancies in Japan, and 50,871 persons died of the disease in 1998.1 Non–small-cell lung cancer (NSCLC) accounts for 85% of all lung neoplasms, approximately 30% to 40% of which are considered locally advanced stage IIIA or IIIB disease at initial diagnosis.2 The combination of platinum-based chemotherapy (CH) and thoracic radiotherapy (RT) has been established as the standard treatment for the disease in patients with good performance status,3-6 but the optimal timing of the CH and RT, the dose and fractionation of RT, and the most optimal chemotherapeutic regimen have not been determined. Systemic CH and thoracic RT can be given either concurrently or sequentially or by alternating the two modalities with each other. Concurrent treatment, which utilizes both modalities at the same time, may produce the greatest tumoricidal effects if the combined toxicity is tolerated. Sequential administration of RT after completion of CH seems to reduce the toxicity but prolongs the treatment time and delays the beginning of RT.7 This may give the opportunity for accelerated tumor cell regeneration after induction chemotherapy. A phase III study of concurrent versus sequential thoracic RT in combination with mitomycin, vindesine, and cisplatin in 320 patients with unresectable stage III NSCLC showed that the response rate, median survival, and 5-year survival rate were better in the concurrent arm.8 However, the thoracic RT used in the study was not standard; the total dose was 56 Gy in continuous course in the sequential arm and 56 Gy administered with 1-week separation in the concurrent arm. A randomized phase II trial of full-dose cisplatin and vinblastine, followed by conventional thoracic RT with cisplatin as a radiosensitizer versus hyperfractionated RT concurrently combined with a moderate dose of cisplatin and oral etoposide, showed no survival benefit of the latter over the former schedule.9 Thus, the superiority of early concurrent chemoradiotherapy over sequential RT has not been established. The alternating approach, in which RT is administered in split courses between the cycles of CH repeated every 4 weeks, is an attempt to integrate both treatments in close proximity without excessive toxicity by allowing time for recovery from each modality.7,10 Looney et al10,11 suggested the following based on the results of their experimental studies: (1) the alternating schedule might be more effective against solid tumors than the sequential or concurrent schedule; (2) the best results might be achieved when the treatment course begins with RT; and (3) RT given in multiple fractions per day might be more effective than single daily radiation fractions. Phase I/II or phase II trials in patients with stage III NSCLC showed that alternating treatment beginning with RT12,13 or with CH14-16 yielded a median survival of 9 to 14 months and a 5-year survival rate of up to 21% with manageable toxicity. Another important issue is the total dose and fractionation of thoracic RT when administered in combination with CH. Although the traditionally administered total dose of 60 Gy over 6 weeks is clearly not sufficient to achieve significant tumor control, the clinical benefit of doses greater than 60 Gy in patients with NSCLC is unclear.17 Hyperfractionated RT administered at the total dose of 69.6 Gy may bring a survival benefit over that of RT at the total dose of 60 Gy.5,18 When combined with CH, however, the elevated total dose using hyperfractionation did not always achieve good results.6,9,19,20 In our previous phase II study for unresectable stage III NSCLC, twice-daily thoracic RT at a total dose of 51 to 60 Gy and two to three cycles of cisplatin and vindesine produced a response rate of 67% with acceptable toxicity.21 The objective of the current study was to evaluate efficacy and toxicity of high-dose twice-daily RT alternating with the same CH regimen used in the previous study. We set the total dose of thoracic RT at 66 to 72 Gy, because such high-dose RT was considered potentially feasible with the use of the alternating schedule.
Patient Selection All patients underwent the following investigations for staging: chest x-ray, conventional chest tomography, and computed tomography (CT) of the chest and fiberoptic bronchoscopy; CT or magnetic resonance imaging of the head; bone scintigraphy; and CT or ultrasonography of the abdomen. The eligibility criteria were as follows: histologically proven NSCLC; unresectable stage IIIA or IIIB disease; tumor within an estimated irradiation field no larger than a half of the hemithorax; age 75 years or less; Eastern Cooperative Oncology Group performance status 0 or 1; no previous treatment; measurable disease; adequate bone marrow reserve (WBC count  4,000/µL, hemoglobin 11.0 g/dL, and platelet count 100,000/µL), liver (total bilirubin  1.5 mg/dL and transaminase levels twice the upper limit of the normal value), and renal (serum creatinine 1.5 mg/dL and creatinine clearance 60 mL/min) functions; and PaO2 70 Torr or more. Mediastinoscopy was not performed. The unresectability of the tumor was determined by discussions among the medical, surgical, and radiation oncologists. Patients were excluded if they had malignant pleural or pericardial effusion, active double cancer, lung fibrosis, cardiac or other diseases contraindicating RT or CH, or pregnancy. All patients gave written informed consent, and the protocol and the consent form were approved by the Clinical Trial Review Committee of Japan Clinical Oncology Group (JCOG) and the institutional review board at all the participating institutions.
Treatment and Monitoring
Two cycles of CH, consisting of cisplatin 80 mg/m2 on day 1 and vindesine 3 mg/m2 on days 1 and 8, were repeated every 4 weeks. A third cycle of CH was added if an objective tumor response was obtained. Cisplatin was administered by intravenous infusion over 60 minutes together with 2,500 to 3,000 mL of fluids for hydration. Vindesine diluted in 20 mL of normal saline was administered by bolus intravenous injection. All patients received a prophylactic antiemetic treatment consisting of a 5-hydroxytryptamine-3 antagonist and a corticosteroid. A complete blood cell count, blood chemistry, blood gas analysis, and chest x-ray film were obtained once a week during the treatment. Examinations performed at the time of initial staging, except for bronchoscopy, were repeated at the end of the treatment and every 6 months thereafter. In addition, CT scanning of the chest was performed during treatment if indicated.
Toxicity Criteria and Dose Modifications
Response Criteria
Data Management and Statistical Analysis The patient registration and data management were performed by the JCOG Data Center (JCOG DC). In-house interim monitoring was performed by JCOG DC for quality control. Monitoring reports were submitted to and reviewed by the JCOG Data and Safety Monitoring Committee semiannually. The late morbidity was additionally surveyed by the study coordinator after closing of follow-up by the JCOG DC. The statistical analysis was performed mostly by JCOG DC with SAS software version 6.12 for Windows (SAS Institute Inc, Cary, NC) and partly, exploratory logistic regression analysis, by the study coordinator with STATISTICA (Three’s Company Inc, Tokyo, Japan).
From February 1994 to November 1995, 41 patients were entered onto this study from four institutions. The first stage decision was made in May 1995, when 25 patients were registered. Fourteen PRs were observed in 19 analyzed patients, resulting in a response rate of 82% (95% confidence interval, 59% to 94%). This result did not meet the stopping criteria defined in the protocol, and the study was continued. At the final analysis, there were four censored cases (9.7%). The median follow-up period for these cases was 60.4 months (range, 53.8 to 69.1 months). Of the total 41 patients, 35 (85%) were male and six (15%) were female, and the median age was 60 years. Twenty-one patients (51%) had squamous cell carcinoma and 31 (76%) had stage IIIB disease (Table 1). One patient was ineligible because of a low level of hemoglobin at registration, but treatment delivery, toxicity, and efficacy were evaluated in all the 41 patients.
Treatment Delivery Treatment was discontinued in two patients because of complications unrelated to treatment. Preexisting ulcerative colitis became worse in the aforementioned ineligible patient when he had received RT up to the dose of 16.5 Gy. The patient did not receive any subsequent RT or CH and died of massive hemorrhage from the colon on day 21 from the commencement of the RT. Another patient developed retinal detachment after receiving 25.5 Gy of RT and one cycle of CH. Subsequent treatment was not given for the treatment of this complication. The median initial radiation field was 163 cm2 (range, 80 to 501 cm2), with a median esophageal involvement of 12.8 cm (range, 6.5 to 25.7 cm) (Table 2). The projected total dose of RT, 66 to 72 Gy, was administered in 35 (85%) of the 41 patients. Reasons for the early termination of RT in the remaining six patients included: severe esophagitis in two, decreased performance status in one, progressive disease in one, and a complication unrelated to treatment in two patients. Delay in RT was the major problem of this study; of 32 patients who completed the projected treatment schedule, 12 (38%) required interruptions of 5 to 14 days, and 12 (38%) required interruptions of 15 days or longer (Table 2). Reasons for the delay of 5 days or longer were leukopenia in 12, esophagitis in seven, infection not related to leukopenia in two, fever not related to infection in one, and causes not related to toxicity in two patients. The median duration of RT was 10.1 weeks (range, 8.4 to 14.4 weeks) in these 32 patients (Table 2). Three cycles of CH were administered in 26 patients (63%) and two cycles were given in eight patients (20%). The reasons for discontinuation of chemotherapy before the completion of two cycles in the remaining seven patients were neutropenia in one, congestive heart failure in one, drug-induced rash in one, patient refusal in one, progressive disease in one, and a complication unrelated to treatment in two patients. Full dose RT was administered without the splits for the second and third cycles of CH in five of the seven patients.
Toxicity Grade 3 or 4 leukopenia was noted in 32 patients (78%), and grade 4 thrombocytopenia was seen in one (2%) of the 41 patients (Table 3). Grade 3 or 4 esophagitis appeared in seven (18%) of 38 (three missing) patients for a median duration of 10 days (range, 6 to 24 days). An exploratory analysis of factors associated with severe esophagitis (grade 3 or higher) showed that the esophageal length in the irradiation field was associated with severe esophagitis (the odds ratio of an increase of 1 cm of esophageal length included in the irradiation field, 1.23 [95% confidence interval, 1.00 to 1.52], P = .05; and the odds ratio of esophageal length 13 cm over esophageal length less than 13 cm, 8.57 (95% confidence interval, 0.93 to 79.3], P = .07). Location of primary tumor and area of the radiation field showed elevated odds ratios (the odds ratio of left lower lobe over other sites, 4.35 [95% confidence interval, 0.74 to 25.6], P = .11; and the odds ratio of the area 164 cm2 over the area less than 164 cm2, 3.17 [95% confidence interval, 0.54 to 18.7], P = .21), but these factors are closely related to the esophageal length. Sex may be also associated with esophagitis. Seven (20%) of 35 male patients, but none of six female patients, developed severe esophagitis (the odds ratio cannot be calculated). Preexisting aortic regurgitation was aggravated during hydration and caused grade 3 cardiac dysfunction in one patient. Grade 4 decrease in PaO2 was observed in the aforementioned ineligible patient with ulcerative colitis in association with multiple organ failure due to massive hemorrhage from the colon. In other patients, the cardiac and pulmonary toxicities were mild, and dyspnea on exertion was not noted (Table 3). Death during treatment or within 30 days after treatment occurred in two patients, one was due to aggravation of preexisting ulcerative colitis described above and the other was due to massive hemoptysis.
Late morbidity was evaluated in 39 patients. One patient developed a bronchoesophageal fistula 50 months after the completion of treatment and died of massive hemoptysis with no tumor at autopsy, and another patient developed an esophageal stricture requiring dilatation 18 months after the completion of treatment. Acute esophagitis in these patients was classified as grade 2 in one and grade 3 in the other patient. Both patients received the RT of 72 Gy and three cycles of CH, with a 6-day delay in the RT. One patient developed pneumothorax requiring admission and tube drainage 10 months after the completion of treatment. One patient died of esophageal carcinoma 10 months after the completion of treatment.
Clinical Responses, First Relapse Sites, and Survival
This study showed that high-dose thoracic RT alternating with CH consisting of cisplatin and vindesine produced a high response rate and a median survival and 5-year survival rate comparable to the results obtained with other alternating,15,16 sequential,3-5,8 and concurrent6,8,9,19,20,27 chemoradiotherapy regimens. Acute and late esophageal toxicity in this trial, however, seemed as severe as, or worse than, toxicity in other trials of concurrent treatment, despite the 2-week split of thoracic RT.6,8,9,19,20 In addition, delay in RT was significant in this trial; a delay of 5 days or longer was observed in 24 (75%) of 32 patients who completed the projected RT and CH. Reasons for the delay were mainly leukopenia (in 12 patients) and esophagitis (in seven patients). In contrast, severe thrombocytopenia was not common in this study. This may be explained by the alternating approach, in which RT is not delivered during the first 2 weeks of CH and severe myelosuppression. Thus, the alternating approach in this trial failed to yield any theoretical advantage in terms of the incidence of acute toxicity, except for thrombocytopenia. The optimal timing of RT and CH is one of the most important issues in the treatment of stage III NSCLC, but it has not been established. The alternating approach of thoracic RT with cisplatin and vindesine does not seem better than other treatment schedules. Interruption and prolonged duration of RT have been considered as the main reasons for the failure of treatment with thoracic RT alone.28,29 We had assumed that cisplatin administered during the interval between two courses of RT would inhibit cellular repair of potentially lethal radiation damage and repopulation of tumor cells after exposure to RT.30,31 In addition, rapidly alternating RT with CH would decrease the emergence of tumor clones resistant to either modality, according to the Goldie-Coldman hypothesis.32 These theoretical advantages of the alternating approach, however, were not proven in this trial. This indicated the limits of extrapolating these preclinical tumor model systems. Since the proportion of local tumor control is 20%, at the most, in the treatment of stage III NSCLC,4 elevation of the total dose of RT may be worth investigating. A randomized phase I/II trial of hyperfractionated RT, in which 1.2 Gy per fraction was delivered twice daily up to total doses of 60 Gy to 79.2 Gy, showed that the best survival was obtained at the dose of 69.6 Gy without any significant increase in the toxicity.18 A randomized trial of conventional RT with 60 Gy versus hyperfractionated RT with 69.6 Gy showed a slight tendency favoring hyperfractionated RT.5 When systemic CH was added, however, the efficacy and toxicity of the treatment schedule varied among reports. A phase III trial of hyperfractionated RT with or without a moderate dose of carboplatin and etoposide yielded a significantly better overall survival (median survival, 22 months v 14 months; 4-year survival rate, 23% v 9%) and local relapse-free survival (42% v 19% at 4 years) in the combination arm.6 Acute and late grade 3 or 4 esophagitis was, surprisingly, observed in only 8% and 5%, respectively, of patients treated with CH and RT, which did not differ from the incidences of 6% and 5%, respectively, in the RT-alone arm.6 A phase II trial of hyperfractionated RT and a moderate dose of cisplatin and etoposide showed a similar median survival of 18.9 months but grade 3 or 4 esophagitis in 53% of patients.20 Two other trials of hyperfractionated RT and CH produced a median survival of only 12 to 14 months and grade 3 or 4 esophagitis in 24% to 38% of patients.9,19 Thus, except for the first trial, hyperfractionated RT at the total dose of 69.6 Gy in combination with CH resulted in a high incidence of severe esophagitis, and survival was not always better than that in trials using conventional RT at the dose of 60 Gy. The current study is one of the first multi-institutional efforts in locally advanced NSCLC to increase total dose of thoracic RT in combination with CH, using the alternating approach. Although the total dose of 70 to 72 Gy could be administered in 73% of patients, treatment delay was significant. Furthermore, the late severe esophageal toxicity was probably due to the high total dose. Thus, this trial failed to show clinical benefit of high-dose thoracic RT and systemic CH in patients with stage III NSCLC. In summary, high-dose RT alternating with cisplatin and vindesine yielded a respectable response rate and median survival and long-term survival rates comparable to chemoradiotherapy in other schedules in patients with stage III NSCLC. Acute and late esophagitis was observed and treatment interruption was required in most of the patients. These findings suggest that approaches such as the one evaluated in this trial should be utilized only in the context of a clinical trial.
The appendix is available online at www.jco.org. Contributing clinicians: Kaoru Kubota, Tetsuro Kodama, National Cancer Center Hospital, Tokyo; Ryutaro Kakinuma, Fumihiko Hojo, Taketoshi Matsumoto, Hironobu Ohmatsu, Michiya Yokozaki, Koichi Goto, Toru Miyamoto, Jun Takafuji, Wakako Shimizu, National Cancer Center Hospital East, Kashiwa; Yuzo Kurita, Satoshi Mitsuma, Hiromi Miyako, Yoshiyuki Suzuki, Niigata Prefectural Cancer Center, Niigata; Tsukasa Ohnishi, Tochigi Prefectural Cancer Center, Utsunomiya; Satoru Watanabe, Takeyuki Makimoto, Shinichi Ishihara, Tomoaki Sunaga, Kouji Satoh, Yoshihiro Saitoh, Ryusei Saitoh, National Nishigunma Hospital, Shibukawa; Miyuki Niimi, Haruhiko Fukuda, JCOG Data Center, Tokyo. External referees: Keiichi Nagao, Chiba University, Chiba; Masahiko Shibuya, Nippon Medical School, Tokyo.
Supported in part by Grants-in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan.
Presented in part at the Eighth World Conference on Lung Cancer, Dublin, Ireland, August 10-15, 1997, and at the Thirty-Sixth Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, May 20-23, 2000.
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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
