Japanese Journal of Clinical Oncology 31:488-494 (2001)
© 2001 Foundation for Promotion of Cancer Research
Randomized Phase I Study of Standard-fractionated or Accelerated-hyperfractionated Radiotherapy with Concurrent Cisplatin and Vindesine for Unresectable Non-Small Cell Lung Cancer: a Report of Japan Clinical Oncology Group Study (JCOG 9601)
1Division of Internal Medicine, National Nishigunma Hospital, Shibukawa, Gunma, 2Department of Internal Medicine, National Cancer Center Hospital, Tokyo, 3Department of Internal Medicine, Aichi Cancer Center, Nagoya, 4Department of Therapeutic Radiology, Aichi Cancer Center, Nagoya, 5Department of Radiology and Radiation Oncology, Gunma University School of Medicine, Maebashi, Gunma, 6Department of Thoracic Diseases, Tochigi Cancer Center, Utsunomiya, 7Internal Medicine III, National Defense Medical College, Tokorozawa, Saitama, 8Department of Respiratory Medicine, Toranomon Hospital, Tokyo, 9Division of Respiratory Medicine, Gifu Municipal Hospital, Gifu, 10Department of Internal Medicine, Nagano Municipal Hospital, Nagano, 11Division of Respiratory Medicine, Shizuoka General Hospital, Shizuoka, 12Department of Respiratory Medicine, Nagoya National Hospital, Nagoya, 13First Department of Internal Medicine, University of the Ryukyus, Okinawa and 14Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Background: We attempted dose escalation of standard-fractionated and accelerated-hyperfractionated radiotherapy combined with concurrent cisplatin and vindesine to improve local control and survival in unresectable non-small cell lung cancer.
Methods: Twenty-one patients were enrolled between June 1996 and August 1997. There were 19 males and two females and their median age was 65 years (range 45–74 years). Performance status was 0 in 10 cases and 1 in 11 cases. Disease stage was IIIA in three cases and IIIB in 18 cases. The cases were randomized to a standard-fractionated arm (n = 10) or an accelerated-hyperfractionated radiotherapy arm (n = 11) with two or three cycles of concomitant cisplatin 80 mg/m2 on day 1 and vindesine 3 mg/m2 on days 1 and 8 every 4 weeks in both arms. Dose escalation from 60 Gy/30 fractions/6 weeks to 70 Gy/35 fractions/7 weeks was planned in the standard-fractionated radiotherapy group and from 54 Gy/36 fractions/3.6 weeks to 60 Gy/40 fractions/4 weeks and then 66 Gy/44 fractions/4.4 weeks in the accelerated-hyperfractionated radiotherapy group.
Results: Grade 3 or 4 hematological toxicities were observed as follows: in the standard-fractionated/accelerated-hyperfractionated radiotherapy group, leukocytopenia 9/10, anemia 2/3 and thrombocytopenia 0/2. Grade 3 non-hematological toxicity consisted of esophagitis 0/3, increased serum total bilirubin 2/0 and hypoxia 0/1. Two patients died of radiation pneumonitis in the standard-fractionated radiotherapy group. Dose-limiting toxicity was observed in four of the 10 and seven of the 11 patients at initial dose level of standard-fractionated radiotherapy, 60 Gy/30 fractions/6 weeks, and of accelerated-hyperfractionated radiotherapy, 54 Gy/36 fractions/3.6 weeks, respectively. Thus, we failed to escalate the dose of radiotherapy in both arms. The overall response rate in the standard-fractionated group and the accelerated-hyperfractionated radiotherapy group was 70 and 73% and the 1-year survival rate was 70 and 64%, respectively.
Conclusions: We concluded that these schedules of radiotherapy with concurrent cisplatin and vindesine were unacceptable for use in patients with unresectable non-small cell lung cancer. Further modifications of the schedule for radiotherapy and evaluation of combination with new chemotherapy are warranted.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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For many years, thoracic radiotherapy has been regarded as the standard treatment for patients with unresectable locally advanced non-small cell lung cancer (NSCLC) (1,2). However, such treatment has not been satisfactory in terms of patient survival because of the high rates of both distant metastasis and local recurrence (3,4). Many strategies have been assessed to improve the response rate and survival, such as dose escalating or hyperfractionated radiotherapy and combined with induction or concurrent chemotherapy (5–11).
The Cancer and Leukemia Group B (CALGB) study concluded that patients who received induction chemotherapy followed by radiotherapy enjoyed a better survival than those who had received radiotherapy alone and meta-analysis of 1780 cases in 11 randomized trials showed that cisplatin-containing chemoradiotherapy was significantly superior to radiotherapy alone in terms of survival (10,12). On the other hand, Kubota et al. reported that addition of radiotherapy to chemotherapy for locally advanced NSCLC significantly improved the 2- and 3-year survival rates compared with chemotherapy alone (13). Thus, both chemotherapy and radiotherapy are essential to the treatment of locally advanced NSCLC. A randomized trial conducted by the North Central Cancer Treatment Group (NCCTG) comparing standard-fractionated (SDF: 2 Gy/day) and accelerated-hyperfractionated (AHF: 1.5 Gy x 2/day) radiotherapy showed a median survival time of 8.7 months in the SDF group versus 12.3 months in the AHF group (9). However, this study was interrupted, because radiotherapy alone was found to be inadequate for the treatment of locally advanced NSCLC.
The Radiation Therapy Oncology Group (RTOG73-01) conducted a study of various irradiation doses and fractionation schedules in radiotherapy for NSCLC and found that the 60 Gy continuous schedule was superior to the same dose given in a split-course fashion (2–4). Thoracic radiotherapy consisting of 60 Gy in 30 fractions over 6 weeks is the most commonly used radiotherapy regimen for locally advanced NSCLC in Japan and the USA. However, the results of some studies have suggested better survival among patients who received higher doses of radiotherapy, such as 70 Gy (5–7). The optimal fractionated schedule and maximum tolerated dose of radiotherapy are still unknown and have not yet been adequately investigated. We therefore planned a comparable dose-escalation study of SDF and AHF radiotherapy with concurrent chemotherapy consisting of cisplatin and vindesine in patients with unresectable stage III NSCLC.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Patient Selection
Patients with histologically and/or cytologically documented NSCLC were eligible to participate in this study. Each patient was required to meet the following criteria: clinical stage III without pleural and/or pericardiac effusion, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1, age 20–74 years, no prior therapy, evaluable or measurable lesion, adequate hematological function (leukocyte count 4.0–<10.0 x 109/l, platelet count
100 x 109/l, hemoglobin 10.0 g/dl), adequate hepatic function (total bilirubin 
2.0 mg/dl, AST and ALT 100 IU/l), adequate renal function (creatinine 1.5 mg/dl, creatinine clearance 60 ml/min), partial pressure of arterial oxygen (PaO2) 70 Torr and % carbon monoxide diffusing capacity of the lung (DLCO) 50%. Patients with active infection, severe heart disease, uncontrolled hypertension or diabetes mellitus, active concomitant malignancy and pregnant/nursing women were excluded. This study protocol was approved by the JCOG Clinical Trials Review Committee and by the Institutional Review Board at each participating center and written informed consent was obtained from each patient.
Evaluation
Pretreatment evaluation consisted of a complete blood cell count, differential count, routine chemistry measurements, chest radiograph, chest computed tomography (CT) scan, abdominal ultrasound or CT scan, whole-brain CT scan and radioisotope bone scan. Complete blood cell counts, differential counts and routine chemistry measurements were performed at least twice per week during treatment.
Objective tumor responses were evaluated according to World Health Organization criteria (14). Complete response (CR) was defined as the complete disappearance of all clinically detectable tumors for at least 4 weeks. Partial response (PR) was defined as an at least 50% reduction in the sum of products of the largest perpendicular diameters of one or more clearly measurable lesions or as a >50% reduction in evaluable malignant disease lasting more than 4 weeks with no new malignant lesions. No change (NC) was defined as: regression of indicator lesions insufficient to meet the criteria for response, a <25% increase in any measurable lesion and no new malignant lesions. Progressive disease (PD) was defined as an increase in any measurable lesion by >25% or new malignant lesions. The toxicity grading criteria of the Japan Clinical Oncology Group (JCOG) were used for evaluation of acute toxicity (15). Radiation-induced late toxicity was scored by the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) late radiation morbidity scoring scheme (16).
Treatment
The eligible patients were randomly assigned to receive SDF or AHF radiotherapy with concurrent chemotherapy consisting of cisplatin and vindesine. In both arms, two or three courses of chemotherapy consisting of cisplatin 80 mg/m2 on day 1 and vindesine 3 mg/m2 on days 1 and 8 every 4 weeks were administered. Radiotherapy was started on day 2 of the first course of the chemotherapy. The initial radiation doses were 60 Gy in 30 fractions over 6 weeks in the SDF arm and 54 Gy in 36 fractions over 3.6 weeks in the AHF arm. Dose escalation was planned in the SDF arm, from 60 Gy in 30 fractions over 6 weeks to 70 Gy in 35 fractions over 7 weeks and in the AHF arm, from 54 Gy in 36 fractions over 3.6 weeks to 60 Gy in 40 fractions over 4 weeks and then to 66 Gy in 44 fractions over 4.4 weeks. X-ray radiotherapy was administered with linear accelerator (6–10 MeV). The primary tumor and ipsilateral hilar and mediastinal lymph nodes with optimal margin were included in the initial volume. The supraclavicular nodes were included in the field, whenever supraclavicular node involvement was observed. No patients received radiotherapy with a field that included the contralateral hilum and more than half of the ipsilateral lung. The boost volume of radiotherapy beyond 40 Gy (SDF arm) or 39 Gy (AHF arm) included the primary tumor and involved lymph nodes. The spinal cord was excluded from the irradiated volume at 40 Gy (SDF arm) and 39 Gy (AHF arm) by using parallel, opposed oblique fields.
Modification of Chemotherapy
Chemotherapy was administered at the full calculated dose when the patient met the following criteria: leukocyte count 3.0 x 109/l, platelet count 75 x 109/l, serum creatinine <1.6 mg/dl, PS 0–2, no fever (<37.5°C), total bilirubin 2.0 mg/dl, AST and ALT 100 IU/l. If the patient did not meet the criteria on the date planned to start the next chemotherapy course, chemotherapy was postponed until the patient met the criteria. If the patient did not meet the criteria except for creatinine <1.6 mg/dl, administration of vindesine was canceled on days 8, 36 and 64. Whenever there was grade 3 or 4 non-hematological toxicity, PS 4 or chemotherapy was postponed more than 2 weeks, then the patient was withdrawn from all chemotherapy. If grade 4 thrombocytopenia, grade 4 leukocytopenia or neutropenia lasting 5 days or more occurred during the first or second course, the doses of cisplatin and vindesine were reduced to 75% in the next course. If the serum creatinine level was >2.0 mg/dl in the previous course, cisplatin was reduced to 75% of the dose.
Modification of Radiotherapy
Radiotherapy was interrupted if the patient met any of the following criteria: grade 4 leukocytopenia or thrombocytopenia, fever (more than 37.5°C), PS 3, 10 Torr decrease in PaO2 or grade 2 radiation-induced esophagitis. Radiotherapy was restarted when the patient no longer met the criteria. Radiotherapy was terminated if the patient met any of the following criteria: grade 3 radiation-induced esophagitis and/or dermatitis, PS 4, PaO2 <70 Torr and 10 Torr decrease from the baseline or more than a 2-week delay of radiotherapy.
Study Design
The trial was designed as a prospective, randomized, non-blinded study. The JCOG Data Center (JCOG DC) stratified patients according to institutions and stage and then randomly assigned them in each stratum to receive either SDF or AHF radiotherapy.
Dose-limiting toxicity (DLT) was defined as any of following: grade 4 leukocytopenia or neutropenia lasting 5 days or more, grade 4 thrombocytopenia, grade 4 neutropenia with fever, grade 3 or 4 non-hematological toxicity except nausea/vomiting, incomplete chemotherapy and/or radiotherapy. Dose escalation was planned according to the following rules. Initially, 10 patients were treated at the initial dose in each arm. If DLT was observed in 0–1 of the 10 patients, the dose escalation was performed. If DLT was observed in 2–3 of the 10 patients, an additional 10 patients were entered at the same dose level. If DLT was observed in four or more of the 10 patients, the dose was concluded to be the maximum tolerated dose (MTD). If DLT was observed in four or fewer of 20 patients, dose escalation was performed. The decisions regarding dose escalation were based on acute toxicity of chemotherapy and radiotherapy alone. Overall survival was calculated from the date of randomization to death or last follow-up evaluation. Survival distribution was estimated by the Kaplan–Meier method.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Patients’ Characteristics
Between June 1996 and August 1997, 21 patients were enrolled at 10 of the 28 participating institutions: Tochigi Cancer Center, National Nishigunma Hospital, National Defense Medical College, Toranomon Hospital, Nagano Municipal Hospital, Gifu Municipal Hospital, Shizuoka General Hospital, Aichi Cancer Center, Nagoya National Hospital and University of the Ryukyus. The clinical characteristics of the patients at the time of registration are listed in Table 1. Ten patients were entered in the SDF arm, median age 55 years (range 45–67 years) and 11 patients in the AHF arm, median age 66 years (range 50–74 years). Bone metastasis was detected by re-evaluation of radioisotope bone scans performed before registration in one patient in the SDF arm; however, the patient was included in all analyses. The eleventh patient was entered in the AHF arm because the patient had been registered before the information that registration had been stopped was obtained.
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Treatment Delivery
The delivery of chemotherapy and radiotherapy is shown in Table 1. Seven of the 10 patients in the SDF arm and 10 of the 11 in the AHF arm received chemotherapy and radiotherapy as defined by the protocol. Two of the 10 patients in the SDF arm and one of the 11 patients in the AHF arm received only one cycle of chemotherapy. Three of the 10 patients and one of the 11 patients could not be given the total dose of radiotherapy planned. Three of the seven and four of the 10 patients who received the total dose planned in the SDF arm and AHF arm, respectively, completed radiotherapy without treatment delay and the median delay in the SDF arm and the AHF arm was 4 days (range 1–7 days) and 3 days (range 1–5 days), respectively.
Acute Toxicity
Acute toxicities of both treatment arms are listed in Table 2. Hematological toxicity, especially, leukocytopenia and neutropenia, was relatively severe in both treatment arms. Grade 3 or 4 leukocytopenia occurred in most of the patients. Radiation-induced esophagitis, however, was more severe in the AHF arm than in the SDF arm. Grade 2 or worse esophagitis never occurred in the SDF arm, but six of the 11 patients in the AHF arm developed grade 2 or 3 radiation-induced esophagitis. Grade 3 pulmonary toxicity was recognized in one patient in the AHF arm. Grade 3 total bilirubin elevation occurred in two patients in the SDF arm. The bilirubin values in these patients were slightly increased, 1.8 and 1.5 mg/dl, at the time of registration. The DLTs observed are listed in Table 3. Unexpectedly, four of the 10 patients in the SDF arm and seven of the 11 patients in the AHF arm met the criteria for DLT. Therefore, we were unable to proceed to the next higher radiotherapy dose in either arm.
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Late Toxicity
The late toxicities in both treatment arms are summarized in Table 4 based on the RTOG/EORTC late radiation morbidity scoring scheme. Two patients died of respiratory failure 19 and 47 weeks after the start of treatment, so the association between the death and treatment could not be neglected. We conclude that these patients died of radiation-induced pulmonary toxicity. Grade 2 pulmonary toxicity occurred in two patients each in the SDF and AHF arms. Other late toxicity was relatively mild. Grade 2 esophageal toxicity was observed in only one patient in the AHF arm.
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Objective Tumor Response and Overall Survival
No patients achieved CR in both arms. Seven of the 10 patients [70%, 95% confidence interval (CI) 35–93%] and eight of the 11 patients (73%, 95% CI 39–94%) achieved PR in the SDF and AHF arm, respectively. The overall survival of all patients treated in the SDF and AHF arms is shown in Fig. 1. The median survival time was 15.2 months (455 days, 95% CI 333–789 days) and 18.4 months (553 days, 95% CI 242–927 days); in the SDF arm and the AHF arm, the 1-year survival rates were 70 and 64% and the 2-year survival rates were 30 and 33%, respectively.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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The combination of radiotherapy and chemotherapy using cisplatin-based regimens has been extensively investigated in locally advanced NSCLC. Recent randomized trials have demonstrated a benefit of the concurrent approach (11,17). The timing of chemotherapy and radiotherapy may be important. Furuse et al. (11) reported superior survival as a result of concurrent chemoradiotherapy consisting of cisplatin, vindesine, mitomycin and 56 Gy of SDF radiotherapy with split courses, compared with the same chemotherapy followed by sequential 56 Gy of SDF radiotherapy without a split. The median survival times and 5-year survival rates in the concurrent arm and the sequential arm were 16.5 months and 15.8% and 13.3 months and 8.9%, respectively (p = 0.039) (11). The RTOG recently reported similar results in a comparison between concurrent and sequential chemoradiotherapy (RTOG9410) (17). The median survival time in the concurrent and the sequential arm was 17.0 and 14.6 months, respectively (p = 0.08) (17). Hence the results of these trials for NSCLC seem to support the concept that early destruction of as many cancer cells as possible by combined-modality treatment is a therapeutic principle that may also apply to the treatment of cancers and that direct enhancement of local control by simultaneous chemotherapy and radiotherapy may improve both local control and long-term survival.
In order to improve local control and long-term survival, we attempted dose escalation of radiotherapy with concurrent chemotherapy consisting of cisplatin and vindesine. However, we were unable to perform the dose escalation of the radiotherapy because of the unexpected incidence of DLTs defined in the protocol (Table 3). Up to 60 Gy of concurrent SDF and AHF radiotherapy with cisplatin and vindesine had already been used in the JCOG phase II trials, JCOG8902 and JCOG9201 (18,19). In the JCOG8902 trial, concurrent 60 Gy SDF radiotherapy was combined with cisplatin and vindesine using a split course. However, only three of the 10 patients completed radiotherapy without delay, suggesting that most patients with locally advanced NSCLC could not tolerate 60 Gy of concurrent chemoradiotherapy by SDF radiotherapy without a break in the radiotherapy. In the JCOG9201 trial, 51–60 Gy concurrent chemoradiotherapy using AHF radiotherapy was administered to the patients. Moreover, 45Gy using AHF with concurrent chemotherapy is widely used for patients with small cell lung cancer. We were concerned that a lower dose might diminish the efficacy of radiotherapy. Therefore, we decided on an initial dose of 54 Gy in the AHF arm. However, 54 Gy concurrent chemoradiotherapy using AHF radiotherapy was regarded as intolerable in this trial. We could not rule out the possibility that the toxicity of the chemoradiotherapy had been underestimated in the JCOG9201 trial. Moreover, Choi et al. judged the MTD of AHF radiotherapy combined with chemotherapy to be 45 Gy in 30 fractions over 3 weeks (20). We therefore concluded that 54 Gy or a higher dose of AHF radiotherapy with concurrent chemotherapy could not be used to treat patients with locally advanced NSCLC, except under the special conditions of a clinical trial. Acute esophagitis was more severe and frequent in the AHF arm than in the SDF arm in this study. Myelosuppression and especially leukocytopenia and neutropenia were relatively severe in both the SDF and AHF arms. This schedule of concurrent chemoradiotherapy may not be feasible for most patients. The toxicity associated with concurrent and continuous radiotherapy with full-dose chemotherapy was tolerable in only a few selected patients.
In this trial we based the decision to escalate the radiotherapy dose on the acute toxicity of the chemoradiotherapy alone. Of course, the late toxicity is also important. However, it is difficult to include late toxicity in the decision to proceed with dose escalation and the decision of MTD, because long-term follow-up of toxicity is essential and the incidence of severe late toxicity is usually not very high. It has been reported that of 448 patients who received thoracic radiotherapy with or without chemotherapy, seven (1.6%) died of radiation-induced pneumonitis (21). In this trial, two of the 10 patients treated in the SDF arm were considered to have died of pneumonitis. However, because the number of patients was too small, we could not conclude that the late pulmonary toxicity after 60 Gy of SDF radiotherapy with concurrent cisplatin and vindesine was unacceptable. A larger number of patients is required to evaluate severe late toxicity, such as radiation-induced late pulmonary toxicity, which occurs in a relatively small proportion of patients. Moreover, late toxicity could not be predicted from acute toxicity. The evaluation of late toxicity of radiotherapy in phase I studies seems very difficult.
We concluded that these schedules of radiotherapy with concurrent cisplatin and vindesine are not acceptable for patients with unresectable non-small cell lung cancer. More effective but less toxic chemotherapy with radiotherapy must be developed to improve the survival and quality of life in patients with locally advanced NSCLC. Further modifications of the schedule for radiotherapy and evaluation of combination with new chemotherapy are warranted.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare (5S-1, 8S-1, 11S-2, -4) and a grant from the Ministry of Health, Labour and Welfare for 2nd term Comprehensive Strategy for Cancer Control (H10-Gan-027, H12-Gan-012), Japan. We thank Ms Miyuki Niimi for data management and Dr Kimio Yoshimura for analyses during periodic interim monitoring by the JCOG Data Center.
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FOOTNOTES |
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+ For reprints and all correspondence: Yuichiro Ohe, Department of Internal Medicine, National Cancer Center Hospital, 1–1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. E-mail: yohe@ncc.go.jp
Abbreviations: JCOG, Japan Clinical Oncology Group; NSCLC, non-small cell lung cancer; CALGB, Cancer and Leukemia Group B; NCCTG, North Central Cancer Treatment Group; SDF, standard-fractionated; AHF, accelerated-hyperfractionated; RTOG, Radiation Therapy Oncology Group; ECOG, Eastern Cooperative Oncology Group; PS, performance status; PaO2, partial pressure of arterial oxygen; DLCO, % carbon monoxide diffusing capacity of the lung; CT, computed tomography; EORTC, European Organization for Research and Treatment of Cancer; DLT, dose-limiting toxicity, MTD, maximum tolerated dose
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Received March 21, 2001; accepted July 17, 2001.
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