© 2005 Foundation for Promotion of Cancer Research
Standard Thoracic Radiotherapy With or Without Concurrent Daily Low-dose Carboplatin in Elderly Patients with Locally Advanced Non-small Cell Lung Cancer: a Phase III Trial of the Japan Clinical Oncology Group (JCOG9812)
1 National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, 2 National Cancer Center Hospital, Tokyo, 3 Kanagawa Cancer Center, Yokohama, 4 Yokohama Municipal Citizen's Hospital, Yokohama, 5 Niigata Cancer Center Hospital, Niigata, 6 Aichi Cancer Center, Nagoya, 7 Kumamoto Regional General Hospital, Kumamoto, 8 National Cancer Center Hospital East, Kashiwa, Chiba and 9 The Statistics and Cancer Control Division, National Cancer Center, Tokyo, Japan
For reprints and all correspondence: Shinji Atagi, National Hospital Organization Kinki-Chuo Chest Medical Center, 1180 Nagasone, Sakai, Osaka, 591-8555, Japan. E-mail: s-atagi{at}kch.hosp.go.jp
Received October 20, 2004; accepted February 14, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: The purpose of this study was to evaluate whether radiotherapy with carboplatin would result in longer survival than radiotherapy alone in elderly patients with unresectable stage III non-small cell lung cancer (NSCLC).
Methods: Eligible patients were 71 years of age or older with unresectable stage III NSCLC. Patients were randomly assigned to the radiotherapy alone (RT) arm, irradiation with 60 Gy; or the chemoradiotherapy (CRT) arm, the same radiotherapy and additional concurrent use of carboplatin 30 mg/m2 per fraction up to the first 20 fractions.
Results: This study was terminated early when 46 patients were registered from November 1999 to February 2001. Four patients (one in the RT arm, three in the CRT arm) were considered to have died due to treatment-related causes. The JCOG Radiotherapy Committee assessed these treatment-related deaths (TRDs) and the compliance with radiotherapy in this trial. They found that 60% of the cases corresponded to protocol deviation and 7% were protocol violation in dose constraint to the normal lung, two of whom died due to radiation pneumonitis. As to the effectiveness for the 46 patients enrolled, the median survival time was 428 days [95% confidence interval (CI) = 212–680 days] in the RT arm versus 554 days (95% CI = 331 to not estimable) in the CRT arm.
Conclusions: Due to the early termination of this study, the effectiveness of concurrent use of carboplatin remains unclear. We re-planned and started a study with an active quality control program which was developed by the JCOG Radiotherapy Committee.
Key Words: non-small cell lung cancer • elderly patients • carboplatin • chemoradiotherapy
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Lung cancer is the leading cause of cancer-related deaths in the USA, Europe and Japan. In Japan, the number of elderly is increasing dramatically. In 2001, the proportion of Japanese population older than 65 years was 18%; in other words, the number of people older than 65 years exceeded 22 million (1). Lung cancer death rates for men and women aged 75 or more have increased to
531 and 138 per 100 000 population, respectively (1). To establish the effective treatment for the elderly with lung cancer has thus become of greater importance. Until recently, the standard treatment for locally advanced non-small cell lung cancer (NSCLC) was radiotherapy alone. However, the 5-year survival rate of patients with stage III remained under 10% (2–4). To improve the survival rates, many clinical trials comparing radiotherapy with chemoradiotherapy have been conducted (5–11). A recent meta-analysis suggested that the combination of chemotherapy containing cisplatin (CDDP) and radiation could improve the survival rate compared with radiotherapy alone (12,13). However, it is still unclear whether the combined chemoradiotherapy is also suitable for elderly patients. This is partly because the elderly had been considered inappropriate as study patients.
Almost all evidence available has thus been derived from subset analysis of trials for locally advanced NSCLC. A secondary analysis of RTOG 94-10 revealed a greater survival benefit for concurrent chemotherapy (14). Schild et al. reported no significant difference in tumor regression between younger and older patients in an NCCTG trial (15). Meanwhile, some reports on inoperable NSCLC patients indicate that chemoradiotherapy has survival benefit compared with radiotherapy, but this may not be applicable for those >70 years of age, for whom radiation alone could be most beneficial (16,17).
Therefore, we cannot treat the elderly in the same way as we can younger patients: first, as elderly patients have poorer prognosis than younger patients, they may think that their quality of life is more important than risking radical treatment. Secondly, the elderly tend to be vulnerable to intensive care and toxicities of treatment drugs (18–21). Less toxic therapy may be more effective for the elderly with NSCLC.
Some clinical trials, in which the elderly were not included, showed some efficacy of carboplatin (CBDCA), an analog of CDDP, having no nephrotoxicity, neurotoxicity or ototoxicity and being much less emesis-provoking than CDDP (22–24). Additionally, some investigators found the same radiosensitizing properties of CBDCA (25–28) as also found for CDDP. Therefore, we hypothesized CBDCA to be more acceptable in the treatment of elderly patients. A phase II study has reported the use of radiotherapy and concurrent low-dose daily CBDCA in elderly patients with locally advanced NSCLC (29). For stage III patients, the median survival time (MST) was 15.1 months. Given an MST of 10 months by radiation alone (5,6,8,9,11,17), this combined chemoradiotherapy seemed promising. Here we performed a randomized study to determine whether this combined chemoradiotherapy has an impact on survival in elderly patients with unresectable locally advanced NSCLC compared with radiotherapy alone.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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PATIENTS
Eligibility criteria for this study were as follows: age
71 years; a histologically confirmed non-small cell carcinoma; unresectable disease; stage IIIA except T3N1M0 and IIIB which does not have disease extended to any contralateral hilar nodes or any supraclavicular nodes, atelectasis of the entire lung or malignant pleural effusions; measurable disease; a required radiation field of less than one half of one lung; no previous chemotherapy or radiotherapy; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2; PaO2 70 torr, white blood cell count 4000/µl, hemoglobin level 9.5 g/dl, platelet count 100 000/µl, serum bilirubin level 
1.5 mg/dl, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) twice the upper limit of normal, and serum creatinine level the upper limit of normal; a life expectancy of at least 3 months; and written informed consent. Exclusion criteria included patients with active infection, interstitial pneumonia or active lung fibrosis, chronic obstructive pulmonary disease (COPD) or uncontrolled heart disease, an active synchronous cancer, or a metachronous cancer within three disease-free years. Staging was performed by chest radiograph in two directions, computed tomography (CT) scan or magnetic resonance imaging (MRI) of the head, CT scan of the chest, CT scan or ultrasound of the abdomen, and bone scintigraphy.
TREATMENT
Patients were randomly assigned to the radiotherapy (RT) arm or the chemoradiotherapy (CRT) arm, by the minimization method of balancing PS (0 or 1 versus 2), stage (IIIA versus IIIB) and institution. The RT consisted of 60 Gy in 30 fractions over 6 weeks. In the CRT arm, patients received the same radiotherapy as in the RT arm and concurrent intravenous administration of CBDCA 30 mg/m2 (30 min infusion) 1 h before every radiation treatment up to the first 20 fractions (Fig. 1).
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Radiotherapy was delivered with megavoltage (6–10 MeV photons) equipment using anterior/posterior opposed fields up to 40 Gy including the primary tumor, the metastatic lymph nodes and the regional node. A booster dose of 20 Gy was given to the primary tumor and the metastatic lymph nodes for a total dose of 60 Gy using bilateral oblique fields. The clinical target volume (CTV) for the primary tumor was defined as the gross tumor volume (GTV) plus 1 cm taking account of subclinical extension. CTV and GTV for the metastatic nodes (>1 cm in shortest dimension) were the same. Regional nodes excluding contra-lateral hilar and supraclavicular nodes were included in the CTV; however, lower mediastinal nodes were included only if the primary tumor was located in the lower lobe of the lung. The planning target volumes for the primary tumor, the metastatic lymph nodes and regional nodes were determined as CTVs plus 0.5–1.0 cm margins laterally and 1.0–2.0 cm margins cranio-caudally taking account of set up variations and internal organ motion. Lung heterogeneity corrections were not used.
The criteria for stopping the treatment are pulmonary toxicities, which include the National Cancer Institute-Common Toxicity Criteria (NCI-CTC; version 2.0) grade 2 respiratory distress and <60 torr PaO2, other than hematopoietic toxicities (leukopenia, neutropenia and thrombocytopenia) or gastrointestinal toxicities (dysphagia).
EVALUATION
To assess the rate of tumor response and toxicity, all patients received a complete blood cell count; blood chemistry, including AST, ALT, lactate dehydrogenase, bilirubin, serum creatinine, blood urea nitrogen, total protein, serum albumin, serum electrolytes and calcium; and weekly chest X-rays during the treatment period. Best overall response was evaluated as tumor response by mono- or bi-dimensional measurement in accordance with the World Health Organization (WHO) criteria (30), and toxicity was evaluated in accordance with the NCI-CTC (version 2.0).
STUDY DESIGN AND STATISTICAL ANALYSIS
This trial was a multi-center randomized phase III study. The study protocol was approved by the JCOG Clinical Trials Review Committee and the institutional review board of each participating institution before the initiation of the study.
The primary end-point was overall survival, which was defined as the interval from randomization to death from any cause. Secondary end-points were response rate, which was the proportion of the patients evaluated as having a complete reponse (CR) or partial response (PR) in best overall response out of all eligible patients; progression-free survival (PFS) defined as the interval from randomization to the diagnosis of progression or death from any cause; sites of progression; and toxicity. The estimate of survival time was performed by the Kaplan–Meier method (31). The trial was designed to have an 80% power to detect 5 months difference in MST (10 months in the RT arm and 15 months in the CRT arm) with a one-sided alpha of 0.05 by log rank test (32). The planned sample size was 190 patients by Shoenfeld and Richter's methods (33) with 1.5 years follow-up after 3 years accrual.
In-house interim monitoring is performed by the JCOG Data Center to ensure data submission, patient eligibility, protocol compliance, safety and on-schedule study progress. The monitoring reports are submitted and reviewed by the JCOG Data and Safety Monitoring Committee (DSMC) twice yearly.
An expedited report was required by the JCOG DSMC to allow rapid identification of any life-threatening adverse events or unexpected toxicities according to the JCOG toxicity reporting system based on the ICH-E2A guidelines.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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From November 1999 to February 2001, 46 patients were enrolled in this study: 23 in the RT arm and 23 in the CRT arm. Four treatment-related deaths (TRDs) had been reported, however, before the forty-sixth patient were assigned. Therefore, we suspended the registration and checked the details of all randomized patients to assess the safety of treatment regimens. As a result, it was revealed that three of these deaths were due to pneumonitis. The JCOG DSMC advised consultation with the JCOG Radiotherapy Committee (RC) about the radiotherapy compliance in all patients. The JCOG RC collected each patient's irradiation planning data retrospectively and found poor protocol compliance which was related to TRD. Consequently, we decided to terminate this trial in August 2001 following the recommendation of the JCOG DSMC.
PATIENTS CHARACTERISITICS
Patient characteristics are listed in Table 1. No specific characteristics of patients were found in the elderly patients with locally advanced NSCLC compared with younger patiests and the two treatment arms were well balanced with respect to age and stage.
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TOXICITY OF TREATMENT
Both hematological and non-hematological toxicities during the treatment and follow-up period were assessed. Table 2 summarizes the hematological toxicity. Patients receiving CBDCA suffered from leukocytopenia, neutropenia and thrombocytopenia more than patients receiving RT alone. There was no grade 4 hematological toxicity in the RT arm. Two (8.7%) and four (17.4%) patients in the CRT arm experienced grade 4 leukocytopenia and neutropenia, respectively.
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Non-hematological toxicity observed in this study is listed in Table 3. None of the patients developed grade 3 esophagitis in either treatment arm. In the RT arm, other grade 3/4 toxicities were edema, fatigue, dyspnea and pneumonitis in one patient each. In the CRT arm, other grade 3/4 toxicities were neutropenic fever, dyspnea and pneumonitis. Grade 3/4 (RTOG/EORTC Radiation Toxicity Score) of late lung toxicity was observed in two patients in the RT arm and four patients in the CRT arm. Four TRDs were observed in this study. Three of these patients were thought to have died as a result of pneumonitis. The details of these cases are follows. Case 1: a 78-year-old man had stage IIIA (T3N2) squamous cell carcinoma. He was treated with RT alone and died of pneumonitis at 28 days after therapy. Case 2: a 79-year-old man had stage IIIB (T4N2) adenocarcinoma. He was treated with CBDCA + RT and died of bacterial pneumonia at 37 days after therapy and had been taking steroid hormone due to radiation pneumonitis. Case 3: a 73-year-old man had stage IIIA (T3N2) squamous cell carcinoma. He was treated with CBDCA + RT and died of pneumonitis at 80 days after therapy. Case 4: a 80-year-old man had stage IIIB (T4N2) squamous cell carcinoma. He was treated with CBDCA + RT and died of pneumonitis at 54 days after therapy. Thus, three out of four TRDs were in the CRT arm and one was in the RT arm.
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PROTOCOL COMPLIANCE
In the RT arm, 22 (95.6%) patients received full treatment doses. In the CRT arm, 20 (87.0%) patients completed the treatment. As to the administration of CBDCA, there were few protocol deviations.
Three of the patients discontinued the protocol treatment: one was due to grade 2 eruption, one was due to cerebral infarction and one was due to insufficient recovery from leukopenia. One patient in the RT arm did not start the treatment due to local progression (Table 4).
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QUALITY ASSURANCE OF RADIOTHERAPY
We evaluated the quality of radiotherapy retrospectively based on the collected radiation therapy planning data. The data of 45 patients were reviewed and evaluated for the analysis. Details of this analysis have been reported by Ishikura et al. (34); three cases were revealed to be protocol violation due to normal lung volume constraint defined in the protocol. Unacceptable protocol deviations were identified as follows; 17, 15 and 31 cases on field border placement for the primary tumor, the metastatic lymph nodes and the elective nodal irradiation, respectively. Overall, 27 of 45 cases (60%) had at least one unacceptable deviation. Most cases judged to have protocol violation were primarily due to a smaller radiation field. Only 18 cases (40%) were judged to be protocol compliant.
RESPONSE AND SURVIVAL
The tumor response in each arm is listed in Table 5. No patients achieved a CR in either arm. Of the 23 patients in the RT arm, 12 [52.2%, 95% confidence interval (CI) = 30.6–73.2%] achieved PR and six (26.1%) had stable disease. Of the 23 patients in the CRT arm, 11 (47.8%, 95% CI = 26.8–69.4%) achieved PR and seven (30.4%) had stable disease.
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Seventeen (73.9%) patients in the RT arm and 15 (65.2%) patients in the CRT arm had died at the time of analysis. The median progression-free survival time was 122 days (95% CI = 88–413 days) on the RT arm versus 248 days (95% CI = 127–416 days) on the CRT arm (Fig. 2.). The MST was 428 days (95% CI = 212–680 days) on the RT arm versus 554 days (95% CI = 331 to not estimable) on the CRT arm (Fig. 3.). The 1-year survival rate was 60.9% (95% CI = 40.9–80.8%) on the RT arm versus 65.2% (95% CI = 45.8–84.7%) on the CRT arm.
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PATTERN OF PROGRESSION/RELAPSE
The first site of disease progression or relapse is listed in Table 6. Sixteen patients in the RT arm and 13 patients in the CRT arm had relapsed or had disease progression at the time of analysis. Eight patients (out of 16, 50.0%) in the RT arm and seven patients (out of 13, 53.8%) in the CRT arm had relapse or disease progression within the radiation field whether relapse outside the radiation field occurred or not.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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We conducted this randomized controlled trial to determine whether chemoradiotherapy was superior to radiotherapy alone with respect to overall survival of elderly patients with locally advanced NSCLC. The study was terminated early when 24% of the planned sample size was accrued because of a high proportion of TRDs due to radiation pneumonitis and protocol violation.
Pulmonary toxicities including radiation pneumonitis and fibrosis caused by radiation therapy are, in general, common but not severe. In this study, however, the risk of TRD was 8.7% (four out of 46) and was much higher than in other trials. For instance, Ohe et al. (35) retrospectively analyzed the incidence of TRDs in the treatment of thoracic radiotherapy and/or chemotherapy for patients with locally advanced NSCLC, and reported that seven of 448 patients (1.6%) died of radiation-induced pneumonitis. The high proportion of pulmonary toxicities in our trial may be due partly to the high age of the patients. Schild et al. (15) reported that they found 6% of elderly (older than 75 years) with NSCLC had grade 4 pneumonitis whereas this was the case in only 1% of younger patients (P = 0.02). It was controversial that the four TRDs out of 46 was sufficient reason to terminate the on-going trial; however, we thought it was serious that half of the TRDs (two out of four) were judged to be associated with protocol violation concerning the radiation field, which was to be less than half of one lung. Because the JCOG had not yet established the quality control/assurance system for radiotherapy before this trial, we concluded that we would not be able to control the risk of radiation pnuemonitis due to protocol deviation if we continued this study. What was an issue in this study was not only the high TRD rate, but also the poor protocol compliance of RT. The reasons for the poor protocol compliance are limited participation of radiation oncologists during protocol development, limited educational resources for attending radiation oncologists and no quality control program. Although the retrospective systematic review of radiation planning and protocol compliance of radiotherapy was the first experience in the JCOG, both the Lung Cancer Study Group and the entire JCOG had become aware of the importance of a quality control system for radiotherapy. The JCOG Executive Committee decided to establish the Radiation Therapy Quality Assurance Center (RTQAC) within the JCOG Data Center under the supervision of the JCOG Radiotherapy Committee. The RTQAC started the prospective quality control and quality assurance (QC/QA) program in September 2002 with a new activated phase III study for limited disease of small cell lung cancer, JCOG0202. Up to 2004, the QC/QA program has been expanded to the other group studies, such as esophageal cancer study, breast cancer study, prostate cancer study and brain tumor study. In addition, the JCOG Executive Committee mandates the QC/QA program by the RTQAC for all JCOG trials when protocol treatment includes radiation therapy.
The clinical question raised in this trial has not been answered. The data from the 46 patients enrolled were not considered to be conclusive because of the small sample size. No remarkable difference was found between the arms in terms of safety and efficacy such as tumor response, PFS and overall survival. We considered that it still remained an important clinical question to be investigated whether the daily low-dose CBDCA plus radiotherapy was effective or not. Therefore, we re-planned and started a new phase III trial (JCOG0301), in which the prospective QC/QA program by the RTQAC is added to the identical design to this JCOG9812. The protocol involves initial review of radiation planning and final review of the actual radiation record for all randomized patients. The JCOG0301 was activated in September 2003, and we have achieved very good protocol compliance upto now.
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Acknowledgments |
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We thank Ms M. Imai and Dr M. Niimi for their data management, and Dr H. Fukuda for his direction of the JCOG Data Center and oversight of management of the study. This study was supported in part by Grants-in-Aid for Cancer Research (11S-2, 11S-4, 14S-2, 14S-4) and for Second Term Comprehensive 10-year Strategy for Cancer Control (H12-Gan-012) from the Ministry of Health, Labour and Welfare.
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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