Phase III Trial Comparing Docetaxel and Cisplatin Combination Chemotherapy With Mitomycin, Vindesine, and Cisplatin Combination Chemotherapy With Concurrent Thoracic Radiotherapy in Locally Advanced Non–Small-Cell Lung Cancer: OLCSG 0007

  1. Mitsune Tanimoto
  1. From Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences and Okayama University Hospital; Okayama Red Cross Hospital; National Hospital Organization (NHO) Okayama Medical Center, Okayama; NHO Shikoku Cancer Center, Matsuyama; Sumitomo Besshi General Hospital, Niihama; Chugoku Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuyama; NHO Fukuyama Medical Center, Fukuyama; NHO Minami-Okayama Medical Center, Tsukubo; NHO Yamaguchi-Ube Medical Center, Ube; and Aichi Cancer Center Research Institute, Nagoya, Japan.
  1. Corresponding author: Katsuyuki Kiura, MD, PhD, Department of Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikatacho, Kitaku, Okayama 700-8558, Japan; e-mail: kkiura{at}md.okayama-u.ac.jp.

  1. Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006 Atlanta, GA, and at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL.

 
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Abstract

Purpose To demonstrate the efficacy of docetaxel and cisplatin (DP) chemotherapy with concurrent thoracic radiotherapy (TRT) for patients with locally advanced non–small-cell lung cancer (LA-NSCLC).

Patients and Methods Patients age 75 years or younger with LA-NSCLC, stratified by performance status, stage, and institution, were randomly assigned to two arms consisting of DP (docetaxel 40 mg/m2 and cisplatin 40 mg/m2 on days 1, 8, 29, and 36) or mitomycin, vindesine, and cisplatin (MVP) chemotherapy with concurrent TRT.

Results Between July 2000 and July 2005, 200 patients were allocated into either the DP or MVP arm. The survival time at 2 years, a primary end point, was favorable to the DP arm (P = .059 by a stratified log-rank test as a planned analysis and P = .044 by an early-period, weighted log-rank as an unplanned analysis). There was a trend toward improved response rate, 2-year survival rate, median progression-free time, and median survival in the DP arm (78.8%, 60.3%,13.4 months, and 26.8 months, respectively) compared with the MVP arm (70.3%, 48.1%, 10.5 months, and 23.7 months, respectively), which was not statistically significant (P > .05). Grade 3 febrile neutropenia occurred more often in the MVP arm than in the DP arm (39% v 22%, respectively; P = .012), and grade 3 to 4 radiation esophagitis was likely to be more common in the DP arm than in the MVP arm (14% v 6%, P = .056).

Conclusion DP chemotherapy combined with concurrent TRT is an alternative to MVP chemotherapy for patients with LA-NSCLC.

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INTRODUCTION

Lung cancer is a leading cause of cancer deaths in the world, although the age-adjusted mortality rate is steadily declining in developed countries.1 Advanced/metastatic non–small-cell lung cancer (NSCLC) is incurable at present.2 In contrast, patients with locally advanced NSCLC (LA-NSCLC) who have a good performance status (PS) and adequate organ function have a chance of long-term disease-free survival and may possibly be cured from primary NSCLC.3 Thus, the treatment goal for LA-NSCLC differs from that for incurable advanced/metastatic NSCLC.

In the 1980s, US cooperative groups and others demonstrated that patients with LA-NSCLC survived significantly longer when treated with cisplatin-based, second-generation chemotherapy followed by thoracic radiotherapy (TRT) than when treated with conventional TRT alone.4,5 In an ex vivo experiment, cisplatin was shown to have a strong radiosensitizing effect, and, in clinical trials, it was shown to yield improved survival when combined with concurrent TRT.6–8

In the 1990s, groups in Japan and the United States demonstrated the superiority of concomitant chemoradiotherapy using cisplatin-based second-generation chemotherapy with and without consolidation chemotherapy over sequential chemotherapy followed by TRT.9,10 Accordingly, cisplatin-based second-generation chemotherapy with concurrent TRT is the standard of care for LA-NSCLC.11

In the late 1990s, LA-NSCLC treatments with third-generation chemotherapy with early concurrent TRT,12–15 induction third-generation chemotherapy followed by late concomitant chemoradiotherapy,16 and early concomitant chemoradiotherapy followed by docetaxel consolidation chemotherapy17 were extensively investigated. At that time, direct comparisons indicated that platinum-based third-generation chemotherapies, such as vinorelbine, docetaxel, and gemcitabine, significantly improved the survival time of patients who had advanced/metastatic NSCLC with good PS compared with cisplatin-based second-generation chemotherapy.18–20 Third-generation chemotherapy was also expected to improve the survival of patients with LA-NSCLC according to phase II trials12–17,21; however, induction carboplatin plus paclitaxel chemotherapy with late concomitant chemoradiotherapy and early concomitant chemoradiotherapy followed by consolidation chemotherapy failed to prolong survival.22,23 To date, comparative trials of combined-modality therapy in LA-NSCLC have failed to demonstrate a survival benefit for third-generation chemotherapy compared with the standard, second-generation, cisplatin-based treatment.23,24 Additionally, few studies investigated LA-NSCLC by comparing the second- to the third-generation chemotherapies in the early concurrent TRT phase. The Okayama Lung Cancer Study Group (OLCSG) carried out a phase I/II study of docetaxel and cisplatin (DP) chemotherapy with concurrent TRT for LA-NSCLC. They reported that 54% of the patients had a 2-year survival with acceptable acute toxicities.15 Between 2000 and 2005, we conducted a randomized, phase III trial, OLCSG 0007, to confirm the phase II results and to establish a standard treatment for patients with LA-NSCLC who had good PS and adequate organ function. The West Japan Lung Cancer Group regimen that consisted of cisplatin, vindesine, and mitomycin (MVP) was selected as a reference arm, because MVP was the only published regimen shown to be better with concurrent TRT than sequential TRT in a randomized, phase III trial.9

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PATIENTS AND METHODS

Patients with histologically or cytologically confirmed NSCLC with unresectable IIIA (bulky N2) or IIIB disease for which the radiation field did not exceed one half of the lung on the chest radiograph were included in the study. Staging work-up, follow-up schedule during concomitant chemoradiotherapy, and other inclusion and exclusion criteria were described previously (Appendix Tables A1 and A2, online only).15

The patients were randomly allocated to two groups by the OLCSG Administrative Office (Aichi Cancer Center) according to stratification for the institution, Eastern Cooperative Oncology Group (ECOG), PS (0 v 1), and clinical stage (IIIA v IIIB). Institution was an adjustment factor in the dynamic allocation.

The study was conducted by the OLCSG, a community-based cooperative group. The protocol was approved by institutional review boards and/or an ethical committee, and all patients provided written informed consent.

Treatment Protocol

The treatment protocol is shown in Figure 2. In the DP arm, docetaxel 40 mg/m2 was administered intravenously over 1 hour followed by a 1-hour infusion of cisplatin 40 mg/m2 before radiation therapy on days 1, 8, 29, and 36.15 In the MVP arm, mitomycin 8 mg/m2 and vindesine 3 mg/m2 were slowly infused intravenously on days 1, 8, 29, and 36, and cisplatin 80 mg/m2 was infused intravenously over a 60-minute period on days 1 and 29. The chemotherapy dose and schedule modifications for toxicity are shown in Appendix Table A3 (online only).

Concurrent TRT began on day 1 of chemotherapy in both arms by using a linear accelerator (6 to 10 megavolt), in 2-Gy, single, daily fractions for 5 consecutive days each week to provide a total dose of 60 Gy.15 Briefly, a curative radiation field was constructed by using a plain chest radiograph and a contrast-enhanced computed tomography (CT) scan. The initial dose (approximately 40 Gy) was administered to the primary tumor, the ipsilateral hilum with a 2-cm margin, and involved mediastinal lymph nodes with a 1-cm margin. Prophylactic radiation fields were not planned except for subcarinal lymph nodes. Subsequently, a 20-Gy dose was given as a boost according to tumor shrinkage. An initial TRT dose of 40 Gy was administered to the anteroposterior parallel–opposed pair of portals; if the cumulative radiation dose to the spinal cord exceeded 40 Gy to the same pair or a pair of oblique fields during the boosted TRT, a dose of 20 Gy was used. The TRT dose and schedule modifications for toxicity are listed in Appendix Table A3. Approximately two thirds of the institutes used CT simulation to construct the radiation field at the beginning of this trial, although CT simulation, quality assurance (QA) of TRT, mediastinoscopy, and positron-emission tomography (PET) scans were not mandatory for this trial.

Toxicity was evaluated during concomitant TRT (Appendix Table A1). After completion of the assigned treatment, physical examinations, complete blood count, blood chemistry, tumor markers, and chest radiographs were assessed at monthly visits for 2 years and then at every 3-month visit. A CT scan of the chest, which included the liver and adrenal glands, was repeated at every 3-month visit for 2 years and then at every 6- to 12-month visit for 3 years.

The treatment response was assessed by extramural reviewers by using the Response Evaluation Criteria in Solid Tumors (RECIST). Toxicity was assessed and graded by using the National Cancer Institute Common Toxicity Criteria, version 2. Treatment response and survival time were determined on an intent-to-treat basis. Overall survival (OS) and progression-free survival (PFS) times were calculated from the beginning of random assignment to death as a result of any cause and to a progressive disease or death as a result of causes other than NSCLC, respectively.

Primary End Point and Sample Size Estimation

We defined the survival time at 2 years as a primary end point in this trial. The sample size was calculated on the basis of a previous report of an approximately 35% 2-year survival rate for the MVP arm,9 and the DP arm was postulated to be 55%.15 We required 96 patients in each arm to detect a difference with an α error of .05 and power of 80%. After considering patient loss as a result of dropout, we set the target number of patients at 100 per group, or 200 in total. The primary analysis population for efficacy was the intent-to-treat population, which was defined as all patients who were randomly assigned.

Statistical Analysis

Patient characteristics were assessed by using χ2 tests. The difference was evaluated using a stratified log-rank test (a primary analysis) and a modified stratified log-rank test (an unplanned analysis) proposed by Fleming et al25 that allowed for a weight difference during the observation period. Survival analysis was planned at 2 years after the last patient began the study. The stratification factors were ECOG PS, clinical stage, and institute. A P value less than .05 by a two-sided test was considered statistically significant. Similar analyses were used to evaluate PFS. The response was evaluated by using applied logistic regression models adjusted for two stratification factors.

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RESULTS

Between July 2000 and July 2005, 200 patients participating in this study were all eligible and were allocated to the DP arm (n = 99) and MVP arm (n = 101), as shown in Figure 1 (CONSORT diagram). We measured toxicity in 199 of the 200 patients. Patient demographics and disease characteristics are listed in Table 1. Approximately 5% of the patients had a 10% or greater weight loss, and one third were in stage IIIA and had adenocarcinomas histology. No statistically significant differences in patient characteristics were found between the two arms, although the MVP arm tended to have a higher percentage of women than the DP arm (12.9% and 7.1%, respectively; P = .172).

Fig 1.
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Fig 1.

CONSORT diagram of the Okayama Lung Cancer Study Group trial OLCSG 0007. DP, docetaxel plus cisplatin; MVP, mitomycin plus vindesine plus cisplatin.

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Table 1.

Characteristics of Patients in Each Treatment Arm

Fig 2.
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Fig 2.

Treatment protocol for the Okayama Lung Cancer Study Group trial OLCSG 0007. Phase III trial of docetaxel plus cisplatin (DP) versus mitomycin plus vindesine plus cisplatin (MVP) with concurrent thoracic radiotherapy for locally advanced non–small-cell lung cancer (NSCLC). WJLCG, West Japan Lung Cancer Group; PS, performance status.

Treatment Administration

As listed in Table 2, dose delivery of the DP chemotherapy and TRT in the previous phase II trial was reproduced in this trial. In both arms, 83% or more of the projected chemotherapy dose and TRT were administered. Dose delivery of TRT in the DP arm was more intensive than in the MVP arm. In contrast, dose delivery of chemotherapy in the MVP arm was more complete than in the DP arm.

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Table 2.

Dose Delivery and Drugs and Radiation in Each Treatment Arm

Treatment Response

In the DP arm, 78 patients were confirmed to have responded to the treatment (78.8%; 95% CI, 69.4% to 86.4%), including four patients (4%) with a complete response (CR), 74 (74.7%) with a partial response (PR), 18 (18.2%) with stable disease (SD), and three (3.0%) with progressive disease (PD). In the MVP arm, 71 patients were confirmed to have responded to the treatment (70.3%; 95% CI, 60.4% to 79.0%), including one patient (1.0%) with CR, 70 (69.3%) with PR, 22 (21.8%) with SD, and seven (6.9%) with PD. One patient (1.0%) could not be evaluated for a response. The response to concomitant chemoradiotherapy in the DP arm was superior to that in the MVP arm; however, the difference in response was not significant (P = .299).

Survival

Figure 3 shows the OS and PFS curves for both arms (Appendix Table A4, online only). The survival time at 2 years, a primary end point, was favorable to the DP arm (P = .059 by a stratified log-rank test as a planned analysis and P = .044 by an early-period, weighted, log-rank as an unplanned analysis). The median survival time (MST) in the DP arm was 26.8 months (95% CI, 23.6 to 33.4 months) compared with 23.7 months (95% CI, 15.9 to 33.2 months) in the MVP arm. The actual survival rate of 60.3% (95% CI, 49.9% to 69.2%) at 2 years in the DP arm was higher than that in the MVP arm (48.1%: 95% CI, 38.0% to 57.5%; Appendix Table A4). The median PFS in the DP arm was 13.4 months (95% CI, 9.8 to 18.2 months) and was also favorable compared with that of the MVP arm (10.5 months: 95% CI, 8.4 to 11.9 months). The PFS at 2 years tended to be greater in the DP arm than in the MVP arm by a modified log-rank test (P = .065), but the PFS was not significant by the log-rank test (P = .208; Fig 3B; Appendix Table A4).

Fig 3.
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Fig 3.

(A) Overall survival and (B) progression-free survival for the two randomly assigned treatment arms. MVP, mitomycin plus vindesine plus cisplatin; DP, docetaxel plus cisplatin.

Recurrence Pattern and Subsequent Treatments

Table 3 shows the initial recurrence pattern in both treatment arms. NSCLC recurred at a local site in approximately half of all patients. In the MVP arm, NSCLC recurred in a distant site in 50 (49.5%) of 101 patients, whereas it recurred in a distant site in 32 (37.4%) of 99 patients in the DP arm (P = .084). In the MVP arm, recurrence at both sites was more frequent than recurrence in the DP arm (P = .013). The incidence of recurrence only in the brain was 8.1% in the DP arm and was 5.9% in the MVP arm.

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Table 3.

Initial Recurrence Pattern in Each Treatment Arm

As shown in Appendix Table A5 (online only), 78.6% of patients with recurrent disease in the DP arm and 67.1% in the MVP arm received subsequent treatment. No bias for subsequent treatments between the two arms was observed except for docetaxel and pemetrexed (P = .010).

Toxicity

Treatment-related toxicity in both arms is listed in Table 4. Grade 3 or greater hematologic toxicity and febrile neutropenia occurred significantly more frequently in patients in the MVP arm than those in the DP arm (P = .012). The incidence of radiation esophagitis (grade 3 or greater) was higher in the DP arm (14%) than in the MVP arm (6%; P = .056; Appendix Table A6, online only). Two patients terminated radiotherapy at 54 Gy and 56 Gy in the DP arm because of radiation esophagitis. Radiation pneumonitis was also severe in the DP arm, in which grade 5 radiation pneumonitis occurred in two patients (2%). In each arm, one patient died as a result of pneumonia, with disease recurrence, within 2 years. Of note, two patients died as a result of pneumonia without diseases at 2.5 and 4 years but only in the DP arm. Other severe toxicities are listed in Appendix Table A7 (online only). The causes of deaths are summarized in Appendix Table A8 (online only). Patients in the DP arm were more likely to die as a result of causes other than NSCLC than those in the MVP arm (18.2% v 9.9%; P = .092).

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Table 4.

Major Toxicity Profile in Each Treatment Arm

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DISCUSSION

We found no significant efficacy difference in the survival time at 2 years between the treatment arms on the basis of primary analysis by the stratified log-rank test (P = .059), but a secondary result that was based on the modified log-rank test (P = .044) appears to indicate that DP has better efficacy for the early follow-up period. Although the response rate, MST, OS, PFS, and 2-year survival rate tended to be greater in the DP arm than in the MVP arm, the differences were not statistically significant (P >.05).

This trial has several limitations. First, the investigation of long-term survival beyond 2 years after chemoradiotherapy was premature. The modified MVP arm (38.1%) transiently overcame the DP arm (35.4%) at 3 years. Similarly, in the West Japan Thoracic Oncology Group (WJTOG) 0105 trial, the 3-year survival rate of 35.3% in the original MVP arm was superior to that of an arm with carboplatin plus paclitaxel (26.4%).24 The presumed causes of the transient survival advantage of the MVP arm at 3 years are as follows: (1) docetaxel, which was only an evidence-based second-line chemotherapy in a clinical practice during this trial, was more used at recurrence in the MVP arm, (2) two cycles of a nonsplit full-dose cisplatin was used in the MVP arm; (3) two patients died of pneumonia without lung cancer beyond 2 years only in the DP arm; and (4) a sample size was small to detect the survival difference because of the unpredictably better survival in the MVP arm. Second, the PFS curves crossed after 2 years. The DP arm did not seem to markedly improve the cure rate. Third, local esophagitis/pneumonitis toxicities were more frequent in the DP arm, although hematologic toxicity and febrile neutropenia were significantly more common in the MVP arm. Severe radiation esophagitis was common in the DP arm. Additionally, two patients (2%) in the DP arm died as a result of radiation pneumonitis. Of note, two patients died as a result of pneumonia without disease recurrence at 2.5 and 4 years after chemoradiotherapy only in the DP arm. Common pulmonary infections might be an issue in long-term survivors after chemoradiotherapy. The incidence of severe acute/late radiation pneumonitis was approximately 10% with cisplatin-based second-generation chemotherapy and with use of old radiation techniques.9 Finally, the radiation technique was out of date. CT simulation, the percentage of lung volume receiving more than 20 Gy (ie, V20),26 and QA of radiotherapy were not mandatory in the OLCSG 0007 trial. Accordingly, when modern radiation technologies with attention to factors such as V20, the standard QA, and stricter patient selections that used other predictive markers (such as forced expiratory volume in 1 second greater than 2 L and strict staging by PET scan) are employed, local toxicity issues raised in this trial might be circumvented in a future trial.

The MVP and DP arms both revealed excellent survival data. The estimated MST for the MVP arm would be 16 months with a 35% 2-year survival rate; however, the MST was 24 months with a 49% 2-year survival rate. Improvements in supportive care and staging techniques (including contrast-enhanced magnetic resonance imaging of the brain and bone scans) might explain the increased survival times. Similar results were found for cisplatin and etoposide (PE) combination chemotherapy with concurrent TRT.23,27 The MSTs of PE/TRT reported in the 1990s and 2000s were 15 months and 23 months, respectively.23,27 In addition, we began concurrent TRT on day 1 and used 60 Gy of TRT without 10 days rest, although the original West Japan Lung Cancer Group regimen split the 56 Gy of TRT with 10 days rest, which included two cycles of consolidation chemotherapy and concurrent TRT that began on day 2. The radiation dose and schedule in our MVP arm may also explain the favorable outcome.

The initial recurrence pattern differed between the DP and MVP arms. There was a trend toward a high distant recurrence rate in the MVP arm (49.5%) compared with the DP arm (37.4%; P = .084). The DP chemotherapy controlled micrometastasis better than the MVP chemotherapy, but it was not sufficient to completely prevent distant recurrences and to produce a higher cure rate. Thus, consolidation chemotherapy is an attractive approach to control distant micrometastasis.28 However, neither treatment arm in this trial used consolidation chemotherapy, because there was no evidence of consolidation chemotherapy for LA-NSCLC. Hanna et al23 recently reported that consolidation chemotherapy did not prolong survival, but the patients in their consolidation arm had worse pulmonary function and less use of a PET scan than patients in the reference arm.23 In theory, consolidation chemotherapy administered safely could eradicate micrometastasis and prevent distant recurrence. The WJTOG conducted a phase III trial of concomitant chemoradiotherapy study that included two cycles of consolidation chemotherapy combined with 60 Gy of TRT; however, consolidation chemotherapy was completed in less than 50% of all three arms and did not reduce distant recurrence.24,29 In addition, around 90% of radiation pneumonitis occurred within 6 months of beginning TRT.26 Patients who receive consolidation chemotherapy after concomitant chemoradiotherapy have a higher risk for radiation pneumonitis.23 Accordingly, consolidation chemotherapy should be assessed carefully in selected patients enrolled on clinical trials.

New strategies—such as radiation dose, radiation methods, molecular targeted agents, and patient selection on the basis of molecular status—are needed to improve the cure rate. Because the DP arm controlled distant recurrence well, we expect that adjuvant surgery will be particularly effective for DP chemotherapy with concurrent TRT,30 which are supported by strict eligibility criteria and new radiation technology.

In conclusion, no significant efficacy difference was observed between two arms on the basis of the primary analysis. However, because DP chemotherapy with concurrent TRT has better efficacy for the early follow-up period, the regimen warrants additional study.

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AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Katsuyuki Kiura, sanofi-aventis; Nagio Takigawa, sanofi-aventis Research Funding: None Expert Testimony: None Other Remuneration: None

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AUTHOR CONTRIBUTIONS

Conception and design: Yoshihiko Segawa, Katsuyuki Kiura, Nagio Takigawa, Haruhito Kamei, Shingo Harita, Shunkichi Hiraki, Yoichi Watanabe, Takuo Shibayama, Toshiro Yonei, Hiroshi Ueoka, Mitsuhiro Takemoto, Ichiro Takata, Keitaro Matsuo

Administrative support: Katsuyuki Kiura, Nagio Takigawa, Hiroshi Ueoka, Susumu Kanazawa, Masahiro Tabata, Keitaro Matsuo

Provision of study materials or patients: Yoshihiko Segawa, Katsuyuki Kiura, Nagio Takigawa, Hiroshi Ueoka, Keitaro Matsuo

Collection and assembly of data: Yoshihiko Segawa, Nagio Takigawa, Haruhito Kamei, Shingo Harita, Shunkichi Hiraki, Yoichi Watanabe, Keisuke Sugimoto, Takuo Shibayama, Toshiro Yonei, Mitsuhiro Takemoto, Susumu Kanazawa, Ichiro Takata, Naoyuki Nogami, Masahiro Tabata

Data analysis and interpretation: Katsuyuki Kiura, Nagio Takigawa, Haruhito Kamei, Hiroshi Ueoka, Katsuyuki Hotta, Akio Hiraki, Keitaro Matsuo

Manuscript writing: Katsuyuki Kiura, Nagio Takigawa, Keitaro Matsuo

Final approval of manuscript: Katsuyuki Kiura, Mitsune Tanimoto

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Acknowledgment

We thank the Efficacy Safety Committee chairpersons: Yasunari Nakata, MD, PhD, Chugoku Central Hospital; Masafumi Fujii, MD, PhD, Department of Health Care Medicine, Kawasaki Medical School; and Hiroshi Date, MD, PhD, Department of Thoracic Surgery, Kyoto University Graduate School of Medicine; and the patients who consented to this trial, their families, medical staffs, and all the members of the Okayama Lung Cancer Study Group.

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Appendix

⇓⇓⇓⇓⇓⇓⇓⇓

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Table A1.

Staging Work-Up and Follow-Up Schedule During Concomitant Chemoradiotherapy

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Table A2.

Inclusion and Exclusion Criteria of OLCSG 0007

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Table A3.

Dose and Schedule Modifications in Each Arm

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Table A4.

Overall Survival and Progression-Free Survival in Each Treatment Arm

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Table A5.

Treatment After Recurrence in Each Arm

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Table A6.

Characteristics of Patients Who Experienced Grade 3 or Greater Esophagitis in Each Arm

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Table A7.

Other Severe Toxicity Profile in Each Treatment Arm

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Table A8.

Causes of Deaths in Each Arm

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Footnotes

  • Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

  • Clinical trial information can be found for the following: UMIN000000085.

  • Received June 26, 2009.
  • Accepted April 13, 2010.
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  1. Published online before print June 7, 2010, doi: 10.1200/JCO.2009.24.7577 JCO vol. 28 no. 20 3299-3306
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