For the NK421 Lung Cancer Surgery Group
Affiliations of authors: Y. Ichinose, M. Ohta, Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan; K. Genka, Department of Surgery, National Okinawa Hospital, Okinawa, Japan; T. Koike, Division of Chest Surgery, Niigata Cancer Center Hospital, Niigata, Japan; H. Kato, Department of Surgery, Tokyo Medical University, Tokyo, Japan; Y. Watanabe, Department of Surgery, Kanazawa University, School of Medicine, Kanazawa, Japan; T. Mori, Department of Thoracic Surgery, National Kinki-Chuo Hospital for Chest Disease, Osaka, Japan; S. Iioka, Department of General Thoracic Surgery, Osaka City General Hospital, Osaka; A. Sakuma, Department of Clinical Pharmacology, Tokyo Medical and Dental University, Tokyo.
Correspondence to: Yukito Ichinose, M.D., Department of Thoracic Oncology, National Kyushu Cancer Center, 3-1-1, Notame, Minami-ku, Fukuoka 8111395, Japan (e-mail: yichinos{at}nk-cc.go.jp).
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ABSTRACT |
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INTRODUCTION |
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Bestatin has antitumor activity. In in vitro studies, bestatin inhibited the invasion of human metastatic tumor cells (12,13) and induced apoptosis in human non-small-cell lung cancer cell lines (17). In tumor-bearing mice, bestatin inhibited metastases or tumor growth and prolonged survival (1820). In clinical studies, bestatin prolonged the survival of patients with acute adult nonlymphocytic leukemia who also received chemotherapy (21,22) and had an immunomodulatory effect in patients with lymphoma after autologous bone marrow transplantation (23). Although a small, single-institution, randomized clinical trial of bestatin as a postoperative adjuvant treatment in patients with resected non-small-cell lung cancer did not obtain conclusive results, a subset analysis indicated that bestatin could prolong the survival of patients with completely resected stage I squamous-cell lung carcinoma (24). This result prompted us to conduct a prospective, multicenter, randomized, double-blind, placebo-controlled trial of bestatin as a postoperative adjuvant treatment for patients whose stage I squamous-cell carcinoma was completely resected.
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PATIENTS AND METHODS |
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This trial was initiated by the NK421 Lung Cancer Surgery Group, in which 80 institutions in Japan registered on July 8, 1992. The trial was closed on March 31, 2000. Enrollment was terminated on March 30, 1995. The institutional review board or the ethics committee of each institution reviewed and approved the protocol.
Patients who had undergone the complete resection of a pathologically documented stage I (T12, N0, M0) squamous-cell carcinoma were eligible for this study. According to the lung cancer staging system used (25), T1 is a primary tumor that measures 3 cm or less in its greatest dimension, with no invasion of a main bronchus or pleural involvement; T2 is a primary tumor that is larger than 3 cm or a primary tumor of any size that involves the visceral pleura or main bronchus or is associated with atelectasis or obstructive pneumonia that extends to the hilar region; and N0 and M0 indicate the absence of lymph node metastasis and distant metastasis, respectively. Other inclusion criteria were as follows: an age of 4075 years; no anticancer treatment before operation; no previous cancer or synchronous multiple cancers; adequate organ function after operation; an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (26); no severe postoperative complications such as pneumonia or pyothorax; and written informed consent from all patients or their representatives.
Confirmation of patient eligibility and randomization were performed by telephone at a central site within 28 days after each patients operation. There were no stratified factors for randomization. The patients were randomly assigned to study groups in blocks of six by a centralized masked-draw system that combined coded numbers with drug allocation. Each block of six numbers was transmitted from the central office to a pharmacist at each institution who was not involved in the care of the trial patients.
No patient, investigator, or other medical or nursing staff member was aware of the treatment assignments until the final analysis of the study. All statistical analyses were also done in a blinded fashion.
One capsule of either the drug (30 mg) or a placebo (vehicle without active drug) was orally administered after breakfast every day for 2 years. Treatment started within 1 week of randomization. No additional treatment, such as chemotherapy, radiotherapy, or any other biologic response modifier, was allowed until a definitive recurrence or the appearance of a second cancer was documented. Toxicity from either bestatin or placebo was graded according to the criteria of the Japan Society of Clinical Oncology, which consist of a minor modification of the World Health Organization criteria (27). Protocol compliance was measured by checking each patients diary card regarding capsule administration, general condition, and symptoms at each clinical visit.
A follow-up examination was performed every 3 months for the first 2 years after the patients operation and every 6 months thereafter. The examination included a physical examination, complete blood count, blood chemistry work-up, serum tumor marker screening, and chest radiography. A computed tomography (CT) scan of the thorax and either a CT scan or an echogram of the upper abdomen were required every 6 months for the first 2 years after the patients operation. A second primary cancer was defined as a new lung lesion that was found by a histologic examination to be other than squamous-cell carcinoma or that was in a location not related to the location of the primary tumor. The primary end point of the study was overall survival, and the secondary end points were cancer-free survival and the safety assessment.
Statistical Analysis
This trial was designed by assuming a 5-year survival rate of 68% in the placebo group and 80% in the bestatin group. The estimated sample size, with an error of .05 (two-sided test) and a
error of .2 with a 2-year registration period and a 5-year observation period after the final enrollment, was 188 patients in each group (28). As a result, the registration of a total of 400 patients was planned.
In this study, overall survival was defined as the time from operation until death from any cause, and cancer-free survival was defined as the time from operation until the appearance of the first recurrence of cancer or of the second cancer or death from any cause. Statistical analyses were based on the intent-to-treat method. Survival was estimated by the KaplanMeier method, and differences in survival were computed with the log-rank test and the generalized Wilcoxon test. Multivariable analyses with the Cox proportional hazard model were used to estimate the simultaneous effects of prognostic factors on survival (29). After confirmation that the data met the assumptions for a proportional hazards analysis, the stepwise selection was used to ensure more parsimonious models. Variables were retained in the model if the associated two-sided P values were .10 or less. Differences between the proportions of patient characteristics were estimated by the 2 or U test. The data were considered statistically significant when the P value was .05 or less. All statistical tests were two-sided.
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RESULTS |
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Of the 402 patients enrolled in the trial, two patients rescinded their informed consent before the start of treatment (Fig. 1). The patient characteristics of 202 patients and 198 patients who were randomly assigned to receive bestatin and placebo, respectively, are shown in Table 1
. There were no statistically significant differences in the baseline characteristics of the patients. Almost all patients underwent a lobectomy, but lobectomy with bronchoplasty was performed in eight patients in the bestatin group and in 18 patients in the placebo group, and lobectomy with either wedge resection or a resection of another lobe was performed in 18 of the patients in the bestatin group and in 11 of the patients in the placebo group. Although nearly all patients had stage I disease, two patients (1%) from the bestatin group and four patients (2%) from the placebo group had a different stage. Stage 0 in two patients from the placebo group was from a carcinoma in situ. Stage II from T1N1 (metastasis in the ipsilateral hilar lymph node) M0 disease was observed in two patients from the bestatin group, and stage II from T2N1M0 disease was observed in one patient from the placebo group. Stage IIIA from T3 (involvement of the parietal pleura) N0M0 disease was observed in one patient from the placebo group.
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Adverse Reactions
Table 2 lists the incidence of treatment-related adverse reactions. Data for anorexia were available for 196 patients of the bestatin group and 189 of the placebo group. Few severe adverse reactions were associated with either treatment, and no statistically significant difference in the incidence of adverse reactions (except for anorexia) was observed between the groups. The bestatin group had 18 patients with grade 1 anorexia, six with grade 2 anorexia, and five with grade 3 anorexia; the placebo group had eight with grade 1 anorexia, one with grade 2 anorexia, and four with grade 3 anorexia. The incidence of anorexia of any grade was 15% (29) of the 196 in the bestatin group and 7% (13) of the 189 in the placebo group (P = .013).
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Overall Survival
The median follow-up for the surviving patients was 76 months (range = 5892 months). Four patients in the bestatin group were lost to follow-up 330, 768, 1461, and 1535 days after operation, and one in the placebo group was lost to follow-up 1298 days after operation. These patients were censored on the respective days in the analysis of overall survival. As shown in Fig. 2, the 5-year survival rate was 81% in the bestatin group and 74% in the placebo group for a difference of 7% (95% confidence interval [CI] = -1.4% to 15.0%). Overall survival was statistically significantly different by KaplanMeier analysis (P = .033 [log-rank test] and P = .027 [Wilcoxon test], without a covariate adjustment).
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The selected covariates (categories compared, and relative risk [RR] with 95% CI; P value) were as follows: age (<65 years versus 65 years, RR = 1.92, 95% CI = 1.24 to 9.95; P = .003), performance status (0 versus 1 plus 2, RR = 1.63, 95% CI = 1.13 to 2.35; P = .010), blood transfusion (no versus yes, RR = 1.63, 95% CI = 1.08 to 2.47; P = .021), and sex (female versus male, RR = 2.28, 95% CI = 1.00 to 5.19; P = .050). After adjustment, the treatment group (bestatin versus placebo, RR = 1.49, 95% CI = 1.03 to 2.16; P = .034) was almost the same as without any adjustment (P = .033).
Pattern of Failure and Cancer-Free Survival
As shown in Table 3, either recurrence or a second primary cancer as the first treatment failure after operation was documented in 29% of the patients in the bestatin group and 37% of those in the placebo group (P = .066). The 5-year cancer-free survival was 71% in the bestatin group and 62% in the placebo group for a difference of 9% (95% CI = -0.7% to 17.8%). The 5-year cancer-free survival was statistically significantly different by KaplanMeier analysis (P = .017 [log-rank test] and P = .022 [Wilcoxon test]).
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DISCUSSION |
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The events leading to the phase III trial described in this article were similar to those for the BCG trial. When we designed the protocol, bestatin had been shown to be an immunostimulator, as had BCG. In 1990, Yasumitsu et al. (24) reported the results of a randomized trial that compared a postoperative bestatin treatment with no treatment in patients with resected non-small-cell lung cancer; a subset analysis of patients with completely resected stage I squamous-cell carcinoma indicated that the 25 patients in the bestatin group had statistically significantly longer survival than the 20 patients in the control group (24). Thus on July 8, 1992, we initiated a multicenter, randomized, double-blind, placebo-controlled trial of bestatin as postoperative adjuvant treatment in 402 stage I patients whose squamous-cell lung carcinoma was completely resected. Because the stage and histology were restricted to stage I of T12N0 and squamous-cell carcinoma, respectively, the subject population of the present study was more homogenous than that of any previous study, and the sample size was the largest for this group of patients.
Patients treated with bestatin had statistically significantly better survival than patients treated with placebo. Patient characteristics of the bestatin and placebo-controlled groups were well balanced. Although the survival of patients in the bestatin group was better than that of patients in the placebo group, the survival of patients in the placebo group was better than that previously reported (24,32,33). In a recent study, the 5-year survival rate of patients with resected stage I squamous-cell carcinoma ranged from 71% to 75% (3436), with survival being defined from operation until lung cancer-related death. Because approximately 30% of patients with resected early-stage lung cancer who died were cancer-free at death (37), the 5-year survival rate of 74% in our placebo group in which mortality was defined as death from any cause, thus, appears to be quite high.
Unlike other immunostimulators, including BCG, bestatin has a well defined chemical structure with a molecular weight of 308 and is absorbed well through the small intestine (1,38). Bestatin inhibits aminopeptidase N/CD13, which is involved in the angiogenesis of tumors (14,15) and invasion of tumor cells (12,13). Bestatin induces apoptosis in cancer cells in vitro (17,39). In the tumor and on the tumor field, bestatin suppresses metastasis and tumor growth in experimental animal models (14,1820). Bestatin, like other nonspecific immunostimulators, enhances the activity of T lymphocytes and monocytes (2,18,19). Aminopeptidase N/CD13 is involved in the presentation of antigens on dendritic cells (40), and thus bestatin may play a role in specific immune responses against tumors or microorganisms. These comprehensive effects of bestatin may have contributed to the positive results of our randomized phase III study.
A result of a National Cancer Institute (NCI) Intergroup phase III, placebo-controlled trial to investigate the effect of retinoid isotretinoin in preventing a second primary cancer in 1166 patients with resected stage I non-small-cell lung cancer has been reported (41). In that trial, oral administration of retinoid isotretinoin for 3 years did not appear to prevent the development of second primary cancers. In animal studies, the incidence of spontaneous or chemically induced tumors was statistically significantly reduced by the administration of bestatin compared with no administration (42,43). Although the aim of the present trial was not to clarify the preventative effect of bestatin on the development of a second primary cancer, the number of patients with second primary cancers as postoperative first treatment failure in the bestatin group appeared to be smaller than that in the placebo group (19 versus 30; P = .080). However, some second primary cancers clinically diagnosed were not verified histologically (four in the bestatin group and five in the placebo group) in contrast to those in the NCI Intergroup trial. Therefore, a portion of the second primary cancers observed in our trial might include recurrences, but treatment for either second primary cancer or recurrence did not influence the overall survival of patients in the bestatin and the placebo groups.
Bestatin is currently available in Japan and three other countries as a maintenance treatment for patients with acute nonlymphocytic leukemia who are in complete remission after chemotherapy, as a result of randomized trials for such patients (21,22). So far, safety assessments of 2164 patients indicate that bestatin is a safe drug. Adverse reactions are mild and infrequent: the incidence of toxicity of any grade is 1.8% for hepatic dysfunction, 1.3% for skin reaction, and 0.9% for gastrointestinal toxicity including nausea, vomiting, and anorexia.
In conclusion, the oral administration of bestatin as a postoperative adjuvant treatment was associated with a statistically significantly prolonged survival of patients with completely resected stage I squamous-cell carcinoma, without adverse toxic events. However, other phase III trials should be conducted to confirm our conclusions.
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APPENDIX |
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M. Kawamura, Akita Nakadori Hospital, Akita; K. Yokoi, Tochigi Cancer Center, Tochigi; T. Sakuma, Sendai Kohsei Hospital, Miyagi; N. Tsubota, M. Yoshimura, Hyogo Medical Center for Adults, Hyogo; N. Yanai, National Seiransou Hospital, Ibaraki; F. Nagasaka, Nihon University Itabashi Hospital, Tokyo; K. Nakagawa, Cancer Institute Hospital Japanese Foundation for Cancer Research, Tokyo; T. Tojo, Nara Medical University, Nara; T. Sato, Yamagata Prefectural Central Hospital, Yamagata; S. Ohta, Shizuoka General Hospital, Shizuoka; N. Yamaoka, Oita Prefectural Hospital, Oita; Y. Matsuzaki, Miyazaki Medical College, Miyazaki; S. Fujimura, Institute of Development, Aging and Cancer, Tohoku University, Miyagi; K. Nagai, National Cancer Center East Hospital, Chiba; H. Miyamoto, Mitsui Memorial Hospital, Tokyo; K. Kobayashi, Keio University, Tokyo; H. Saito, Kouseiren Takaoka Hospital, Toyama; J. Isobe, National Gifu Hospital, Gifu; T. Yasumitsu, Osaka Prefectural Habikino Hospital, Osaka; O. Doi, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka; O. Kuwahara, National Toneyama Hospital, Osaka; T. Hatta, Hyogo Prefectural Awaji Hospital, Hyogo; N. Katakami, Kobe City General Hospital, Hyogo; S. Maebeya, Wakayama Medical College, Wakayama; N. Shimizu, Okayama University Medical School, Okayama; J. Nakagawa, Kagawa Prefectural Central Hospital, Kagawa; A. Motohiro, National Minami Fukuoka Chest Hospital, Fukuoka; T. Hirata, Asahikawa Medical College, Hokkaido.
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NOTES |
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We thank Brian Quinn for his critical review and Yumiko Oshima for her help in preparing the manuscript.
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Manuscript received August 9, 2002; revised January 29, 2003; accepted February 21, 2003.
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