Int J Clin Oncol (2015) 20:767–775 DOI 10.1007/s10147-015-0784-9
ORIGINAL ARTICLE
Preventive effect of Goshajinkigan on peripheral neurotoxicity of FOLFOX therapy (GENIUS trial): a placebo‑controlled, double‑blind, randomized phase III study Eiji Oki · Yasunori Emi · Hiroshi Kojima · Jun Higashijima · Takeshi Kato · Yasuhiro Miyake · Masanori Kon · Yutaka Ogata · Kenichi Takahashi · Hideyuki Ishida · Hiroshi Saeki · Yoshihisa Sakaguchi · Takeharu Yamanaka · Toru Kono · Naohiro Tomita · Hideo Baba · Ken Shirabe · Yoshihiro Kakeji · Yoshihiko Maehara
Received: 8 September 2014 / Accepted: 7 January 2015 / Published online: 28 January 2015 © Japan Society of Clinical Oncology 2015
Abstract Background Peripheral sensory neurotoxicity is a frequent adverse effect of oxaliplatin therapy. Calcium and magnesium (Ca/Mg) infusions are frequently used as preventatives, but a recent phase III trial failed to show that they prevent neurotoxicity. We therefore conducted a multicenter randomized phase III trial to compare fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) with and without Goshajinkigan (GJG), a traditional Japanese herbal medicine (Kampo), to determine GJG’s potential
Electronic supplementary material The online version of this article (doi:10.1007/s10147-015-0784-9) contains supplementary material, which is available to authorized users. E. Oki · H. Saeki · K. Shirabe · Y. Maehara (*) Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan e-mail:
[email protected]‑u.ac.jp E. Oki e-mail:
[email protected]‑u.ac.jp Y. Emi Department of Surgery, Saiseikai Fukuoka General Hospital, Fukuoka, Japan H. Kojima Department of Gastroenterological Surgery, Aichi Cancer Center Aichi Hospital, Nagoya, Japan J. Higashijima Department of Digestive and Pediatric Surgery, Faculty of Medicine, University of Tokushima, Tokushima, Japan T. Kato Department of Surgery, Kansai Rosai Hospital, Amagasaki, Japan
for reducing peripheral neuropathy in patients with colorectal cancer. Methods Patients with colon cancer who were undergoing adjuvant therapy with infusional mFOLFOX6 were randomly assigned to GJG (7.5 mg three times daily) or placebo in a double-blind manner. The primary endpoint was the time to grade 2 or greater neuropathy, which was determined at any point during or after oxaliplatin-based therapy using version 3 of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Findings An interim analysis was performed when 142 of the planned 310 patients had been enrolled and the safety assessment committee recommended that the study be
M. Kon Department of Surgery, Kansai Medical University, Osaka, Japan Y. Ogata Department of Surgery, Kurume University Medical Center, Kurume, Japan K. Takahashi Department of Surgery, Aomori Prefectural Central Hospital, Aomori, Japan H. Ishida Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical School, Saitama, Japan Y. Sakaguchi Department of Gastroenterological Surgery, Kyushu National Medical Center, Fukuoka, Japan T. Yamanaka Department of Biostatistics, Yokohama City University, Yokohama, Japan
Y. Miyake Department of Surgery, Minoh City Hospital, Minoh, Japan
13
768
discontinued. One hundred eighty-two patients were evaluable for response. They included 89 patients in the GJG group and 93 patients in the placebo group. The incidence of grade 2 or greater neurotoxicity was 50.6 % in the GJG group and 31.2 % in the placebo group. A Cox proportional hazards analysis indicated that the use of GJG was significantly associated with the incidence of neuropathy (hazard ratio, 1.908; p = 0.007). Conclusion Goshajinkigan did not prevent oxaliplatinassociated peripheral neuropathy in this clinical trial. The clinical study was therefore terminated. Keywords Adjuvant chemotherapy · Colon cancer · Colorectal cancer · Goshajinkigan · Herbal medicine, Kampo · Peripheral neuropathy
Introduction In recent years, the standard chemotherapy for advanced/ recurrent colorectal cancer has been continuous intravenous infusion of 5-fluorouracil (5-FU) or oral 5-FU derivatives combined with either oxaliplatin [CapeOX, FOLFOX4, or modified FOLFOX6 (mFOLFOX6)] or irinotecan (CapeIRI, FOLFIRI) [1–5]. In a pivotal phase III trial, FOLFOX was found to be superior to fluorouracil and leucovorin (FU/LV) in patients with resected stage III colon cancer in disease-free survival and overall survival [6]. However, peripheral neuropathy is a complication of oxaliplatin therapy, and therefore the oxaliplatin dose must be limited to avoid toxicity. The first strategy for avoiding oxaliplatin-linked neuropathy involves stop-and-go regimens such as the OPTIMOX series, which includes oxaliplatin-free intervals to reduce grade 3 sensory neuropathy [7]. This stop-and-go regimen avoids the problem of oxaliplatin-induced neurotoxicity by using the dose-intense FOLFOX7 regimen for a defined period, stopping the therapy before severe neurotoxicity develops and then reintroducing the same regimen. However, this is unsuitable as an adjuvant treatment, and is T. Kono Sapporo Higashi Tokushukai Hospital, Sapporo, Japan N. Tomita Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan H. Baba Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan Y. Kakeji Department of Gastrointestinal Surgery, Kobe University, Kobe, Japan
13
Int J Clin Oncol (2015) 20:767–775
instead used for patients with recurrent or nonresectable cancer. As an alternative, neurologic symptoms may be reduced by administering agents such as calcium (Ca) and magnesium (Mg) preparations [8]. Gamelin et al. [9, 10] reported that the administration of calcium gluconate and magnesium sulfate (Ca/Mg) before and after oxaliplatin therapy alleviated peripheral neurotoxicity. Other similar treatments have been described, which include carbamazepine [11] and glutathione [12], but no effective remedy for oxaliplatin-induced peripheral neurotoxicity has been established to date. Goshajinkigan (GJG), a traditional Japanese herbal medicine (Kampo), is composed of 10 crude herbs: Rehmanniag lutinosa, Achyranthes spp. root, Cornus officinalis, Dioscorea spp. rhizome, Plantago spp. seed, Alisma orientale, Porica cocos, Moutan cortex, Cinnamomum cassia, and aconite tuber [13–15]. In Japan, GJG is primarily used to improve symptoms such as numbness, cold sensation, and limb pain associated with diabetic neuropathy [13, 16]. Goshajinkigan is also reportedly useful for coping with paclitaxel- and oxaliplatin-induced peripheral neuropathy [17, 18]. Furthermore, Kono et al. [19] recently reported that oxaliplatin-induced peripheral neurotoxicity was relieved by the administration of GJG in patients with advanced colorectal cancer who were receiving FOLFOX therapy. The GJG group experienced an improvement in peripheral neurotoxicity, and these patients tended to receive more oxaliplatin before peripheral neurotoxicity developed [19]. To confirm the preventive effect of GJG on oxaliplatin-induced peripheral neurotoxicity, we conducted a double-blind, placebo-controlled, multicenter, randomized phase III trial of GJG as an adjuvant therapy for patients with resected stage III colon cancer.
Methods Eligibility criteria Patients who had histologically confirmed adenocarcinoma of colorectal cancer, with the lower edge of the tumor located at a site above the pouch of Douglas, were included if they met all of the following criteria: they had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; their cancer status was pathological stage III (based on the 7th edition of the Japanese Classification of Colorectal Carcinoma) [20]; they had undergone complete radical resection (R0); the surgery had taken place within 8 weeks; and they had adequate hepatic, renal, respiratory, and bone marrow function. All patients provided written informed consent before their enrollment in the study. Patients were not allowed to participate in the trial if they had pre-existing peripheral neuropathy of any grade. The study was approved by the institutional review boards of all
Int J Clin Oncol (2015) 20:767–775
participating institutions, and was registered in the University Hospital Medical Information Network (UMIN) clinical trial registry (UMIN000004282). Treatment schedule and investigational medicinal products Patients and all clinical study personnel who interacted with them were blinded to the treatment arm. Patients were allocated randomly to a 12-course mFOLFOX6 regimen with GJG at 7.5 g/day (Tsumura and Co., Akasaka, Japan) or an identical placebo. The quality of the investigational medicinal products (i.e., the placebo and GJG) was approved by the Quality Assurance Unit of Tsumura in accordance with current good manufacturing practice (cGMP). Tsumura prepared and stored GJG. The placebo was prepared and stored by Yamato Logistics (Tokyo, Japan) in a room in which humidity and temperature were managed by a pharmacist during the study period. The designated numbered drug was sent to each institution at every registration. The drug was handled by a management representative (but not the researchers) in each institution. Storage, shipment, receipt at the company, management, use, and remaining checks at each institution were managed by an electronic data capture (EDC) system. Goshajinkigan and the placebo were administered on the first day of mFOLFOX6 therapy and continued to be administered orally before meals or between meals on a daily basis until the end of the 12 courses. Other sensory neuromodulatory agents such as calcium–magnesium infusions or antiepileptic agents were forbidden. The mFOLFOX6 chemotherapy regimen consisted of a 2-h intravenous infusion of oxaliplatin (85 mg/m2) combined with l-LV (100 mg/m2), followed by a rapid intravenous infusion of 5-FU (400 mg/m2), and then a 46-hour continuous infusion of 5-FU (2400 mg/m2). This regimen comprised one course of therapy and was repeated once every 2 weeks. Oxaliplatin dose modifications and skipping were not allowed for patients who experienced grade 1 neurotoxicity. However, a dose reduction of oxaliplatin to 75 mg/ m2 was allowed for patients who experienced persistent grade 2 sensory neurotoxicity. Endpoints The primary endpoint was the time to the onset of grade 2 or greater sensory neurotoxicity [i.e., time to neuropathy (TTN)] during therapy. Primary neuropathy was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 3.0); the Neurotoxicity Criteria of Debiopharm (DEB-NTC) was used for comparison [21]. Standardized questions regarding symptoms of neurotoxicity and examples of answers were used to facilitate the more accurate classification of patient-reported symptoms as grade 1, 2, 3, or 4. These grades were determined by physicians from patient records.
769
Statistical considerations Eligible patients were assigned randomly to receive GJG or placebo in the ratio 1:1. Treatment allocation was stratified by institution, sex, age (65 years). The EDC system was used to screen patients for treatment allocation. Patient and drug identification numbers were allocated sequentially in the order in which the patients were enrolled. A two-arm, randomized, placebo-controlled, doubleblind, phase III design was employed. The TTN was compared between groups using Kaplan–Meier survival curves and log-rank testing. In the MOSAIC trial, among the patients receiving FOLFOX, and 44 % experienced grade 2 and 48 % experienced grade 1 sensory neurotoxicity, respectively. In Japan, the Kyushu Study Group of Clinical Cancer 0501 (KSCC0501) (FOLFOX4) and SWIFT2 (mFOLFOX6) prospective studies reported grade 2 or greater sensory neurotoxicity in 43 % and 26 % of the patients, respectively. Thus, the cumulative incidence of peripheral neuropathy was approximately 40 % after the 12-course chemotherapy regimen among patients in the placebo group in this study. We expected the cumulative incidence of peripheral neuropathy in the GJG group to be 25 %. Ninety-five cases per arm were required for the log-rank test to detect a difference of 15 % with 80 % power, and 291 cases were needed to achieve this during the 6-month follow-up. The original study design thus included 155 patients per arm. The secondary endpoints were of the proportions of patients who reported adverse events and the dose intensity of oxaliplatin, both of which were also compared between the groups. The EDC system was used for patient enrollment and for the preparation of a case report form (CRF) from start to finish. The EPS Corporation (Tokyo, Japan) conducted central monitoring every 6 months to manage quality control and guarantee quality. The statistical section of the EPS Corporation was in charge of statistical analyses under the direction of YT (who was the representative of statistics management). An interim analysis was scheduled, based on the data for one-half of the patients (i.e., 150 patients). The purpose of the interim analysis was to curtail the recruitment when we found that the Goshajinkigan arm was superior to the control arm, with the significance level determined by the Lan– DeMets alpha spending function (i.e., O’Brein–Fleming type), or the futility of the Goshajinkigan arm given the low value of the Bayesian predictive power. Stopping boundaries according to the Lan–DeMets function were computed using the East software, version 5.3 (Cytel, Cambridge, MA, USA). Statistical analysis of the study data was conducted using SAS software, version 9.2 (SAS Institute, Cary, NC, USA).
13
770
Int J Clin Oncol (2015) 20:767–775
Fig. 1 CONSORT flow diagram for this study. The initial plan was to enroll 310 patients in this clinical trial. This flow diagram pertains to the 188 patients who were enrolled before the trial was discontinued. Two patients in the Goshajinkigan (GJG) group were excluded from the primary analysis because one patient had a stoma and the other patient had a primary tumor that could not be assessed
Enrolled N=188 (N=320 planned enrollment) Excluded for nonelligibility N=2 Randomization N=186 93 assigned goshaginkigan
93 assigned placebo
89 included in primary analysis 2 not treated 1 made stoma 1 no information of primary tumor
Results After including 155 patients (one-half the number of the planned registration), a preplanned interim analysis was undertaken for 142 patients who had undergone more than one course of adjuvant chemotherapy by May 7, 2012. After careful examination of the interim data, the independent data monitoring committee (IDMC) recommended that the entry of new patients into the study should be halted. During the temporary halting of the trial, the IDMC inspected the placebo formulation and the storage conditions in some hospitals. No switching of the placebo and GJG was found to have taken place in any hospital, and on August 2, 2012 the IDMC finally recommended that the study should be discontinued. At the time of study closure, 189 patients were enrolled and 186 patients had been randomly assigned from 39 hospitals. Goshajinkigan had been prescribed to 91 patients and the placebo had been prescribed to 93 patients (Fig. 1). Two patients from the GJG group were excluded: one patient had a stoma and the other patient had a primary tumor that could not be assessed. There was no difference between the groups in patient background (Table 1). The most common comorbidities were hypertension and diabetes, but there was no difference between the groups in the incidence of either disorder. The incidence of grade 1 peripheral neuropathy based on the NCI CTCAE classification was 43.8 % in the GJG group and 62.4 % in the placebo group. By contrast, the incidence of grade 2 or greater peripheral neuropathy was
13
93 included in primary analysis
50.6 % in the GJG group and 31.2 % in the placebo group (Table 2). Figure 2 shows the TTN curve, based on the incidence of grade 2 peripheral neuropathy, which was the primary endpoint of the study. Surprisingly, in the interim analysis, the TTN was significantly less in the GJG group. The TTN was measured according to the criteria of NCI CTCAE version 3.0 (Fig. 2) and DEB-NTC (see Fig. S1 in the Electronic supplementary material, ESM). It was significantly less in the GJG group in both assessments. The difference was more significant in the updated analysis performed 8 months after the first data cutoff point (Figs. S1C and S1D in the ESM). A Cox proportional hazards model analysis indicated that the hazard ratio (HR) was 1.908 (p = 0.007) in the final analysis performed in accordance with NCI CTCAE criteria. Figure S2 in the ESM shows the TTN for each grade by course. Goshajinkigan did not reduce the TTN, even for grade 1. The forest plot indicated that the risk of peripheral neuropathy was greater among patients in the GJG group in most parameters (Fig. 3). Adverse events other than neurotoxicity were also evaluated, and no between-group differences in hematologic and nonhematologic events were noted (Table 3). A secondary endpoint of this trial was a comparison of the FOLFOX6 dose intensity and of the rates of discontinuation as a result of neuropathy in the two arms. The total dose of L-OHP was 793.47 mg/m2 in the GJG group and 749.69 mg/m2 in the placebo group. The average cycle of chemotherapy was 9.0 in the GJG group and 8.3 in the placebo group. The mean relative dose intensity planned protocol of oxaliplatin up until the onset of grade 2 or greater
Int J Clin Oncol (2015) 20:767–775
771
(%)
Table 1 Background data for the patients
Sex Male Female Age (years, mean ± SD)
Goshajinkigan
Placebo
89
93
48 (53.9) 41 (46.1) 62.4 ± 10.6
51 (54.8) 42 (45.2) 60.4 ± 11.5
Stage p-Stage IIIA 61 (68.5) p-Stage IIIB 28 (31.5) Tumor location Right 32 (36.0) Left 57 (64.0) Tumor T1 + T2 13 (14.6) T3 + T4 76 (85.4) Lymph node metastasis N1 60 (67.4) N2, N3 29 (32.6) Cr
