Int J Clin Oncol DOI 10.1007/s10147-015-0911-7
Multicenter randomized phase II clinical trial of oxaliplatin reintroduction as a third‑ or later‑line therapy for metastatic colorectal cancer—biweekly versus standard triweekly XELOX (The ORION Study) Chu Matsuda1 · Michitaka Honda2 · Chihiro Tanaka3 · Mutsumi Fukunaga4 · Keiichiro Ishibashi5 · Yoshinori Munemoto6 · Taishi Hata7 · Hiroyuki Bando8 · Mitsuru Oshiro9 · Michiya Kobayashi10 · Yukihiko Tokunaga11 · Akitomo Fujii12 · Naoki Nagata13 · Koji Oba14 · Hideyuki Mishima15 Received: 23 August 2015 / Accepted: 28 September 2015 © Japan Society of Clinical Oncology 2015
Abstract Background The aim of this multicenter, open-label, randomized phase II trial was to evaluate the efficacy of a dose-dense capecitabine and oxaliplatin (XELOX) regimen in patients with metastatic colorectal cancer (mCRC) for whom reintroduction of oxaliplatin had been planned as a third- or later-line regimen. Methods The patients with mCRC who had received prior chemotherapy including oxaliplatin and were scheduled for reintroduction of oxaliplatin were randomized to capecitabine (1,000 mg/m2) twice daily on days 1–14 and oxaliplatin (130 mg/m2) on day 1 every 21 days (Q3W group)
or capecitabine (2,000 mg/m2) twice daily on days 1–7 and oxaliplatin (85 mg/m2) on day 1 every 14 days (Q2W group). The primary endpoint was the time-to-treatment failure (TTF). Other endpoints included overall survival (OS), progression-free survival (PFS) and other adverse events (AEs). Results A total of 46 patients were enrolled in the trial— 22 patients were randomly assigned to the Q3W group and 23 to the Q2W group. The median TTF was 3.4 months in both groups (hazard ratio [HR] 1.053; p = 0.880). The median PFS and OS were 3.3 and 9.2 months in the Q2W group and 4.3 and 12.1 months in the Q3W group, respectively (HR 1.15; p = 0.153 and 0.672; p = 0.836). The most common grade 3−4 AEs in the Q3W and Q2W
C. Matsuda and M. Honda contributed equally to this study. * Michitaka Honda [email protected]
Department of Surgery, Osaka General Medical Center, Osaka, Japan
Department of Gastroenterological Surgery, Gastroenterological Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3‑10‑6 Ariake, Koto‑ku, Tokyo 135‑8550, Japan
Department of Surgery, Ishikawa Prefectural Central Hospital, Kanazawa, Ishikawa, Japan
Department of Surgery, Toho University, Sakura Hospital, Sakura, Japan
Department of Surgery, Kochi Medical School, Kochi University, Kochi, Japan
Department of Surgery, Japan Post Kyoto Teishin Hospital, Kyoto, Japan
Department of Surgery, Gifu Prefectural General Medical Center, Gifu, Japan
Department of Surgery, Rinku General Medical Center, Osaka, Japan
Department of Surgery, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Japan
Kitakyushu General Hospital, Kitakyushu, Japan
Department of Epidemiology & Biostatistics, University of Tokyo, Tokyo, Japan
Clinical Cancer Center, Aichi Medical University, Nagakute, Aichi, Japan
Department of Surgery, Saitama Medical University, Saitama, Japan
Department of Surgery, Fukui Saiseikai Hospital, Fukui, Japan
Department of Gastroenterological Surgery, Osaka University, Osaka, Japan
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groups were fatigue (27.3 vs 21.7), neuropathy (9.1 vs 0 %) and diarrhea (9.1 vs 0 %), respectively. Conclusion There was no significant inter-group difference in any of the efficacy and safety endpoints, including TTF, OS, RFS and AEs. The results of this clinical trial were convincingly negative.
The aim of the present phase II trial was to evaluate whether the dose-dense Q2W regimen has superior sustainability to the standard Q3W schedule in mCRC patients for whom reintroduction of oxliplatin has been planned as a third- or later-line regimen.
Keywords Oxaliplatine · Reintroduction · Metastatic colorectal cancer
Patients and methods Study design
Introduction Combination chemotherapy using fluorouracil, folinic acid (5-FU/LV) and oxaliplatin (FOLFOX) is a well-established first-line regimen for metastatic colorectal cancer (mCRC) . However, one of the limitations of this regimen is oxaliplatin-induced sensory neuropathy, and a clinical trial has demonstrated that the incidence of grade 3 neurotoxicity became more frequent as the number of cycles increased, being 10 % after 9 cycles, 25 % after 12 cycles and 50 % after 14 cycles using a dose of 85 mg/m2 per cycle . The National Comprehensive Cancer Network (NCCN) guidelines stipulate that administration of oxaliplatin to patients who develop severe neuropathy during treatment should be withdrawn until the toxicity completely resolves . In such cases, since the oxaliplatin-related neurotoxicity is reversible, reintroduction of oxaliplatin after failure of a second-line regimen has been considered a promising strategy, referred to as the ‘stop and go’ approach [4, 5]. On the other hand, a pivotal phase III study  and a meta-analysis  have recently demonstrated that a combination of capecitabine and oxaliplatin, the ‘XELOX’ regimen, is not inferior in terms of efficacy to FOLFOX4 as a first-line treatment for patients with mCRC. Because capecitabine is an orally administered fluoropyrimidine carbamate, it might be useful as a third- or later-line therapy in terms of treatment continuity. The standard XELOX regimen with or without bevacizumab is a triweekly (Q3W) schedule for mCRC that falls within the NCCN guidelines . Besides the Q3W schedule, an alternative regimen of oxaliplatin at 85 mg/m2 on day 1 and capecitabine at 2,500–4,000 mg/m2/day on days 1–7 every 2 weeks (Q2W) has been developed [8, 9] to suppress the adverse effects while maintaining the efficacy. A phase II randomized trial using oxaliplatin (85 mg/m2) on day 1 and a high-dose schedule of capecitabine at 3,500 mg/m2/d on days 1–7 (Q2W) demonstrated quite promising results, with significantly longer progression-free survival (PFS) than that obtained with Q3W, comparable safety, and a 34 % greater delivered dose intensity .
A multicenter, open-label, randomized phase II trial was conducted at 13 Japanese institutions (http://www.umin. ac.jp/:UMIN000004122). Patients were enrolled between September 2010 and April 2012. The trial was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice Guidelines, and all applicable local laws and regulations. Approval for the protocol was obtained from the institutional review boards of all the participating hospitals. All of the patients provided signed informed consent before initiation of the trial treatment. Participants The patients enrolled in this study had histologically confirmed mCRC, had received prior chemotherapy including both oxaliplatin and irinotecan with more than SD effectiveness, and were scheduled for reintroduction of oxaliplatin as a third-line or later regimen. Other eligibility criteria were aged ≥20 years, presence of a measurable lesion based on the response evaluation criteria in solid tumors (RECIST) , an Eastern Cooperative Oncology Group performance status (ECOG-PS) score of ≤2, and adequate hematologic, renal, and hepatic function. Exclusion criteria included the presence of brain tumors or brain metastases, uncontrolled ascites, ≥grade 3 current peripheral neuropathy, bleeding diathesis or bowel obstruction, clinically significant cardiovascular disease, pulmonary disease, cerebral diseases, metabolic disorder, active infection or psychiatric conditions. Randomization and intervention Patients were randomized to receive either capecitabine (1,000 mg/m2) twice daily on days 1–14 and oxaliplatin (130 mg/m2) on day 1 ±bevacizumab (7.5 mg/kg) on day 1 every 21 days (Q3W group) or capecitabine (1,000 mg/m2) twice daily on days 1–7 and oxaliplatin (85 mg/m2) on day 1 ±bevacizumab (5 mg/kg) on day 1 every 14 days (Q2W group). As all of the study patients had already suffered some adverse effects of previous chemotherapy or surgery,
Int J Clin Oncol
there were concerns that the high-dose biweekly regimen  might not be suitable for them. Therefore, we decided to employ this modified regimen with a reduced dose of capecitabine. This regimen was also applied for elderly patients with CRC . Random assignment was performed using a minimization technique, stratifying patients according to center, ECOG-PS (0–1 vs 2), use of bevacizumab, institution, and the period from final administration of oxliplatin to reintroduction (80 %. The treatment-related AEs are summarized in Table 2. Common AEs in the Q3W and Q2W groups included anemia (90.9 vs 91.3 %), fatigue (77.3 vs 82.6 %), neuropathy (68.2 vs 65.2 %), hand−foot syndrome (HFS; 59.1 vs 60.9 %), nausea (59.1 vs 52.2 %) and thrombocytopenia (45.5 vs 69.6 %), respectively. The most common grade 3 to 4 AEs were fatigue (27.3 vs 21.7 %), neuropathy (9.1 vs 0 %) and diarrhea (9.1 vs 0 %), respectively. There were no treatment-related deaths in either group. AEs necessitated discontinuation of treatment in four patients in the Q3W group (neuropathy, diarrhea, and patient refusal) and three patients in the Q2W group (allergic reaction, bone fracture, and patient refusal).
Int J Clin Oncol
Fig. 1 CONSORT diagram. All participants except for one patient who did not meet the study criteria were randomly allocated to triweekly XELOX or biweekly XELOX
Discussion The results of this clinical trial were convincingly negative; there was no significant inter-group difference in any of the efficacy endpoints, including TTF, OS, and RFS. With regard to whether high-dose biweekly XELOX was useful as an oxaliplatin reintroduction regimen, we reviewed other related trials. Our study plan was based on a phase I/II study reported by Scheithaue et al. —the bi-weekly regimen including capecitabine at 3,500 mg/m2 exerted equivalent effects and safety in comparison with the standard triweekly regimen. They also reported that the biweekly regimen was better able to ensure a drug-free period 1.5 times longer than that for the standard regimen. Furthermore, the subsequent phase II trial demonstrated a significant benefit of the biweekly regimen in terms of response rate and PFS . In addition, Kakolyris et al.  demonstrated the effectiveness and safety of the biweekly regimen as a salvage treatment for patients who had previously received irinotecanbased chemotherapy. Based on these reports, we conducted the present study to clarify the usefulness of this regimen in a large cohort of patients previously treated for mCRC. However, after our study had commenced, an RCT comparing biweekly versus triweekly as a first-line regimen in an
American population produced unexpected results — there was no significant difference between the treatment groups in terms of the median time-to-progression or the median OS time, and the TTF was significantly shorter in the Q2W group than in the Q3W group. In terms of safety, patients in the Q2W group were more likely to experience HFS and to discontinue treatment because of severe diarrhea or HFS. Treatment was discontinued because of AEs in 30 % of patients in the Q3W group and 47 % of patients in the Q2W group. In our study, which yielded similar findings, PFS was better in the Q3W group than in the Q2W group, and the latter showed higher hematological toxicity. It had remained uncertain whether the biweekly regimen could be performed safely in previously treated Japanese patients with mCRC. Although this was a smallscale phase II trial, TTF point estimation and both OS and RFS were equivalent with few apparent differences between the groups, suggesting that the negative results were not attributable to low statistical power. From our results, we conclude that a third- or later-line regimen using biweekly XELOX at the doses studied in this trial cannot be recommended, and that standard triweekly XELOX remains the preferred schedule for patients with mCRC.
Int J Clin Oncol Table 1 Patient characteristics Variable
Q3W (n = 22)
Q2W (n = 23)
No. of patients
No. of patients
Sex Male 12 Female 10 Age (years) Mean (SD) 65.3 Range 48–80 ECOG-PS 0 15 1 7 2 0 Primary tumor site Colon 10 Rectum 12 Metastatic site Liver 12 Lung 12 Lymph node 7 Bone 0 Peritonum 4 Others 2 Treatment line Third 13 Fourth or later 9 TOR >6 months 5 6−12 months 3