© 2007 Foundation for Promotion of Cancer Research
Phase II Study of Oxaliplatin in Japanese Patients with Metastatic Colorectal Cancer Refractory to Fluoropyrimidines
1 Division of Gastrointestinal Oncology and Gastroenterology, National Cancer Center Hospital East, Kashiwa, Chiba
2 Department of Clinical Research and Internal Medicine, National Hospital Organization Shikoku Cancer Center, Ehime
3 Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo
4 Department of Gastroenterology, Saku Central Hospital, Saku, Nagano
5 Department of Medical Oncology, Kinki University, Osakasayama, Osaka
6 Department of Gastrointestinal Oncology, Kobe University, Hyogo
7 Department of Medical Oncology, Japanese Foundation for Cancer Research, Tokyo
8 Department of Pharmacy, Keio University Hospital, Tokyo, Japan
For reprints and all correspondence: Narikazu Boku, Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777 Japan. E-mail: n.boku{at}scchr.jp
Received December 22, 2006; accepted February 5, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Background: Although oxaliplatin (L-OHP) combined with infusional 5-fluorouracil (5-FU) and leucovorin (LV) is one of the standard chemotherapy regimens for metastatic or recurrent colorectal cancer, its introduction to Japan has been delayed. Phase I studies of L-OHP monotherapy in Japan showed no dose-limiting toxicity at the internationally recommended dose of 130 mg/m2 every 3 weeks, as well as no racial differences in pharmacokinetics as compared with Western subjects. This study aimed to clarify the efficacy and safety of L-OHP monotherapy in patients with metastatic colorectal cancer refractory to fluoropyrimidines.
Methods: Patients with metastatic colorectal cancer who had failed to respond to fluoropyrimidine-based chemotherapy received L-OHP at a dose of 130 mg/m2 every 3 weeks.
Results: Sixty patients were enrolled. Two ineligible patients and one untreated patient were excluded from analysis. The median number of treatment cycles was 4 (range, 1–6). The overall response rate was 9% (5/57, 95% CI: 4–19%). The median time to progression was 2.7 months, and the median survival time was 11.1 months. Grade 3 major toxicity comprised thrombocytopenia (12%) and nausea (11%). There was no grade 4 toxicity. All patients experienced mild to moderate sensory neurotoxicity without functional impairment interfering with activities of daily living.
Conclusions: The efficacy and toxicity of L-OHP in Japanese patients with metastatic colorectal cancer refractory to fluoropyrimidines is apparently similar to those in Western patients.
Key Words: oxaliplatin • monotherapy • colorectal cancer • phase II
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Oxaliplatin (L-OHP) is a platinum analogue that differs from cisplatin or carboplatin by having a diaminocyclohexane moiety that is retained after drug aquation (1,2). This bulky side chain is believed to contribute to its distinct spectrum of activity as demonstrated in preclinical models and clinical trials (3). Whereas other platinum antitumor agents show little or no activity against colorectal cancer, preclinical studies have shown that L-OHP was significantly active against six of the eight colorectal cancer cell lines in the National Cancer Institute's Human Tumor Cell Line Screen panel and inhibited tumor-colony formation in one third of explanted human colorectal cancers (4).
As first-line monotherapy in patients with colorectal cancer, L-OHP produced response rates of 12–24%, with a median progression-free survival time (PFS) of approximately 4 months and a median survival time (MST) of 13–15 months (5,6). Randomized controlled studies have shown that regimens combining L-OHP with infusional 5-fluorouracil (5-FU) plus leucovorin (LV) (FOLFOX) have significantly higher response rates and longer PFS with acceptable toxicity, as compared with infusional 5-FU plus LV regimens (FL) (7,8). The efficacy of FOLFOX4 as first-line treatment for metastatic colorectal cancer is supported by the results of the North American Inter-group study N9741. In that study, patients treated with FOLFOX4 had significantly longer PFS, better overall survival, a higher response rate, and lower toxicity than patients treated with a bolus FL plus irinotecan (CPT-11) regimen (IFL) (9). These results have established L-OHP as a key drug for the treatment of metastatic colorectal cancer.
The clinical development of L-OHP in Japan has been delayed. A phase I study in which Japanese patients received L-OHP in doses of 90 mg/m2 (n = 3) or 130 mg/m2 (n = 6) showed no dose-limiting toxicity and no racial differences in pharmacokinetics as compared with Western patients. These results suggested that the internationally recommended dose of L-OHP 130 mg/m2 every 3 weeks was feasible for Japanese patients (10). However, the small number of patients in the phase I study precluded conclusions about dosage. To further clarify the efficacy and safety of L-OHP monotherapy, we conducted a phase II study in Japanese patients with metastatic colorectal cancer refractory to previous treatment with 5-FU.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Study Design
The primary endpoint was response rate. The expected response rate was 15%, and the required sample size was estimated to be 49 patients, so that the lower limit of the 95% confidence interval (CI) would not be less than 5%. Thus, 60 patients were scheduled to be recruited. If none of the first 20 patients responded to treatment, the study would be terminated.
Eligibility Criteria
Eligibility criteria were as follows: (i) histologically confirmed colorectal cancer; (ii) unresectable or metastatic disease; (iii) a history of treatment with one prior fluoropyrimidine-based regimen, excluding adjuvant therapy; (iv) radiologically confirmed progressive disease (PD) during the prior chemotherapy; (v) 4 weeks' rest from the last dose of prior chemotherapy; (vi) a performance status of 
2 on the Eastern Cooperative Oncology Group scale; (vii) an age of 
20 to 75 years; (viii) a life expectancy of 12 weeks; (ix) at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST); (x) adequate organ functions, leukocytes 3000/mm3 and 10 000/mm3, neutrophils 1500/mm3, platelets 100 000/mm3, total bilirubin 2-fold the upper limit of normal, aspartate aminotransferase and alanine aminotransferase 2.5-fold the upper limit of normal and creatinine 1.5-fold the upper limit of normal; and (xi) written informed consent. Exclusion criteria were as follows: (i) a history of blood transfusion or treatment with G-CSF within 7 days before entry; (ii) a history of severe drug allergy; (iii) prior therapy with platinum-containing chemotherapy; (iv) prior hepatic arterial infusion of antitumor agents; (v) symptomatic brain metastasis; (vi) massive ascites or pleural effusion; (vii) no measurable lesions besides bone metastasis; (viii) poorly controlled hypercalcemia; (ix) poorly controlled hypertension; (x) poorly controlled diabetes; (xi) active infection; (xii) positive for hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus antibody; (xiii) severe diarrhea; (xiv) heart disease such as congestive heart failure, symptomatic coronary artery disease, or poorly controlled arrhythmias; (xv) severe lung disease such as interstitial pneumonitis, pulmonary fibrosis, or emphysema; (xvi) mental disease or a history of central nervous system disorders; (xvii) peripheral sensory neuropathy; (xviii) women who refuse to use contraception or are pregnant or nursing; and (xix) patients whom the investigators considered unsuitable for this study.
Treatment Schedule
L-OHP was administered at a dose of 130 mg/m2 (diluted in 500 ml of 5% glucose) as an intravenous infusion over the course of 2 h. Treatment was repeated every 3 weeks and continued until the completion of six cycles or the confirmation of tumor progression or unacceptable toxicity. A 5-HT3 receptor antagonist (40 µg/kg of granisetron hydrochloride) was given intravenously before treatment with L-OHP.
Before each dose of L-OHP, the following conditions had to be met: leukocyte count 2500/mm3, platelets 75 000/mm3, diarrhea grade 1, and other toxicity (except for neurotoxicity and alopecia) grade 2. If these conditions were not satisfied, treatment was postponed until recovery. The dose of L-OHP was reduced to 90 mg/m2 if grade 4 leukopenia, neutropenic fever, or other grade 3 adverse events (except nausea, alopecia, or electrolyte imbalance) occurred during the preceding cycle. If treatment was not possible within 22 days after the day scheduled according to the protocol, the patient was withdrawn from the study. If neurotoxicity remained on the day scheduled for treatment, administration of L-OHP was delayed until the disappearance of such toxicity. If the patient did not recover from neurotoxicity within 7 days, the dose was reduced to 90 mg/m2 and given 7 days after the originally scheduled treatment day, regardless of the presence or absence of neurotoxicity. In patients in whom the dose of L-OHP had already been reduced to 90 mg/m2, treatment was continued without further dose reduction, even if a lower dose was indicated because of neurotoxicity.
Evaluations
Tumor lesions were assessed by computed tomographic scanning, magnetic resonance imaging, or both every 4 weeks. Response was evaluated according to RECIST by an independent panel of diagnostic radiologists. Laboratory tests, physical examinations, and symptom assessments were performed weekly. Toxic effects other than neurotoxicity were evaluated according to the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), version 2.0. Neurological toxicity was assessed according to the Neurotoxicity Criteria of Debiopharm (DEB-NTC; see Table 4). PFS was calculated from the date of initiating therapy to the date of radiologically confirming PD according to RECIST. Survival time was calculated from date of initiating therapy to the date of death. For patients lost to follow-up, data were censored on the date on which the patient was last known to have stable disease to calculate PFS; to calculate survival time data were censored on the date on which the patient was last known to be alive.
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Ethics
This trial was approved by the institutional review board at each participating hospital and was conducted in accordance with Japanese Good Clinical Practice guidelines.
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RESULTS |
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Subjects
Sixty patients were enrolled in this study from April 2001 through July 2002. In all patients, disease progression during previous treatment with 5-FU-based regimens was confirmed by an independent panel of diagnostic radiologists. Two patients were ineligible: 1 had no target lesion and the other had neuropathy caused by cervical spondylosis. L-OHP was not administered to another patient, who was suspected to have double cancers. Data from the remaining 57 patients were analyzed to assess efficacy and safety.
Patient characteristics are summarized in Table 1. The median age was 61 years (range, 23–74). All patients had a performance status of 0 or 1 at baseline. The number of organs involved by metastatic lesions was 1 (74%) in 42 patients and 2 or more in 15 (26%). Metastases were present in the liver alone in 23 patients (40%), in the lung alone in 12 (21%), in the liver plus other sites in 12 (21%) and in other sites in 10 (18%). Previous chemotherapy was 5-FU ± l-LV in 39 patients, CPT-11 + 5-FU ± l-LV in 17 and UFT/LV in one. Six patients had received radiation therapy.
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Administration of L-OHP
The total number of cycles administered was 166. The median number of cycles per patient was four (range, 1–6). L-OHP was administered on the scheduled day or within a 3-day delay in 148 cycles (89%). Nine patients completed the planned six cycles. The dose of L-OHP was reduced during 17 cycles (8%) in nine patients (16%). Persistent neurotoxicity necessitated dose reduction during two cycles (1.2%) in two patients (4%) and delayed treatment during two cycles (1.2%) in two patients (4%). The median dose intensity was 129 mg/m2 every 3 weeks (range, 93–130), corresponding to 99% (range, 72–100%) of the planned dose. Treatment was stopped because of disease progression in 45 patients (79%). One patient (2%) discontinued treatment because of grade 3 vomiting, persisting even after dose reduction. Two patients (4%) refused to continue treatment for other reasons than toxicity.
Antitumor Effects
Table 2 shows the response to therapy. Five patients (9%) had partial responses and 27 (47%) had stable disease. The response (CR + PR) rate was thus 9% (95% CI: 3–19%), and the disease-stabilization (CR + PR + SD) rate was 56% (95% CI: 42–69%). The median time to response was 1.6 months (95% CI: 0.9–2.1 months), and the median duration of response was 3.0 months (95% CI: 1.8–4.3 months). The median PFS was 2.7 months (Fig. 1), and the MST was 11.1 months with a 1-year survival rate of 43% (Fig. 2). The MST calculated from the date of initiating the previous regimen of chemotherapy was 20.2 months (95% CI: 16.4–22.0 months).
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Toxicity
Table 3 summarizes the incidences of toxic effects other than neurotoxicity. There was no grade 4 toxicity. The most common types of severe toxicity were gastrointestinal reactions and thrombocytopenia. No grade 3 toxic effect had an incidence above 12%. Table 4 shows the incidences of neurotoxicity. Cold-related transient paresthesia/dysesthesia occurred in all patients. Cold-related paresthesia/dysesthesia was grade 1 in 12 patients (21%) and grade 2 in 45 (79%). Persistent paresthesia/dysesthesia without pain was grade 1 in 15 patients and grade 2 in 20 (35%). Persistent paresthesia/dysesthesia with pain was grade 1 in 13 patients (23%) and grade 2 in 6 (11%).
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Figure 3 shows the relation between the number of treatment cycles and the incidence of neurotoxicity according to grade. Nearly all patients had neurotoxicity in all cycles, and the incidence of grade 2 neurotoxicity increased gradually with increasing numbers of treatments cycles. The median time to the resolution of neurotoxicity after the last dose of L-OHP was 9 days for cold-related transient paresthesia/dysesthesia (n = 57), 7 days for persistent paresthesia/dysesthesia without pain (n = 24), and 4 days for persistent paresthesia/dysesthesia with pain (n = 11).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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L-OHP is a key drug for the treatment of metastatic colorectal cancer and FOLFOX regimens are recognized as one standard regimen for first-line chemotherapy (7,9). However, the introduction of L-OHP to Japan has been delayed. It was unclear whether the efficacy and safety of L-OHP in Japanese patients would be similar to those in Western patients. Therefore, initial clinical trials were conducted to examine the feasibility of using L-OHP alone or in combination with other drugs in Japan. A phase I study of L-OHP monotherapy showed no dose-limiting toxicity or racial differences in pharmacokinetics (10). That study recommended the internationally used dosage of L-OHP 130 mg/m2 every 3 weeks as monotherapy for the further Japanese trials.
Neurotoxicity is the major drawback of L-OHP. The incidence of grade 3 neurotoxicity increases rapidly when the cumulative dose of L-OHP exceeds 800–1000 mg/m2 or higher (11). In our study, no patient had grade 3 neurotoxicity. The median number of treatment cycles administered per patient was four (range, 1–6). This relatively short duration of treatment might have resulted in the absence of grade 3 neurotoxicity. Nonetheless, the incidence of grade 2 neurotoxicity increased with increasing numbers of treatment cycles. Although there was no grade 4 toxicity in this study, major grade 3 gastrointestinal toxic effects such as nausea, vomiting and appetite loss occurred in 7–11% of the patients. The major hematologic toxicity was thrombocytopenia, and the incidence of grade 3 thrombocytopenia was 12%. Both hematologic and nonhematologic toxic effects, including neurotoxicity, were generally mild. The relative dose intensity of L-OHP was 99%. These results suggest that monotherapy with L-OHP at a dose of 130 mg/m2 every 3 weeks is feasible for Japanese patients.
Two phase II studies of single-agent L-OHP as second-line therapy for patients with metastatic colorectal cancer previously treated with 5-FU ± LV have been performed in Europe. The objective response rates in those studies were 10 and 11%, respectively (12). Our study, in which L-OHP was given as second-line treatment similar to recent Western trials, yielded a comparable response rate of 9% (8/57).
Although one limitation of our study is the possibility of selection bias, MSTs calculated from the date of starting treatment with L-OHP and from the date of initiating the previous regimen of chemotherapy were 11.1 and 20.2 months, respectively. Recently, the MST of patients with metastatic colorectal cancer has been reported to be about 20 months (9,13). This improvement in survival has been attributed to the increased use of three key drugs, 5-FU, CPT-11 and L-OHP (14,15). The MST in our study suggests that the inclusion of L-OHP in the therapeutic strategy for Japanese patients with colorectal cancer may further prolong survival, resulting in results comparable to those of recent Western trials of regimens including L-OHP.
All of our subjects had received first-line chemotherapy with fluoropyrimidine-based regimens, including those containing CPT-11. Progressive disease during these prior regimens was strictly confirmed by an independent panel of diagnostic radiologists. The median PFS in our study was 2.7 months. In previous studies of second-line chemotherapy with CPT-11 after failure to 5-FU, median PFS was 4 months, with MST ranging from 10 to 14 months (16,17). In contrast, monotherapy with L-OHP as second-line treatment has resulted in an MST of 8.2 months (12). Although there are limitations in comparing the results of different studies, available evidence suggests that monotherapy with L-OHP may not be as effective as irinotecan or other combination chemotherapy regimens when used for second-line therapy. In Europe, monotherapy with L-OHP had been approved in the second-line setting at first. Thereafter, in a phase III study for the patients in whom IFL had failed, monotherapy with L-OHP showed a lower response rate and a shorter progression-free survival time than combination with 5-FU (18), so monotherapy with L-OHP cannot be recommended after failure of 5-FU and irinotecan at present.
Clinically, L-OHP is often combined with infusional FL. L-OHP in combination with infusional 5-FU and l-LV was approved in Japan in March 2005, but the dosage of L-OHP is limited to 85 mg/m2 every 2 weeks. In Western countries, several regimens including various dose levels of L-OHP once every 2 or 3 weeks, such FOLFOX6 (13) and FOLFOX7 (19), have been developed. Our findings suggest that a dosage of L-OHP similar to that used in Western trials may be feasible in Japan.
In conclusion, our results suggest that the efficacy and toxicity of monotherapy with L-OHP at a dose of 130 mg/m2 every 3 weeks in Japanese patients with metastatic colorectal cancer refractory to fluoropyrimidines are similar to those reported in Western trials.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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Acknowledgments |
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We are grateful to Drs H. Furue, T. Taguchi, Y. Sakata, Y. Sasaki and H. Takiuchi for their kind advice, as well as to Drs A. Sato, K. Yoshikawa and K. Miyakawa, who served on the extramural review board. This study was supported by Yakult Honsha Co. Ltd., Tokyo, Japan.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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