© 2006 Foundation for Promotion of Cancer Research
Phase I/II Study of Oxaliplatin with Weekly Bolus Fluorouracil and High-Dose Leucovorin (ROX) As First-Line Therapy for Patients with Colorectal Cancer
1 Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo, 2 Gastrointestinal Oncology & Endoscopy Division, National Cancer Center Hospital East, Kashiwa, Chiba, 3 Gastrointestinal Oncology & Endoscopy Division, Shizuoka Cancer Center Hospital, Suntoh-gun, Shizuoka, 4 Gastroentorology Division, Saku Central Hospital, Nagano and 5 Department of Pharmacy, Keio University, Tokyo, Japan
For reprints and all correspondence: Yasuhide Yamada, Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. E-mail: yayamada{at}ncc.go.jp
Received November 1, 2005; accepted December 27, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: Infusional fluorouracil (5-FU) and leucovorin (LV) with oxaliplatin is one of the current standard regimens for the treatment of patients with metastatic colorectal cancer. Weekly bolus 5-FU with high-dose LV (Roswell Park Memorial Institute Regimen: RPMI) is the most commonly used regimen in Japan. The objectives of this study were to determine the recommended dose (RD) of RPMI combined with oxaliplatin and to evaluate the toxicity and efficacy at the RD.
Methods: The subjects were 18 patients with metastatic colorectal cancer. Oxaliplatin (85 mg/m2) was given intravenously over 2 h on days 1 and 15 with l-LV (250 mg/m2) given intravenously over 2 h and 5-FU as an intravenous bolus on days 1, 8, and 15. This treatment was repeated every 4 weeks. The dose of 5-FU was escalated from 400 mg/m2 (level 1) to 500 mg/m2 (level 2).
Results: A total of 14 patients received level 1, and 4 received level 2. Three of the patients had dose-limiting toxicity (DLT) in cycle 1 of level 2 (grade 3 thrombocytopenia, grade 4 neutropenia and grade 2 neutropenia in one patient each), requiring that treatment was delayed for longer than 7 days. None of the 14 patients given level 1 had DLT or grade 3 or 4 gastrointestinal toxicity. Sensory neuropathy occurred in all patients. Objective response rates were 61% in the 18 patients studied and 64% at level 1. The median time to progression was 171 days, and the median overall survival time was 603 days in the 18 patients studied.
Conclusions: Oxaliplatin (85 mg/m2) with weekly bolus 5-FU (400 mg/m2) and high-dose l-LV (250 mg/m2) is recommended for further phase III studies in patients with metastatic colorectal cancer.
Key Words: colorectal cancer • bolus 5-fluorouracil • leucovorin • oxaliplatin • RPMI
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Infusional fluorouracil (5-FU) and leucovorin (LV) with oxaliplatin is one of the current standard regimens for first- and second-line chemotherapy in patients with metastatic colorectal cancer (1–3). The combination of oxaliplatin with infusional 5-FU and LV (FOLFOX4) has been shown to be superior to infusional 5-FU plus LV (LV5FU2) and single-agent oxaliplatin in terms of response rate, median time to progression (TTP), and alleviation of tumor-related symptoms in patients with metastatic colorectal cancer who have disease progression after irinotecan with bolus 5-FU plus leucovorin (IFL, Saltz regimen) (2). Objective response rates were 9.9% for FOLFOX4, 1.3% for oxaliplatin alone and 0% for LV5FU2 (P < 0.0001). Median TTP was 4.6 months for FOLFOX4, 1.6 months for oxaliplatin and 2.7 months for LV5FU2 (P < 0.0001).
FOLFOX4 has also been evaluated as first-line therapy, and a randomized study (N9741) has shown a significantly better response rate, median TTP and median overall survival time (MST) as compared with conventional regimens (3). The response rate in patients given FOLFOX4 (45%) was higher than that in patients given IFL (31%, P = 0.002). Moreover, TTP was significantly longer with FOLFOX4 (8.7 months) than with IFL (6.9 months; P = 0.0014). The MST in patients treated with FOLFOX4 was 19.5 months as compared with only 15.0 months in those treated with IFL (P = 0.0001).
Infusional 5-FU regimens were shown by de Gramont (4) to provide a higher response rate with marginal survival benefit as compared with bolus 5-FU regimens. However, infusional 5-FU with LV has the drawbacks of increased inconvenience, cost and morbidity, related to the use of a portable infusion pump and a central venous catheter. Weekly bolus 5-FU with high-dose LV (RPMI regimen) is the most commonly used schedule in Japan and the United States, and bolus 5-FU plus low-dose LV with irinotecan (modified Saltz regimen) has been shown to have high antitumor activity with a favorable toxicity profile in Japanese patients (5–8). Single-agent oxaliplatin (130 mg/m2) in a tri-weekly regimen has also been found to be effective and tolerable in Japanese as well as Western patients (9). Phase II studies of oxaliplatin as second-line therapy in patients with fluoropyrimidine-pretreated metastatic colorectal cancer reported objective response rates of 9–11% and an MST of 8.2–11.3 months (10–11). However, whether bolus 5-FU plus LV can be combined safely with oxaliplatin in Japanese patients remains unclear.
The primary objectives of this phase I/II study were to estimate the maximal tolerated dose (MTD) and determine the recommended dose of bolus 5-FU plus l-LV in combination with oxaliplatin. In the phase II part, we also evaluated the toxicity and antitumor activity of this regimen at the recommended dose.
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PATIENTS AND METHODS |
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PATIENT ELIGIBILITY
Patients with histologically confirmed colorectal cancer who had measurable metastatic disease were eligible for the study. Prior chemotherapy and radiotherapy for metastatic disease were not permitted. Patients who had received adjuvant oral fluorouracil-based therapy were eligible if they had remained free of disease for at least 6 months after the completion of such therapy. Other eligibility criteria included an age of 20–75 years; an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; adequate baseline bone marrow function (white blood cell [WBC] count more than the lower limit of normal at each hospital and <12 000/µl, neutrophil count >2000/µl and platelet count >100 000/µl), hepatic function (serum bilirubin level 1.5 times the upper limit of normal or less, and serum aspartate aminotransferase and alanine aminotransferase 2.5 times the upper limit of normal or less) and renal function (serum creatinine level 1.5 times the upper limit of normal or less); and a life expectancy of at least 12 weeks. All patients gave written informed consent.
Patients were excluded if they had symptomatic brain metastasis; pre-existing watery diarrhea; concomitant nonmalignant disease, such as cardiac, pulmonary, renal or hepatic disease; or uncontrolled infection. This study was approved by the institutional review board of each center. Before enrollment, all patients underwent a physical examination (including documentation of measurable disease), a complete blood cell count with differential count, serum chemical analysis, chest radiography, electrocardiography, and computed tomographic (CT) scanning or magnetic resonance imaging (MRI).
TOXICITY AND RESPONSE CRITERIA
Toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria, Version 2.0 (NCI-CTC) (12). Neurotoxicity was reported according to the following grading scale: grade 1, dysesthesia or paresthesia that completely regressed within 6 days; grade 2, dysesthesia or paresthesia persisting for 7 days or longer; and grade 3, dysesthesia or paresthesia causing functional impairment. During the study, all patients were evaluated weekly for signs and symptoms of toxicity. Complete blood cell counts including differential count; liver function tests; measurement of urea nitrogen, creatinine and electrolyte levels; and urinalysis were performed weekly in cycle 1 and every 2 weeks in subsequent cycles.
The response of measurable and assessable disease sites was evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) (13). Tumor dimensions were assessed by CT scanning or MRI every month to confirm response and every 2 months subsequently. Partial response (PR) was defined as more than a 30% decrease in the sum of the products of the greatest perpendicular diameters of measurable lesions, without the development of any new lesions. Stable disease was defined as a steady state of response less than a PR or as progression of <20% over the course of at least 6 weeks. Progressive disease (PD) was defined as an unequivocal increase of at least 20% in the sum of the products of the greatest perpendicular diameters of individual lesions. The appearance of new clinically significant lesions also constituted a PD.
TREATMENT PLAN
Oxaliplatin was supplied as a freeze-dried powder in 100 mg vials by Yakult Honsha Co., Ltd. (Tokyo, Japan) and was reconstituted in a solution of 5% glucose in water. The reconstituted solution was then diluted with 250 ml of 5% glucose infusion solution. Oxaliplatin was administered as a 2 h infusion every 2 weeks. The duration of infusion could be extended to 6 h in patients who had pharyngolaryngeal dysesthesia during infusion. l-Leucovorin (Wyeth Ltd., Tokyo, Japan) was administered at a dose of 250 mg/m2 in 500 ml of 5% glucose solution, given as a 2 h intravenous infusion on days 1, 8 and 15 of a 28 day cycle. 5-FU (Kyowa Hakko Kogyo Co., Ltd., Tokyo, Japan) was given by bolus intravenous injection 1 h after starting the l-LV infusion. All patients received premedication with a 5-hydroxytryptamine-3-receptor antagonist with or without dexamethasone, given as a 30 min drip infusion before chemotherapy. Treatment cycles were repeated every 4 weeks. Treatment was routinely given on an outpatient basis, except for cycle 1 of the dose-escalation portion of the protocol (see below). Subsequent treatment was withheld until the WBC, neutrophil,and platelet counts were >3000, 1500 and 75 000 µl, respectively, and diarrhea, stomatitis and hand-foot syndrome had resolved to grade 0 or 1. Treatment was repeated until the onset of disease progression or severe toxicity.
DOSE-ESCALATION SCHEDULE
The dose of oxaliplatin was fixed at 85 mg/m2 and that of l-LV was fixed at 250 mg/m2. 5-FU was studied in dose levels of 400 and 500 mg/m2. A minimum of three patients were studied per dose level. Dose-limiting toxicity (DLT) was defined as any of the following findings during cycle 1: (i) a neutrophil count of <500/µl, (ii) grade 3 febrile neutropenia, (iii) a platelet count of <50 000/µl, (iv) grade 3 or 4 non-hematologic toxicity, excluding nausea, anorexia, and electrolyte imbalance according to the NCI-CTC, or (v) a longer than 1 week delay in treatment as a result of drug-related toxicity in the dose-escalation portion of the protocol. If DLT occurred in 1 of the first 3 patients assigned to a given dose level, 3 other patients were additionally assigned to receive that dose level. The MTD was defined as the dose that induced DLT during cycle 1 in at least 50% of the subjects. In the second portion of the study, the recommended dose was given to 11 other patients to confirm tolerability.
The dose was modified for each patient according to a nomogram, based on hematologic or non-hematologic toxicity. If DLT occurred, the subsequent dose of oxaliplatin was reduced to 75% of the initial dose and that of 5-FU was decreased by one dose level. If the WBC count on days 8, 15 and 22 was <3000/µl, the neutrophil count <1500/µl, or the platelet count <75 000/µl, further treatment was delayed for up to 1 week until recovery. Recombinant granulocyte colony-stimulating factor was subcutaneously injected if patients had grade 4 neutropenia or grade 3 febrile neutropenia, but prophylactic use was not allowed.
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RESULTS |
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PATIENT CHARACTERISTICS
From March 2002 to March 2003, a total of 18 patients were enrolled. All patients received at least one cycle of the study treatment. The first 7 patients participated in the dose-escalation portion of the protocol. After identification of the MTD, 11 other patients received the recommended dose below the MTD to further evaluate the tolerability and toxicity of the study regimen. The patient characteristics are summarized in Table 1. Two patients had received adjuvant oral fluorouracil-based therapy.
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TOXICITY
No DLT occurred during cycle 1 in the first 3 patients given a dose of 400 mg/m2 of 5-FU. Two of the 3 patients initially treated with 500 mg/m2 of 5-FU had dose-limiting myelosuppression. One patient had grade 3 thrombocytopenia, and the other had prolonged grade 2 neutropenia, requiring that treatment was delayed for longer than 1 week. The fourth patient given 5-FU 500 mg/m2 had grade 4 neutropenia. DLT thus comprised neutropenia and thrombocytopenia. The recommended dose was determined to be 400 mg/m2 of 5-FU in combination with 250 mg/m2 of l-LV and 85 mg/m2 of oxaliplatin (Table 2).
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Eleven patients were subsequently enrolled in the second portion of this study.
Combined with the 3 initially treated patients, a total of 14 patients received the recommended dose. The median number of administered cycles was 5.5 (range, 2–11), and the total number of cycles in the 14 patients was 74. At the recommended dose, 2 patients (14%) had grade 3 neutropenia; there was no grade 4 toxicity. The relative dose intensity was 82.5% for oxaliplatin and 84.9% for 5-FU during the first 6 cycles. The causes of treatment discontinuation at the recommended dose were PD in 8 patients, almost a complete response in 1, delayed recovery from thrombocytopenia in 2 and sensory neuropathy in 3.
Sensory neuropathy occurred in all patients. There was no neurotoxicity with functional impairment in this study. The most common types of non-hematologic toxicity were anorexia, nausea, vomiting and diarrhea. No patient had grade 3 or 4 gastrointestinal toxicity at the recommended dose. Most cases of nausea and vomiting responded to dexamethasone and granisetron or other antiemetic drugs, and good oral intake was maintained. Another mild adverse event related to treatment was injection site reactions (79%). Two patients had mild allergic reactions such as skin rash or fever, typical platinum-related reactions.
RESPONSE TO THERAPY
The objective tumor response was determined by an external review board. Of the 14 patients given the recommended dose (level 1) 9 had a PR, yielding a response rate of 64% (95% CI: 35–87%). One of 9 responders underwent hepatectomy following this chemotherapy. Two of the 4 patients given level 2 had a PR. In the 18 patients studied, the response rate was 61% (95% CI: 36–83%), the median time to progression was 171 days (95% CI: 142–227 days) and the median overall survival time (cut-off date: March 27, 2005) was 603 days (95% CI: 442–979 days) (Fig. 1). The 1-year and 2-year survival rates were 94 and 31%, respectively.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Our results suggest that bolus 5-FU plus l-LV with oxaliplatin may be a safe and effective first-line treatment for metastatic colorectal cancer. The recommended dose was determined to be 400 mg/m2 of 5-FU plus 250 mg/m2 of l-LV on days 1, 8 and 15 with 85 mg/m2 of oxaliplatin on days 1 and 15 of a 28 day cycle. DLT comprised neutropenia and thrombocytopenia at level 2. At the recommended dose (level 1), the toxicity profile was acceptable, with grade 3 neutropenia occurring in 14% of the patients; there was no other grade 3 or 4 hematologic or non-hematologic toxicity, including neurotoxicity (table3).
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Two consecutive compassionate-use studies of oxaliplatin were conducted in North America until December 2000 in more than 5000 patients with metastatic colorectal cancer who had had treatment failure with at least 1 prior chemotherapy regimen (14). Patients were assigned to treatment with either single-agent oxaliplatin or oxaliplatin plus 5-FU with or without LV in various regimens. The most frequently used regimen was RPMI with oxaliplatin, received by 43–45% of the patients in both studies. Continuous infusion of low-dose 5-FU (Lokich regimen) was given to 14–20% of the patients, a modified Mayo regimen to 9–15% and LV5FU2 to only 8–10%. US and Canadian oncologists have preferred bolus regimens in combination with oxaliplatin, despite the availability of infusion schedules. The incidence of grade 3 and 4 hematologic toxicity was 17% with RPMI plus oxaliplatin and 52% with FOLFOX4 and that of grade 3 and 4 gastrointestinal toxicity was 28% with RPMI and 18% with FOLFOX4. Neurological toxicity occurred at a rate of 2% with RPMI and 8% with FOLFOX4.
Hochster et al. (15) reported the results of phase II studies of weekly bolus 5-FU (500 mg/m2, days 1, 8 and 15, every 4 weeks) plus low-dose LV (20 mg/m2, days 1, 8 and 15, every 4 weeks) with oxaliplatin (85 mg/m2, days 1 and 15, every 4 weeks) (bFOL), given as first-line therapy to patients with metastatic colorectal cancer. The response rate was 63%, with a median TTP of 9.0 months and an MST of 15.9 months. Common toxicity included grade 3 and 4 neutropenia in 10% of patients, grade 3 and 4 diarrhea in 29%, and grade 3 cumulative neuropathy in 12%. Welles et al. (16) reported the results of a randomized phase II study assessing the safety and tolerability of 3 oxaliplatin-based regimens as first-line treatment for advanced colorectal cancer (‘TREE 1’ study). One arm was bFOL; the other 2 arms were modified FOLFOX6 (oxaliplatin 85 mg/m2, LV 350 mg, 5-FU bolus 400 mg/m2 and infusional 2400 mg/m2 over the course of 46 h, every 2 weeks) and CapeOx (oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 1000 mg/m2 twice daily for 14 days, every 3 weeks). The primary endpoint was the overall incidence of grade 3 and 4 toxicity during the first 12 weeks of each study therapy, and secondary endpoints were overall response rate and TTP. The overall incidence of grade 3 and 4 toxicity was significantly higher with modified FOLFOX6 (mFOLFOX6) (77%) than with bFOL (44%, P < 0.001). Moreover, mFOLFOX6 (37%) had a significantly higher incidence of grade 3 and 4 neutropenia than bFOL (14%, P < 0.01) and CapeOx (8%) (P < 0.001). Grade 3 and 4 diarrhea occurred in similar proportions of patients given bFOL (22%), mFOLFOX6 (22%) or CapeOx (25%). The overall response rate did not significantly differ among the 3 arms and was 52% (21/40) with mFOLFOX6, 38% (14/37) with bFOL and 50% (17/34) with CapeOx. Median times to discontinuation of study therapy were 5.7 months with mFOLFOX6, 4.8 months with bFOL and 4.2 months with CapeOx. These results suggested that bFOL is as active and safe as the other two regimens.
Other schedules of bolus 5-FU and low-dose LV (Mayo Clinic regimen) with oxaliplatin have also been investigated. Zori Comba et al. (17) reported the results of a phase II study of the Mayo Clinic regimen (5-FU 425 mg/m2, days 1–5, every 4 weeks) plus low-dose LV (20 mg/m2, days 1 to 5, every 4 weeks) with oxaliplatin (85 mg/m2, days 1 and 15, every 4 weeks) in previously untreated patients with metastatic colorectal cancer. The response rate was 45%, with a median TTP of 3.9 months. Grade 3 and 4 neutropenia occurred in 23% of the patients, diarrhea in 34%, vomiting in 14% and stomatitis in 14%. This regimen was unacceptable because of the high incidence of severe toxicity. Ravaioli et al. (18) used the Machover scheme (5-FU 350 mg/m2, days 1–5, every 3 weeks) and low-dose LV (20 mg/m2, days 1–5, every 3 weeks) with oxaliplatin (130 mg/m2, day 1, every 3 weeks) as first-line treatment for metastatic colorectal cancer. The response rate was 40%, with a median TTP of 5.9 months and an MST of 14 months. Grade 3 or severer neutropenia or diarrhea occurred in 20 and 29% of the patients, respectively. Sørbye et al. (19) performed a phase II study of Nordic bolus 5-FU (500 mg/m2, days 1 and 2, every 2 weeks) and low-dose LV (60 mg/m2, days 1 and 2, every 2 weeks) with oxaliplatin (85 mg/m2, day 1, every 2 weeks) (Nordic FLOX), given as first-line therapy to patients with metastatic colorectal cancer. The response rate was 62% with a median TTP of 7.0 months and an MST of 16.1 months. Common toxicity included grade 3 and 4 neutropenia in 58% of patients, grade 3 and 4 diarrhea in 7%, and grade 3 cumulative neuropathy in 13%. Febrile neutropenia developed in 8%. That study concluded that Nordic FLOX is an effective and feasible regimen, despite the high incidence of neutropenia.
In our study, the most frequent types of non-hematologic toxicity were mild anorexia, nausea, vomiting, fatigue and diarrhea. Grade 3 neutropenia occurred in only 14% of our patients at the recommended dose. Our regimen was active and safe and may thus be a new alternative treatment for metastatic colorectal cancer. Further clinical phase II/III studies should compare RPMI plus oxaliplatin with FOLFOX to more objectively confirm our findings before our regimen is widely used clinically.
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Acknowledgments |
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We are grateful to Drs H. Furue, T. Taguchi, Y. Sakata, Y. Sasaki, H. Takiuchi and F. Nagamura for their kind advice and to Drs. A. Sato, K. Yoshikawa, K. Miyakawa, who performed the external review board. We also thank S. Sugimoto, N. Sekine, T. Miyazaki, M. Matsuo and H. Ogawa for their assistance in data management. This study was supported by Yakult Honsha Co., Ltd., Tokyo.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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1 de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938–47.
2 Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK, et al. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 2003;21:2059–69.
3 Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22:23–30.
4 de Gramont A, Bosset JF, Milan C, Rougier P, Bouche O, Etienne PL, et al. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol 1997;15:808–15.
5 Yoshino M, Ota K, Kurihara M, Akazawa S, Tominaga T, Sasaki T, et al. Late phase II trial of high-dose l-leucovorin and 5-fluorouracil in advanced colorectal carcinoma. l-Leucovorin and 5-FU Study Group (Japan Eastern Group). Jpn J Cancer Chemother 1995;22:785–92 (in Japanese).
6 Konishi K, Yabushita K, Taguchi T, Ota J, Takashima S, Abe T, et al. A late phase II trial of l-leucovorin and 5-fluorouracil in advanced colorectal cancer. l-Leucovorin and 5-FU Study Group (Japan Western Group). Jpn J Cancer Chemother 1995;22:925–32 (in Japanese).
7 Saltz LB, Kanowitz J, Kemeny NE, Schaaf L, Spriggs D, Staton BA, et al. Phase I clinical and pharmacokinetic study of irinotecan, fluorouracil, and leucovorin in patients with advanced solid tumors. J Clin Oncol 1996;14:2959–67.[Abstract]
8 Goto A, Yamada Y, Hosokawa A, Ura T, Arai T, Hamaguchi T, et al. Phase I/II study of irinotecan, 5-fluorouracil, and l-leucovorin combination therapy (modified Saltz regimen) in patients with metastatic colorectal cancer. Int J Clin Oncol 2004;9:364–8.[Medline]
9 Shirao K, Matsumura Y, Yamada Y, Muro K, Gotoh M, Boku N, et al. Tolerability and pharmacokinetic profile of oxaliplatin in Japanese solid tumor patients. Proc ASCO 2001;20: 94b (abstr 2124).
10 Machover D, Diaz-Rubio E, de Gramont A, Schilf A, Gastiaburu JJ, Brienza S, et al. Two consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines. Ann Oncol 1996;7:95–8.
11 Hyodo I, Shirao K, Boku N, Ohtsu A, Miyata Y, Nakagawa K, et al. Phase II trial and pharmacokinetic analysis of oxaliplatin (L-OHP) as second-line treatment in patients (pts) with metastatic colorectal cancer (MCRC). Proc ASCO 2003;22:344 (abstr 1383).
12 Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Center Institute of Canada. J Natl Cancer Inst 2000;92:205–16.
13 Shimoyama M. The Japanese edition of the National Cancer Institute—common toxicity criteria. Jpn J Cancer Chemother 1999;26:1084–144 (in Japanese).
14 Ramanathan RK, Clark JW, Kemeny NE, Lenz HJ, Gococo KO, Hallar DG, et al. Safety and toxicity analysis of oxaliplatin combined with fluorouracil or as a single agent in patients with previously treated advanced colorectal cancer. J Clin Oncol 2003;21:2904–11.
15 Hochster H, Chachoua A, Speyer J, Escalon J, Zeleniuch-Jacquotte A, Muggia F. Oxaliplatin with weekly bolus fluorouracil and low-dose leucovorin as first-line therapy for patients with colorectal cancer. J Clin Oncol 2003; 21:2703–7.
16 Welles L, Hochster H, Ramanathan R, Wong L, Hart L, Shpilsky A, et al. Preliminary results of a randomized study of the safety and tolerability of three oxaliplatin-based regimens as first-line treatment for advanced colorectal cancer (CRC) (‘Tree’ study). Proc ASCO 2004;23:254 (abstr 3537).
17 Zori Comba A, Blajman C, Richardet E, Bella S, Vilanova M, Coppola F, et al. A randomised phase II study of oxaliplatin alone versus oxaliplatin combined with 5-fluorouracil and folinic acid (Mayo Clinic regimen) in previously untreated metastatic colorectal cancer patients. Eur J Cancer 2001;37:1006–13.[CrossRef][Web of Science][Medline]
18 Ravaioli A, Marangolo M, Pasquini E, Rossi A, Amadori D, Cruciani G, et al. Bolus fluorouracil and leucovorin with oxaliplatin as first-line treatment in metastatic colorectal cancer. J Clin Oncol 2002;20:2545–50.
19 Sørbye H, Glimelius B, Berglund A, Fokstuen T, Tveit KM, Braendengen M, et al. Multicenter phase II study of Nordic fluorouracil and folinic acid bolus schedule combined with oxaliplatin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2004;22:31–8.
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