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© 2002 American Society for Clinical Oncology Biweekly Chemotherapy With Oxaliplatin, Irinotecan, Infusional Fluorouracil, and Leucovorin: A Pilot Study in Patients With Metastatic Colorectal CancerByFrom the Division of Medical Oncology, Department of Oncology, Civil Hospital, Livorno; Division of Pharmacology and Chemotherapy, Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa; and Division of Medical Oncology, Department of Oncology, S. Chiara Hospital, Pisa, Italy. Address reprint requests to Alfredo Falcone, MD, Divisione di Oncologia Medica, Presidio Ospedaliero, V.le Alfieri, 36, 57121 Livorno, Italy; email: a.falcone{at}med.unipi.it
PURPOSE: To determine the feasibility, recommended doses, plasma pharmacokinetics, and antitumor activity of a biweekly chemotherapy regimen with oxaliplatin (L-OHP), irinotecan (CPT-11), infusional fluorouracil (5-FU), and leucovorin (LV) in metastatic colorectal cancer patients. PATIENTS AND METHODS: Patients received CPT-11 followed by L-OHP and LV 200 mg/m2 and followed by 5-FU 3,800 mg/m2 as a 48-hour infusion, repeated every 2 weeks. In the first part of the study, an escalation of CPT-11 dose and/or a decrease of the L-OHP dose were planned. Once the recommended doses of CPT-11 and L-OHP were determined, all subsequent patients were treated at the recommended doses. RESULTS: Forty-two patients entered the study. CPT-11 175 mg/m2 and L-OHP 100 mg/m2 in combination with LV 200 mg/m2 and 5-FU 3,800 mg/m2 could be administered with acceptable toxicities; 39 patients were treated at these dose levels. The pharmacokinetics parameters of the agents used and their metabolites did not seem to be influenced by the concomitant use of the other drugs. The most relevant toxicities were diarrhea and neutropenia, with 14% of patients experiencing one episode of febrile neutropenia. In five patients (11.9%) a complete and in 25 (59.5%) a partial response was demonstrated, for an objective response rate of 71.4% (95% confidence interval, 47% to 83%). In 11 patients (26%), a surgical resection of residual disease could be performed. Median progression-free and overall survival times were 10.4 and 26.5 months, respectively. CONCLUSION: This biweekly regimen is feasible and has acceptable and manageable toxicities and no apparent relevant pharmacokinetics interactions. This combination is associated with a promising antitumor activity, time to progression, and survival. A phase III randomized trial in Italy planned by the Gruppo Oncologico Nord Ovest has just started.
FLUOROURACIL (5-FU)-based chemotherapy has been demonstrated to prolong survival and to improve quality of life in patients with metastatic colorectal cancer.1,2 New agents such as irinotecan (CPT-11) and oxaliplatin (L-OHP) have also demonstrated antitumor activity in this disease.3-6 Because of the different mechanisms of action and dose-limiting toxicities (DLTs) of 5-FU, CPT-11, and L-OHP, the combination of these agents has been extensively explored both in experimental and in clinical studies. In preclinical studies, a clear synergism or additivity between CPT-11 and 5-FU, L-OHP and 5-FU, and CPT-11 and L-OHP was observed7-13 and, therefore, these combinations have been evaluated in clinical studies. The combination of CPT-11 and 5-FU plus leucovorin (LV) has shown, in phase III studies, significant improvements in response rate, time to progression, and overall survival when compared to 5-FU plus LV alone.14,15 Also, L-OHP, when added to 5-FU/LV, has demonstrated, in phase III studies, to significantly improve response rate and time to progression.16,17 The combination of CPT-11 and L-OHP, so far, has been studied in phase I and II studies, where it has been shown to be feasible and active both in chemotherapy-naive and in pretreated metastatic colorectal cancer patients.18-21 Therefore, chemotherapy of metastatic colorectal cancer has profoundly changed in the past few years, moving from a fluoropyrimidine-modulated treatment to a more aggressive approach that includes two active agents.22,23 Of interest is that the phase III studies with CPT-11 plus 5-FU/LV have clearly demonstrated that the advantage of an up-front, more aggressive approach is still evident even if active second-line therapies are offered to patients whose disease is progressing on 5-FU/LV.14,15 Furthermore, studies with L-OHP plus 5-FU/LV have indicated that a highly active first-line chemotherapy regimen may permit, in a subgroup of initially unresectable metastatic colorectal cancer patients, a secondary radical surgical approach on metastases. Of interest is that approximately 30% to 40% of these patients will survive without evidence of disease over 5 years.16,24,25 Therefore, these data suggest that, in metastatic colorectal cancer patients, a more active first-line treatment can also be more effective, and the relation between tumor response to first-line chemotherapy and survival is also supported by a recent meta-analysis.26 On the basis of these considerations, in the present study we have attempted to develop a new and highly active chemotherapy regimen. Because of the different mechanisms of action; noncomplete cross-resistance; different DLTs of 5-FU, CPT-11, and L-OHP; and the previous experimental and clinical studies with the two-drug combinations, we designed a three-drug regimen including CPT-11, L-OHP, and 5-FU/LV. Our objectives were to determine the feasibility of this combination, the recommended doses of the agents used, possible pharmacokinetic interactions and, finally, to preliminarily evaluate the antitumor activity of this new regimen in metastatic colorectal cancer patients.
Patient Selection Main eligibility criteria included histologically confirmed diagnosis of colorectal adenocarcinoma with metastatic disease; age less than 75 years; Eastern Cooperative Oncology Group performance status  2; measurable disease; leukocyte count  3,500/mm3; neutrophil count 1,500/mm3; platelet count 100,000/mm3; serum creatinine 1.3 mg/dL; serum bilirubin less than 1.5 mg/dL; and AST, ALT, and alkaline phosphatase 2.5 times normal values ( 5 times normal values if liver metastases were present). Previous adjuvant or palliative 5-FU with or without LV or raltitrexed was allowed. Exclusion criteria were previous chemotherapy including CPT-11 or L-OHP, symptomatic cardiac disease, myocardial infarction in the past 24 months, uncontrolled arrhythmia, active infections, inflammatory bowel disease, or total colectomy. The study was approved by the local ethics committee, and patients were informed of the investigational nature of the study and provided their written informed consent before registration onto the study.
Study Design and Treatment To prevent nausea and vomiting, 5-hydroxytryptamine-3 antagonists intravenously (IV) plus dexamethasone 16 mg IV were administered before chemotherapy and oral 5-hydroxytryptamine-3 antagonists were given orally at standard doses in the 2 days after chemotherapy. Atropine 0.25 mg subcutaneously was given in the event of cholinergic syndrome and given prophylactically in the subsequent cycles. Loperamide 2 mg orally every 2 hours and oral rehydration were prescribed in the event of delayed diarrhea. No prophylactic treatment with cytokines was recommended.
Pharmacokinetics
Assessability, Toxicity, and Response Criteria
Statistical Analysis
Patients and Study Treatment A total of 42 patients with metastatic colorectal carcinoma entered the study. Median age was 62.5 years (range, 43 to 73 years) and Eastern Cooperative Oncology Group performance status was 1 to 2 in 16 patients (38%). Thirty-two (76%) had liver metastases and, among these, 10 (32%) had a liver involvement more than 50% (evaluated by CT scan), 17 (40%) had multiple metastatic sites, and 20 (48%) had received previous adjuvant (16 patients) or palliative (four patients) chemotherapy with 5-FU/LV (20 patients) or raltitrexed (one patient) (one patient had received both adjuvant raltitrexed and palliative 5-FU/LV) (Table 1). The first three patients received CPT-11 at 125 mg/m2 and, because after two cycles no DLTs had occurred, the subsequent group of three patients received CPT-11 at 175 mg/m2. Also, at this dose level DLTs were not observed after the first two cycles. However, as previously planned, doses were not further escalated, because for each single drug the dose reached was approximately its recommended dose when this agent was used alone or in combination with 5-FU. Therefore, all subsequent patients were treated at the CPT-11 dose of 175 mg/m2 in combination with L-OHP (100 mg/m2), LV (200 mg/m2), and 5-FU (3,800 mg/m2) given biweekly (Fig 1). Among all 42 patients entered onto the study, a total of 468 cycles of chemotherapy were administered, with a median number of cycles of 12 per patient (range, six to 15 cycles).
Toxicity and Dose-Intensity All patients were assessable for toxicities. The most common toxicities were neutropenia, diarrhea, nausea and vomiting, stomatitis, peripheral neurotoxicity, alopecia, and thrombocytopenia. However, grade 3 and 4 toxicities were uncommon, except for neutropenia. In particular, 7% of cycles were associated with grade 4 neutropenia, although only 1.3% were complicated by fever, 1% were associated with grade 3 or 4 thrombocytopenia, 3% were associated with grade 3 diarrhea, and 0.8% were associated with grade 3 stomatitis (Table 2). Among all 42 patients, 23 (55%) experienced at least one episode of grade 4 neutropenia, six (14%) had an episode of grade IV febrile neutropenia, nine (21%) had at least one episode of grade 3 diarrhea, four (10%) had at least one episode of grade 3 stomatitis, and 16 (38%) developed a grade 2 or 3 peripheral neurotoxicity (Table 3). In five patients (12%), oxaliplatin was prematurely interrupted because of neurotoxicity. Seventeen patients (40%) and 163 cycles (35%) required dose reductions of at least one drug; 128 cycles (27%) were delayed 1 week because of neutropenia (10%), other toxicities (6%), or non–treatment-related reasons (11%). Five patients required hospitalization because of toxicities (febrile neutropenia and/or diarrhea), but no toxic deaths occurred. Median dose intensities of CPT-11, L-OHP, and 5-FU calculated during the entire treatment period among the 39 patients treated at the CPT-11 dose of 175 mg/m2 were 67 mg/m2/wk (77% of planned), 39 mg/m2/wk (78% of planned), and 1.512 mg/m2/wk (80% of planned), respectively. Although the use of granulocyte colony-stimulating factor was not planned, it was used in 151 cycles (32%) because of grade 4 neutropenia associated or not with fever or because persistent neutropenia on the day of recycle did not permit maintaining the planned biweekly schedule.
Antitumor Activity and Survival With respect to the evaluation of antitumor activity of treatment, all 42 patients were assessable for response. Five patients (11.9%) with liver (three patients), lung (one patient), and liver plus lung (one patient) metastases obtained a complete response and 25 (59.5%) a partial response, for an objective response rate of 71.4% (95% confidence interval, 47% to 83%). The external panel was able to review CT and/or magnetic resonance imaging scans of 29 of 30 patients who at the investigators’ assessment were recorded as having objective responses. The panel confirmed all 29 responses reviewed (five complete and 24 partial), thus resulting in an intent-to-treat externally confirmed response rate of 69%. Responses lasted a median period of 11.3 months (range, 4 to 24 months). In the remaining 12 patients, three (7.1%) minor (25% to 50%) responses, eight (19%) disease stabilizations, and one (2.4%) progression were observed (Table 4). The response rate among the 39 patients treated at the CPT-11 dose of 175 mg/m2 was 69%; among the 20 patients who had received previous adjuvant or palliative chemotherapy, the response rate was 60%; and among the 22 patients who were chemotherapy-naive, the response rate was 82%. Surgical removal of residual disease was attempted after chemotherapy in 15 patients (36%) and a radical resection was performed in 11 (26%) (eight patients with liver involvement only, two patients with liver and lymph nodes metastases, and one patient with liver and peritoneal localizations). After a median follow-up of 21.5 months, median progression-free and overall survival were 10.4 and 26.5 months, respectively, and curves estimated by the Kaplan-Meier method from the first day of treatment are reported in Fig 2.
Pharmacokinetics The plasma concentration-time profiles of CPT-11, SN-38, SN-38 glucuronide, and total and ultrafiltrable platinum are reported in Fig 3. 5-FU and 5-FDHU levels at 4, 6, and 24 hours after the start of 5-FU infusion were 0.21 ± 0.03, 0.45 ± 0.08, and 0.61 ± 0.09 µg/mL (5-FU), respectively, and 0.75 ± 0.09, 0.81 ± 0.12, and 0.93 ± 0.1 µg/mL (5-FDHU), respectively. In addition to this, main pharmacokinetic parameters of CPT-11, SN-38, SN-38 glucuronide, and total and ultrafiltrable platinum are listed in Table 5. Overall, the pharmacokinetic parameters did not seem to be influenced by the concomitant use of the other drugs used in combination.
In about 10 years, the debate on the management of advanced colorectal cancer has moved from the question of whether to treat the patient with chemotherapy to the question of how to combine the active agents available.22,23 The studies conducted with CPT-11 plus FU/LV14,15 and with L-OHP plus 5-FU/LV16,17 strongly support the use of these combinations in patients with unresectable metastatic colorectal cancer. In particular, the results of phase III studies with CPT-11 plus 5-FU/LV suggest that an up-front more active treatment can also be more effective in patients with metastatic colorectal cancer. In fact, the advantage in survival for this combination was obtained even though second-line chemotherapy, including CPT-11 in patients who had received only 5-FU/LV, was allowed and most patients received it. This indicates that, although second-line chemotherapy can benefit some patients in terms of survival and quality of life as demonstrated in the phase III studies with CPT-11,33,34 the benefit can be greater if the more active therapy is administered up-front. This is probably because at the time of progression after first-line chemotherapy, a proportion of patients will not be appropriate for second-line chemotherapy or also that the benefit that can be obtained is smaller because of a higher degree of chemoresistance (larger tumor mass and longer time to develop genetic mutations). In addition, studies with L-OHP plus 5-FU/LV have suggested that a highly active combination may permit, in a subgroup of initially unresectable metastatic colorectal cancer patients, performance of a radical operation on residual metastases after chemotherapy and that this approach can be potentially curative.24,25 Therefore, metastatic colorectal cancer, if left untreated, leads to death after a median period of 5 to 6 months; however, if treated with an active combination, its median survival is tripled, reaching 15 to 18 months, and if "adjuvant" surgery is also performed, it can sometimes be cured. These results support the strategy to identify new and more active drug combinations in metastatic colorectal cancer. In fact, if this treatment exists, it might lead to further improvements in survival, at least in the subgroup of patients with more aggressive and advanced disease (which, if it progresses, cannot be salvaged by a second-line therapy), and in the subgroup of patients who will undergo radical resection after response to chemotherapy.
Therefore, we designed the present study in the attempt to develop a new and more active chemotherapy regimen. On the basis of the experimental and clinical results obtained in the last years with CPT-11, L-OHP, and 5-FU/LV indicating their activity as single agents, potential additivity or synergism, noncomplete cross-resistance, and different DLTs that allow their combination without significant dose reductions, we decided to explore the possibility of combining these three agents and evaluating the antitumor activity of this new regimen in unresectable metastatic colorectal cancer patients. A recent in vitro study on two human colon cancer cell lines that has evaluated the ternary combination of CPT-11 plus L-OHP plus 5-FU/LV further supports the clinical evaluation of this association and the treatment sequence we used (CPT-11 The comparison of the present pharmacokinetic results concerning CPT-11 and its metabolites with those of a previous study37 revealed that plasma profiles of CPT-11, SN-38, and SN-38 glucuronide were unaffected by the infusion of L-OHP, in agreement with previous studies.40-42 5-FU was administered as a semi-intermittent infusion, which allowed the administration of 67% of the dose between 4 PM and midnight, thus reducing the probability that the fluoropyrimidine could affect CPT-11 or SN-38 metabolism. Indeed, plasma levels of 5-FU were below 1 µg/mL, and less than those of the catabolite 5-FDHU. These results are consistent with an extensive catabolism of 5-FU to 5-FDHU. Other groups are also evaluating similar three-drug combinations, although in a more heavily pretreated population. Lerebours et al43 are evaluating an every-3-week schedule in combination with a 4-day infusion of 5-FU; Calvo et al44 are evaluating an every-4-week therapy of CPT-11 and L-OHP with 24-hour infusional 5-FU on days 1 and 15; and Gil Delgado et al45 and Conroy et al46 are evaluating a biweekly schedule with CPT-11 at doses up to 180 to 220 mg/m2, L-OHP up to 85 mg/m2, and 5-FU given according to the classic De-Gramont schedule with bolus 5-FU 400 mg/m2 followed by a 600-mg/m2 22-hour continuous infusion on days 1 and 2. The preliminary results so far reported confirm the feasibility of these three-drug combinations, with neutropenia and diarrhea being the DLTs and with a promising antitumor activity (response rates of 32% to 69%). Because of the promising results of this pilot study, a multicenter, randomized, phase III trial comparing a standard two-drug biweekly combination with CPT-11 plus 5-FU/LV with our three-drug regimen has been planned in Italy by the Gruppo Oncologico Nord Ovest and is now accruing patients.
We thank Cinzia Orlandini and Michele Andreuccetti for data analysis and technical assistance and Michele Malventi, MD (Division of Radiology, Livorno), for coordinating the external response review committee.
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30. Kern W, Braess J, Bottger B, et al: Oxaliplatin pharmacokinetics during a four-hour infusion. Clin Cancer Res 5: 761-765, 1999 31. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47: 207-214, 1981[CrossRef][Medline] 32. Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10: 1-10, 1989[Medline] 33. Cunningham , Pyrhonen S, James RD, et al: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352: 1413-1418, 1998[CrossRef][Medline] 34. Rougier P, Van Custem E, Bajetta E, et al: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352: 1407-1412, 1998[CrossRef][Medline] 35. Fischel JL, Rostagno P, Formento P, et al: Ternary combination of irinotecan, fluorouracil-folinic acid and oxaliplatin: Results on human colon cancer cell lines. Br J Cancer 84: 579-585, 2001[CrossRef][Medline]
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37. Falcone A, Di Paolo A, Masi G, et al: Sequence effect of irinotecan and fluorouracil treatment on pharmacokinetics and toxicity in chemotherapy-naive metastatic colorectal cancer patients. J Clin Oncol 19: 3456-3462, 2001 38. Levi F, Zidani R, Misset JL, et al: Randomised multicenter trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. Lancet 350: 681-686, 1997[CrossRef][Medline] 39. Scheithauer W, Kornek GV, Ulrich-Pur H, et al: Oxaliplatin plus raltitrexed in patients with advanced colorectal carcinoma. Cancer 91: 1264-1271, 2001[CrossRef][Medline] 40. Chabot GG: Clinical pharmacokinetics of irinotecan. Clin Pharmacokinet 33: 245-259, 1997[Medline] 41. Rothemberg ML, McKinney J, Hande KR, et al: A phase I clinical and pharmacokinetic trial of oxaliplatin and irinotecan (CPT-11) given every two weeks to patients with refractory solid tumors. Clin Cancer Res 5: 3853-3859, 1999
42. Wasserman E, Cuvier C, Lokiec F, et al: Combination of oxaliplatin plus irinotecan in patients with gastrointestinal tumors: Results of two independent phase I studies with pharmacokinetics. J Clin Oncol 17: 1751-1759, 1999 43. Lerebours F, Cottu P, Hocini H, et al: Oxaliplatin (OXA), irinotecan (CPT-11), and 4-day continuous infusion 5-fluorouracil (CVI/FU) every three weeks (Q3W): A phase I study in advanced gastrointestinal tumors. Proc Am Soc Clin Oncol 19: 313a, 2000 (abstr 1237) 44. Calvo E, Cortes J, Rodriguez J, et al: Irinotecan, oxaliplatin plus 5-FU/leucovorin in advanced colorectal cancer. Proc Am Soc Clin Oncol 20: 136a, 2001 (abstr 542) 45. Gil-Delgado M, Bastian G, Guinet F, et al: Final results of oxaliplatin (LOHP) + irinotecan (CPT11) and FU-FOL (LV5 FU2) combination and pharmacokinetic (PK) analysis in advanced colorectal cancer (ACRC) patients (pts). Proc Am Soc Clin Oncol 20: 140a, 2001 (abstr 558) 46. Conroy T, Seitz J, Capodano G, et al: Phase I study of triple combination of oxaliplatin + irinotecan + LVFU2 in patients with metastatic solid tumors. Proc Am Soc Clin Oncol 20: 236a, 2000 (abstr 921G) Submitted December 18, 2001; accepted June 14, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
L-OHP 
