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© 1999 American Society for Clinical Oncology Combination of Oxaliplatin Plus Irinotecan in Patients With Gastrointestinal Tumors: Results of Two Independent Phase I Studies With PharmacokineticsFrom the Hôpital Paul Brousse, Villejuif; Hôpital Saint-Louis, Paris; Centre René Huguenin, Saint-Cloud; Bellon/Laboratoires Rhône-Poulenc Rorer, Montrouge; Sanofi-Winthrop, Gentilly; and Cvitkovic & Associés Consultants, Kremlin-Bicêtre, France. Address reprint requests to E. Cvitkovic, MD, FSMSIT, Hôpital Paul Brousse, 12-14 Ave Paul Vaillant Couturier, 94804 Villejuif, Cedex, France; email e.cvitkovic{at}cvitkovic-ac.fr
PURPOSE: Two phase I studies of the oxaliplatin and irinotecan combination were performed in advanced gastrointestinal cancer patients to characterize the safety and pharmacokinetics of the regimen.
PATIENTS AND METHODS: Patients with a performance status (PS) of RESULTS: Thirty-nine patients with gastrointestinal carcinomas (24 with colorectal cancer [CRC], four with pancreas cancer, four with gastric cancer, three with hepatocarcinoma, and four with other) received 216 treatment cycles. Median age was 54 years (range, 21 to 72 years); 95% had PS of 0 to 1; all but six had failed fluorouracil (5-FU) chemotherapy. The maximum-tolerated dose was oxaliplatin 110 mg/m2 plus irinotecan 200 mg/m2 in one study and oxaliplatin 110 mg/m2 plus irinotecan 250 mg/m2 in the other study. Grade 3 to 4 diarrhea and febrile neutropenia were dose-limiting toxicities; other toxicities included emesis and dose-cumulative neuropathy. Recommended dose for phase II studies is oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2. At this dose (12 patients, 65 cycles), grade 3 and 4 toxicities per patient included the following: emesis in 42% of patients, neutropenia in 33% (febrile episodes in 17%), peripheral neuropathy in 25%, delayed diarrhea in 17%, and thrombocytopenia in 8%. Two patients with Gilbert's syndrome experienced severe irinotecan toxicity. No plasmatic pharmacokinetic interactions were detected. Seven partial responses were observed in 24 CRC patients. CONCLUSION: This combination is feasible, with activity in 5-FU–resistant CRC patients. Phase I studies that explore the every-2-weeks schedule, in addition to phase II studies of this schedule (as well as in combination with 5-FU) as second-line therapy of metastatic CRC, are ongoing.
FOR SEVERAL DECADES, the standard chemotherapy for advanced colorectal cancer (CRC) has been fluorouracil (5-FU).1 Recently, two new cytotoxic compounds with different mechanisms of action and lack of cross-resistance between them and with 5-FU have been proven clinically active in the treatment of advanced CRC patients: irinotecan and oxaliplatin. Irinotecan is a water-soluble, semisynthetic derivative of camptothecin that exhibits potent topoisomerase I inhibition. It exerts an antitumoral effect, mainly through its active metabolite SN-38, which is 100- to 1,000-fold more active than its parent compound.2 Irinotecan has shown consistent antitumoral activity in metastatic CRC, regardless of the administration schedule, in both chemotherapy-naive and pretreated patients. In the largest phase II study reported to date,3 in which the schedule of 350 mg/m2 once every 3 weeks was used, an objective response rate of 17.7% was observed in the subset of pretreated patients, with a median time to tumor progression (TTP) of 4.2 months. With a weekly regimen, an objective response rate of 23% was reported in patients who experienced disease progression during or within 6 months of one prior 5-FU–based regimen.4 A similar consistency across studies has been observed in first-line therapy. Response rates ranging from 19% to 32% have been reported, with a median TTP of approximately 6 months.3,5,6 These results are quite similar to those achieved with bolus 5-FU plus leucovorin (LV).1 More recently, two large phase III studies including more than 360 patients have shown a definite survival benefit of irinotecan in CRC patients resistant to a first 5-FU–based regimen, versus either supportive care7 (median survival, 9.2 v 6.5 months) or second-line infusional 5-FU (median survival, 10.8 v 8.5 months),8 thus establishing this new compound as standard treatment in this clinical setting with usefulness as second-line chemotherapy in CRC. Clinical trials in Europe, the United States, and Japan have consistently reported severe neutropenia and delayed diarrhea as the dose-limiting toxicities (DLTs) for this regimen, regardless of the schedule administered. With the early use of intensive loperamide therapy, diarrhea has become manageable. Of the many 1,2 diaminocyclohexane (DACH) platinum compounds that have been evaluated, only oxaliplatin has successfully reached late clinical development. Molecular biology studies and in vitro cytotoxic screening performed at the National Cancer Institute showed that DACH-platinum salts such as oxaliplatin belong to a distinct cytotoxic family that differs from cisplatin and carboplatin. The mechanism of action of oxaliplatin, like cisplatin, is through the formation of DNA adducts, but DACH-platinum adducts are bulkier and more hydrophobic than cisplatin adducts.9,10 Furthermore, the mismatch-repair protein complex may be prevented from binding to oxaliplatin adducts because of particular conformational DNA distortions in the region of the adducts.11 The most extensive clinical experience has been gathered in the treatment of advanced CRC and ovarian cancers. Unlike other platinum salts, oxaliplatin has consistently shown preclinical and clinical antitumoral activity against CRC. Its administration as a single drug (130 mg/m2 every 3 weeks) in pretreated patients with metastatic CRC achieved an 11% response rate and a median survival time of 8.2 months,12 whereas in chemotherapy-naive patients, an objective response rate of 20% to 24% and a median survival time of 13 to 14.5 months were reported.13,14 Phase II studies conducted with oxaliplatin combined with 5-FU and LV in advanced CRC patients who were previously refractory to 5-FU showed overall response rates ranging from 21% to 58% and median survival times ranging from to 12 to 17 months.15-17 These results were obtained with oxaliplatin administered at doses ranging from 125 to 130 mg/m2 every 3 weeks or 80 to 100 mg/m2 every 2 weeks, in short intravenous (IV) or continuous infusion (flat or chronomodulated). In first-line chemotherapy of metastatic CRC, two recent multicenter randomized trials that included a total of 620 patients and compared 5-FU/LV with the same regimen plus oxaliplatin have shown a definite advantage for the addition of oxaliplatin in terms of response rates (34% v 12% in the first trial18 and 57% v 26% in the second trial19) and TTP (8.9 v 5.2 months18 and 9.5 v 6.5 months,19 respectively). The most common side effects associated with oxaliplatin are nausea/vomiting and a transient peripheral neuropathy, which is characterized by paresthesia and dysesthesia in the hands, feet, and perioral area and is triggered and/or enhanced by contact with cold temperatures. This toxicity is cumulative, usually mild to moderate, and, in most patients, fully reversible 6 to 8 months after treatment discontinuation.20 Oxaliplatin is neither nephrotoxic nor ototoxic and is associated with only sporadic, mild hematologic toxicity at recommended doses. In vitro studies with the combination of oxaliplatin and SN-38 have shown a strong cytotoxic synergism in the human colon cancer cell line HT29, regardless of the sequence of administration.21 The synergism between topoisomerase I inhibitor and platinum salts has been shown to be due to the stabilization of DNA platinum adducts, when cells were exposed to the topoisomerase I inhibitor after the platinum compound.22,23 Furthermore, the clinical experience with both drugs as single agents has shown a nonoverlapping toxicity profile. Thus the clinical assessment of this non–5-FU–cross-resistant combination in gastrointestinal tumors was strongly warranted. In this article, we report the results of two independent single-center phase I trials that were conducted simultaneously with an identical design in patients with advanced gastrointestinal malignancies.
Patients Eligibility criteria included documentation of incurable, histologically proven gastrointestinal malignancies. All patients were required to have World Health Organization (WHO) performance status  2; age between 18 and 70 years; life expectancy of greater than 12 weeks; and normal hepatic, renal, and bone marrow function (defined by WBC count  4 x 109/L; absolute neutrophil count 1.5 x 109/L; platelet count 100 x 109/L; hemoglobin 10 g/dL; serum creatinine 1.5 x upper limit of normal [ULN]; total bilirubin level 1.25 x ULN; and AST, ALT, and alkaline phosphatase < 2.5 x ULN, or < 5 x ULN if hepatic metastases were present). Exclusion criteria included the following: chemotherapy or radiotherapy within 4 weeks before study entry (6 weeks for nitrosourea and mitomycin), prior chemotherapy with oxaliplatin or irinotecan, previous malignancies (with the exception of excised cervical carcinoma-in-situ or basal/squamous cell skin carcinoma), peripheral neuropathy, pregnant or childbearing women, and concomitant uncontrolled, nonmalignant disease (cardiac, pulmonary, renal, or hepatic disease, active infection). Patients with a prior history of chronic enteropathy, chronic diarrhea, extensive intestinal resection, unresolved bowel obstruction/subobstruction, or extensive abdominopelvic radiation therapy were also excluded. The protocols were approved by the ethics committees of each institution, and signed informed consent was obtained from all patients.
Pretreatment evaluation included a complete medical history, physical examination, ECG, chest x-ray, and computed tomography scan of assessable target lesions, although measurability of disease was not a mandatory eligibility clause. Complete blood cell counts and differential, blood chemistry, and tumor markers (when suitable) were obtained at baseline and before each cycle. Complete blood cell counts were repeated weekly. Patients were evaluated for toxicity weekly while on study, and all toxicities, except peripheral sensitive neuropathy, were graded using the National Cancer Institute common toxicity criteria. Diarrhea was graded as follows: grade 1, increase of two or three stools per day over the pretreatment number; grade 2, increase of four to six stools per day, nocturnal stools, or moderate cramping; grade 3, increase of seven to nine stools per day, or with a moderate weight loss (3% to 7%) or worsening of performance status (no more than one grade in the WHO/Eastern Cooperative Oncology Group scale) attributable to the diarrhea; and grade 4, increase of 10 or more stools per day, bloody diarrhea, need for parenteral support, or presence of life-threatening complications related to diarrhea. Peripheral sensitive neuropathy was graded according to a WHO-modified specific grading system.12 Grade 1, peripheral paresthesias/dysesthesias of moderate intensity lasting
Treatment Plan
A minimum of three patients were entered at each dose level, with a minimum 1-week interval between the entry of the first patient and the next two patients of a given dose level. Before escalating to the next dose level, all three patients should have received at least one treatment cycle and been observed for acute toxicity for a minimum of 2 weeks, with at least one patient receiving two cycles and being observed for acute toxicity for a minimum of 2 weeks. If one of three patients at a given dose level developed a DLT, then at least three more patients were to be entered at the same dose level. The maximum-tolerated dose (MTD) was defined as the dose that resulted in at least three of six patients developing the same DLT on the first two treatment cycles. The recommended dose was to be the dose immediately below the MTD, provided its feasibility and tolerability on repeated cycles were demonstrated in additional patients. Early cholinergic reactions to irinotecan were prevented with atropine sulfate (0.25 mg subcutaneously) administered immediately before irinotecan. No prophylaxis was given for delayed diarrhea. Specific guidelines for curative treatment of delayed diarrhea (onset > 24 hours from the end of irinotecan infusion) were provided as follows: as soon as the first loose stool occurred, the patient was to immediately start loperamide 4 mg plus racecadotril 100 mg (a new enkephalinase inhibitor; Tiorfan, Bioprojet, Paris, France), both administered orally every 8 hours for 48 hours. This combination seems as effective as high-dose loperamide, but the tid administration was deemed to be more convenient for patient compliance.25 If diarrhea persisted beyond 48 hours of treatment, a standard high-dose loperamide regimen was to be started (2 mg orally every 2 hours) for at least 12 hours after the last loose stool and for a maximum of 48 hours. Patients were to be hospitalized when they presented grade 3 to 4 diarrhea and fever, grade 3 to 4 neutropenia and diarrhea, diarrhea with signs of dehydration, or impaired performance status. Standard doses of ondansetron or granisetron and corticosteroids were administered to prevent nausea and vomiting. Treatment duration depended on the response to therapy. Patients without objective tumor progression after six cycles could continue treatment until evidence of disease progression, unacceptable toxicity, or patient refusal.
Pharmacokinetics The pharmacokinetic analysis of the study combination was performed at the first and second treatment cycle, and when possible, at the sixth or later cycles to detect any eventual cumulative effect.
Statistical Methods The detailed pharmacokinetic/pharmacodynamic relationship of the study combination will be the subject of a separate report.
Patients Forty patients were entered in both phase I studies: 27 and 13 patients at Hôpital Paul Brousse (study A) and Hôpital Saint-Louis (study B), respectively. One patient with gastric cancer never received the study drugs because of a case of peritonitis that developed two days before the planned treatment as the result of a gastrostomy that was performed to resolve a gastric obstruction. Thirty-nine treated patients were assessable for toxicity and efficacy. A summary of patient characteristics is included in Table 2. Due to the proven activity of both drugs as single agents in metastatic CRC, accrual focused on such patients (62%). Among the 24 patients with CRC, 19 (79%) had experienced tumor progression while on 5-FU–based treatment, including 14 (58%) who experienced outright disease progression while on initial 5-FU therapy. All patients with unresectable locally advanced pancreatic cancer except one had metastatic disease. Six of 13 patients in study B, who had unfavorable prognostic factors and diagnoses of advanced pancreas cancer, hepatocarcinoma, tumor of unknown site, or CRC that progressed while on adjuvant chemotherapy, received the study combination as a first palliative chemotherapy regimen.
Study Treatment Exposure
Early discontinuation (maximum number of cycles received
Safety
Gilbert's Syndrome
Determination of MTD
Pharmacokinetics
A slight difference in pharmacokinetic parameters for irinotecan, SN-38, and SN-38G between the first and following cycles, although suspected at the beginning of the study, was not confirmed at the end. Oxaliplatin pharmacokinetics were linear within the range of doses used for total and ultrafiltrable platinum. A slight increase of the irinotecan plasma clearance was observed when the dose was increased, but this was not statistically significant. SN-38 and SN-38 glucuroconjugate areas under the curve showed interpatient variability, with a coefficient of variations greater than 100%. For both drugs, the pharmacokinetic parameters did not seem to be influenced by the concomitant use of the other drug. The pharmacokinetic results were similar, for each drug, to those obtained when the drugs were used as single agents in previous studies.29-32
Efficacy
The primary objective of these dose-finding studies of oxaliplatin combined with irinotecan administered every 3 weeks in pretreated gastrointestinal tumors was to determine the MTD and the recommended dose of the two drugs in combination. The MTD was determined to be dose level 3 (oxaliplatin 110 mg/m2 and irinotecan 200 mg/m2) in one study and level 4 (110mg/m2 and 250 mg/m2) in the other. Nevertheless, when three additional patients were entered at level 3 in study B, they experienced severe toxicity, and investigators jointly agreed that the recommended dose for further phase II studies should be level 2: oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2. At the recommended dose, the main severe toxicities per patient were nausea/vomiting (42%), neutropenia (33%), peripheral neurotoxicity (25%), diarrhea (17%), and febrile neutropenia (17%). The overall acceptability and feasibility of this combination regimen is highlighted by the fact that many patients had long treatment duration, with 44% receiving at least six cycles. Severe nausea and vomiting seem common as compared with incidence in either single-drug experience, despite a systematic optimal premedication.3-8 This toxicity seems characteristic of the combination, but it never led to treatment discontinuation. Except for nausea/vomiting, the toxicity profiles of the two study drugs do not overlap, with irinotecan inducing diarrhea and neutropenia and oxaliplatin inducing cumulative peripheral neurotoxicity. The incidence of nausea/vomiting reflects the different emetogenic profile induced by the two drugs. For irinotecan, the symptoms occur soon after treatment administration as a hyperacute toxicity; for oxaliplatin, the symptoms have an acute but more delayed toxicity pattern. The fact that the recommended dose in this trial is established at approximately 60% of the single-agent recommended dose for either agent (irinotecan 350 mg/m2, oxaliplatin 130 mg/m2), as is the case for the irinotecan and cisplatin combination,33 indicates that there is a potentialization of the single-agent toxicities by the combination. The clinical synergism or additivity confirms preclinical data.21,23 Finally, an advantage that may arise from the use of a lower oxaliplatin dose than that recommended for single agent is the possibility to administer a high number of cycles without an early excess likelihood of cumulative severe neurosensory toxicity. The pharmacokinetic evaluation did not find any modification in the plasmatic levels as compared with the expected parameters of either single agents. However, such a finding does not contradict the supposition concerning potentialization of irinotecan toxicity by oxaliplatin, given the known interpatient variability of the plasmatic levels of SN-38 and the small patient samples by dose level. Furthermore, the potentialization may likely take place at the intracellular target (DNA) level. The study population was obviously selected for patients with reasonably good general condition: the median age was 54 years, 67% of patients had a performance status of 0 at study entrance, there was a median of one organ involved, and a median of one prior chemotherapy regimen. Although clinical response was not the primary end point of this phase I trial, sufficient activity has been observed in advanced CRC to warrant further clinical investigations. Among 24 CRC assessable patients, a response rate of 29% was reported, with seven partial responses, nine cases of stable disease (38%), and eight cases of progressive disease (33%). Particular attention should be given to the 16 patients (67%) who achieved partial responses or stable disease because of the recently suggested value of either response or stabilization as surrogate markers of efficacy.34,35 It is interesting that in a CRC population, with 58% of patients characterized as 5-FU refractory by the strict criteria of proven progression while undergoing optimal 5-FU–based treatment, the median number of cycles administered was seven (range, two to 15 cycles), and the median TTP was 7.4 months. The median survival of 15.8 months is also of note, even when considering the limited size of the disease-specific cohort. These results have motivated several ongoing clinical studies, some with a controlled randomized design to better assess the clinical benefit of this combination in a multicentric accrual basis. Scheithauer et al36 recently reported a 31% objective response rate in second-line CRC patients using another treatment schedule of this combination: oxaliplatin 85 mg/m2 (days 1 and 15) and irinotecan 80 mg/m2 (days 1, 8, and 15) every 4 weeks ± G-CSF support. Of note, dose reductions were required in 31% of patients; a clear dose recommendation was not given. We have not seen any evidence of enhanced incidence or severity of irinotecan-related toxicity,37,38 but this trial has elicited a possible link between Gilbert's syndrome and enhanced susceptibility to irinotecan-induced diarrhea and neutropenia28 and has demonstrated the usefulness of baseline bilirubin as a prognostic factor for these DLTs. Two patients with Gilbert's syndrome were included in this trial; both were subject to repeated severe toxic episodes and both experienced DLTs in conjunction with transient bilirubin rise. Given that SN-38, the active metabolite of irinotecan, shares a glucuronidation pathway with bilirubin,39 elevated baseline levels of unconjugated bilirubin—which is reflective of decreased efficiency of the conjugation pathway—may predict an increased risk of irinotecan-induced toxicities through higher plasma exposure to SN-38. This hypothesis has retrospectively been investigated and confirmed on the basis of data from this and other trials40 and will be the subject of prospective investigation. This finding must be kept in mind in any further irinotecan dose-finding studies, because it may be responsible for underestimation of the MTD, given the few patients included in each level of a phase I trial. Until recently, the only therapeutic approach to CRC was the optimization of fluoropyrimidine-based therapy. The oxaliplatin/irinotecan combination is the first active combination that is not thymidylate synthase (TS)–dependent, and the regimen provides new therapeutic approaches for CRC, either in patients who experience treatment failure with 5-FU or in triple combination with TS inhibitors in chemotherapy-naive patients. The oxaliplatin/irinotecan biweekly administration phase I study is near completion41 and a study on the weekly administration schedule of the same combination is planned (N. Kemeny, personal communication, August 1998). Several multicenter randomized phase II and III trials are evaluating the positioning of irinotecan, oxaliplatin, and the combination of these with 5-FU/LV through the exploration of sequential or alternated treatment schedules. These exciting new therapeutic possibilities are evolving simultaneously with rapid progress in clinicobiochemical studies that correlate molecular parameters (p53, TS, mismatch repair deficiency, and so on) with therapeutic outcome and natural history parameters. In ongoing and future clinical trials, new treatments and prognosis factors may allow us to define the maximal benefit for the greatest proportion of patients through more individualized patient management.
Supported by grants from Rhône-Poulenc Rorer SA and Sanofi-Winthrop France.
Presented in part at the Thirty-Third Annual Meeting of the American Society of Clinical Oncology in Denver, CO, May 17-20, 1997, and the Eighth Conference on DNA Topoisomerases in Therapy in Amsterdam, the Netherlands, October 1997.
1. Moertel C: Chemotherapy for colorectal cancer. N Engl J Med 330:1136-1142, 1994
2.
Kaneda N, Nagata H, Furuta T, et al: Metabolism and pharmacokinetics of the camptothecin analogue irinotecan in the mouse. Cancer Res 50:1715-1720, 1990
3.
Rougier P, Bugat R, Douillard JY, et al: Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 15:251-260, 1997
4.
Rothenberg ML, Eckardt J, Kuhn J, et al: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 14:1128-1135, 1996 5. Pitot HC, Wender DB, O'Connell MJ, et al: Phase II Trial of Irinotecan in Patients With Metastatic Colorectal Carcinoma. J Clin Oncol 15:2910-2919, 1997[Abstract]
6.
Conti J, Kemeny NE, Saltz LB, et al: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 14:709-715, 1996 7. Cunningham D, Pyrhönen S, James RD, et al: A phase III multicenter randomized study of CPT-11 versus supportive care alone in patients with 5-FU-resistant metastatic colorectal cancer. Proc Am Soc Clin Oncol 17:1, 1998 (abstr 1) 8. Van Cutsem E, Bajetta E, Niederle N, et al: A phase III multicenter randomized trial comparing CPT-11 to infusional 5-FU regimen in patients with advanced colorectal cancer after 5-FU failure. Proc Am Soc Clin Oncol 17:256, 1998 (abstr 984) 9. Woynarowski JM, Chapman WG, Napier C, et al: Oxaliplatin effects on naked and intracellular DNA. Proc Am Assoc Cancer Res 38:311, 1997 (abstr 2083)
10.
Mamenta EL, Poma EE, Kaufmann WK, et al: Enhanced replicative bypass of platinum-DNA adducts in cisplatin-resistant human ovarian carcinoma cell lines. Cancer Res 54:3500-3505, 1994 11. Scheef ED, Howell SB: Computer modeling of the primary cisplatin and oxaliplatin DNA adducts and relevance to mismatch repair recognition. Proc Am Assoc Cancer Res 39:158, 1998 (abstr 1082)
12.
Machover D, Diaz-Rubio E, de Gramont A, et al: Two consecutive phase II studies of oxaliplatin for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines. Ann Oncol 7:95-98, 1996
13.
Diaz-Rubio E, Sastre J, Zaniboni A, et al: Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: A phase II multicenter study. Ann Oncol 9:105-108, 1998 14. Becouarn Y, Ychou M, Ducreux M, et al: Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients: Digestive Group of French Federation of Cancer Centers. J Clin Oncol 16:2739-2744, 1998[Abstract] 15. Levi F, Misset JL, Brienza S, et al: A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump. Cancer 69:893-900, 1992[Medline] 16. Bertheault-Cvitkovic F, Jami A, Itzhaki M, et al: Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer. J Clin Oncol 14:2950-2958, 1996[Abstract] 17. De Gramont A, Vignoud J, Tournigand C, et al: Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48 hour continuous infusion in pretreated metastatic colorectal cancer. Eur J Cancer 33:214-219, 1997 18. Giacchetti S, Zidani J, Di Palma M, et al: Phase III trial of 5-fluorouracil, folinic acid, with or without oxaliplatin in previously untreated patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 16:229, 1997 (abstr 805) 19. De Gramont A, Figer A, Seymour M, et al: A randomized trial of leucovorin and 5-fluorouracil with or without oxaliplatin in advanced colorectal cancer. Proc Am Soc Clin Oncol 17:257, 1998 (abstr 985) 20. Brienza S, Vignoud J, Itzhaki M, et al: Oxaliplatin: Global safety in 682 patients. Proc Am Soc Clin Oncol 14:209, 1995 (abstr 513) 21. Zeghari-Squalli N, Misset JL, Goldwasser F: Cellular pharmacology of SN38 in combination with oxaliplatin or 5-fluorouracil in human colon cancer cell lines. Proc Am Soc Clin Oncol 16:255, 1997 (abstr 906) 22. Zeghari-Squalli N, Misset JL, Cvitkovic E, et al: Mechanism of the in vitro synergism between SN 38 and oxaliplatin. Proc Am Assoc Cancer Res 38:3, 1997 (abstr 20) 23. Raymond E, Djelloul S, Buquet-Fagot C, et al: Oxaliplatin and cisplatin in combination with 5-FU, specific thymidylate synthase inhibitors (AG337, ZD1694) and topoisomerase I inhibitors (SN38, irinotecan), in human colonic, ovarian and breast cancers. Proc Am Assoc Cancer Res 37:291, 1996 (abstr 1981) 24. Miller AB, Hoogstrated B, Staquet M: Reporting of cancer treatment. Cancer 47:207-214, 1981[Medline] 25. Saliba F, Hagipantelli R, Misset JL, et al: Pathophysiology and therapy of irinotecan-induced delayed-onset diarrhea: A prospective assessment. J Clin Oncol 16:2745-2751, 1998[Abstract] 26. Barilero I, Gandia D, Armand JP, et al: Simultaneous determination of camptothecin analogue irinotecan and its active metabolite SN-38 by high-performance liquid chromatography: Applications to plasma pharmacokinetic studies in cancer patients. J Chromatogr 575:275-280, 1992[Medline] 27. Chabot G: Development of limited sampling models for the simultaneous estimation of irinotecan and active metabolite SN-38 pharmacokinetics. Cancer Chemother Pharmacol 36:463-472, 1995[Medline]
28.
Wasserman E, Myara A, Lokiec F, et al: Severe irinotecan toxicity in patients with Gilbert's syndrome: Two case reports. Ann Oncol 8:1049-1051, 1997 29. Massari C, Brienza S, Rotarski M, et al: Oxaliplatin, comparative pharmacokinetics in normal and impaired renal function patients. Proc Am Assoc Cancer Res 35:242, 1994 (abstr 1445) 30. Rothenberg M, Kuhn J, Burris H, et al: Phase II trial of CPT-11 in patients with 5-FU refractory colorectal cancer. Ann Oncol 5:190, 1994 (abstr) (suppl 5)
31.
Gupta E, Lestingi T, Mick M, et al: Metabolic fate of irinotecan in humans: Correlation of glucuronidation with diarrhea. Cancer Res 54:3723-3725, 1994
32.
Abigerges D, Chabot G, Armand JP, et al: Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients. J Clin Oncol 13:210-221, 1995 33. Verweij J, de Jonge M, Sparreboom A, et al: Phase I and pharmacokinetic study of irinotecan and cisplatin in patients with solid tumors. Proc Am Soc Clin Oncol 17:188, 1998 (abstr 724) 34. Graf W, Pahlman L, Bergstrom R, et al: The relationship between an objective response to chemotherapy and survival in advanced colorectal cancer. Br J Cancer 70:559-563, 1994[Medline] 35. Fages B, Cote C, Gruia G, et al: Tumor response and stabilization rates are worthwhile surrogate efficacy end points in metastatic colorectal cancer: Analysis of data in 455 5-FU resistant patients treated with irinotecan. Proc Am Soc Clin Oncol 16:288, 1997 (abstr 1022) 36. Scheithauer W, Lathan B, Kornek G, et al: Irinotecan plus oxaliplatin ± G-CSF as second line therapy in patients with advanced 5-FU/leucovorin-refractory colorectal cancer. 10th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam, the Netherlands, March 1998 (abstr 658) 37. Valencak J, Raderer M, Kornek GV, et al: Irinotecan-related cholinergic syndrome induced by coadministration of oxaliplatin. J Natl Cancer Inst 90:160, 1998 (letter) 38. Cvitkovic E, Marty M, Wasserman E, et al: Re: Irinotecan-related cholinergic syndrome induced by coadministration of oxaliplatin. J Natl Cancer Inst 90:1016, 1998 (letter) [Medline] 39. Iyer L, King CD, Whitington PF, et al: Genetic predisposition to the metabolism of Irinotecan (CPT-11): Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 101:847-854, 1998[Medline] 40. Wasserman E, Lokiec F, Myara A, et al: Baseline serum bilirubin, a good predictor of CPT-11 neutropenia: A pharmacokinetic/pharmacodynamic correlation. Proc Am Assoc Cancer Res 39:597, 1998 (abstr 4065) 41. Chouaki N, Goldwasser F, Buthaud X, et al: Oxaliplatin/irinotecan combination every two weeks: Preliminary results of a phase I study in advanced digestive malignancies. Proc Am Assoc Cancer Res 39:321, 1998 (abstr 2191) Submitted August 24, 1998; accepted February 22, 1999.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
