1Mayo Clinic and Mayo Foundation, Rochester, MN; 2Missouri Valley Cancer Consortium, Omaha, NE; 3Wichita Community Clinical Oncology Program, Wichita, KS; 4Duluth CCOP, Duluth, MN; 5Scottsdale CCOP, Scottsdale, AZ; 6Cedar Rapids Oncology Project CCOP, 7Cedar Rapids, IA, USA
Received 29 May 2001; revised 10 September 2001; accepted 25 September 2001.
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Abstract |
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The study was performed to determine the maximum tolerated dose (MTD) of gemcitabine and oxaliplatin in patients with advanced or metastatic pancreatic adenocarcinoma (ACA).
Patients and methods
Pancreatic ACA patients, with previously untreated advanced or metastatic disease, were enrolled in a dose escalation study of gemcitabine and oxaliplatin. Oxaliplatin was given intravenously on day 1 and gemcitabine intravenously on days 1 and 8 of a 3-week cycle. Doses of both drugs were increased with sequential cohorts of patients until dose-limiting toxicity (DLT) was observed.
Results
A total of 18 patients were enrolled to three dose levels. DLT of neutropenia and a severe infection was noted at a dose of gemcitabine 1250 mg/m2 and oxaliplatin 130 mg/m2. Hematological toxicity and nausea and vomiting were the most common grade 3/4 toxicities. The MTD, gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2, was well tolerated. Three confirmed responses were seen.
Conclusions
The MTD of gemcitabine and oxaliplatin in patients with pancreatic ACA was determined. A phase II study of this combination is ongoing and will be reported separately at a later date.
Key words: gemcitabine, oxaliplatin, pancreatic cancer, phase I
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Introduction |
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Oxaliplatin is a platinum-based compound with a spectrum of activity different from that seen with cisplatin (CDDP). In preclinical studies, oxaliplatin has shown activity in tumor cell lines that are either intrinsically resistant or have acquired resistance to CDDP [10]. In a separate study, oxaliplatin showed potent in vitro cytotoxic activity against three different pancreatic cancer cell lines [11]. To date, only the preliminary results of a study have been published, in abstract form, reporting the antitumor activity of oxaliplatin as a single agent in the treatment of pancreatic cancer [12]. In this study, oxaliplatin 130 mg/m2 every 3 weeks produced no objective responses. However, further testing of oxaliplatin in this setting, when combined with other agents, is needed given the unique properties of oxaliplatin. A high rate of microsatellite instability is observed in pancreatic ACA [13]. The diaminocyclohexane in oxaliplatin leads to increased activity in CDDP-resistant cell lines with microsatellite instability. Oxaliplatin should retain activity under these conditions, when resistance to CDDP would be expected [14]. In previous preclinical studies, oxaliplatin has shown activity in other upper gastrointestinal tumors, including cancer of the pancreas, stomach and esophagus [10, 11].
Synergic activity is observed when oxaliplatin is combined with other agents, including 5-FU [15]. The combination of gemcitabine and oxaliplatin showed supra-additive, sequence-dependent synergy in human colon cancer cells [16]. The sequence of gemcitabine followed by oxaliplatin inhibited cell growth more effectively than the opposite sequence. In a recently published interim report of a phase I study, gemcitabine was given on days 1 and 8 and oxaliplatin on day 8, with treatment cycles repeated every 3 weeks [17]. At the time of the report the doses reached for gemcitabine and oxaliplatin were 1600 mg/m2 and 110 mg/m2, respectively. Dose-limiting toxicity (DLT) had not occurred. However, grade 3 and 4 neutropenia and grade 3 asthenia occurred at several of the dose levels evaluated.
Given the synergic activity between gemcitabine and oxaliplatin, with proven or potential activity of these agents in pancreatic ACA, we performed a phase I study and subsequently a phase II trial in patients with pancreatic ACA. This paper reports the results of the phase I study. The phase II study is ongoing and will be reported at a later date.
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Materials and methods |
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Pretreatment evaluation and follow-up studies
History and physical examination were performed prior to registration and before each subsequent course of chemotherapy. Studies carried out at the time of registration included: a complete blood cell count (CBC); measurement of serum AST, alkaline phosphatase, total and direct bilirubin, calcium, creatinine, sodium, potassium and glucose; and a chest X-ray. CBCs were repeated weekly, and chemistries were repeated prior to each subsequent cycle of therapy.
Drug administration
Commercially available gemcitabine was purchased as a lyophilized powder in 200 mg and 1000 mg vials and stored at room temperature. It was reconstituted with normal saline to yield a concentration of 40 mg/ml and administered as an i.v. infusion in 250 ml NS over 30 minutes. Oxaliplatin was supplied, by Sanofi-Synthelabo Research through a Cooperative Research and Development Agreement (CRADA) agreement with the National Cancer Institute (NCI), as a lyophilized powder in 50 mg and 100 mg vials and stored at room temperature in a light protected package. It was reconstituted with 5% dextrose to yield a concentration of 5 mg/ml and administered as an i.v. infusion in 250500 ml dextrose 5% in water over 2 h following gemcitabine. Both drugs were administered on day 1 and gemcitabine was given alone on day 8 of a planned 3-week cycle. Cycles of treatment were repeated every 3 weeks if patients met the criteria for retreatment.
Study design and toxicity criteria
Three patients were initially treated at each dose level (Table 1) and observed for a minimum of 6 weeks before new patients were treated. Doses were not escalated in any individual patient. Using the National Cancer Institute Common Toxicity Criteria (NCI CTC), DLT for this study was defined as any of the following: grade 4 neutropenia or thrombocytopenia; serum creatinine 2 times baseline or upper limit of normal, whichever was less; grade 4 nausea and vomiting despite maximal anti-emetic treatment; grade 4 diarrhea in spite of intensive loperamide therapy; grade 3 or higher other non-hematological toxicity; or failure to recover to grade 1 or lower toxicity by day 43.
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Disease assessment
Patients were considered to have a complete response (CR) to therapy if evidence of the tumor disappeared. A partial response (PR) was defined as a 50% reduction in the sum of the products of the largest perpendicular diameters of the indicator lesion(s), single or multiple sites, chosen prior to therapy. A regression was defined as a reduction in the size of evaluable tumor that did not fit the definition of either a CR or PR. A response to therapy was accepted if it persisted on two or more consecutive scans at least 4 weeks apart.
Statistical considerations
The primary end point for this dose-seeking study was to determine the MTD for the combination of gemcitabine and oxaliplatin. Descriptive statistics formed the primary basis of analysis for the data collected in this study.
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Results |
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Table 3 outlines the toxicities occurring during cycle 1. One of six patients at dose level 1 and two of six at dose level 3 experienced DLT with their first cycle of therapy. DLT was determined at dose level 3 based on grade 4 neutropenia in one patient and grade 5 myocardial infarction in a second patient. This second patient also had a fever with a grade 3 infection and grade 3 neutropenia at the time of their death. Upon further review it was felt that the grade 5 event was unrelated to the chemotherapy. However, the infection was felt to be related to treatment and was therefore considered a DLT event. Based on these findings, dose level 3 was judged to have exceeded the MTD.
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Hematological toxicities
All grade 3 or 4 toxicities associated with administration of gemcitabine combined with oxaliplatin, occurring during cycle 1, are summarized in Table 3 according to the NCI CTC grading criteria. Grade 3 neutropenia occurred in two of six of patients with the first cycle of therapy at the MTD (dose level 2). One of these patients continued to have recurrent grade 3 neutropenia with the subsequent five cycles of therapy. The other patient had grade 2/3 neutropenia or thrombocytopenia through eight cycles of treatment. No other grade 3 or 4 hematological toxicities were reported in the six patients at the MTD. Of the patients treated at dose level 3 (DLT), grade 3/4 neutropenia occurred in two of six patients. Four patients also developed grade 3 thrombocytopenia with subsequent cycles of therapy. No episodes of neutropenic sepsis occurred.
Non-hematological toxicities
Table 3 outlines grade 3 or 4 non-hematological toxicities occurring with cycle 1 of therapy. Grade 3 nausea and vomiting occurred in one patient at the MTD, leading to grade 3 dehydration. No other grade 3 or 4 toxicities were seen at the MTD. At the dose associated with DLT, one patient developed grade 3 nausea and vomiting. A variety of grade 1 or 2 toxicities occurred, including fatigue and constipation. Five patients developed grade 1 or 2 peripheral paresthesias and three patients developed laryngeal dysesthesia.
Three patients died while receiving therapy. All three deaths were thought to be unrelated to the chemotherapy. Two patients died of myocardial infarctions, both with a history of heart disease, and one of a pulmonary embolism.
Tumor response
Two patients obtained a PR (dose level 2 and 3) and one patient achieved a CR (dose level 3). The PRs have persisted for 34 months and the CR for 2 months. At the time of this report, none of these three patients has progressed. As such, the true duration of the responses is yet to be determined. One patient had regression of disease, but did not meet the criteria for a PR. The overall confirmed response rate was 16.7% (95% confidence interval 6% to 48%).
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Discussion |
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The results of our dose-seeking study showed that patients with advanced or metastatic pancreatic ACA were able to tolerate a maximum dose of gemcitabine 1000 mg/m2 on days 1 and 8, and oxaliplatin 100 mg/m2 on day 1, with treatment cycles repeated every 3 weeks. In general, this combination appeared to be well tolerated. The DLT was neutropenia in one patient and severe infection in a second patient. Over half of the patients (53%) enrolled in this dose-seeking study were able to receive four or more cycles of therapy. All but one of these patients required at least one dose reduction because of hematological toxicity in subsequent cycles of therapy. For all 18 patients, hematological toxicity was by far the most common toxicity. At the MTD, two-thirds of the patients developed grade 3 neutropenia. In all of the patients enrolled who completed at least four cycles of therapy, both neutropenia and thrombocytopenia were commonly observed, suggesting cumulative bone marrow suppression. It is possible that a higher dose of either oxaliplatin or gemcitabine may have been achieved had our study used a graduated approach in our dose-seeking study.
The non-hematological toxicities were generally mild. Two-thirds of patients developed sensory neuropathy consistent with that typically seen with oxaliplatin [18]. In prior phase I trials, neurotoxicity was generally the DLT [19]. The neurotoxicity of oxaliplatin consists of both peripheral dysesthesia and laryngopharyngeal dysesthesia. Only one patient developed grade 3 neurotoxicity, experiencing both peripheral and laryngopharyngeal dysesthesia. Nausea and vomiting did not appear to be any more common than that seen with oxaliplatin given alone, and was severe in only two patients. No unexpected side effects were seen with this chemotherapy combination.
This study has provided information on the MTD of oxaliplatin combined with gemcitabine when used in the schedule outlined in this study. Promising activity was observed. A phase II study of this combination in patients with locally advanced or metastatic pancreatic ACA recently completed accrual. Results of this study will be published in a separate report at a later date.
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Acknowledgements |
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Footnotes |
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Additional participants are listed in the Acknowledgements
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References |
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2. Burris HA 3rd, Moore MJ, Andersen J et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997; 15: 24032413.[Abstract]
3. Hansen R, Quebbeman E, Ritch P et al. Continuous 5-fluorouracil (5FU) infusion in carcinoma of the pancreas: a phase II study. Am J Med Sci 1988; 295: 9193.[ISI][Medline]
4. Bertheault-Cvitkovic F, Levi F, Soussan S et al. Circadian rhythm-modulated chemotherapy with high-dose 5-fluorouracil: a pilot study in patients with pancreatic adenocarcinoma. Eur J Cancer 1993; 29A: 18511854.
5. Stolinsky DC, Pugh RP, Bateman JR. 5-Fluorouracil (NSC-19893) therapy for pancreatic carcinoma: comparison of oral and intravenous routes. Cancer Chemother Rep 1975; 59: 10311033.[ISI][Medline]
6. Di Costanzo F, Tagliaventi M, Carlini P et al. High-dose folinic acid and fluorouracil with or without ifosfamide is an inactive combination in advanced pancreatic cancer. A randomized phase II study of the Italian Oncology Group for Clinical Research (G.O.I.R.C.). Am J Clin Oncol 1996; 19: 307310.[ISI][Medline]
7. Rubin J, Gallagher JG, Schroeder G et al. Phase II trials of 5-fluorouracil and leucovorin in patients with metastatic gastric or pancreatic carcinoma. Cancer 1996; 78: 18881891.[ISI][Medline]
8. DeCaprio JA, Mayer RJ, Gonin R, Arbuck SG. Fluorouracil and high-dose leucovorin in previously untreated patients with advanced adenocarcinoma of the pancreas: results of a phase II trial. J Clin Oncol 1991; 9: 21282133.[Abstract]
9. Crown J, Casper ES, Botet J et al. Lack of efficacy of high-dose leucovorin and fluorouracil in patients with advanced pancreatic adenocarcinoma. J Clin Oncol 1991; 9: 16821686.[Abstract]
10. Raymond E, Lawrence R, Izbicka E et al. Activity of oxaliplatin against human tumor colony-forming units. Clin Cancer Res 1998; 4: 10211029.[Abstract]
11. Kornmann M, Fakler H, Butzer U et al. Oxaliplatin exerts potent in vitro cytotoxicity in colorectal and pancreatic cancer cell lines and liver metastases. Anticancer Res 2000; 20: 32593264.[ISI][Medline]
12. Rougier P, Ducreux M, Kaci MO et al. Randomized phase II study of oxaliplatin alone (OXA), 5-fluorouracil (5FU) alone, and the two drugs combined (OXA-FU) in advanced or metastatic pancreatic adenocarcinoma (APC). Proc Am Soc Clin Oncol 2000; 19: 262a (Abstr 1018).
13. Brentnall TA, Chen R, Lee JG et al. Microsatellite instability and K-ras mutations associated with pancreatic adenocarcinoma and pancreatitis. Cancer Res 1995; 55: 42644267.[Abstract]
14. Fink D, Nebel S, Aebi S et al. The role of DNA mismatch repair in platinum drug resistance. Cancer Res 1996; 56: 48814886.[Abstract]
15. Raymond E, Buquet-Fagot C, Djelloul S et al. Antitumor activity of oxaliplatin in combination with 5-fluorouracil and the thymidylate synthase inhibitor AG337 in human colon, breast and ovarian cancers. Anticancer Drugs 1997; 8: 876885.[ISI][Medline]
16. Faivre S, Raymond E, Woynarowski JM, Cvitkovic E. Supraadditive effect of 2',2'-difluorodeoxycytidine (gemcitabine) in combination with oxaliplatin in human cancer cell lines. Cancer Chemother Pharmacol 1999; 44: 117123.[ISI][Medline]
17. Mavroudis D, Kourousis C, Kakolyris S et al. Phase I study of the gemcitabine/oxaliplatin combination in patients with advanced solid tumors: A preliminary report. Semin Oncol 2000; 27: 2530.
18. Extra JM, Espie M, Calvo F et al. Phase I study of oxaliplatin in patients with advanced cancer. Cancer Chemother Pharmacol 1990; 25: 299303.[ISI][Medline]
19. Raymond E, Chaney SG, Taamma A, Cvitkovic E. Oxaliplatin: a review of preclinical and clinical studies. Ann Oncol 1998; 9: 10531071.[Abstract]