1 Department of Medical Oncology A, Regina Elena Cancer Institute, Roma; 2 Unit of Medical Oncology, Umberto I Hospital, Frosinone; 3 Unit of Biostatistic and Trial Data, Regina Elena Cancer Institute, Roma, Italy
Received 28 January 2003; revised 4 April 2003; accepted 14 April 2003
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Abstract |
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Capecitabine and oxaliplatin are both active anticancer agents in the treatment of patients with advanced colorectal cancer. The aim of this phase II study is to determine the efficacy and tolerability of combining oxaliplatin with capecitabine in the treatment of advanced non-pretreated colorectal cancer.
Patients and methods:
Forty-three chemotherapy-naïve patients were enrolled. Capecitabine 2500 mg/m2/day was administered orally twice a day continuously for 14 days and oxaliplatin 120 mg/m2 was administered as a 2-h infusion on day 1, repeated every 3 weeks.
Results:
Forty-three patients were assessable for toxicity and 39 for clinical activity: the main toxicity was grade 3 or 4 diarrhea, which occurred in 28% of the patients. The response rates were 44% [95% confidence interval (CI), 29.3% to 59.0%] and 48.7% (95% CI 33.0% to 64.4%) (intention-to-treat and per protocol analysis, respectively). The median overall survival was 20 months (95% CI 1228).
Conclusions:
Combining capecitabine and oxaliplatin yields promising activity in advanced colorectal cancer; therefore, the capecitabine dose we utilized is probably too high. The main toxicity is diarrhea, which is manageable with appropriate dose reductions.This combination may be preferable compared to a standard combination with infusional fluorouracil/leucovorin as it is more convenient and practical with similar efficacy. Thus, phase III trials are needed to clarify its role in the treatment of chemotherapy-naïve advanced colorectal cancer patients.
Key words: advanced colerectal cancer, capecitabine, first-line chemotherapy, oxaliplatin
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Introduction |
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Two large randomized studies have shown higher tumor response rates and at least equivalent time to disease progression and overall survival (OS) with the oral treatment compared with intravenous (i.v.) bolus fluorouracil/leucovorin [2, 3]. Most importantly in view of the indirect costs caused by the treatment, hospitalization was significantly reduced with capecitabine in comparison with i.v. fluorouracil/leucovorin.
Oxaliplatin is a new third-generation cisplatin analog. In combination with infusional 5-fluorouracil (5-FU) and folinic acid (FA) in randomized phase III trials, it has shown a high antitumoral activity in advanced colorectal cancer patients [4, 5].
Combining oxaliplatin with oral capecitabine instead of infusional fluorouracil is an interesting alternative in view of the practicability of the treatment and the lack of major overlapping toxicities of the two drugs. This is confirmed by the results of two dose-finding studies: Diaz-Rubio et al. [6] achieved the maximum tolerated dose (MTD) of capecitabine (2500 mg/m2/day) on days 114 in combination with a fixed dose of oxaliplatin (130 mg/m2) on day 1 in a 21-day treatment cycle in chemotherapy-pretreated patients with various solid tumors. The DLTs in the eight patients on the highest dose level were one case each of diarrhea grade 3 with thrombocytopenia and diarrhea grade 4 with neutropenia. Thus, the capecitabine dose recommended by the authors for further studies with this combination was 2000 mg/m2/day. Furthermore, 25 pretreated advanced colorectal cancer patients were treated in our institution in a dose-escalation setting: DLTs were diarrhea (grade 3: 27%) and stomatitis (grade
3: 9%) at dose level 6 (capecitabine 2500 mg/m2/day and oxaliplatin 130 mg/m2). Dose level 5 (capecitabine 2500 mg/m2/day and oxaliplatin 120 mg/m2) was found to be the MTD. Hematological toxicity was minimal; overall neurotoxicity (grade 14) was 27% with 1% grade 34. The global response rate was 17% [95% confidence interval (CI) 2% to 32%] and the median OS was 12 months [7]. In our experience the recommended dose for further phase II studies should be capecitabine 2500 mg/m2/day with intermittent schedule and oxaliplatin 120 mg/m2 every 3 weeks.
We report the results of a phase II study in which chemotherapy-naïve advanced colorectal cancer patients were treated with capecitabine 2500 mg/m2/day in combination with oxaliplatin 120 mg/m2 to better characterize the efficacy and tolerability of the combination at this dose level which corresponds to the recommended single-agent dose for both drugs.
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Patients and methods |
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Pretreatment evaluation included a complete clinical history, physical examination, neurological status, electrocardiogram, chest X-ray, and computed tomography scan or ultrasound of assessable target lesions. Complete blood cell counts and differential blood chemistry were obtained at baseline and were repeated every chemotherapy cycle. Toxicities were graded using the NCI common toxicity criteria.
Objective response was the primary end point and was recorded according to the RECIST response criteria [8]. Assessment of response was performed every three chemotherapy cycles and the scans were reviewed blind in our institution. The number of cycles was not limited. Treatment was continued until disease progression, unacceptable adverse effects or withdrawal of consent by the patient.
Capecitabine was supplied as film-coated tablets in two dose strengths (150 and 500 mg) and was delivered daily for 2 weeks followed by 1 week of rest. It was self-administered in the patients homes as two separated doses 12 h apart, taken within 30 min after ingestion of food.
Capecitabine intake was interrupted in the case of grade 3 non-hematological toxicity and was not resumed until the adverse effect improved to grade 1. Capecitabine doses were reduced by 25% in subsequent treatment cycles in the case of grade 3 or 4 non-hematological toxicity in the previous cycle.
Oxaliplatin was administered over a 2-h infusion on day 1 of treatment. This treatment cycle was repeated every 21 days. Before chemotherapy, patients were systematically given i.v. ondansetron or granisetron plus steroids before chemotherapy to prevent emesis. Patients were warned to avoid exposure to cold and cold drinks after therapy with oxaliplatin to reduce related neuropathy episodes or their exacerbation. Oxaliplatin infusion duration was further lengthened to 4 or 6 h if the patients had neurotoxicity superior to grade 2. In the case of grade 3 non-hematological or grade 4 hematological toxicity in the previous cycle, the oxaliplatin dose was reduced by 25% in the subsequent cycles.
Statistical analysis
An optimal two-stage design as described by Simon [9] was used. In the first stage, a total of 13 patients were included and at least four responses (both complete and partial responses) were required to continue to the second stage. In the second stage, 30 additional patients were included to a total sample size of 43. Thirteen responses were needed to conclude with a 95% confidence that the response rate was >40%. Overall survival time was measured from start of treatment and analyzed by the KaplanMeier method. Statistical analyses were performed using SPSS version 11 packages for Windows.
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Results |
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During the whole treatment period there were only six hospitalizations because of prolonged refractory diarrhea (four patients) and tumor progression (two patients).
Two patients died while receiving treatment. One was hospitalized in another institution because of severe febrile neutropenia and probably died due to diffuse septicemia, and one patient died of myocardial infarction probably unrelated to treatment.
Clinical activity
The results of the response evaluation are summarized in Table 5 according to intention-to-treat (ITT) and per protocol (PP) analysis. The response rates were 44.2% (95% CI 29.3% to 59.0%) and 48.7% (95% CI 33.0% to 64.4%) for ITT and PP analysis, respectively. Non-assessable patients in PP analysis received only one treatment cycle (n = 4) due to early death (two patients) and refusal of treatment (two patients).
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Because dose intensity has been related to tumor response [10], we examined whether patients requiring dose reductions were less likely to respond to treatment. There was no significant association between dose modifications due to toxicity and partial or complete tumor remissions.
The median follow-up time for all patients was 6 months. The KaplanMeier curve for median survival is depicted in Figure 1. The estimated median OS was 20 months (95% CI 1228). The median time to treatment failure was 8.2 months (95% CI 6.69.8). The activity of this combination regimen in terms of time to treatment failure and OS needs to be confirmed with longer follow-up.
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Discussion |
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Therefore, oral capecitabine offers an advantage over infusional fluorouracil/leucovorin in terms of convenience, practicability and cost of health care.
The results of this phase II study establish the feasibility and efficacy of combining capecitabine with oxaliplatin in advanced colorectal cancer. The 48% response rate in non-pretreated patients compared well with the 50.753% objective responses observed with oxaliplatin plus continuous infusion fluorouracil/leucovorin in first-line treatment [4, 5, 11, 12].
Besides efficacy, toxicity is a critical end point with which to assess the utility of a new treatment combination. In our study no unexpected adverse event occurred, and the most common toxicities observed were those of each drug: main toxicities consisted of diarrhea, sensory neuropathy and vomiting, and only one case of severe neutropenia and thrombocytopenia occurred. It is noteworthy that the doses of each drug in this combination regimen were as high as that recommended for single-agent therapy. Thus, the toxicity of our treatment regimen in non-pretreated patients seems to be higher compared with the results of the studies using infusional fluorouracil instead of oral capecitabine in combination with oxaliplatin. This is probably due to the dose of capecitabine we utilized, which was higher than that reported in a recent large phase II trial in which the tolerability of treatment seems to be more acceptable [13]. In conclusion, combining oxaliplatin with capecitabine may be preferable compared with a standard combination with infusional fluorouracil/leucovorin as it is more convenient and practical with similar efficacy and toxicity.
This recommendation is supported by the results of a recently completed phase II study with this combination in which the authors report similar conclusions [14].
Phase III trials are needed to clarify the role of combination capecitabine/oxaliplatin in the treatment of chemotherapy-naïve advanced colorectal cancer patients.
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Acknowledgements |
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Footnotes |
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References |
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