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Randomized Multicenter Phase II Trial of Two Different Schedules of Capecitabine Plus Oxaliplatin as First-Line Treatment in Advanced Colorectal Cancer

Werner Scheithauer, Gabriela V. Kornek, Markus Raderer, Birgit Schüll, Katharina Schmid, Erwin Kovats, Bruno Schneeweiss, Fritz Lang, Alfred Lenauer, Dieter Depisch

From the Department of Internal Medicine I, Division of Clinical Oncology, University Hospital of Vienna, Vienna; Department of Internal Medicine, General Hospitals of Kirchdorf/Krems; and Departments of Surgery, General Hospitals of Baden, Neunkirchen, and Wiener Neustadt, Austria.

Address reprint requests to Werner Scheithauer, MD, Department of Internal Medicine I, Division of Clinical Oncology, University Hospital, Waehringer Guertel 18-20, A-1090 Vienna, Austria; email: werner. scheithauer{at}akh-wien.ac.at.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: Capecitabine and oxaliplatin, two new agents with potential synergistic activity, have demonstrated promising antitumor efficacy in advanced colorectal cancer (ACC). Preclinical and clinical evidence indicating that dose intensification of the oral fluorouracil prodrug might result in improved therapeutic results led us to the present randomized multicenter phase II study.

Patients and Methods: Eighty-nine patients with bidimensionally measurable ACC previously untreated for metastatic disease were randomly allocated to receive oxaliplatin 130 mg/m² day 1 plus capecitabine 2,000 mg/m²/d days 1 to 14 every 3 weeks (arm A) or to receive oxaliplatin 85 mg/m² days 1 and 14 combined with capecitabine 3,500 mg/m² days 1 to 7 and 14 to 21 every 4 weeks (arm B). In both treatment arms, chemotherapy was continued for a total of 6 months unless there was prior evidence of progression of disease.

Results: Patients allocated to the high-dose capecitabine combination arm B had a higher radiologically confirmed response rate (54.5% v 42.2%) and a significantly longer median progression-free survival time than those allocated to control arm A (10.5 v 6.0 months; P = .0013). Median overall survival times cannot be calculated for either treatment arm at this point. Despite a 34% higher dose intensity of capecitabine in arm B, there was no difference in hematologic toxicity between treatment arms (neutropenia/thrombocytopenia: 60%/43% in arm B v 56%/33% in arm A). Similarly, the incidence rate and degree of nonhematologic adverse events were comparable: The most commonly encountered symptoms (all grades, arm A and arm B) included nausea/emesis (A: 58%; B: 62%), diarrhea (A: 44%; B: 31%), peripheral sensory neuropathy (A: 80%; B: 83%), and fatigue (A: 40%; B: 50%).

Conclusion: Results of this study indicate that both combination regimens are feasible, tolerable, and clinically active. The dose-intensified bimonthly capecitabine arm, however, seems to be more effective in increasing both response rate and progression-free survival time.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
UNTIL A FEW years ago, treatment options for patients with advanced colorectal cancer (ACC) were limited to fluorouracil (FU)—a therapy plagued by poor response rates and dismal median survival. The introduction of biochemical modulators such as leucovorin (LV) or methotrexate has lead to improvements in response rates, but progression-free and overall survivals have remained unaffected. Similarly, various modifications of the original FU bolus administration schedule, such as continuous infusion or chronomodulation, have yielded only marginal improvement.¹ Within the last 5 years, a number of new, promising anticancer agents with unique and different mechanisms of action, synergism with FU, or reduced toxicity have been introduced.^1–3 Oral FU prodrugs, specifically capecitabine, characterized by high and predictable oral bioavailability, as well as a preferential conversion to FU in neoplastic tissues, are notable examples.^4,5 In two recently published randomized trials, each comprising about 600 patients, a superior therapeutic index was reported for capecitabine compared with bolus FU/LV.^6,7 Another promising agent, the third-generation 1,2-diaminocyclohexane-platinum derivate oxaliplatin, was approved for the treatment of ACC in Europe in 1999 but remains commercially unavailable in the United States. This drug inhibits DNA synthesis, primarily by causing inter- and intrastand cross-links, and has shown activity in chemotherapy-naive as well as FU/LV-pretreated patients.⁸ Moreover, a synergistic effect has been noted with use in combination with fluoropyrimidines: In randomized controlled trials of continuous infusional FU/LV with or without oxaliplatin, significantly higher objective response rates and progression-free survival (PFS) were reported for the three-drug combination as compared with FU/LV alone.^9–11

Among several different combination regimens with the novel agents that are currently being investigated to improve the treatment of ACC, the combination of oxaliplatin and capecitabine seems particularly attractive. In addition to the experimentally and clinically confirmed supra-additive effect of the platinum derivative with a thymidylate synthase inhibitor and the simplicity of concomitant administration without the need for indwelling vascular devices or pumps, the two drugs have a different and relatively mild toxicity profile. Preliminary results of a number of clinical phase I/II trials evaluating this combination in both chemotherapeutically pretreated and previously untreated ACC patients have demonstrated feasibility and antitumor activity that is encouraging.^12–17

Preclinical studies in human tumor xenografts indicate that inhibition of tumor growth depends on the total dose of capecitabine but not on its administration schedule.¹⁸ Because short-term intermittent rather than prolonged or continuous administration of this drug may allow an increase in dose intensity (and potential antitumor efficacy) without increasing toxicity (by incorporation of longer drug-free intervals),^13,18 we have recently performed a phase I/II study in ACC. In this study, we have defined a recommended dose of 85 mg/m² oxaliplatin every 2 weeks combined with capecitabine 3,500 mg/m²/d for 7 days. Using this regimen, a 105% to 131.25% dose increment of the oral FU prodrug can be administered when compared with conventional capecitabine administration schedules—days 1 to 14 every 3 weeks—currently being investigated in combination with oxaliplatin by other study groups.^12,16 In addition to demonstrating feasibility of a safe dose intensification of capecitabine, this phase I/II study shows an encouraging (externally reviewed) objective response rate of 50% and a median PFS of almost 9 months.¹⁷

The aim of the present randomized multicenter phase II study was to reconfirm the potential superior therapeutic activity of intermittent weekly high-dose capecitabine plus oxaliplatin versus a conventional dose regimen of these two drugs as described by Diaz-Rubio et al¹² and Taberno et al.¹⁶

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection
Patients with histologically confirmed, nonresectable metastatic or locally recurrent colorectal adenocarcinoma and bidimensionally measurable disease (defined as presence of at least one index lesion capable of two-dimensional measurement by computed tomographic [CT] scan outside any irradiated zone and 2 cm in diameter) were considered candidates for this study. Eligibility criteria also included age between 19 and 75 years, a World Health Organization (WHO) performance status of 2 or less, adequate bone marrow reserve (leukocyte count 4,000/µL, platelet count 100,000/µL), adequate renal function (serum creatinine concentration < 132 µmol/L), and adequate hepatic function (serum bilirubin level < 34 µmol/L and serum transaminase level < two times the upper limits of normal). Patients could have previously received adjuvant fluoropyrimidine-based chemotherapy or radiation therapy, which had to have been completed at least 6 months before study entry. Similarly, previous palliative radiation therapy was permitted, provided that less than 20% of the bone marrow was involved, a target lesion outside the radiation port was present, and full resolution of toxicities had occurred. Patients with serious or uncontrolled concurrent medical illness, CNS metastases, or a history of other malignancies (with the exception of excised cervical or basal skin/squamous cell carcinoma) were not eligible for treatment. All patients gave informed consent according to institutional guidelines before study registration.

Randomization procedures. Before randomization, patient eligibility was confirmed by a protocol-specific checklist. After signing informed consent documents, patients were stratified according to WHO performance status (score 0 to 1 v 2), number of metastatic sites (single v multiple sites), and prior adjuvant (radio) chemotherapy. Patients were then randomly assigned to one treatment regimen by the central office located at the University of Vienna. Balance across strata was attained using the method of Pocock and Simon.¹⁹

Treatment protocol. Chemotherapy consisted of courses once every 3 weeks of oxaliplatin 130 mg/m²/d day 1, given as a 2-hour infusion in 250 mL of dextrose 5%, plus capecitabine 2,000 mg/m²/d PO in two divided doses from days 1 to 14 (arm A) or of courses once every 2 weeks of oxaliplatin 85 mg/m²/d day 1 plus capecitabine 3,500 mg/m²/d from days 1 to 7 (arm B). Capecitabine was supplied as film-coated tablets in two dose strengths, 150 and 500 mg, which were not to be split and were taken orally within 30 minutes after ingestion of food. Compliance with the oral medication regimen was assessed by tablet counts at each clinical visit. In both treatment arms, chemotherapy was continued for a total of 6 months (eight courses in arm A and six courses in arm B) unless there was prior evidence of progressive disease. Concomitant medications routinely given before oxaliplatin administration included 8 mg of ondansetron plus 8 mg of dexamethasone.

Toxicity and Dosage Modification Guidelines
Adverse reactions were evaluated according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC).²⁰ In the event of grade 4 hematologic or any other severe ( grade 3) organ toxicity in individual patients, chemotherapeutic drug doses were reduced by 25% for subsequent courses in both treatment arms. The oxaliplatin dose was reduced by 25% in case of persistent ( 14 days) or temporary (7 to 14 days) painful paresthesia or functional impairment. In case of persistent painful paresthesia or functional impairment, or if a patient experienced any other severe neurotoxicity despite a 25% dose attenuation, oxaliplatin was omitted in subsequent cycles. Treatment could be delayed for up to 2 weeks if symptomatic toxicity persisted, the absolute neutrophil count was lower than 1,000/µL, or the platelet count was lower than 75,000/µL. Subcutaneous administration of granulocyte colony-stimulating factor 5 µg/kg/d on 5 consecutive days was recommended in the former group of patients. Any patient who required more than 2 weeks for recovery from adverse reactions was excluded from the study.

Pretreatment and Follow-Up Evaluation
Within 2 weeks before initiating chemotherapy, all patients were assessed by physical examination, routine hematology and biochemistry analyses, ECG, chest x-ray, and CT scans to define the extent of disease. Complete blood cell counts with platelet and differential counts were determined weekly during chemotherapy, and serum chemistries were repeated at least once every course. Subjective symptoms, body weight, physical examination, performance status, and all adverse reactions were recorded before each treatment course. Measurable lesions were reassessed every 8 weeks by CT scan, x-ray, or any other technique that allowed retrospective and independent evaluation.

Study Objectives and Assessment of Response
The primary study end point was PFS. Secondary objective study end points included overall survival and response rate, which were assessed every 2 months using WHO standard criteria.²¹ In case of partial response or complete response, a second assessment 4 weeks later was required for confirmation of response; all tumor measurements were reviewed and confirmed by an independent panel of radiologists and oncologists (IRC).

Sample Size and Statistical Considerations
The primary end point of this study was PFS, which was calculated as the time from the first infusion to disease progression or death. Data from previous phase II trials investigating arm A indicate a median PFS of approximately 6 months.^14,16 The hypothesis for this study was that, using the dose-intensified bimonthly capecitabine plus oxaliplatin arm, 75% of patients would be progression free 6 months after treatment onset. It was calculated that 41 evaluable patients would have to be recruited to yield a 90% power of detection with an alpha error of 0.05.²² Differences in distribution of patients between the two arms of the trial were evaluated with the ² test.²³ The exact binominal confidence interval was applied to estimate the response rates. PFS and overall survival were examined with the Kaplan-Meier product-limit method.²⁴ No formal statistical comparison between the regimens was planned. The conclusion from this study was to be based on the ranking defined by PFS. However, a log-rank test was performed for explanatory reasons.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Between May 2000 and September 2001, a total of 89 patients entered the study and received the allocated treatment subsequent to randomization. Forty-five patients were randomly assigned to arm A (oxaliplatin 130 mg/m² plus capecitabine 2,000 mg/m²/d for 14 days every 3 weeks), and 44 patients were randomly assigned to arm B (bimonthly oxaliplatin 85 mg/m² plus capecitabine 3,500 mg/m²/d for 7 days). As shown in Table 1, the two groups were well matched for pretreatment characteristics with the exception that more patients in arm A were female and more had poorly differentiated tumors on histologic examination. No significant imbalances in major prognostic variables, however, occurred in the randomization. The median age of the study population was 66 years, most patients (87%) had a WHO performance status of 0 or 1, and the majority had two or more metastatic sites (58.4%) involving the liver (73%). The primary tumor site was colon in 54 patients and rectum in 35 patients. About one third (29.2%) of study participants had received adjuvant FU/LV with or without radiotherapy.

Antitumor Efficacy
Treatment responses and progression-free and overall survival data are summarized in Table 2. The overall response rates according to the IRC assessment were 42.2% (95% confidence interval [CI], 27.7% to 57.9%) in arm A versus 54.5% (95% CI, 38.8% to 69.6%) in the dose-intensified capecitabine combination arm B. In both treatment groups, three complete responses were noted, including one histopathologically confirmed complete response in arm B as assessed during secondary surgery for liver metastases. The median response duration was 5.0 v 8.0 months, favoring arm B. Disease stabilization was noted in 20 (44%) and 12 (27%) additional patients, lasting for a median duration of 5.5 v 8.2 months for arms A and B, respectively.

View larger version (14K): [in this window] [in a new window]   Fig 1. Progression-free survival.

At the time of this report, an irinotecan-based second-line regimen was administered in 39 patients, including 22 of 35 (63%) patients with progressive disease in arm A and 17 of 27 (63%) patients in arm B.

Toxicity
Toxicity was recorded for all 45 patients, who received a median of six courses once every 3 weeks in arm A (range, 1 to 8; 268 courses were analyzed). In the dose-intensified capecitabine combination arm, in which patients received a median of six courses once every 4 weeks (range, 1 to 6; 206 courses were analyzed), toxicity was recorded in 43 of 44 patients. Side effects associated with treatment are listed in Table 3. A comparison of the severe toxicities observed in each treatment group (grade 3 and 4 adverse events) is presented graphically in Fig 2. On the whole, the data indicate that both chemotherapeutic drug regimens were well tolerated throughout the study. The most frequently encountered toxicity was myelosuppression, although grade 3 or 4 neutropenia occurred in only seven (16%) and three (7%) patients in arm A and arm B, respectively. There was only one serious infection in arm A, and grade 3 or 4 thrombocytopenia was rarely observed. As listed in Table 3, drug-related symptomatic toxicity was also generally mild to moderate in both treatment groups. Interestingly, the only adverse reaction that was more commonly noted in the conventional capecitabine dose arm A was diarrhea (44% v 31%), although only a small number of patients required a dose attenuation because of severe (grade 3) symptoms. Other symptomatic toxicities were equally distributed between the two treatment groups and included predominantly minor (grades 1 or 2) nausea/emesis (58% v 62%), fatigue (40% v 50%), oxaliplatin-associated peripheral sensory neuropathy (80% v 83%), hand-foot syndrome (22% v 31%), and transient elevations in liver functional parameters (49% v 57%) in arm A and B, respectively.

View larger version (12K): [in this window] [in a new window]   Fig 2. Worst grade 3/4 toxicity data observed in the two treatment groups.

Dose reductions for adverse reactions were required in 13 patients in the conventional dose capecitabine plus oxaliplatin arm (because of grade 3 nausea/emesis and diarrhea in three patients each, progressive peripheral neuropathy [PNP] in five, and acute neurotoxicity in two) and in 11 patients in the dose-intensified capecitabine plus oxaliplatin group (because of grade 3 diarrhea in four patients; progressive PNP in four; and nausea, hand-foot syndrome, and acute neurotoxicity in one patient each). Adverse reactions led to treatment discontinuation in 10 patients in arm A (because of PNP in seven patients, poor compliance in two, and anaphylaxis after the first course in one) and in eight patients in arm B (PNP in four patients, poor compliance in two, and acute neurotoxicity and protracted nausea/emesis despite dose adjustment in one patient each).

In arm A, the mean dose intensity of oxaliplatin was 87.6% of the projected dose and 90.8% for capecitabine. The mean dose of oxaliplatin was 36.4 mg/m²/wk, and the mean dose of capecitabine was 8,478 mg/m²/wk. In arm B, the relative dose intensities of the two drugs were 82.9% (oxaliplatin) and 92.6% (capecitabine). This corresponds to a mean given dose of 35.2 mg/m²/wk and 11,346 mg/m²/wk, respectively.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
With recent availability of a number of new active anticancer agents with different cellular targets, some of which exert synergistic activity with FU/LV, treatment options for patients with ACC have improved considerably.^25,26 Despite expanded therapeutic options in this common malignancy, however, additional investigational efforts will be necessary to achieve further improvements in terms of antitumor activity, treatment tolerance, and ease of administration.

Because of the documented activity of capecitabine and oxaliplatin in ACC, their different and potentially synergistic mechanisms of action, the nonoverlapping toxicity profiles, and the ease of administration, this cytotoxic drug combination is of particular interest. A number of phase I/II studies in advanced colorectal cancer using different dose regimens have already been published, and therapeutic results are encouraging.^12–17

In this randomized multicenter phase II trial comparing two different capecitabine plus oxaliplatin combination regimens in patients with previously untreated metastatic colorectal cancer, we were able to reconfirm preclinical and early clinical evidence that dose intensification of the oral FU prodrug is likely to result in enhanced antitumor activity.^17,18,27 The PFS in the intermittent weekly high-dose capecitabine combination arm was 10.5 months compared with 6.0 months in the conventional capecitabine dose combination arm. This difference in PFS, the primary study end point, was statistically significant (P = .0013). Furthermore, superior response activity (54.5% v 42.2%), prolonged response duration (5 v 9 months), and a somewhat higher rate of secondary resections for metastatic disease (11% v 16%) were noted in the dose-intensified capecitabine combination arm. The data regarding activity in the experimental arm are in agreement with the results of our previous phase I/II study of this combination regimen.¹⁷ The therapeutic outcome in the other treatment arm is comparable with the results of two recently published phase II investigations, which also evaluate the conventional 2-week capecitabine administration schedule (using an identical dose of 2,000 mg/m²/d or 2,500 mg/m²/d plus oxaliplatin 130 mg/m² day 1).^12,14 Despite evidence of higher, though non-IRC confirmed, objective response rates of 49% in the study of Diaz-Rubio et al¹² and 55% in that reported by Borner et al,¹⁴ median PFS was also only 5.9 months (95% CI, 4.8 to 7.3 months) and 7.4 months (95% CI, 6.4 to 8.1 months), respectively.

With respect to treatment tolerance, despite a 34% increase in the dose intensity of capecitabine in arm B, no difference was noted between the two treatment groups, either in terms of hematologic or symptomatic toxicities. This observation is likely to be related to the longer duration of nonexposure to cytotoxic medication ("drug holidays") in the weekly dose-intense capecitabine administration schedule, which was another advantage of arm B. With the conventional 2-week intermittent schedule within a 3-month period, patients are only unexposed to drugs for 4 weeks, as compared with 6 weeks with the weekly regimen. Severe adverse events requiring dose attenuation and/or early discontinuation of the study medication occurred in 15 (33%) patients in arm A versus 11 (25%) in arm B. In both groups, severe adverse events mainly comprised grade 3 gastrointestinal and/or neurologic toxicities. The overall tolerance of treatment thus seems acceptable and comparable with other clinically well established FU/LV plus oxaliplatin combination regimens.^9–11 Whereas the observed toxicity data are also almost superimposable on the "XELOX regimen" reported by Diaz-Rubio et al,¹² a much higher rate of severe diarrhea was described by Borner et al,¹⁴ using capecitabine 2,500 mg/m²/d for 2 weeks. In the latter trial, grade 3 or 4 diarrhea occurred in 35% of the nonpretreated and 50% of the chemotherapeutically pretreated patients.

In conclusion, this randomized phase II trial demonstrated that both capecitabine plus oxaliplatin regimens show substantial antitumor activity in patients with previously untreated advanced colorectal cancer. According to the superior treatment outcome noted in the weekly dose-intensified capecitabine combination arm, the latter is recommended for further investigations in thefront-line setting in randomized phase III studies; for example, in a comparative trial with other potent drug combinations such as the recently described triplets with LV-modulated FU, oxaliplatin, and irinotecan.^27–29

	NOTES

 
Supported, in part, by the Gesellschaft zur Erforschung der Biologie und Behandlung von Tumorkrankheiten.

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Submitted September 3, 2002; accepted December 20, 2002.

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