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Phase II Study of Capecitabine in Patients With Fluorouracil-Resistant Metastatic Colorectal Carcinoma

From the Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Hoffmann-La Roche Labs Inc, Nutley, NJ

Address reprint requests to Paulo M. Hoff, MD, FACP, The University of Texas M.D. Anderson Cancer Center, Department of Gastrointestinal Medical Oncology, Unit 426, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: phoff{at}mdanderson.org

	ABSTRACT

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PURPOSE: Capecitabine is an oral fluoropyrimidine converted to fluourouracil (FU) preferentially in tumor tissue. It has proven clinical activity against colorectal cancer when used as first-line therapy. The objectives of this study were to assess the safety and efficacy of capecitabine in patients with metastatic colorectal carcinoma who progressed despite previous FU therapy.

PATIENTS AND METHODS: According to the group sequential analysis design of this study, accrual would stop if no responses were observed in the first 20 patients treated. If one or more objective responses were confirmed, the trial would be expanded. Patients received capecitabine 1,250 mg/m² twice a day for 14 days, every 3 weeks. Tumor lesions were assessed every 6 weeks, and patients were followed for survival every 3 months after completing treatment.

RESULTS: Twenty-three patients were enrolled onto the study; 22 fulfilled all the eligibility criteria. No objective responses were observed among the 22 eligible patients; 11 patients (50%) had stable disease for a median duration of 141 days (range, 88–289 days). The Kaplan-Meier estimate of median time to disease progression was 64 days (95% CI, 41 to 134 days). The median survival time estimate was 389 days (95% CI, 267 to 637 days). The most frequent treatment-related adverse events were hand-foot syndrome, diarrhea, and nausea or vomiting. There were no grade 4 toxicities and no treatment-related deaths.

CONCLUSION: Single-agent capecitabine in patients with metastatic colorectal carcinoma refractory to FU showed no objective responses and clinical benefit that was, at best, modest. The use of capecitabine in combination with other treatments in this patient population is under investigation.

	INTRODUCTION

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Colorectal cancer is one of the most common malignant diseases in the world and is the second cause of cancer-related deaths in the United States.¹ Although 75% of the patients are operable at the time of diagnosis, approximately 50% to 60% of them ultimately die as a result of colorectal cancer. Recent improvements in therapy allow most patients to receive more than one regimen of therapy during their lifetime, and it is very important for oncologists to be aware of the potential and limitations of the different agents available for use in this setting.^2-5

Fluorouracil (FU)-based therapy has been the main treatment for metastatic colorectal cancer for the last 40 years. Bolus injections or short infusions of FU are associated with response rates usually less than 20%^6-8 and side effects (specifically, gastrointestinal toxicities and myelosuppression) that limit treatment intensity and duration. Low-dose, continuous FU infusion regimens have been shown to have better response rates and less severe acute toxicities, such as mucositis and neutropenia, when used as first-line chemotherapy for colorectal cancer; however, other toxicities, such as hand-foot syndrome, were associated with chronic exposure to FU or its metabolites. Clinical benefit from a continuous infusion regimen was observed even among patients unresponsive or resistant to previous FU. Disease stabilization was documented in several trials, although typically only a few or no objective responses were noted.^9,10 The use of infusional FU regimens is limited by the permanent indwelling catheters required, which introduce the risk of infection, complicate drug administration, and increase the cost of care.

Capecitabine, an oral fluoropyrimidine carbamate, was designed to be converted to FU primarily in tumor tissues. Capecitabine passes through the intestinal mucosa essentially unchanged and is subsequently metabolized by a sequential 3-enzyme pathway. First, capecitabine is converted to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase, primarily in the liver. 5'-DFCR is then converted to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase, which is located in both the liver and tumor tissues. The metabolism of 5'-DFUR to the pharmacologically active agent FU is mediated by thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor (PD-ECGF). Concentrations of TP are higher in tumor tissue than in normal tissue, which accounts for the preferential intratumoral release of FU.¹¹

Capecitabine is the only oral fluoropyrimidine approved in the United States for the treatment of metastatic breast and colorectal cancer.¹² Capecitabine was approved as first-line treatment of colorectal cancer based on its superior antitumor activity and favorable safety profile when compared with intravenous (IV) FU/leucovorin (Mayo regimen). Results of two pivotal phase III clinical trials revealed response rates of 26% for capecitabine (603 patients treated) and 17% for FU/leucovorin (604 patients treated).¹³ Consistently superior response rates were demonstrated in patient subpopulations that included patients with prior adjuvant chemotherapy (21% v 8% with FU/LV). Capecitabine demonstrated an improved safety profile when compared to FU/LV; specifically, there were lower incidences of overall diarrhea, stomatitis, nausea, and alopecia (P < .0002), lower incidences of grade 3 and 4 stomatitis and neutropenia (P < .0001), and a lower rate of hospitalization compared with bolus FU/LV (11% v 20%, P = .003).

This phase II study evaluated capecitabine therapy in patients with metastatic colorectal carcinoma who had progressed despite earlier treatment with FU. The decision to use capecitabine was based on the demonstrated efficacy and safety of capecitabine in patients with previously untreated colorectal cancer¹⁴ and the known clinical benefit of using continuous infusion FU as second-line treatment following bolus regimens of the same agent.¹⁰

	PATIENTS AND METHODS

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Patient Selection
Entry criteria included male and female patients, 18 years of age or older, with a Karnofsky performance status (KPS) greater than 70%, histologically or cytologically confirmed metastatic colorectal carcinoma, and a life expectancy of at least 3 months. Patients had to have at least one measurable lesion, with a minimum size of > 20 mm for liver and soft tissue lesions and > than 10 mm for lung, skin, and lymph node lesions. Ascites and pleural effusion were not considered measurable disease. Patients were also required to have objective evidence of progressive disease, defined by one of the following criteria: (1) progression while receiving or within 3 months after receiving a FU bolus–containing regimen as the sole prior chemotherapy for advanced colorectal cancer, (2) progression within 6 months after receiving an adjuvant FU-containing regimen, or (3) progression more than 6 months after receiving adjuvant therapy and a subsequent FU bolus regimen as sole therapy for advanced disease and progressing while on or within 3 months after receiving the FU. FU therapy was defined as IV bolus FU, administered as a 5-day or weekly regimen. Patients exposed to infusional FU regimens were not eligible. All patients were required to have adequate hematologic, renal, and hepatic functions.

The main exclusion criteria were as follows: pregnant or nursing women, female patients of childbearing potential, and sexually active men not using a reliable and appropriate contraceptive method; patients with other primary tumors within 5 years of study entry (except basal cell carcinoma of the skin); patients with clinically significant cardiac disease or myocardial infarction within 12 months of study entry, evidence of CNS metastases or a history of uncontrolled seizures, CNS disorders, or clinically significant psychiatric disability; patients with organ allografts, serious uncontrolled intercurrent infection(s), or lack of physical integrity of the upper gastrointestinal tract; patients who had radiotherapy within 4 weeks of treatment start, prior radiotherapy to the indicator lesion(s) being measured, incomplete resolution of toxicities related to radiotherapy; and patients who had major surgery within 4 weeks of the start of study treatment without complete recovery.

Study Protocol and Assessments
The institutional ethics committee approved the study, and all patients gave written informed consent. Baseline studies included a full medical history and physical examination, blood work, urinalysis, electrocardiograms, chest x-rays, and tumor measurements based on computed tomography scans.

After the start of therapy, study visits were scheduled for study weeks 4, 7, 10, 13, 19, 25, 31, 37, and 48. A physical examination, including an assessment of vital signs, physical measurements, and clinical laboratory tests, was performed at all study visits. Adverse events and related treatments were monitored throughout the study and for 28 days after the last treatment.

Tumor assessments were performed after every two cycles (6-week intervals). Duration of treatment was based on tumor response. Patients with documented progressive disease were withdrawn from the study. Patients with stable disease (SD) or partial response (PR) continued treatment for up to a total of 48 weeks. Patients with a complete response (CR) were treated for at least an additional 12 weeks after confirmation of CR. After 48 weeks, patients with continuing response or SD could continue to receive capecitabine off study at the discretion of the investigator. A survival census was taken every 3 months after the patient completed treatment.

Treatment Regimen
Capecitabine (Xeloda; Hoffmann-La Roche Inc, NJ) was supplied as film-coated tablets at two dose strengths, 150 mg and 500 mg. The capecitabine dose was calculated as milligrams of drug per square meter of body-surface area (mg/m²) as measured at baseline. Capecitabine was taken in two daily doses of 1,250 mg/m² each (total daily dose of 2,500 mg/m²), approximately 12 hours apart, within 30 minutes after ingestion of food. Patients were instructed to swallow the tablets with approximately 200 mL of water. The treatment regimen consisted of an intermittent schedule, where one cycle consisted of 2 weeks of capecitabine followed by 1 week of rest.

Toxicity and Dose Modification Guidelines
The capecitabine dosage was adjusted for treatment-related adverse events of grade 2 or greater, as defined by the National Cancer Institute of Canada common toxicity criteria (identical to those of the NCI in the United States). At the first occurrence of any grade 2 toxicity, treatment was interrupted; after resolution of the toxicity to grade 1 or better, treatment was resumed at the same dose. Subsequent occurrences of the same grade 2 toxicity were managed by treatment interruption until resolution of the toxicity to grade 0–1; this was followed by a 25% dose reduction (second occurrence) and then a 50% dose reduction (third occurrence). If the same grade 2 toxicity occurred a fourth time, treatment was discontinued, and the patient was withdrawn from the study. If a patient experienced recurrent grade 2 toxicity at the end of the 2-week treatment period and the toxicity resolved to grade 0 to 1 within the scheduled treatment-free rest period, the investigator could continue to administer the same dose. If a grade 3 toxicity occurred, treatment was interrupted until the toxicity resolved to grade 0 to 1; this was followed by a 25% dose reduction (first occurrence) and then a 50% dose reduction (second occurrence). If the same grade 3 toxicity occurred a third time, treatment was discontinued permanently. If a grade 4 toxicity occurred, treatment was discontinued unless the investigator considered it in the best interest of the patient to continue at 50% of the original dose after the toxicity resolved to grade 0 to 1. In the event of grade 2 or 3 diarrhea, nausea, or vomiting, capecitabine was stopped, and the adverse event was treated symptomatically. Capecitabine could be restarted at 100% of the original dose if the toxicity was considered adequately controlled within 2 days of initiation of treatment. If control took longer or if the adverse event recurred despite prophylaxis, then dose modifications were made as described earlier. Diarrhea of more than 2 days' duration required prompt medical evaluation. Once the dose of capecitabine was reduced, it was not subsequently increased.

Evaluation of Response
All tumor lesions were assessed by computed tomography scans. Objective response of measurable disease was determined in accordance with the WHO criteria.¹⁵ A CR was defined as the disappearance of all clinically detectable disease, determined by 2 observations not less than 4 weeks apart. A PR was defined as a 50% or greater decrease in total tumor size of the lesions (the sum of the products of the two greatest perpendicular diameters of all measurable lesions), determined by two observations not less than 4 weeks apart, and no appearance of new lesions or progression of any lesion. A response of SD was assigned if a less than 50% decrease in bidimensional lesions as defined above was not established and a 25% or greater increase in the size of any measurable lesions was not demonstrated throughout the treatment period. Progressive disease was defined as a 25% or greater increase in the sum of perpendicular diameters of one or more measurable lesions with individual minimal area greater than 2cm² or the appearance of new lesions. For malignant lesions with individual minimal areas less than 2cm², increase in size of any individual lesion of at least 1cm² in area was required.

The primary efficacy end points were objective response rate (CR or PR) and survival (calculated as time from the date of initiation of therapy to death). Secondary efficacy end points included time to objective response, duration of objective response, and time to progression (calculated from the date of initiation of therapy to date when progressive disease was first observed).

Statistical Methods
The size of the study population was calculated to detect an objective response rate of at least 15%. Patients were accrued in three stages, using a group sequential analysis design.¹⁶ If no objective responses (CRs or PRs) were observed in the first 20 patients treated, a response rate of 15% or greater could be excluded, and accrual would stop. If there was at least one CR or PR, 10 additional patients would be entered onto the study. If there was only one responder among 30 patients, the study would be abandoned as unlikely to provide evidence of a response rate of 15% or greater; however, if there were at least four responders, a 15% response rate could be assumed with a cumulative significance level of 0.019 and a cumulative power of 0.676. If more than one response was observed in the first 30 patients, the protocol allowed for a third stage of enrollment (10 additional patients) to validate the response rate more accurately.

At each stage of analysis, the overall objective response and complete response rates were calculated with exact 95% Clopper-Pearson CIs. Patients with no tumor assessments after baseline were classified as nonresponders. The Kaplan-Meier product-limit method was used to estimate median survival time and time to progression.

The efficacy analysis was based primarily on the intent-to-treat population (all eligible patients who received at least one dose of test drug). All analyses of safety were based on the safety population (all patients who received at least one dose of study medication and had at least one follow-up safety assessment).

	RESULTS

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Patient Population and Treatment Summary
A total of 23 patients were enrolled into this study at a single center (The University of Texas M. D. Anderson Cancer Center, Houston, TX) from June 1998 to December 1999. Demographic and other baseline characteristics of the patient population are summarized in Table 1. There were 18 men and five women, with a median age of 63 years (range, 44 to 75 years). The median KPS was 90 (range, 80 to 100). Median time from first diagnosis of colorectal cancer to start of study treatment was 234 days (range, 105 to 1,543 days). The stage at first diagnosis was local-regional in 43% of the patients and metastatic in 57% of the patients. At study entry, the disease had progressed or recurred in all 23 patients; 83% of the patients had documented baseline liver metastases, 39% of the patients had lung metastases, and 52% had other metastases.

Response to Treatment and Survival
There were no complete or partial responses among the first 22 eligible patients enrolled in the study and the study was closed to further accrual. One patient had previously received infusional FU and, although she had a partial response to capecitabine, she was not considered eligible. Stable disease was observed in 11 patients (50%), with a median duration of 141 days (range, 88 to 289 days). Eleven patients (50%) progressed on treatment. Twenty-two patients received third-line irinotecan after progression.

The median survival time (Kaplan-Meier estimate) was 389 days or 12.9 months (95% CI, 267 to 637 months; Fig 1). The Kaplan-Meier estimate for median time to disease progression was 64 days (95% CI, 41 to 134 days; Fig 2).

View larger version (11K): [in this window] [in a new window]   Fig 1. Survival following treatment with capecitabine: estimated percentage of patients alive in the intent-to-treat population.

View larger version (10K): [in this window] [in a new window]   Fig 2. Time to progressive disease (PD): estimated percentage of patients with PD in the intent-to-treat population.

View this table: [in this window] [in a new window]   Table 2. Treatment-Related Adverse Events With Incidence Rate 10% (all grades) or Grade 3 Incidence

	DISCUSSION

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More than 40 years after its development, FU-based therapy remains the mainstay of treatment for metastatic colorectal cancer.^2,18 Responses to this treatment are usually limited, and most patients eventually develop disease progression and become candidates for further therapy. Irinotecan, a semisynthetic camptothecin derivative, is a topoisomerase I inhibitor approved for second-line treatment of patients with metastatic colorectal cancer, based on an overall response rate of 15%.¹⁹ However, significant toxicities are associated with irinotecan treatment, including early and late diarrhea, leukopenia, neutropenia, nausea, abdominal pain, vomiting, and asthenia. More recently, irinotecan was approved in combination with FU as first-line treatment for colorectal cancer.²⁰

Based on the antitumor activity and good tolerability profile of capecitabine, this phase II study was designed to evaluate the use of capecitabine in patients with metastatic colorectal carcinoma who had progressed despite earlier treatment with FU. There were no complete or partial responses among the first 22 eligible patients enrolled onto the study, and it was closed per protocol to further accrual. One patient showed an objective response but was found to have previously received infusional FU and was therefore considered ineligible and removed from the study. Capecitabine showed a modest clinical benefit in this population, with 50% of the patients presenting with disease stabilization for a median duration of 141 days (range, 88 to 289 days). An additional 50% progressed despite treatment, with a median time to disease progression of 64 days. The Kaplan-Meier estimate for median survival time was 389 days. However, most patients received irinotecan as third-line treatment, and any conclusions based solely on the median survival would be inappropriate. The most frequent treatment-related grade 3 adverse events were mild to moderate hand-foot syndrome, diarrhea, nausea, and vomiting. There were no observed grade 4 toxicities.

The experience with capecitabine in the second-line metastatic setting is consistent with that of continuous infusion FU. The results of this study indicate that capecitabine used as a single agent will produce clinical benefit that is, at best, modest in patients with metastatic colorectal carcinoma who have progressed on treatment with FU. Our study was designed to show a response rate of at least 15% but, retrospectively, this target may have been too high considering the real activity of infusional FU as a second-line treatment. Nevertheless, this response is currently the minimum expected from any new agent targeting second-line treatment for colorectal cancer. Traditionally, it is believed that approximately 10% of the patients who have experienced failure of a bolus regimen of FU will respond to an infusional regimen of FU. However, this number is based on small series only.²¹ Mori et al¹⁰ used a standard regimen of infusional FU (300 mg/m²/d) in a cohort of 15 patients with advanced, measurable colorectal cancer whose disease was progressing after failing to respond to bolus treatment with FU alone or combined with high-dose leucovorin. Only one of the fifteen patients had an objective response. More recently, Rothenberg et al²² reported the results of a large three-arm phase III trial including more than 450 patients who had experienced failure of previous fluoropyrimidine-based therapy. The trial compared FU/leucovorin in combination with oxaliplatin (FOLFOX) versus infusional FU/leucovorin or oxaliplatin monotherapy as second-line treatment for colorectal cancer. There were no objective responses observed among the patients treated with infusional FU/leucovorin.

When our phase II study was designed, continuous infusion FU was the mainstay of therapy for colorectal cancer in patients previously treated with FU. Since then, further studies have demonstrated superior efficacy in the second-line metastatic setting for irinotecan monotherapy and for FU in combination with other agents.^22-26 Phase II studies have demonstrated the high efficacy and added convenience of capecitabine and oxaliplatin (the XELOX regimen) as both first-line and second-line treatment of colorectal cancer.^27-29 Investigators have reported an objective response rate of 55%, a stable disease rate of 32%, lasting greater than 3 months, a median progression-free survival of 7.6 months, and a median overall survival of 19.5 months.^27,30 This combination is being further evaluated in phase III trials as first- or second-line treatment of metastatic disease as well as in adjuvant treatment of colon cancer.

	Authors' Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Received more than $2,000 a year from a company for either of the last 2 years: Dvorit Samid, Roche Labs Inc; Diane Polito, Roche Labs Inc; Paulo Hoff, Roche Labs Inc.

	NOTES

Presented in part at the 36th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, May 2000.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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30. Sastre J. Personal communication based on the following abstract: Sastre J, Butts C, Cassidy J, et al: Capecitabine-oxaliplatin combination (XELOX) effective 1^st line therapy for patients with metastatic colorectal cancer: Survival update of an international phase II study. Ann Oncol 2002 (abstr 288P)

Submitted May 12, 2003; accepted February 27, 2004.

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