New treatment strategies for advanced breast cancer have focused on both the development of new molecular targets in breast cancer cells, as well as improving the therapeutic index of presently available therapy. The
ABSTRACT: New treatment strategies for advanced breast cancer havefocused on both the development of new molecular targets in breast cancer cells,as well as improving the therapeutic index of presently available therapy. Thedevelopment of capecitabine (Xeloda), a new oral fluoropyrimidine, is an exampleof a chemotherapy drug that has single-agent activity in heavily pretreatedpatients with advanced breast cancer, with the added convenience of good oralbioavailability. Capecitabine is an excellent treatment option for patients whorequire symptom palliation and who prefer oral medications. The discussion thatfollows reviews the clinical data on the use of capecitabine in advanced breastcancer. [ONCOLOGY 15(Suppl 2):69-72, 2001]
Significant advances in the management of metastatic breastcancer have been made over the last decade. Not only have new chemotherapy,endocrine therapies, and biologic therapies provided patients with bettertreatment options, but supportive measures, such as hematopoietic growth factorsand more effective antiemetics, have also made treatment more tolerable.
Though metastatic breast cancer remains a disease that is notcurable with currently available therapies, one avenue of clinical research hasfocused on the development of drugs that have effective antitumor activity andthe potential for greater patient convenience and acceptance. One suchexample is the development of capecitabine (Xeloda), an oral fluoropyrimidine,that has been approved by the FDA and is commercially available for thetreatment of metastatic breast cancer.
5-fluorouracil (5-FU) has been an integral component ofcytotoxic chemotherapy regimens for breast cancer in both the adjuvant andadvanced-disease setting for several decades. Infusional 5-FU offersantitumor activity in some patients with metastatic disease who have beenheavily pretreated (response rates of approximately 20%).[3,4] One of theconstraints associated with 5-FU is schedule dependency and poor oralabsorption.
As discussed by others in this supplement, strategies have beendeveloped to enhance the absorption of 5-FU by using a prodrug or by inhibitingthe degradation of 5-FU in the gastrointestinal tract. Capecitabine wasdeveloped as an oral drug that would simulate the effect of infusional 5-FU, andat the same time have greater tumor selectivity. The latter property exploitsthe observation that many tumors have higher levels of thymidine synthase (TS)compared to normal tissues.
Capecitabine is an oral precursor of 5´-deoxy-5-fluorouridine(5´-DFUR) that is absorbed intact through the intestinal mucosa.[7,8]Capecitabine is not affected by the TS present in the intestinal mucosa, and asa result, less diarrhea is reported compared to that associated with 5-FU.Capecitabine is then metabolized in the liver by carboxylesterase to5´-deoxy-5-fluorocytidine (5´-DFCR). 5´-DFCR is converted to 5´-DFUR bycytidine deaminase, an enzyme located primarily in the liver and tumortissue. 5´-DFUR is then converted to 5-FU by TS in the tumor cells.
The net effect of this multistep metabolic process is higherconcentrations of 5-FU in tumor tissue compared to adjacent normal tissue.[6,10]This has been confirmed in animal models and in human colorectal livermetastases.[8,11] Capecitabine produces plasma concentrations comparable tocontinuous-infusion 5-FU administered at 300 mg/m2/day.
The pivotal trial of capecitabine was conducted in patients withmetastatic breast cancer who had disease progression on paclitaxel (Taxol).For the majority of patients participating in the trial, capecitabinerepresented the third or fourth treatment for metastatic disease. The primaryobjective of this study was to determine the overall objective response rate tocapecitabine. Secondary objectives were to determine the duration of response,time-to-disease progression, survival, toxicity, and clinical benefitresponse.
Capecitabine was administered at a dose of 2,510 mg/m2/day intwo divided doses. A 21-day treatment cycle consisted of 14 consecutive daysof capecitabine, followed by 7 days without treatment. The dosing schedule usedin this trial was determined from the results of a phase I, dose-escalated trialof capecitabine. Dose adjustments were based on grade 2 or 3 toxicities. Atotal of 162 patients were recruited to participate in this trial from 25centers in the United States and Canada. The median age of patients was 55.8years and the median Karnofsky score was 86%. Of the 162 patients, 135 hadmeasurable disease (83%), and 27 of the 162 patients had only evaluable disease(17%). The median time from diagnosis of breast cancer to recurrence was 917days, and to enter into the study was 1,276 days.
The patient population of this trial was typical of those withmetastatic disease. The majority of patients had multiorgan metastases, with 43%reporting liver metastases. All patients had prior treatment with paclitaxel,and 84% had received doxorubicin. In addition, 67% of patients had receivedprior tamoxifen (Nolvadex) therapy. Patients were categorized based on theirresponse to prior paclitaxel therapy: disease progression while receivingpaclitaxel (primary resistance) and disease progression within 1 to 12 months ofcompleting paclitaxel therapy (failure).
The overall objective response rate with capecitabine in thistrial was 20% (complete response rate, 2%; partial response rate, 18%). Anadditional 40% of patients maintained a status of stable disease. There waslittle difference in overall response rate with capecitabine therapy, whether itwas administered as third- or fourth-line therapy (third-line, 18%; fourth-line,20%). Of the 27 patients with measurable disease who responded to capecitabine,all were primarily refractory to paclitaxel, all had received prior doxorubicintherapy, and 67% had been treated with 5-FU. Even of the 43 patients who wereresistant to both treatment with an anthracycline and paclitaxel, the responserate was a respectable 25%. The median duration of response was 241 days andthe median survival was 384 days.
Clinical benefit response was assessed in three categories: painscore, analgesic consumption, and Karnofsky performance status. Each ofthese parameters was objectively assessed at baseline and then throughout thetrial. It was required that a response be sustained for 4 weeks in order to bescored as a response. In the analysis of clinical benefit response, 20% ofpatients showed improvement in each of the parameters, and an additional 31% ofpatients remained stable. For those patients showing an improvement,clinical benefit responses lasted more than 18 weeks.
Treatment with capecitabine was generally well tolerated in thisheavily pretreated group of patients with metastatic breast cancer. Grade 3 or 4toxicities are listed in Table 1. Diarrhea and palmar-plantar erythrodysesthesia(PPE) were the most common side effects, occurring in 15% and 11% of patients,respectively. Only 3% of patients experienced grade 4 toxicity, and 7% ofpatients withdrew from the study due to treatment-related events.
Other Phase II Trials
A second multicenter, single-arm, phase II study ofcapecitabine, using the same dose and schedule, in a similar taxane-refractorypopulation of 75 patients with metastatic breast cancer confirmed the efficacyand safety of capecitabine. The response rate was 24% (confidence interval[CI]: 14%-35%). Docetaxel (Taxotere)-refractory patients achieved a responserate to capecitabine similar to the paclitaxel-refractory patients. Responseduration, time-to-disease progression, and survival were similar to thosereported in the previous study. Diarrhea (18%), PPE (18%), and nausea (11%) werethe only treatment-related adverse events that occurred at a grade 3 or 4intensity of > 10%. Alopecia did not occur and myelosuppression wasuncommon.
A smaller randomized phase II trial evaluated the efficacy ofcapecitabine at the same dose regimen (2,510 mg/m2/day) in patients pretreatedwith an anthracycline, using paclitaxel at a dose of 175 mg/m2 every 3 weeks, asthe reference arm. In this trial, which was terminated early due torecruitment difficulties, 8 patients showed objective responses for an overallresponse rate of 36% (CI: 17%-59%) among 22 patients treated with capecitabine,with a median response duration of 9.4 months and time-to-disease progression of3 months. There was a 23% incidence of grade 3 and 4 toxicities.
Results from these clinical trials confirmed the activity ofcapecitabine in heavily pretreated patients with metastatic breast cancer andled to the FDA approval of capecitabine as treatment for paclitaxel-resistant,metastatic breast cancer. The registered dose is 2,510 mg/m2 administered in twodivided doses for 14 days every 21 days.
Another small, randomized, phase II trial suggests thatcapecitabine has potential as first-line treatment for metastatic breast cancersin women aged ³ 55 years. Patients were randomized to treatment withcapecitabine or CMF (cyclophosphamide, methotrexate, and 5-FU). Patientcharacteristics were well matched in terms of performance status, metastaticsites, and prior hormonal therapy. The median age of patients in thecapecitabine arm was 69 years, and 70 years for those receiving CMF.
Results showed that the response rate with capecitabine was 30%,which compared favorably with a response rate of 16% observed in patientsreceiving intravenous CMF. The median survival in the capecitabine group was21.6 months compared to 17.2 months in the CMF group. However, the differencewas not statistically significant.
As the general oncology community has gained more experiencewith capecitabine, the issue of optimal dosing has been readdressed. O’Shaughnessyand colleagues recently reported on the impact of dose reduction of capecitabineon clinical outcome in patients with metastatic breast cancer. A total of321 patients from four phase II trials of capecitabine in advanced or metastaticbreast cancer were included in the analysis.
Dose reductions were deemed necessary in 131 patients, while 190patients received capecitabine at the standard dose (2,510 mg/m2/day for 14 of21 days). The first dose reduction was by 25% (131 patients), while 29 patientsrequired a second dose reduction to 50%. Interestingly, the analysis showed thatdose reduction had no effect on achieving a response, duration of response,time-to-treatment failure, or overall survival. These results suggest thatthe dose of capecitabine could be reduced to minimize toxicity withoutcompromising efficacy.
Investigators at The University of Texas M. D. Anderson CancerCenter reported on the post-marketing use of capecitabine in 141 consecutivepatients with metastatic breast cancer who received the drug, but did notparticipate in a clinical trial. Patients were stratified according to thestarting dose of capecitabine (2,375-2,625 mg/m2/day; 2,101-2,374mg/m2/day; or ≤ 2,100 mg/m2/day), clinical response, and adverse events.
According to this analysis, the therapeutic index favored astarting dose of 2,000 mg/m2/day. Clinical response was maintained at thelower starting dose of capecitabine, but the rate of PPE, diarrhea, andstomatitis occurred less frequently compared to patients receiving the higherstarting doses of capecitabine. These findings and those reported by O’Shaughnessyet al suggest that dosing of capecitabine can be individualized withoutnecessarily compromising the effectiveness of the drug.[17,18]
As might be expected, capecitabine is now being evaluated incombination with other chemotherapy drugs. Preclinical data have shown thatanimal tumors exposed to paclitaxel upregulate TS. By combining paclitaxeland capecitabine, the increased expression of TS may result in more 5¢-DFURbeing converted to 5-FU in the tumor cell.
Ongoing clinical trials are evaluating the combination ofcapecitabine plus paclitaxel or docetaxel. The taxane is administered either onan every 3-week or weekly schedule. Results from these trials will beforthcoming. Other trials in development or actively accruing patients includecapecitabine/vinorelbine (Navelbine), capecitabine/liposomal doxorubicin, andcapecitabine/anthracycline combinations. Whether these combinations offer anyadvantage over the use of single-agent capecitabine remains to be determined.
Capecitabine has clearly established its role in the treatmentof metastatic breast cancer. In some patients who have already receivedtreatment with taxanes, anthracyclines, and even high-dose chemotherapy andperipheral blood stem-cell transplantation, capecitabine offers the convenienceof an oral medication. Capecitabine also offers the chance for tumor responseand symptom palliation.
Daniel Haller, MD: Just a question about the dose forcapecitabinein terms of what people do and what the data show. The data youpresented showed 11% grade 3, 0% grade 4 diarrhea in the pivotal trial, so whatis it that people are seeing in their practicethat wasn’t seen in the trialthatconvinces them to make an a priori dose reduction?
William Gradishar, MD: Once people have started usingcapecitabine, myself included, we saw more diarrhea in more patients than wasreported in the pivotal trial. Of course, you’re looking at smaller numberswhen your first few patients run into problems. And I’ve heard this frompeople in practice at our own institutionpeople are getting into problemsearly on. It’s anecdotal, but when people backed off the approved dose, thereseemed to be better acceptability by both the physician and the patients.
Dr. Haller: So what’s the right dose?
Dr. Gradishar: I think how people are using the drug isgoing to end up defining what’s correct in this case.
Dr. Haller: So then shouldn’t there be a trial to findout what the efficacy is of the dose that people are actually using?
Dr. Gradishar: Well there are such trials going forward,if I’m not mistaken, looking at lower doses of the drug. I think the waypeople are using it in the community is not at the established approved dose,though.
Paulo Hoff, MD: Going back to that question about whypeople are using a lower dose, we pooled our experience with capecitabine andour incidence of hand-foot syndrome was higher than 60%. Our grade 3 rate wasonly 10%. But even grade 2 is bothersome to patients. Off protocol, we use 2grams per meter squared. All those people were on protocol and so were veryclosely watched, so they probably stopped at grade 2 and that’s why we havelower grade 3.
Leonard Saltz, MD: But if I understood you correctly, yousaid diarrhea was the concern that people were running into.
Dr. Gradishar: Hand-foot syndrome as well. People in thecommunity were hesitant to use this. Perhaps there were some financial issues.They weren’t quick to adopt it but once there was a response rate that waspretty consistently identified in patients who were heavily pretreated, theylooked to it as a reasonable drug. We use it as third- or fourth-line therapy.These patients are not willing to accept a lot of toxicity when they’vealready gotten three or four other regimens for metastatic disease.
Dr. Haller: Isn’t there an obligation, in developing adrug, to actually use regimens that people agree are doable and then find out ifyou’re still seeing the same response rates? I mean, devising protocols thatare based on treatments that people don’t use seems silly to mean adjuvanttrial based on a dose that nobody takes. Where is the efficacy drop-off?
Dr. Hoff: We only have retrospective data but we areplanning to do prospective studies.
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