• Breast Cancer Disease Site Group. Tomiak E, Verma S, Trudeau M, Robinson P. Capecitabine in stage IV breast cancer [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2003 Nov 26 [online update]. 17 p. (Practice guideline report; no. 1-16). [31 references]

Stage IV breast cancer

Assessment of Therapeutic Effectiveness
Evaluation
Treatment

Oncology

Physicians

• To provide recommendations about the role of capecitabine as second-, third-, or fourth-line chemotherapy in stage IV (metastatic) breast cancer, specifically in anthracycline or taxane failure
• To provide recommendations about the role of capecitabine as first-line chemotherapy in stage IV (metastatic) breast cancer

Women with stage IV (metastatic) breast cancer who are anthracycline-resistant or who have previously received an anthracycline as adjuvant therapy

Treatment

1. Capecitabine plus docetaxel in anthracycline-pretreated breast cancer
2. Capecitabine as a single agent after previous anthracycline treatment
3. Capecitabine as first-line therapy
4. Capecitabine as second-, third-, or fourth-line therapy

• Tumour response rates
• Time to progression
• Survival rates
• Quality of life
• Toxicity

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases

One randomized phase III trial, two randomized phase II trials, and two non-comparative phase II trials were reviewed.

Expert Consensus (Committee)

Not applicable

Systematic Review

Results from the three randomized trials included in this overview were not pooled because of differences in the interventions evaluated. One trial compared capecitabine as a single agent to cyclophosphamide/methotrexate/fluorouracil (CMF), the second compared capecitabine as a single agent to paclitaxel, and the third compared capecitabine plus docetaxel to docetaxel alone.

Expert Consensus

The Breast Cancer Disease Site Group (DSG) discussed the evidence about capecitabine in the context of three clinical scenarios:

• Patients with metastatic breast cancer whose tumours are refractory to anthracyclines and for whom a taxane-based chemotherapy regimen is being considered. Based on their review of a randomized trial of capecitabine plus docetaxel versus docetaxel alone, the DSG decided to formulate a recommendation for the use of capecitabine with docetaxel in selected patients (i.e., those with good performance status or younger age).
• Patients considering capecitabine as first-line chemotherapy for metastatic breast cancer. The Breast Cancer DSG recognized the appeal of an oral outpatient regimen with an acceptable toxicity profile to women with metastatic breast cancer but felt that the limited data currently available do not support a recommendation at this time for capecitabine's use as a single agent in the first-line setting.
• Patients with metastatic breast cancer who have already received anthracycline- and taxane-containing chemotherapy (either in the adjuvant or metastatic settings) and whose tumours are felt to be refractory to these classes of agents. In this clinical situation, if second-, third- or fourth-line chemotherapy is considered to be an appropriate treatment option, the Breast Cancer DSG agreed that capecitabine would be a reasonable treatment choice. The DSG recognized that, at the current time, no standard regimen has been defined for these patients and encouraged further trials evaluating capecitabine's place among other available agents (vinorelbine, Herceptin, 5-fluorouracil (5FU)-based regimens).

Not applicable

A formal cost analysis was not performed and published cost analyses were not reviewed.

External Peer Review
Internal Peer Review

Practitioner feedback was obtained through a mailed survey of 86 medical oncologists in Ontario. The survey consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommendations should be approved as a practice guideline. Written comments were invited. The practitioner feedback survey was mailed out on February 18, 2003. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again). The Breast Cancer Disease Site Group (DSG) reviewed the results of the survey.

This practice guideline reflects the integration of the draft recommendations with feedback obtained from the external review process. It has been approved by the Breast Cancer Disease Site Group and has been approved by the Practice Guidelines Coordinating Committee (PGCC).

• In selected patients (e.g., those with good performance status, less than 70 years of age, and with no other major comorbidities) who are anthracycline-resistant or who have previously received an anthracycline as adjuvant therapy, the combination of docetaxel and capecitabine is an appropriate therapeutic option.
• If docetaxel and capecitabine are used in combination, the recommended starting dose for most patients is 950 mg/m² twice daily of capecitabine (75% of full dose) on days 1 to 14 plus docetaxel 75 mg/m² intravenously on day 1 of a 21-day cycle.
• In patients who have been pretreated with anthracyclines and/or taxanes, capecitabine alone (1,250 mg/m² twice daily, for 21 days) is a reasonable treatment option.
• There is insufficient evidence for the use of capecitabine as a first-line chemotherapy in metastatic breast cancer.
• Warnings:
  • Patients receiving concomitant capecitabine and coumarin-derivative therapy should have their anticoagulant response monitored, as coagulant response time is significantly increased in patients stabilized on anticoagulants at the time of capecitabine introduction.
  • In patients with renal impairment, capecitabine therapy can increase systemic exposure to alpha-fluoro-beta-alanine (FBAL) and 5’-deoxy-5-fluorouridine (5’- DFUR). Specifically, capecitabine is contraindicated in patients with severe renal impairment (calculated creatinine clearance <30 mL/min) and should be reduced to a starting daily dose of 1,900 mg/m2 for patients with moderate renal impairment (calculated creatinine clearance 30-50 mL/min). Patients with mild renal impairment should be closely monitored.

None provided

The references are supported by phase II and III randomized trials.

• One randomized phase III trial that compared docetaxel plus capecitabine to docetaxel alone detected superior response, time to progression, and survival for the combination, with high rates of toxicity from both treatments and no differences in measures of quality of life (N=511).
• Two randomized phase II trials evaluated capecitabine as a single agent. One trial compared capecitabine with intravenous cyclophosphamide/methotrexate/fluorouracil (CMF) in patients receiving first-line chemotherapy for metastatic breast cancer (N=93) and the second trial compared capecitabine to paclitaxel following anthracycline therapy (N=41). Both studies failed to demonstrate any significant difference in response, time-to-progression, or survival when capecitabine was compared to CMF as first-line treatment or with paclitaxel as second- or third-line treatment. However, it must be noted that both trials were small and underpowered to detect significant differences in outcomes between the respective treatment arms. Thus, it is not possible to draw meaningful conclusions from these trials.
• Two multicentre uncontrolled phase II trials that evaluated the efficacy of capecitabine in heavily pretreated patients with taxane-refractory metastatic breast cancer reported response rates of 20% and 26%, median time to progression of 3 months, and median survival of 12 months (N=162, N=74).

In randomized trials, grade 3 or 4 gastrointestinal adverse effects and hand-foot syndrome were more common with capecitabine plus docetaxel than with docetaxel alone and with capecitabine as a single agent than with cyclophosphamide/methotrexate/fluorouracil (CMF); serious clinical adverse effects were less common with capecitabine than with paclitaxel. Grade 3 or 4 neutropenia was less common with capecitabine than with either cyclophosphamide/methotrexate/fluorouracil or paclitaxel. Outside of clinical trials, 74% of patients treated with capecitabine experienced hand-foot syndrome, 44% diarrhea, 37% stomatitis, and 47% nausea and vomiting; grade 3 or 4 adverse events were more common at doses of capecitabine >2,100 mg/m².

In patients with renal impairment, capecitabine therapy can increase systemic exposure to alpha-fluoro-beta-alanine (FBAL) and 5’-deoxy-5-fluorouridine (5’- DFUR). Specifically, capecitabine is contraindicated in patients with severe renal impairment (calculated creatinine clearance <30 mL/min) and should be reduced to a starting daily dose of 1,900 mg/m² for patients with moderate renal impairment (calculated creatinine clearance 30-50 mL/min). Patients with mild renal impairment should be closely monitored.

• In patients who have been heavily pretreated, a reduction in the starting dose of single-agent capecitabine (75% of full dose) may be considered.
• Available data are limited and do not allow a firm clinical recommendation to be made for capecitabine's optimal use in metastatic breast cancer. Further studies are needed to evaluate its role in combination and sequential therapies.
• Capecitabine needs to be further evaluated as an alternative to paclitaxel or docetaxel in patients whose tumour has progressed on an anthracycline-based regimen, and in selected women, as first-line therapy as an alternative to more toxic standard combination chemotherapy regimens.
• Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or warranties of any kind whatsoever regarding their content or use or application and disclaims any responsibility for their application or use in any way.

An implementation strategy was not provided.

End of Life Care
Living with Illness

Effectiveness

• Breast Cancer Disease Site Group. Tomiak E, Verma S, Trudeau M, Robinson P. Capecitabine in stage IV breast cancer [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2003 Nov 26 [online update]. 17 p. (Practice guideline report; no. 1-16). [31 references]

Not applicable: The guideline was not adapted from another source.

2003 Nov 26

Program in Evidence-based Care - State/Local Government Agency [Non-U.S.]

The Practice Guidelines Initiative (PGI) is the main project of the Program in Evidence-based Care (PEBC), a Province of Ontario initiative sponsored by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.

Cancer Care Ontario, Ontario Ministry of Health and Long-Term Care

Breast Cancer Disease Site Group

Members of the Breast Cancer Disease Site Group disclosed potential conflict of interest information.

None available

This NGC summary was completed by ECRI on April 19, 2004. The information was verified by the guideline developer on April 29, 2004.