• Kocha W, Maroun J, Jonker D, Rumble RB, Zuraw L, Gastrointestinal Cancer Disease Site Group. Oral capecitabine (Xeloda) in the first-line treatment of metastatic colorectal cancer: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2005 Feb 11. 27 p. (Evidence-based series; no. 2-15). [30 references]

Metastatic colorectal cancer

Assessment of Therapeutic Effectiveness
Treatment

Gastroenterology
Oncology

Physicians

To evaluate the use of oral capecitabine (Xeloda™) in the first-line treatment of patients with metastatic colorectal cancer where monotherapy with fluoropyrimidines or other thymidylate synthase inhibitors is favoured

Adult patients with metastatic colorectal cancer who have not received prior chemotherapy for metastatic disease in whom monotherapy with fluoropyrimidines or other thymidylate synthase inhibitors is favoured. For patients who are at a high risk following curative resection and who received adjuvant chemotherapy, adjuvant treatment should have been completed at least six months prior to being diagnosed with metastatic disease.

1. Standard combination chemotherapy consisting of infusional 5-fluorouracil (5-FU) plus leucovorin calcium with either irinotecan or oxaliplatin
2. Oral capecitabine

• Survival
• Time to progression
• Tumour response

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Searches of Unpublished Data

A randomized phase II study, two fully-published randomized phase III trials, a meta-analysis combining the two phase III trials, and a related meta-analysis in abstract form were reviewed. In addition, an abstract report of interim safety data and a phase III study examining capecitabine in the adjuvant setting were reviewed.

Update February 2005

Two new trials were obtained.

Expert Consensus (Committee)

Not applicable

Review of Published Meta-Analyses
Systematic Review with Evidence Tables

The results of phase III trials of capecitabine as first-line therapy for metastatic colorectal cancer were not pooled because of the availability of an up-to-date, published meta-analysis of two randomized phase III trials of capecitabine as first-line treatment for metastatic colorectal cancer. This meta-analysis, based on summary data, has been published in full.

Expert Consensus

The data from the two phase III trials revealed no statistically significant difference between capecitabine and 5-fluorouracil (FU) plus leucovorin as first-line therapy for metastatic colorectal cancer. Although irinotecan has now moved into first-line therapy (given in combination with 5-FU plus leucovorin), a subgroup of patients will select or be selected for thymidylate synthase-inhibitor monotherapy because of age, frailty, coexistent morbid conditions, or preference. Capecitabine would certainly be one of the alternatives to consider, and may be preferable to many patients because it is taken orally. Its pharmacokinetics and toxicity pattern are concordant with 5-FU administered as a continuous infusion. There is evidence that 5-FU continuous infusions have some activity where there is resistance to 5-FU bolus therapy. Capecitabine may therefore have similar activity.

There was speculation that capecitabine might replace or represent an alternative to 5-FU therapy given as a continuous infusion in combination with other chemotherapy or with radiation therapy. The Gastrointestinal Cancer Disease Site Group (DSG) will integrate the results of trials exploring the effects of capecitabine in combination with other drugs, such as irinotecan and oxaliplatin, when available.

Opinions in the Disease Site Group differed as to the effect of the dominant toxicity of palmar-plantar erythrodysesthesia (hand-foot syndrome). Some felt the syndrome was a major drawback to the use of the drug while others believed it to be a minor discomfort that is easy to manage and not life threatening.

As patients with colorectal cancer frequently have liver involvement with consequent effects on liver function, it was felt that more data should be included on the use of capecitabine in this group of patients, but little evidence exists on the subject. A section on the management of hyperbilirubinemia was added.

Not applicable

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

External Peer Review
Internal Peer Review

External Review

Following review and discussion of sections 1 and 2 of the original guideline document, the Gastrointestinal Cancer Disease Site Group circulated the clinical practice guideline and systematic review to clinicians in Ontario for review and feedback.

Practitioner feedback was obtained through a mailed survey of 103 practitioners in Ontario (29 medical oncologists, 3 gastroenterologists, and 71 surgeons). 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. Follow-up reminders were sent at two-weeks (post card) and four weeks (complete package mailed again). The Gastrointestinal Cancer Disease Site Group (DSG) reviewed the results of the survey.

Practice Guidelines Coordinating Committee Approval Process

The practice guideline report was circulated to 14 members of the Practice Guidelines Coordinating Committee for review and approval.

None provided

The recommendations are supported by randomized controlled trials and meta-analyses.

• Two randomized phase III trials demonstrate that single-agent capecitabine administered orally yields higher response rates than 5-fluorouracil plus leucovorin. Pooled response rates were 26% with capecitabine versus 17% with 5-fluorouracil plus leucovorin (p<0.0002) in a meta-analysis of both trials that has been published in abstract form. Similar median time to progression and median duration of survival was observed with capecitabine and 5-fluorouracil plus leucovorin.
• In the subgroup of patients who relapsed more than six months after completing adjuvant therapy with 5-fluorouracil and leucovorin, capecitabine was associated with higher response rates compared with retreatment with 5-fluorouracil plus leucovorin. Pooled response rates were 21% with capecitabine versus 9% with 5-fluorouracil plus leucovorin in this subgroup of patients (p-value not reported).

Capecitabine appears to have a lower incidence of stomatitis, alopecia, and neutropenia compared with 5-fluorouracil and leucovorin. There is, however, a considerably higher incidence of hand-foot syndrome with capecitabine.

• Monotherapy with fluoropyrimidines (e.g., 5-fluorouracil [FU], capecitabine) or other thymidylate synthase inhibitors (e.g., raltitrexed, pemetrexed) may be favoured in patients with prior pelvic radiotherapy, elevated liver enzymes, age greater than 65 years, Eastern Cooperative Oncology Group (ECOG) performance status <1, and those with a lactate dehydrogenase (LDH) above the upper limit normal. This may also include patients who prefer to avoid intravenous therapy, where travel to a chemotherapy unit would be difficult, or who live in remote locations where an infusional pump program is not available, or in whom placement of a central line catheter is contraindicated. It is also an option for patients with concerns about the toxicity profile of combination chemotherapy (such as hair loss or risk of toxic death), or for whom there is insufficient data regarding the use of combination chemotherapy, or in those subgroups of patients for whom there is no clear survival benefit over single agent anti-thymidylate synthase therapy.
• Preliminary data from a subgroup analysis suggest that capecitabine may be the preferred treatment for patients who had received prior adjuvant therapy at least six months earlier with 5-FU plus leucovorin, while either capecitabine or 5-FU plus leucovorin therapy is reasonable for patients who have never received adjuvant therapy. Further trials are needed to confirm this observation.
• The decision to use capecitabine may be influenced by its toxicity. While capecitabine is associated with a lower incidence of stomatitis, alopecia, and neutropenia compared with 5-FU plus leucovorin, the incidence of hand-foot syndrome is considerably higher with capecitabine.
• Using capecitabine will require dose adjustments in patients with a creatinine clearance less than 60%. This is particularly important in thin elderly patients in whom reductions in creatinine clearance are not adequately reflected in the serum creatinine level alone.
• Where there is hyperbilirubinemia with bilirubin values exceeding 1.5 times normal, it has been recommended that capecitabine treatment be interrupted until the bilirubin drops below the 1.5 times normal value.
• 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.

Living with Illness

Effectiveness

• Kocha W, Maroun J, Jonker D, Rumble RB, Zuraw L, Gastrointestinal Cancer Disease Site Group. Oral capecitabine (Xeloda) in the first-line treatment of metastatic colorectal cancer: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2005 Feb 11. 27 p. (Evidence-based series; no. 2-15). [30 references]

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

2003 Dec (revised 2005 Feb 11)

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

The Program in Evidence-based Care (PEBC) is 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

Provincial Gastrointestinal Cancer Disease Site Group

Not stated

None available

This NGC summary was completed by ECRI on May 14, 2004. The information was verified by the guideline developer on June 2, 2004. This NGC summary was updated by ECRI on August 18, 2006. The updated information was verified by the guideline developer on August 23, 2006.