First line treatment
The evidence supporting this protocol is provided by a phase 3 randomised controlled trial involving 325 patients comparing intermittent capecitabine or continuous capecitabine to classical cyclophosphamide methotrexate fluorouracil (CMF) in patients with metastatic breast cancer.r
Between July 2001 and June 2005 325 patients who were not suitable for more intensive chemotherapy were randomised to receive intermittent capecitabine (1000 mg/m² twice daily on days 1-14 and repeated every 3 weeks), continuous capecitabine (650 mg/m² twice daily on days 1-21 and repeated every 3 weeks), or classical CMF (oral cyclophosphamide 100 mg/m² on days 1-14, methotrexate 40 mg/m², and fluorouracil 600 mg/m² on days 1-8, and repeated every 4 weeks). The primary endpoint was quality-adjusted progression-free survival (PFS); secondary endpoints included PFS, overall-survival (OS), objective tumour response, and adverse events.
Second line treatment
A search of the literature did not find strong evidence to support the use of capecitabine in the second line treatment of metastatic breast cancer. The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the phase II trial by Blum et al.r
Source |
Study & year published |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase II |
Blum et al 1999r |
Yes |
No |
|
Meta-analysis |
Ershler et al 2006r |
N/A |
N/A |
|
Guidelines |
Date published/revised |
Supports use |
Is the dose and regiment consistent with the protocol |
Comments |
NCCN |
N/A |
N/A |
N/A |
First line treatment only |
CCO |
2003 |
Yes |
No |
- |
BCCA |
N/A |
N/A |
N/A |
First line |
ESMO |
2018 |
Yes |
N/A |
|
In the phase II study by Blum et al. 163 patients were enrolled into the study and 162 patients received treatment with capecitabine.r All patients had received at least 2 but not more than 3 prior chemotherapy regimens, one of which had to have contained paclitaxel for metastatic disease.
Ershler et al. performed a systematic review of capecitabine monotherapy in 1st and 2nd line metastatic breast cancer patients.r There were 28 studies which used single agent capecitabine in the 2nd line setting, but most were Phase 2 studies or conference abstracts and none were randomised controlled trials.
Overall, monotherapy capecitabine was active in previously treated patients. The median complete response rate was 3% and the median objective response rate was 28%. The median time to progression was 4.7 months and median overall survival was 11.0 months.
Efficacy
First line treatment
The overall response rate was 22% in the intermittent capecitabine arm, 20% in the continuous capecitabine arm, and 18% in the CMF arm.r The quality-adjusted PFS was similar between capecitabine versus CMF (mean, 8.8 v 7.6 months). OS was longer in the capecitabine group (median, 22 v 18 months). There was no survival difference between the intermittent and continuous capecitabine arms.
Progression free survival and overall survivalr
©Journal of Clinical Oncology 2011
Second line treatment
In the study by Blum et al, the overall response rate was 20%. 3 complete responses were seen and the median duration of response was 8.1 months, median survival time was 12.8 months and median time to disease progression was 93 days.r
Relationship between tumour response and survival r
© Journal of Clinical Oncology 1999
Toxicity
The most common treatment-related adverse events reported by both Stockler et al and Blum et al. were hand-foot syndrome (HFS), diarrhoea, nausea, vomiting, infection and fatigue.
Treatment related adverse events in first line treatmentr
© Journal of Clinical Oncology 2011
Frequently reported treatment-related adverse events in second line treatment r
© Journal of Clinical Oncology 1999
Ershler et al. reviewed the grade 3 or 4 adverse events reported in studies where capecitabine was used in the second-line or subsequent setting.r Overall, the most frequently reported grade 3 or 4 non-haematological adverse events were hand-foot syndrome (median 13%, range 0% - 42%), diarrhoea (median 7.5%, range 0% - 30%), nausea (median 6.5%, range 0% - 35%), mucositis (median 6%, range 0% - 12%), and vomiting (median 4%, range 0% - 19%). Haematologic adverse events were uncommon (median neutropenia incidence of 1%, thrombocytopenia and leukopenia 0%).