Oral Capecitabine/Cyclophosphamide for Treatment of Metastatic Breast Cancer

ABSTRACT & COMMENTARY

Synopsis: In a small, multicenter, randomized Phase 2 trial, the all-oral combination of cyclophosphamide and capecitabine demonstrated a trend toward an increasing response rate when compared to capecitabine alone in the treatment of locally advanced or metastatic breast cancer. The combination was well tolerated.

Source: Harvey VJ, et al. A randomized phase II study comparing capecitabine alone with capecitabine and oral cyclophosphamide in patients with advanced breast cancer-cyclox II. Ann Oncol 2013;24:1828-1834.

Capecitabine, the prodrug of 5-fluorouracil (5FU), is effective and well tolerated in the treatment of breast cancer.1,2 Its antitumor activity is attributed to its conversion by thymidine phosphorylase to 5FU. Because cyclophosphamide is known to upregulate thymidine phosphorylase in certain tissues,3 there is reason to expect that the drugs would have synergistic antitumor activity, and indeed this has been demonstrated in preclinical studies.3,4 Further, these two drugs have non-overlapping toxicities and both may be administered orally, an attractive attribute for palliative treatment of metastatic breast cancer.5 The current randomized Phase 2 study was undertaken to assess whether the combination of capecitabine and oral cyclophosphamide would be superior to capecitabine alone for treatment of metastatic breast cancer.

This was a multicenter trial conducted at each of the six major New Zealand cancer centers in the years 2004 to 2007. Patients with locally advanced or metastatic measurable breast cancer who had adequate baseline bone marrow reserve and liver function, a calculated creatinine clearance > 50 mL/min, WHO performance status 0-3, and no more than one prior chemotherapy regimen for advanced disease were randomized to receive either capecitabine given continuously (666 mg/m2 bid days 1-28) alone (C) or with oral cyclophosphamide (100 mg/m2 as a single daily dose on days 1-14 of a 28-day cycle) (CCy).

Eighty-two patients were randomized. There was no complete response in either arm. The proportions with partial response were 36% on C and 44% on CCy, a difference of 7.9% (95% confidence interval [CI], -13.4 to 29.1). Significant toxic effect was uncommon: grade ≥ 3 diarrhea in 4 (10%) vs 1 (3%) patients; grade ≥ 3 fatigue in 2 (5%) vs 5 patients (13%), and grade ≥ 2 hand-foot syndrome in 7 (17%) vs 11 (28%) patients receiving C vs CCy, respectively. Median progression-free survival was 3.1 months on C and 6.9 months on CCy (not significantly different statistically). There was no difference in overall survival.

COMMENTARY

This study further supports the development of capecitabine and cyclophosphamide as a reasonable, all-oral chemotherapy regimen for the palliative treatment of advanced breast cancer. The combination has been studied primarily in Japan in non-randomized Phase 2 trials with notable results. Yoshimoto and colleagues6 used doxifluridine, an intermediate metabolite of capecitabine, with oral cyclophosphamide given first or second line in 94 patients with metastatic breast cancer. They reported a 60% response rate, a median progression-free survival of 11.7 months, and a median overall survival of 40.3 months. Similarly, Tanaka and colleagues7 conducted a Phase 2 study of capecitabine (1657 mg/m2) and cyclophosphamide (65 mg/m2) given for 14 days every 21 days as first- or second-line therapy for a median of six cycles in metastatic breast cancer. They reported a 36% response rate, including 65% in predominant liver disease and 40% in triple negative disease, a median progression-free survival of 6.6 months, and a median overall survival of 22 months. More recently, in a similar Phase 2 study to that noted above, Yoshimoto et al8 treated 51 patients using the same eligibility criteria and treatment regimen. At a median follow-up of 18 months, they reported a response rate of 44% and a median progression-free survival of 12.3 months.

The observed low level of toxicity for the combination was an important finding and, looking forward, may be a reassuring feature when considering this treatment for older patients or those with existing comorbidities. Indeed, there is a perception held by some physicians and patients that oral chemotherapy may not be as successful as parenterally administered drugs.9 For example, in the current study of 196 eligible patients, 28 were not enrolled because more "aggressive" treatment was considered required. Yet, despite the relatively small sample size, the data would suggest a reasonable chance that the combination of capecitabine and cyclophosphamide is superior to capecitabine alone. Because of the obvious advantages in administration, favorable toxicity profile, and lower overall costs, this combination should be studied more extensively as palliative treatment for selected patients with metastatic breast cancer.

References

1.  Ershler WB. Capecitabine monotherapy: Safe and effective treatment for metastatic breast cancer. Oncologist 2006;11:325-335.

2.  O’Shaughnessy JA, et al. Randomized, open-label, phase II trial of oral capecitabine (Xeloda) vs a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer. Ann Oncol 2001;12:1247-1254.

3.  Endo M, et al. Induction of thymidine phosphorylase expression and enhancement of efficacy of capecitabine or 5’-deoxy-5-fluorouridine by cyclophosphamide in mammary tumor models. Int J Cancer 1999;83:127-134.

4.  Sawada N, et al. Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res 1998;4:1013-1019.

5.  Liu G, et al. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 1997;15:110-115.

6.  Yoshimoto M, et al. The potential for oral combination chemotherapy of 5’-deoxy-5-fluorouridine, a 5-FU prodrug, and cyclophosphamide for metastatic breast cancer. Br J Cancer 2003;89:1627-1632.

7.  Tanaka M, et al. Oral combination chemotherapy with capecitabine and cyclophosphamide in patients with metastatic breast cancer: A phase II study. Anticancer Drugs 2010;21:453-458.

8.  Yoshimoto M, et al. Metronomic oral combination chemotherapy with capecitabine and cyclophosphamide: A phase II study in patients with HER2-negative metastatic breast cancer. Cancer Chemother Pharmacol 2012;70:331-338.

9.  Catania C, et al. Perception that oral anticancer treatments are less efficacious: Development of a questionnaire to assess the possible prejudices of patients with cancer. Breast Cancer Res Treat 2005;92:265-272.