CAPECITABINE ADDED TO STANDARD CHEMOTHERAPY INCREASES RFS IN BREAST CANCER PATIENTS

November 10, 2009 — Adding the oral drug capecitabine (Xeloda) to standard chemotherapy regimens appears to reduce the risk for recurrence in early breast cancer. Finnish researchers report that for patients with moderate- to high-risk early breast cancer, capecitabine combined with a regimen containing a taxane and an anthracycline was more effective in lowering the risk for disease recurrence than standard therapy.

The authors of the study, published online November 10 in the Lancet Oncology, note that the effect of adding capecitabine was "substantial," and "could be comparable to or greater than that achieved with the introduction of taxanes to adjuvant treatment of early breast cancer."

At a median follow-up of 35 months, recurrence-free survival was 93% for women in the capecitabine group and 89% for those in the standard-therapy group (hazard ratio [HR], 0.66; 95% confidence interval, 0.47 - 0.94; P = 0.20). Overall survival data are not yet mature because this study was a planned interim analysis. However, the authors note that the hazard ratio for overall survival was similar to that for recurrence-free survival.

They also point out that adding capecitabine to the treatment regimen was associated with frequent discontinuation of planned chemotherapy, although most patients were able to tolerate all of the scheduled cycles.

Lead author Heikki Joensuu, MD, PhD, from Helsinki University Central Hospital in Finland, believes that the study results are promising, and that "the benefits likely exceed the harms when the risk for breast cancer recurrence is considered substantial."

"I'm encouraged about the early efficacy, and find that this regimen can be selected for women who have moderate or high risk for breast cancer recurrence," he told Medscape Oncology. "The final results of the study are awaited with great interest."

Although these findings are not practice-changing, they are intriguing, and could merit further assessment in a larger trial, writes Ruth M. O'Regan, MD, from the Emory Winship Cancer Institute in Atlanta, Georgia, in an accompanying editorial. But the significant toxicity associated with the addition of capecitabine "dampens enthusiasm for further studies of this approach," she adds.

One Size Does Not Fit All

The study authors found that the addition of capecitabine seemed more effective in estrogen-receptor (ER)-positive than in ER-negative breast cancers, Dr. O'Regan points out.

"The positive findings in the capecitabine group could be explained by the fact that over three quarters of patients had ER-positive cancers," she writes. "There is currently no plausible mechanism to explain why capecitabine would be more effective in ER-positive disease, but this might warrant further study."

The editorialist also comments that this study represents yet another "one size fits all" approach to managing early-stage breast cancer. "More importantly, it is imperative that we take a more rational approach to the treatment of early-stage breast cancer by tailoring our treatment approaches to molecular phenotypes," Dr. O'Regan writes.

Capecitabine Improves Outcomes

Standard adjuvant chemotherapy regimens for women with moderate- to high-risk early breast cancer generally consist of a taxane, an anthracycline, and cyclophosphamide. In this study, Dr. Joensuu and colleagues investigated whether integrating capecitabine into a standard adjuvant regimen would enhance outcomes.

The study, conducted between January 27, 2004 and May 29, 2007, involved 1500 patients with moderate- to high-risk early breast cancer were who were randomized to 3 cycles of capecitabine and docetaxel followed by 3 cycles of cyclophosphamide, epirubicin, and capecitabine (n = 753), or to 3 cycles of docetaxel followed by 3 cycles of cyclophosphamide, epirubicin, and fluorouracil (n = 747).

The women were stratified by node status and HER2 status, and the primary end point was recurrence-free survival. Secondary end points were overall survival, defined as the time from randomization to death, and treatment safety.

At the 3-year planned interim analysis, recurrence-free survival was better with the capecitabine regimen than with the standard regimen (93% vs 89%). There were a total of 134 events (deaths, distant or local relapses) — 54 (7%) in the capecitabine group and 80 (11%) in the standard-therapy group.

Disease-free survival, including invasive contralateral breast cancers and second cancers, was longer in patients who received capecitabine than in those who received standard therapy (HR, 0.68; P = .020). In exploratory subgroup analyses, the researchers noted that recurrence-free survival was better in the capecitabine group, with the exception of patients with HER2-positive disease.

Exploratory Subgroup Analyses for Recurrence-Free Survival

Characteristics	Capecitabine, Patients/Events	Standard Therapy, Patients/Events	Hazard Ratio (95% CI)
Positive Axillary Nodes
0–3	547/32	537/39	0·81 (0·51–1·29)
>3	204/22	208/41	0·52 (0·31–0·88)
Estrogen-Receptor Status
Positive	580/28	563/45	0·60 (0·37–0·96)
Negative	171/26	182/35	0·77 (0·46–1·27)
HER2 Status
Positive	146/20	139/13	1·56 (0·78–3·14)
Negative	605/34	606/67	0·49 (0·33–0·75)

More Adverse Events With Capecitabine

Patients receiving capecitabine had more cases of grade 3 or 4 diarrhea (6% vs 3%) and hand–foot syndrome (11% vs <1%)>

A total of 6 patients died from possible treatment-related causes — 4 in the capecitabine group (septic colitis, suicide, myocardial infarction, unknown cause [suspected cardiac arrhythmia]), and 2 in the control group (pulmonary arterial embolism, septicemia).

The authors note that most of the patients who interrupted capecitabine administration were able to continue treatment with other study agents and complete 6 cycles of chemotherapy.

The study was funded by Roche, Sanofi-Aventis, AstraZeneca, and the Cancer Society of Finland. Several of the authors report receiving honoraria or consulting fees from Roche and/or from Sanofi-Aventis.

Lancet Oncol. Published online November 10, 2009.