Is There a Best Adjuvant Chemotherapy Regimen for Breast Cancer?

Many adjuvant treatment options exist, and yet there is no definitive go-to regimen to treat women with early breast cancer. At the 29th Annual Miami Breast Cancer Conference, three prominent breast cancer clinicians and researchers presented overviews of three adjuvant components: anthracyclines, fluoropyrimidines, and taxane agents.

Adjuvant chemotherapy regimens have seen an evolution of three successive generations. Insights into these treatment trends are gleaned from adjuvant early- stage breast cancer clinical trial data that are pooled together every five years in the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).

Cytotoxic therapy consisting of cyclophosphamide— methotrexate–5-fluorouracil (CMF)-based regimens showed a 24% reduction in breast cancer recurrence and 14% reduction in death, compared with placebo.¹ Anthracycline therapy showed an advantage, although modest, over CMF-based chemotherapy.² The reduction in risk of recurrence was 11%, and reduction in risk of breast-cancer mortality was 16% for anthracyclines compared with CMF. Finally, the 2006 EBCTCG overview showed that the thirdgeneration adjuvant therapy of anthracycline and taxane-based chemotherapy further reduced the risk of breast cancer recurrence by 17% compared with anthracycline-based chemotherapy.³ The breast cancer-specific, absolute improvement in survival with these generations of adjuvant chemotherapy is approximately 4% to 5%.

Julie R. Gralow, MD

The Anthracyclines

Julie R. Gralow, MD, director of Breast Medical Oncology at the Fred Hutchinson Cancer Research Center in Seattle, Washington, provided an overview of the evidence for anthracycline-based adjuvant therapies. “Anthracyclines have been extensively tested in clinical trials over several decades,” said Gralow. “Currently, there are insufficient data to recommend replacing them in adjuvant treatment of breast cancer.”

She added that for a patient with a “high enough risk of recurrence to warrant chemotherapy, it is hard to confidently identify a population who will not benefit from an anthracycline-based regimen”—channeling the key message of a 2009 review on the topic.⁴ “We are desperately looking for anthracycline response and resistance,” she added.

In Gralow’s view, most patients are eligible for anthracyclines— except when heart toxicity may be an issue—but she generally gives maximal endocrine therapy over a chemotherapy regimen.

The current anthracycline regimens use a 60 mg/m2 dose based on the Cancer and Leukemia Group B (CALGB) 9344 trial that did not show an added benefit in increased anthracycline (doxorubicin) dosage. In contrast, epirubicin trials have not stuck to a consistent dose, according to Gralow.

Gralow highlighted major trials that led to the utilization of anthracyclines in the adjuvant setting. The EBCTCG 2006 meta-analysis of CMF versus anthracycline regimens showed a 5% absolute difference in mortality at 10 years, favoring anthracycline. The magnitude of the benefit was probably underestimated in this analysis, as many of the included studies used anthracyclines at much lower doses than those used today, Gralow said.

Two large North American trials have compared anthracycline with CMF. The NCIC-CTG MA5 trial, which compared CMF with cyclophosphamide-epirubicin-fluorouracil (CEF) in node-positive patients, showed an overall survival of 58% to 62%, respectively.⁵ “Clearly a positive trial,” Gralow stated. However, the conclusion of the SWOG-8897 node-negative patient trial (new analysis is expected shortly) at the 10- year mark suggested that a regimen of cyclophosphamide, doxorubicin, and fluorouracil (CAF) is not superior to the CMF regimen. Gralow stated that she did not agree with the conclusion of that study, mainly because the disease-free survival was likely confounded by events that could not have been impacted by the adjuvant regimen.⁶

Kathy D. Miller, MD

Fluoropyrimidines

Kathy D. Miller, MD, of the Simon Cancer Center, Indiana University, Indianapolis, discussed the evolution of fluoropyrimidine in breast cancer treatment. “Once the mainstay of adjuvant therapy, a crucial component of CMF, the use of 5-fluorouracil plummeted through the last two decades,” according to Miller. Based on clinical trials, it is difficult to determine the actual contribution of fluoropyrimidine to multicomponent adjuvant regimens.

A reason for reviving the question of whether fluoropyrimidines contribute to long-term patient benefit is the recent introduction of capecitabine, a pro-drug that is metabolized to 5-fluorouracil in the tumor. Capecitabine had the promise of a targeted chemotherapy with lower toxicity and greater efficacy, said Miller, but the results never panned out. Adding or substituting capecitabine increases toxicity but without an increase in efficacy, Miller stated, citing the CALGB 49907 trial, among others.⁷

Capecitabine has not shown an improvement in any primary endpoint when added to standard therapy, and with an increase in toxicity that has led to dose omissions and reductions. Miller sees this as “worrisome in a curative setting.” Miller’s final conclusion about the fluoropyrimidines: “More relic than relevant.”

Matthew J. C. Ellis, BChir, PhD

Taxanes

Taxanes have been tested in more than 20 trials involving over 35,000 women with early-stage breast cancer. While taxanes have been shown to be beneficial for a wide range of patients, irrespective of lymph node status, hormone receptor expression, or HER2 status, their optimal use has still not been established.

Matthew J. C. Ellis, BSc, MB, BChir, PhD, director of the Breast Cancer Program at the Siteman Cancer Center in St. Louis, Missouri, provided an overview of the taxane-based regimens. Ellis emphasized that the three standard chemotherapy drugs— taxane, anthracycline, and cyclophosphamide— can be given together, sequentially, as a combination of anthracycline plus cyclophosphomide followed by a taxane, or as a combination of any of the two chemotherapies. The actual benefit of an anthracycline-taxane combination for recurrence is modest, analogous to the benefit of anthracycline compared with CMF, Ellis said.

Paclitaxel, a widely used taxane, can be given every three weeks, every two weeks, or weekly, said Ellis. He pointed out that the biweekly or weekly dosage schedule is preferred over the every three-week dosage schedule. However, he was not sure whether biweekly or weekly paclitaxel is better.⁸ Ellis said he prefers the weekly schedule largely due to its lower cost.

Because the absolute benefit of paclitaxel on mortality is only about 3%, Ellis recommended that therapy should be stopped if a patient cannot tolerate the toxicity. “I don’t give a taxane in combination with anthracycline. It is toxic, and it looks like the sequential approach is effective and safe,” he said.

As with the other discussed adjuvant chemotherapy options, “We need to do a lot more work on prediction of taxane efficacy, because clearly a lot of patients are receiving these drugs for very little benefit,” Ellis concluded.

References

1. Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;352(9132):930-942.
2. Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717.
3. Peto R, for the Early Breast Cancer Trialists’ Collaborative Group. The worldwide overview: new results for systemic adjuvant therapies. Presented at the 30th Annual San Antonio Breast Cancer Symposium; December 13-16, 2007. San Antonio, TX.
4. Gianni L, Norton L, Wolmark N, et al. Role of anthracyclines in the treatment of early breast cancer. J Clin Oncol. 2009;27(28):4798-4808.
5. Levine MN, Pritchard KI, Bramwell VHC, et al. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol. 2005;23(22):5166-5170.
6. Hutchins LF, Green SJ, Ravdin PM, et al. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol. 2005;23(33):8313-8321.
7. Muss HB, Berry DA, Cirrincione CT, et al. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009;360:2055-2065.
8. Martin M, Rodriguez-Lescure A, Ruiz A, et al. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst. 2008;100:805-814.