Anthracyclines

Does the evidence still support their use in the first-line treatment of breast cancer?
The anthracycline debate continues.

In 2007, the National Breast Cancer Coalition took the position that “for the vast majority of women with breast cancer, anthracycline-based chemotherapy is no more effective and has the potential for more serious toxicities than other known regimens.” Some cancer centers, including the Jonsson Cancer Center at the University of California, Los Angeles, stopped using anthracyclines for first-line breast cancer treatment that year (Young, 2009).

But why, three years later, are so many oncologists still prescribing anthracyclines as part of a first-line treatment regime? They argue that although there is evidence against anthracyclines, it is not strong enough or is conflicting. What are their arguments?

All work on evaluating anthracyclines has been done either in patients not selected for Her2 status in prospective trials or in retrospective studies (Young, 2009).
The number of patients in the US Oncology 9735 (1016) was too small to warrant a major revision in first-line anthracycline use (Young, 2009).
Though retrospective analysis of tissue samples have indicated that the benefit of anthracycline was limited to patients with overexpression of HER2, analysis of a Scottish trial showed that adding an anthracycline to conventional chemotherapy benefited Her2-normal women (Gianni, 2009).
Not all studies support the suggestion that adjuvant anthracyclines may be most effective in patients whose tumors have the topoisomerase IIα co-amplification (Topo II) (Harris, 2009; Knoop, 2005; MacArthur, 2008).
All breast cancers are not the same, so it makes sense that treatments can no longer be one-size-fits-all. However, once a treatment regimen is in place and becomes standard, it can take a long time to remove it from practice, even when scientific evidence no longer supports its use.

Many women diagnosed with invasive breast cancer of different subtypes continue to receive the same adjuvant chemotherapy regimen, one including a controversial class of drugs called anthracyclines, though evidence shows that the drugs may only provide benefit to a small group of patients, and could be replaced with a less toxic substitute.

The class of chemotherapy drugs called anthracyclines includes doxorubicin (Adriamycin®) and epirubicin (Ellence®). Side effects include short-term nausea and hair loss and potential long-term effects such as heart damage (1-2% of patients) and leukemia (less than 1% of patients)(Barlett-Lee, 2009).

History

During the 1990s, chemotherapy regimens containing anthracyclines largely replaced previous regimens of cyclophosphamide, methotrexate, and 5-FU (CMF) for the treatment of breast cancer, based primarily on a meta-analysis of 11 clinical trials, done by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Results of individual studies were inconclusive, but when the results were pooled, the Group found that regimens containing anthracyclines slightly improved disease-free and overall survival (EBCTCG, 1998).

Data published from as far back as 1994 has suggested that the benefit of anthracyclines in the adjuvant setting is limited to the HER2-positive molecular subtype of breast cancer, which accounts for 25% or less of breast cancers (Muss, 1994; Paik, 1998). More recently, a meta-analysis of 5,354 early breast cancer patients in Italy came to similar conclusions (Gennari, 2008).

The Impact of Trastuzumab

The development of a targeted treatment for HER2-positive cancers, trastuzumab (Herceptin®), decreases the importance of previous evidence on anthracyclines. Recent evidence shows that for those whose tumors are HER2-positive, treatment with trastuzumab, along with a non-anthracycline chemotherapy regimen, provides the same benefit as an anthracycline-containing regimen and trastuzumab, with less toxicity (Slamon, 2009). On the basis of these results, the US Food and Drug Administration approved trastuzumab for adjuvant treatment of early breast cancer, in combination with other drugs, with or without an anthracycline.

Progress and improvements in treatment require that adjustments be made as new evidence becomes available.

Recent Research

Recent research continues to support a move away from anthracyclines. The U.S. Oncology’s 9735 trial randomized 1,016 women to four cycles of docetaxel (Taxotere®)-cyclophosphamide or doxorubicin-cyclophosphamide. After 7 years, there was a statistically significant improvement in overall survival in the taxane (docetaxel) group compared with the anthracycline (doxorubicin) group (Jones, 2009).

For women who are HER2-positive, evidence for a move away from anthracyclines comes from a Breast Cancer International Research Group trial (BCIRG 006) that has been following 3,222 women with node-positive, or high-risk node-negative, HER2-positive breast cancer, since 2001. Women were randomized to receive an anthracyline-containing regimen alone, an anthracycline-containing regimen with trastuzumab, or a non-anthracycline regimen with trastuzumab. The third efficacy analysis of this trial was presented at the 2009 San Antonio Breast Cancer Symposium (Slamon, 2009).

After 65 months on the study, the disease-free survival rate was 84% for the group receiving an anthracycline regimen with trastuzumab, 81% for the group receiving a non-anthracycline regimen with trastuzumab, compared to 75% for those receiving an anthracycline regimen and no trastuzumab.

Women receiving the anthracycline-containing regimen with trastuzumab had slightly less chance of metastasis or spread of the breast cancer, compared to those receiving the non-anthracycline containing regimen and trastuzumab. The difference was not statistically significant and came with a higher cost in toxicity. The group receiving anthracyclines and trastuzumab had five times as many cases of congestive heart failure as the group not receiving anthracyclines (2% vs. 0.4%). The difference was statistically significant.

There were eight cases of leukemia in the study, six (0.6%) in the non-trastuzumab group, and one (0.1%) in each of the trastuzumab groups, but the difference was not statistically significant. All patients who developed leukemia had received an anthracycline at some point during their treatment.

Results from BCIRG 006, along with results from several other studies, have suggested that a smaller subset of patients gain benefit from anthracycline-based therapy – those with HER2-positive tumors that also show amplification of another gene – the topoisomerase IIα or topo IIα, about 35% of the HER2-positive cancers (Slamon, 2009; O’Malley, 2009; Tubbs, 2009). Even within this subset, a comparable benefit was seen in the BCIRG 006 trial with the non-anthracycline regimen with trastuzumab, without the long-term toxicities.

Treatment regimens must keep pace with the increasing knowledge of different subtypes of breast cancer and the variation in responses to treatment within the different subtypes. Patient-centered care requires that removing a treatment from standard care should happen as quickly and easily as adding a new one, once the evidence supports a change.


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