By Joyce Bichler, Deputy Director
Dosing and the duration of adjuvant chemotherapy was a prominent theme in the first two days of the San Antonio Breast Cancer Symposium (SABCS). Adjuvant chemotherapy is a very common treatment for breast cancer patients—it’s what patients are given after primary treatments, such as surgery or radiation. There’s been a lot of discussion in the past few years about how much and how long adjuvant therapy should continue. There is still surprisingly limited data on what’s the optimal duration time. And because every treatment has some sort of risk or adverse effect, finding the most effective dose/duration is crucial. This year, several presentations focused on the issue.
Wednesday’s General Session included a presentation on a large meta-analysis of 21,000 women in 16 randomized trials looking at early breast cancer and the use of adjuvant chemotherapy. Dr. Richard Gray of the Early Breast Cancer Trialist’s Collaborative Group (a collaboration of data from researchers around the world) reported on a study that has significant treatment implications.
But first, some relevant background. Adjuvant chemotherapy with anthracycline and taxane-based combinations for early breast cancer is known to reduce the risk of death from breast cancer by about one-third. Certain models suggest that increasing the dose of this chemotherapy may enhance its efficacy. But there are really only three ways to increase dosing for patients: 1) use higher doses of the medication in each chemo cycle; 2) reduce the time between each treatment cycle; or 3) give drugs sequentially rather than concurrently.
The researchers found that there was no benefit in outcome by just increasing the doses of the drugs—and of course we know there are likely to be more adverse effects with higher doses. But looking at shortening intervals between doses (giving them every two weeks rather than every 3 weeks) had a highly significant impact on the reduction in risk of recurrence, and ten year breast cancer mortality rates were 3.0 percent lower (16.7 percent vs.19.7 percent). Similarly sequential versus concurrent drug administration showed 10 year breast cancer mortality was 2.3 percent lower.
This is intriguing. If how chemotherapy is administered makes even the smallest of improvements in mortality, then these are changes that can be made for patient benefit. Of course, the big question is: How does this impact how well a patient tolerates the treatment? There was no data presented on tolerability. If changing how this treatment is given makes it more difficult for patients to tolerate it, due to an increase in adverse effects, then more patients will stop treatment—and that defeats the whole purpose. Clearly, we need more data on tolerability and the effects of the treatment.
In another presentation Wednesday morning, Dr. Wolfgang Janni from the University of Ulm presented on the results of the SUCCESS trial on the use of adjuvant bisphosphonate treatment in high risk early breast cancer patients. Bisphosphonate treatment has been shown to reduce the risk of breast cancer recurrence in the bone, especially in postmenopausal women. However, there is no data showing what the optimal treatment duration should be.
The study randomized 3,754 patients post chemotherapy to either 2 or 5 years of bisphosphonate zoledronate treatment. The study looked at Disease Free Survival (DFS) and Overall Survival (OS). The researchers found that there was no significant difference in either DFS or OS between patients, irrespective of menopausal status, that received 2 or 5 years of zoledronate after adjuvant chemo for early breast cancer. However, there was an increased frequency of adverse effects associated with 5 years of treatment vs. 2 years (37 percent vs. 6.4 percent). This included a range of adverse effects, from bone and joint pain to fatigue and even jaw necrosis. A significant limitation of the study is that the follow-up observation time was limited to 2-4 years. So it’s hard to know if over time there will be any benefit to a longer time on zoledronate, but until more data comes in, the results indicate that extended treatment with zoledronate does not improve DFS or OS in high-risk early breast cancer patients and does not warrant the increase in adverse effects.
On Thursday, there was a presentation about another study that looked at the optimal length of time on adjuvant therapy—this time regarding adjuvant endocrine therapy for hormone receptor positive postmenopausal women. Dr. Michael Gnant, Medical University of Vienna, presented the study. For women who have recurrences, 50 percent of the recurrences happen 5 years or more after their initial follow-up. This fact has prompted recommendations for prolonged (more than 5 years) treatment with tamoxifen or Aromatase Inhibitors (AI’s). But what is the optimal duration of extended adjuvant AIs? This study enrolled 3,469 patients who were followed for 10 years and looked at the outcome effects of an additional 2 years vs. additional 5 years of anastrozole, after 5 years of adjuvant endrocrine therapy. The findings showed that in postmenopausal hormone-receptor positive patients receiving 5 years of standard adjuvant endocrine therapy, (tamoxifen or an AI), an additional 5 years of anastrozole did not improve DFS or OS compared to just an additional 2 years of anastrozole. However, the women who were on the additional 5 years of anastrozole had more bone fractures. This study seems to indicate that there may be less benefit to continuing endocrine therapy beyond 7 years.
This was just a sampling of studies presented on dose and duration issues. Understanding who benefits from which therapies and for how long are critical questions for patients. More is not always better. Understanding the risks vs. the benefits of duration and dose of therapy is essential for patients and their health care providers in making the best treatment decisions for survival and for retaining the best quality of life.