Alternative Chemotherapy Dosing Strategies Improve Breast Cancer Outcomes

Virginia G. Kaklamani, MD

Shortening the intervals between chemotherapy cycles or administering the drugs sequentially reduced early-stage breast cancer recurrence and mortality compared with standard dosing techniques, according to meta-analysis results presented at the 2017 San Antonio Breast Cancer Symposium.

The 2 most commonly used chemotherapy regimens, anthracycline- and taxane-based combinations, are proven to reduce mortality among women with early breast cancer by one-third. However, pivotal trials have demonstrated there may be an added benefit from dose intensification.

“We are still trying to find ways in improving how we deliver this chemotherapy,” said Richard Gray, MSc, professor of medical statistics in the Nuffield Department of Population Health at University of Oxford in the United Kingdom. “The rationale for this is if you look at computer models about how cancer cells get knocked back by chemotherapy and then regrow again, it seems if you increase dose intensity, you might be more likely to eradicate more cancer cells.” Gray and colleagues collected data from the Early Breast Cancer Clinical Trialists' Collaborative Group (EBCTCG), a worldwide collaboration designed to assess the long-term benefits and adverse effects associated with a variety of treatment options for patients with early-stage breast cancer. In particular, the researchers focused on whether increasing the dose intensity of chemotherapy would induce superior outcomes compared with standard chemotherapy regimens. Dose intensification trials used the same chemotherapy agents at the same doses as in standard regimens but patients received the drugs every 2 weeks versus every 3 weeks, resulting in an average weekly dose that is 1.5 times higher. Additionally, doses may be intensified by administering chemotherapy in sequence rather than concurrently.

Individualized patient data were analyzed from 25 trials, including the following:

• Seven randomized trials, designed to test chemotherapy given every 2 weeks compared with every 3 weeks (n = 10,004)
• Nine randomized trials, which tested sequential versus concurrent anthracycline- and taxane-based chemotherapies (n = 11,533)

The researchers evaluated reductions in disease recurrence and morality, as well as safety.

Patients who received chemotherapy every 2 weeks appeared 17% less likely to experience disease recurrence (rate ratio [RR], 0.83; 95% CI, 0.76-0.91; P = .00004), with a 14% reduction in the risk of death from breast cancer within 10 years (RR, 0.86; 95% CI, 0.77-0.95; P = .004), compared with patients who received the same treatment every 3 weeks.

Similarly, patients who received sequential chemotherapy every 3 weeks demonstrated a 13% reduction in the risk for disease recurrence (RR, 0.87; 95%CI, 0.80-0,94; P = 0006), and were 11% less likely to die from breast cancer within 10 years (RR, 0.89; 95% CI, 0.80-0.99; P = .03) compared with patients who were treated with concurrent therapy ever 3 weeks.

In a pooled analysis of the 25 identified trials, patients who received dose-intensification therapy showed a 15% reduction in the risk for disease recurrence (RR, 0.85; 95% CI, 0.81-0.89; P <.00001) and a 13% reduction in the risk for breast cancer mortality (RR, 0.87; 95%CI, 0.82-0.92; P <.00001) compared with those who received standard therapy.

“This reduction [in mortality] may seem a very marginal difference, but when you think that we have already made a lot of improvements with chemotherapy … you can then [administer] dose intensification, and a one-third reduction comes to almost half a reduction in breast cancer mortality,” Gray said. “These increments have made a really big difference in breast cancer survival by identifying little ways of improving what we are doing already.”

“Whichever way these trials are achieving dose intensification they seem to be finding benefit in fewer recurrences,” Gray added. “This is quite remarkable how consistent all of these different approaches work in showing fewer recurrences and breast cancer mortalities.”

Despite concerns about safety, the researchers also found few additional adverse events among those who received dose-intense treatments, including fewer patients who died from non-breast cancer causes.

Virginia G. Kaklamani, MD, co-director of the symposium and leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center, commended these findings, noting the win-win therapeutic approach. “The beauty of these approaches is [we are using the] exact same drugs and similar doses. It is just the schedule that changes,” she said. “What is interesting is we used to give chemotherapy over 6 months and with this approach we can give it over 4 months. The patients prefer it, and the toxicity can be less. So, everyone wins here.”

Moving forward, Gray noted the need for more trials to be conducted.

“The problem is, often, that we have not looked well enough at simple questions on how long to give chemotherapy, which is really important for women to get more benefit without extra toxicity,” he said. “What we need is more trials to test simple concepts, very simple bread-and- butter questions that should be addressed more often in clinical trials.”

Gray R, Bradley R, Braybrooke J, et al; for the EBCTCG. Increasing the dose density of adjuvant chemotherapy by shortening intervals between courses or by sequential drug administration significantly reduces both disease recurrence and breast cancer mortality: An EBCTCG meta-analysis of 21,000 women in 16 randomised trials. Presented at: 2017 San Antonio Breast Cancer Symposium; Dec. 5-9; Atlanta. Abstract GS1-01. abstracts2view.com/sabcs/view.php?nu=SABCS17L_1396&terms=