Candidate for the Lee B. Lusted Student Prize Competition
Purpose: To examine the trade-offs between effectiveness and long-term cardiotoxicity for adjuvant treatment of women with early-stage breast cancer as a function of recurrence risk.
Methods: We developed a Markov model to simulate a hypothetical cohort of breast cancer patients under three scenarios: no treatment and two kinds of adjuvant chemotherapies with different efficacies and associated risks of cardiac toxicity. Newly diagnosed women with breast cancer face an annual risk of developing distant recurrence, and women with metastasis face an annual risk of dying from breast cancer. We also modeled cause of death using a competing risk framework. We used an efficacy for an anthracycline-based (AC) and cyclophosphamide, methotrexate and fluorouracil (CMF) adjuvant chemotherapies on reducing distant recurrence risk by 64% and 55%, respectively. We used an annual rate for cardiac toxicity of 1% and 0.5% for AC and CMF, respectively. We varied the 10-year risk of distant recurrence across a wide range (0-70%). Outcomes of interest were 10-year mortality risks, life expectancy and cause of death for 55 and 65-year-old women.
Results : For 55-year-old women with a 10-year risk of metastatic recurrence less than 10%, no chemotherapy resulted in the greatest life expectancy (i.e., the risks of cardiac toxicity outweighed the benefits). CMF was optimal as long as the 10-year risk of metastatic recurrence was 46%. Chemotherapy reduced the risk of recurrence but also increased the risk of dying from cardiotoxicity-related causes. Cause of death associated with cardiac toxicity is higher (3.7%) compared with metastasis (1.6%) at a lower distant recurrence rate under AC therapy. This relationship is reversed as the risk of distant recurrence increases. The results hold for 65-year-old women. Causes of death for low and high risk of recurrence (7% and 30%, respectively) are illustrated in the figure.
Conclusions: The use of more efficacious drugs with increased risk of cardiac toxicity in women at low risk of distant recurrence results in an increased risk of mortality relative to a no therapy strategy. At lower risk of recurrence the less efficacious drug with reduced risk of cardiac toxicity results as the optimal strategy in terms of reduced risk of mortality. As competing risks between efficacy and side effects impact life expectancy, the decision on adjuvant treatment must consider the risk of recurrence.
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