SMART designs in cancer research: Past, present, and future

Abstract

Background: Cancer affects millions of people worldwide each year. Patients require sequences of treatment based on their response to previous treatments to combat cancer and fight metastases. Physicians provide treatment based on clinical characteristics, changing over time. Guidelines for these individualized sequences of treatments are known as dynamic treatment regimens (DTRs) where the initial treatment and subsequent modifications depend on the response to previous treatments, disease progression, and other patient characteristics or behaviors. To provide evidence-based DTRs, the Sequential Multiple Assignment Randomized Trial (SMART) has emerged over the past few decades.

Purpose: To examine and learn from past SMARTs investigating cancer treatment options, to discuss potential limitations preventing the widespread use of SMARTs in cancer research, and to describe courses of action to increase the implementation of SMARTs and collaboration between statisticians and clinicians.

Conclusion: There have been SMARTs investigating treatment questions in areas of cancer, but the novelty and perceived complexity has limited its use. By building bridges between statisticians and clinicians, clarifying research objectives, and furthering methods work, there should be an increase in SMARTs addressing relevant cancer treatment questions. Within any area of cancer, SMARTs develop DTRs that can guide treatment decisions over the disease history and improve patient outcomes.

Figure 1

Two dynamic treatment regimens, (A,C) and (B,C) where the initial response rate is best for treatment A, but the overall best response rate is for DTR (B,C).

Figure 2

SMART design from an acute myelogenous leukemia trial [7] including 4 embedded DTRs.

Figure 3

Survival curves of marginal treatment regimens from [28].

Figure 4

Survival curves of four DTRs using weighted risk set estimator.

Figure 5

SMART design from a small cell lung carcinoma trial [25]. There are four embedded DTRs in this SMART which will be denoted by CAV-E-RIFA, CAV-T-RIFA, CAV-E-N, CAV-T-N. The DTR CAV-E-RIFA reads as, ‘treat with CAV-E followed by recombinant interferon-alpha (RIFA) if complete response, continue CAV-E if partial or no response’. Another DTR, CAV-E-N, reads as, ‘treat with CAV-E followed by nothing (observation) for those with complete response and continue CAV-E for those without complete response.’