Adjuvant Therapies: Time to Fold or Double Down?

Larger Prostates Predict Higher Risk of Lower Urinary Tract Symptoms
Larger Prostates Predict Higher Risk of Lower Urinary Tract Symptoms

Adjuvant therapies are the elusive holy grail of cancer surgery. To date, level 1 evidence demonstrates benefit only in breast, colorectal cancer, GIST and melanoma. Improvements in disease-free and overall survival are modest, ranging from 0%–11% and 0%–6%, respectively.

No adjuvant strategies for urologic tumors exist, though not for lack of trying. Decades of clinical trials evaluating hormones, chemotherapy, vaccines and other immunotherapies have failed to yield an effective systemic strategy to improve post-operative survival metrics in kidney, bladder or prostate cancers. The result is that we simply measure, communicate, and monitor a patient's risk of recurrence.

The new era of targeted therapies, particularly in kidney cancer, brought hope and anticipation that improved survival observed in metastatic disease with these agents would be translatable to the adjuvant setting. At least 6 clinical trials were launched evaluating various agents as well as their dosing and timing schedules. The largest of these studies, sponsored by the Eastern Cooperative Oncology Group (the ASSURE trial), recently reported negative results early.i Other trial results are expected soon.

So why have adjuvant therapies been so ineffective? First, we are currently unable to optimize patient selection. The most robust measures of recurrence risk remain tumor stage, grade, and type. While gene arrays and other biomarkers have been proposed, developed, and marketed, no clinically compelling predictive tool has emerged for genitourinary tumors. Second, the timing, dose, and duration of adjuvant therapies have not been established. Third, solid tumors are heterogeneous, pathways are promiscuous, and resistance emerges. Finally, current systemic agents may simply be too ineffective.

So, do we fold or double down on urologic adjuvant systemic therapies? If the strategy of adjuvant therapy remains to follow incompletely effective surgery with incompletely effective systemic therapy, then existing data suggest it is time to put our resources elsewhere. However, when effective biomarkers improve patient selection and novel therapies decrease the evasiveness of micrometastases, it will be time to double down. We can all hope that time will be soon.

Benjamin T. Ristau, MD, is a Fellow of Urologic Oncology at Fox Chase Cancer Center in Philadelphia, PA. Robert G. Uzzo, MD, FACS, is the G Willing "Wing" Pepper Chair in Cancer Research Professor and Chairman at the Department of Surgery Fox Chase Cancer Center at the Temple University School of Medicine in Philadelphia, PA. 

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