Possible Selection Bias and Lack of Mortality Endpoints Prevent Conclusions About New Standards of Care

In this issue of ONCOLOGY, Bittner et al provide a thoughtful review of the literature to advocate for the viewpoint that interstitial brachytherapy should be standard of care for the treatment of high-risk prostate cancer.

First, they point out that improvements in brachytherapy technique have led to improved outcomes for high-risk patients, as measured by biochemical disease-free survival. They then suggest that a typical amount of extraprostatic extension in a patient with high-risk disease (≤ 5 mm) should be treatable with brachytherapy. They refer to randomized external-beam radiation therapy (EBRT) data showing that dose escalation improves biochemical recurrence–free survival, and suggest that outcomes could be improved even further by the additional dose that could be delivered with brachytherapy, especially as a significant component of treatment failure is local.

Finally, they provide figures and tables comparing the biochemical recurrence–free survival among high-risk patients in separate series employing either brachytherapy, radical prostatectomy (RP), or EBRT, showing that brachytherapy outcomes were comparable to or superior to the outcomes achieved with other modalities. Based on all these data, they conclude that "high-risk, localized prostate cancer is largely curable with an aggressive locoregional approach that incorporates interstitial brachytherapy as the cornerstone of treatment."

Data Shortcomings

However, the primary data presented in the paper have two significant shortcomings. The first is uncontrolled patient selection. Specifically, while Figures 4 and 5 and Table 1 show good biochemical control in brachytherapy series compared to RP and EBRT series, comparisons across series and across modalities are difficult to interpret due to the likelihood of differences in underlying patient populations. For example, when looking at outcomes for men with prostate-specific antigen (PSA) levels > 20 ng/mL, no adjustment is made for how many men on each of the curves also had Gleason score 8 to 10 cancers. It is known that the risk of recurrence and death from prostate cancer increases as the number of adverse risk factors increases.[1-4]

The second issue with the data as presented is the endpoint selected for study, namely PSA recurrence. Due to PSA bounce following brachytherapy and PSA rebound following the withdrawal of androgen-suppression therapy, PSA recurrence can be difficult to interpret. Moreover, PSA recurrence may or may not translate into metastases and death from prostate cancer.[5] As patients with high-risk prostate cancer have a significant risk of death due to the disease, recommendations about the best treatments for these patients should ideally refer to data from randomized trials about endpoints such as all-cause death, cancer-specific death, and perhaps metastases, but not biochemical recurrence alone.

Currently, several randomized trials of patients with high-risk localized and locally advanced disease have demonstrated an overall survival and/or prostate cancer–specific survival benefit for EBRT plus androgen deprivation therapy (ADT) over EBRT alone, reflecting the risk of micrometastatic disease faced by such patients and establishing EBRT plus ADT as a standard of care for high-risk disease.[6-9] In comparison, the randomized trials of dose escalation have shown a PSA failure–free survival benefit, but none has demonstrated a mortality benefit as yet.[10-12] Therefore, based on the randomized data, strategies that add systemic therapy to radiation for men with high-risk disease should be considered standard of care, while pure dose-escalation strategies have not yet been fully proven.

Conclusions

If EBRT plus ADT is accepted as the starting point for patients with high-risk disease, it is reasonable to ask whether overall outcomes could be improved even further by adding a dose-escalation strategy such as a brachytherapy boost. In the breast cancer literature, it has become apparent that as systemic therapies were better able to control distant disease, local control made a larger contribution to overall survival.[13] It may certainly also be the case for high-risk prostate cancer that if effective therapy is given to control micrometastatic disease, achieving maximal local control will have a significant impact on overall survival. Therefore, properly designed randomized trials are needed to evaluate what a brachytherapy boost may add to EBRT plus ADT in terms of cancer-specific and all-cause mortality for men with high-risk disease

-Paul L. Nguyen, MD
-Anthony V. D'Amico, MD, PHD

References:

References
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