There’s a saying that less is more. However, The Minimalists wonder, “But is less really more? And if so, is the opposite true? Is more actually less?” For some patients with intermediate-risk prostate cancer (PCa), more may be too much—at least in the short term after treatment. I came across two newsworthy April 2023 journal articles that shed light on a possible tradeoff when androgen deprivation therapy (ADT) is added to external beam radiation treatment (EBRT).

In theory, putting temporary brakes on PCa activity by depriving the cancer cells of testosterone may enhance the effectiveness radiation, possibly extending survival. Both articles address the effectiveness, survival rates, and impact on quality of life when ADT is combined with radiation.

It has long been debated whether adding ADT to external beam radiation actually gives a survival advantage by reducing the chance of recurrence. If that’s true, then more treatment should mean more survival benefit (more is more). The trade-off is ADT’s side effects when testosterone is cut off: loss of sex drive, hot flashes, mood swings, breast tenderness, loss of bone mass, possible cardiac and neurological risks (these effects diminish when ADT is stopped and eventually washes out of the body). For men who don’t find that idea palatable, more treatment means less quality of life (more is less). So, the question becomes, does adding ADT offer enough added survival to offset an unknown period of physical and emotional discomfort or even distress?

Most studies suggest adding ADT offers better cancer control and in some, better overall survival. For example, a 2020 review of six published randomized clinical trials found that omitting a course of ADT for radiation patients with unfavorable intermediate- to high-risk PCa had inferior overall survival. The authors concluded, “ADT for these men should remain a critical component of treatment regardless of radiotherapy delivery method until randomized evidence demonstrates otherwise. [Emphasis mine]”^[i]

Here’s where the two new journal articles come in. Both papers are indeed based on a randomized study called the NRG/RTOG 0815 trial. Its purpose was to explore the true benefit and/or harm of ADT in men with intermediate-risk prostate cancer treated with dose-escalated RT. This landmark trial randomized 1,538 men to either dose-escalated RT alone +/- short-term ADT for six months. The 2- year follow up results presented in October, 2021 showed that adding ADT lowers the chances for distant metastasis, implying better long-term chances for survival.

Now, two years later, the newly published 5-year follow up findings amplify the previous report with data on 1492 patients randomly assigned to EBRT alone (arm 1) or EBRT plus 6-month ADT (arm 2).

The first paper found no significant survival difference between the two arms. However, those who were in arm 2 (EBRT+ADT) had improved oncological control, i.e., lower rates of metastasis, PCa-specific deaths, and biochemical failure (rising PSA).^[ii] However, they had higher incidence of adverse events (negative side effects). Thus, the authors caution that prior to treatment, doctors should discuss with patients the benefits vs. the risk of adverse effects.

The second paper reveals how the study patients themselves experienced treatment effects on their quality of life. Pre-treatment baseline questionnaire scores for both arms were obtained, covering general prostate function (urinary incontinence/symptoms, sexual function, bowel function, hormone therapy side effects), fatigue, and quality of life. At one year after treatment, nearly 90% of patients again completed the battery of questionnaires, while at 5 years, nearly 75% of the patients completed them. The scores were compared across the period of follow up.

A news story summed up the patient self-reports:

The ADT group reported clinically meaningful declines in hormonal and sexual quality of life over the short term, but these effects diminished by 1 year, Benjamin Movsas, MD, of Henry Ford Cancer Institute in Detroit, Michigan, and colleagues reported. The investigators found no between-group differences in fatigue and bowel or urinary symptoms. The quality of instruments did not capture the effects of short-term ADT on bone and cardiovascular health.^[iii]

The ROTG 0815 trial is considered a landmark study, especially finding such close 5-year survival rates between the two arms (219 total deaths, with 91% in arm 1, 90% in arm 2). Yet it remains to be seen what even longer mortality rates would be. It is my hope that follow-up for this study continues out to 10 years, and that more such randomized trials will be conducted.

Today’s prostate cancer patients have more treatment options than ever, with excellent diagnostic and MRI information before choosing a treatment. This means treatment choices can be matched for optimal results that balance cancer control with patient lifestyle preferences. For patients with higher risk PCa who require more aggressive treatment, the two papers I describe in this blog are examples of clinicians’ awareness that they need to understand their patients’ priorities and discuss tradeoffs with them. The power to choose responsibly must be based in the best available information at the time, which is why the Sperling Prostate Center emphasizes the importance of research.

NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.

References

[i] Jackson WC, Hartman HE, Dess RT, Birer SR et al. Addition of Androgen-Deprivation Therapy or Brachytherapy Boost to External Beam Radiotherapy for Localized Prostate Cancer: A Network Meta-Analysis of Randomized Trials. J Clin Oncol. 2020 Sep 10;38(26):3024-3031.
[ii] Krauss DJ, Karrison T, Martinez AA, Morton G et al. Dose-Escalated Radiotherapy Alone or in Combination With Short-Term Androgen Deprivation for Intermediate-Risk Prostate Cancer: Results of a Phase III Multi-Institutional Trial. J Clin Oncol. 2023 Apr 27:JCO2202390.
[iii] Persaud, Natasha. “Adding ADT to Radiation Does Not Up Survival in Intermediate-Risk Prostate Cancer.” Renal&Urology News, May 17, 2023. https://www.renalandurologynews.com/home/news/urology/prostate cancer/adding-adt-to-radiation-does-not-up-survival-in-intermediate-risk-prostate-cancer/