Dose-Escalation in Moderately Hypofractionated Prostate Cancer. Are we Ready for it?

Presenting author: Comron Jon Hassanzadeh, MD, MPH

When discussing dose escalation in prostate cancer, a special consideration should be taken to four questions:

• Will a higher dose of radiation worsen the toxicity profile?
• Will a higher dose of radiation improve the outcomes?

Assuming the first two questions are correct, we have two secondary questions:

• Is this improvement in outcome meaningful?
• Can this benefit overcome an increased toxicity profile?

Since the dose escalation trial from MDACC was published in 2002, demonstrating a benefit in freedom from biochemical failure favoring dose escalation for localized prostate cancer (higher in patients with PSA >10ng/ml),¹ questions have arisen if this benefit could be translated to the hypofractionated regimens as well. The main hypothesis of this trial is to test if dose-escalated hypofractionation could improve outcomes in localized prostate cancer without increasing treatment toxicity. The regimens elected were 75.6Gy in 42 fractions (EQD2 of 71Gy2 at a/b1.5) in the Conventional IMRT (CIMRT) arm vs. 72Gy in 30 fractions EQD2 of 80Gy2 at a/b 1.5) in the Hypofractionated IMRT (HIMRT) experimental arm.

To test that, this superiority trial was designed with 91% power to detect a 20% difference (10% x 30%) in freedom from failure at five years, anticipating a total of 39 required events.

The initial publication² with an 8.5-year median follow-up (mFU) and 31 events, demonstrated a significant difference in treatment failure favoring HIMRT (20.6%) in the CIMRT group vs. 9.7% in the HIMRT group, p = 0.036).

Comron Hassanzadeh, MD, MPH, presented at ASTRO 2024 the long-term data of this trial. Now, with a mFU of 11 years and a total of 35 events, this update shows a failure rate of 21% (CIMRT) vs. 11% (HIMRT) with a p = 0.076. In addition, toxicity remained similar between CIMRT and HIMRT without a late spike in GI or GU toxicity; however, with a trend for worse GI toxicity with HIMRT (10-year late GI, 5% CIMRT vs 13% HIMRT, p=0.08).

The authors disclosed at the first publication that the failure rate was lower than anticipated, which made the study underpowered to detect a difference. The estimated 39 events are not yet reached at the time of this update. This could result from the amount of low (27.7%) or intermediate (71.4%) risk patients accrued in this trial. This makes it harder to statistically recognize smaller benefit.

Bringing this data to the present, most of the low-risk patients accrued in this trial would not receive radiation treatment, once the treatment paradigm has been changed favoring active surveillance. In addition, we currently have consolidated data, including multiple randomized trials and at least one meta-analysis, demonstrating that moderate hypofractionation is safe and at least as effective as standard fractionation, when compared with the same biological effective dose (B.E.D.).

The ASTRO ASCO, and AUA Guideline endorses two hypofractionation regimens as preferred (60Gy in 20 fractions or 70Gy in 28 fractions), since they are supported by the largest evidentiary base.³ This represents an equivalent dose of 78-80 EQD2Gy (a-to-b 1.5), which is equivalent to the 78Gy dose in the experimental arm of this trial.¹

The main strength of this trial is that this data represents one of the largest follow-ups published so far for hypofractionated regimes, and substantially helps to bring to the literature more robust long-term data endorsing the safety and efficacy of hypofractionated regimens in prostate cancer. A risk-stratified systematic review and meta-analysis, including this new data, could help us to further assess which specific group of patients could benefit the most from this strategy.

Congratulations Dr. Hassanzadeh for this collaboration to the scientific community.

References:

1. Kuban DA, Tucker SL, Dong L,et al. Long-Term Results of the MD Anderson Randomized Dose-Escalation Trial for Prostate Cancer. International Journal of Radiation Oncology, Biology, Physics. 2008/01/01;70(1)
2. Hoffman KE, Voong KR, Levy LB, et al. Randomized Trial of Hypofractionated, Dose-Escalated, Intensity-Modulated Radiation Therapy (IMRT) Versus Conventionally Fractionated IMRT for Localized Prostate Cancer. Journal of Clinical Oncology. 2018;36(29):2943-9.
3. Morgan SC, Hoffman K, Loblaw DA, et al. Hypofractionated Radiation Therapy for Localized Prostate Cancer: Executive Summary of an ASTRO, ASCO, and AUA Evidence-Based Guideline. Practical Radiation Oncology. 2018/11/01;8(6).

Abstract 185, Hypofractionated, Dose-Escalated Radiation vs. Conventionally Fractionated Radiation for Localized Prostate Cancer: Long-Term Update of a Phase 3, Prospective, Randomized Controlled Trial, was presented during SS 15 - GU 3: Prostate Cancer Treatment Intensification session of the 66th ASTRO Annual Meeting.