ASTRO 2021: Impact of High Dose Radiotherapy (HEAT) in Localized Prostate Cancer: An Individual Patient Data Meta-Analysis of 15 Randomized Trials

(UroToday.com) The 2021 American Society for Radiation Oncology (ASTRO) Hybrid Annual Meeting included a presentation by Dr. Amar Kishan discussing the impact of high dose radiotherapy in localized prostate cancer based on an individual patient data meta-analysis of 15 randomized trials.

Low dose external beam radiotherapy was first reported as the standard of care for prostate cancer in the 1960s. Years of rigorous investigation and multiple trials have explored, largely in parallel but more recently in combination, two forms of treatment intensification: adding and/or prolonging androgen deprivation therapy (ADT) and escalating radiotherapy dose. All intensifications improve PSA-derived endpoints, but only the use/prolongation of ADT has improved metastasis-free survival. Due to the parallel investigation of these intensification strategies, there remains an absence of multiple head-to-head randomized comparisons. Nearly all trials have compared only two of the following strategies against one another: (i) low dose radiotherapy (<74 Gy) alone, (ii) low dose radiotherapy with short-term ADT (4-6 months), (iii) low dose radiotherapy with long-term ADT (18-36 months), (iv) high dose radiotherapy (>= 74 Gy) alone, (v) high dose radiotherapy with short-term ADT, and (vi) high dose radiotherapy with long-term ADT.

A network meta-analysis allows direct and indirect pair-wise comparisons of treatment, facilitating comparisons that were never directly evaluated in randomized trials. The purpose of the High DosE Radiotherapy or Androgen Deprivation Therapy (HEAT) meta-analysis was to evaluate the optimal treatment intensification strategy (compared to low dose radiotherapy alone) by using individual patient data from randomized trials. The primary endpoint for this analysis was metastasis-free survival, and pre-specified secondary endpoints were biochemical recurrence-free survival and overall survival. A PRISMA-concordant literature search was performed with the following critical exclusion criteria: no data on distant metastasis and survival, single center, only used non-steroidal anti-androgen therapy, and used lifelong ADT, resulting in 15 trials included. The MARCAP Consortium of available trials is as follows:

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 The baseline characteristics, stratified by treatment approach, for the study are as follows: 

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The results of the network meta-analysis suggest that dose-escalation alone does not improve metastasis free survival, while the addition of short term ADT or long-term ADT improves metastasis free survival. By P-score ranking, high dose radiotherapy + long-term ADT appears to be the “optimal” strategy, though low dose radiotherapy + long-term ADT also ranks favorably. When assessing metastasis free survival by risk group (intermediate and high-risk), dose-escalation alone does not improve metastasis free survival in either risk group, and precision is lost due to low numbers-at-risk in individual strata. For overall survival, dose-escalation alone does not improve overall survival, while the addition of short term and long-term ADT does: 

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Once again, by P-score ranking, high dose radiotherapy + long-term ADT appears to be the “optimal” strategy, with a larger margin over low dose radiotherapy + long-term ADT. For biochemical recurrence free survival, dose-escalation improves the outcome in the absence of ADT, and quantitatively does so in the presence of ADT (short- or long-term) as well. Again, by P-score ranking, high dose radiotherapy + long-term ADT appears to be the “optimal” strategy, with a larger margin over low dose radiotherapy + long-term ADT.

While robust, the network meta-analysis is limited by limited loop connectivity with respect to several comparisons. Thus, Dr. Kishan and colleagues also performed a cohort-based analysis that included an additional 7 trials from the MARCAP consortium (ICORG 97-01, RTOG 9413, RTOG 9910, RTOG 9902, PCS IV, OTT0101, CHHiP) and categorized each treatment strategy as a cohort. This analysis was adjusted for age, ln(iPSA), T category, Gleason score, and midpoint of enrollment for any given trial. Based on this analysis, high dose radiotherapy + short-term ADT improved metastasis free survival versus low dose radiotherapy + short-term ADT (HR 0.86, 95% CI 0.76-0.96), as did high dose radiotherapy + long-term ADT versus low dose radiotherapy + long-term ADT (HR 0.78, 95% CI 0.64-0.96).

Dr. Kishan concluded his presentation with the following take-home messages:

  • The network meta-analysis shows that dose-escalation does not improve metastasis free survival, irrespective of ADT use or duration. In contrast, adding short term ADT and particularly long-term ADT significantly improve metastasis free survival, irrespective of radiotherapy dose
  • Radiotherapy dose does have a modest to high probability of improving biochemical recurrence free survival irrespective of short term or long-term ADT
  • High-dose radiotherapy + long-term ADT may be the optimal treatment strategy
    • Network meta-analysis is limited by loop connectivity with respect to several randomized comparisons
    • Cohort-based analysis supports this conclusion, but has inherent limitations

 

Presented by: Amar U. Kishan, MD, Associate Professor, Vice Chair of Clinical and Translational Research, University of California, Los Angeles, CA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 American Society for Radiation Oncology (ASTRO) Hybrid Annual Meeting, Sat, Oct 23 – Wed, Oct 27, 2021.

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