The Surgical Imprint: How Operative Trauma May Shape Radiation Tolerance After Prostatectomy

Abstract

In a recent multicenter analysis of 454 patients undergoing post-prostatectomy salvage radiotherapy, the open surgical approach, as opposed to minimally invasive surgery, emerged, unexpectedly, as the strongest predictor of acute gastrointestinal and genitourinary toxicity. Patients treated with laparoscopic or robotic prostatectomy experienced significantly lower rates of ≥grade 2 toxicity compared to those who had undergone open retropubic surgery, irrespective of total dose, treatment margins, or radiation delivery platform. This finding, which to our knowledge has not been previously reported, raises the hypothesis that surgical technique leaves a lasting biological imprint on irradiated tissues. Drawing on current knowledge in radiobiology, cytokine signaling, wound healing, and pelvic dosimetry, we explore potential mechanisms by which open surgery may create a more hypoxic, inflamed, and fibrotic microenvironment, thereby amplifying radiation damage. We further discuss how target volume margins may biologically interact with this tissue state to increase normal tissue exposure. This Perspective aims to provide a conceptual framework for understanding this unexpected association, highlighting its clinical relevance for individualizing margins, counselling high-risk patients, and designing future studies at the interface of surgery and radiation oncology. This paper does not introduce additional patients or statistical models; instead, it offers an in-depth clinical and mechanistic interpretation of previously published ICAROS findings.

Keywords: CTV–PTV margin; acute toxicity; gastrointestinal toxicity; genitourinary toxicity; minimally invasive surgery; open prostatectomy; post-prostatectomy radiotherapy; radiosensitivity; salvage radiotherapy; surgical trauma.

Figure 1

Predictive model of acute gastrointestinal toxicity (grade ≥ 2). The numbers in parentheses represent the patient count within each specific subgroup, whereas the values highlighted on a red background denote the percentages of acute toxicity incidence (ADT: Androgen deprivation therapy, CCI: Charlson Comorbidity Index, CTV: Clinical target volume, EQD2: Equivalent dose in 2 Gy fractions, Gy: Gray, HDB: High-dose bicalutamide, LH-RH agonist: Luteinizing hormone-releasing hormone agonist, PTV: Planning target volume, RT: Radiotherapy).

Figure 2

Predictive model of acute genitourinary toxicity (Grade ≥ 2). The numbers in parentheses represent the patient count within each specific subgroup, whereas the values highlighted on a red background denote the percentages of acute toxicity incidence (CTV: Clinical target volume, Gy: Gray, the unit of absorbed radiation dose, PTV: Planning target volume).