Higher-than-expected Severe (Grade 3–4) Late Urinary Toxicity After Postprostatectomy Hypofractionated Radiotherapy: A Single-institution Analysis of 1176 Patients

doi:10.1016/j.eururo.2014.06.012

European Urology

Volume 66, Issue 6, December 2014, Pages 1024-1030

https://doi.org/10.1016/j.eururo.2014.06.012 Get rights and content

Abstract

Background

Dose escalation and hypofractionation may have a role in postprostatectomy radiotherapy (RT), but at the risk of increasing urinary toxicity.

Objective

To address predictors of severe (Grade ≥3) late urinary toxicities (LGUTOX3) after postoperative irradiation.

Design, setting, and participants

A single-institution cohort of 1176 patients treated between 1993 and 2010 with adjuvant or salvage RT was analyzed. A total of 929 patients underwent conventionally fractionated (CF) RT (1.8 Gy per fraction; median dose to the prostatic bed: 70.2 Gy) with nonconformal RT (n = 169), three-dimensional conformal RT (n = 657), or intensity-modulated RT (n = 103) technique, while 247 patients received hypofractionated helical TomoTherapy (median: 2.50 Gy per fraction) at the following doses: 117 patients at 65.8 Gy (2.35 Gy in 28 fractions), 80 patients at a median of 71.4 Gy (2.5–2.6 Gy in 28 fractions), and 50 patients at 58 Gy in 20 fractions. Total doses were converted into 2 Gy–equivalent doses (EQD2) following the linear quadratic model taking α/β = 5.

Outcome measurements and statistical analysis

Univariable and multivariable Cox regression models tested the relationship between clinicodosimetric variables and the risk of LGUTOX3 retrospectively, graded according to Common Terminology Criteria for Adverse Events v.4.0.

Results and limitations

After a median follow-up of 98 mo, the 5-yr risk of LGUTOX3 was 6.9% and 18.1% in the CF and hypofractionated cohorts, respectively. At univariable analysis, the risk of LGUTOX3 was predicted by dose per fraction (hazard ratio [HR]: 2.96), acute Grade ≥2 toxicity (HR: 2.37), EQD2, pT4, and year of irradiation. At multivariable analyses, acute Grade ≥2 toxicity and dose per fraction independently predicted LGUTOX3 in the population, while an interaction analysis indicated a predictive role of hypertension in the hypofractionated cohort only. These findings are limited by their retrospective nature.

Conclusions

In the postprostatectomy setting, the logistic convenience of hypofractionation should be carefully balanced against the risk of severe late urinary sequelae.

Patient summary

This study investigated the causes of urinary adverse effects after postprostatectomy radiotherapy. Hypofractionation resulted in an increased risk of severe urinary toxicities.

Introduction

Both hypofractionation [1], [2], [3] and moderate dose escalation [4], [5], [6] have an attractive role in postprostatectomy irradiation, as the former may lead to a significant reduction of treatment length and the latter, to a potential improvement of local control. Apart from some recent skepticism concerning the real radiobiologic effectiveness of hypofractionation in prostate cancer (PCa) [7], it is unquestionable that increasing the dose to the prostatic bed, especially when larger daily doses are used, could result in an unacceptable risk of acute and, more important, late urinary toxicity. Despite a striking refinement of irradiation techniques that has led to the possibility of truly sculpting the dose distribution around the tumoral target, the tendency of PCa to recur at the level of the vesicourethral anastomosis renders urinary toxicity the real dose-limiting adverse effect of postoperative radiotherapy (RT), even when delivered with more modern intensity-modulated RT (IMRT) techniques.

While evidence of the feasibility and possible impact of moderate dose escalation at conventional fractionation is rapidly increasing in both adjuvant settings [6], [8] and salvage settings [5], [9], [10], experience with moderate hypofractionation (ie, daily dose of 2.2–3.0 Gy per fraction) in the postoperative setting is limited [2], [3], [11], [12]. Despite the promising results in terms of both acute toxicity and early clinical outcome [1], [2], [3], these preliminary reports regarding postprostatectomy hypofractionation lack a thorough assessment of late urinary toxicity.

The purpose of this analysis was therefore to retrospectively address, with special emphasis on a possible role of both dose escalation and hypofractionation, predictors of the most severe (Grade ≥3) late urinary toxicities (LGUTOX3) after postoperative irradiation in a very large single-institution cohort of patients treated with adjuvant or salvage RT with different irradiation techniques, doses, and fractionations.

Section snippets

Patients and methods

From 1993 to 2010, 1192 consecutive patients underwent postprostatectomy irradiation at the Department of Radiotherapy of the San Raffaele Scientific Institute in Milan, Italy. For the purpose of this analysis, 16 patients dead or lost to follow-up within 12 mo of the beginning of RT were excluded from the analysis. This exclusion resulted in a population of 1176 patients submitted to postoperative irradiation with adjuvant intent (n = 804) or salvage intent (n = 372).

With respect to fractionation (

Results

After a median follow-up of 98 mo (95 mo for patients without an event), 115 patients experienced LGUTOX3. To explain in more detail, 68 patients required surgical procedures for urethral stenosis and/or bladder neck strictures, 30 patients underwent blood transfusion and/or hyperbaric oxygen therapy for severe and persistent gross hematuria, and 47 patients reported postirradiation onset or worsening of Grade 3 incontinence. Accounting for postsurgical onset, 88 patients developed Grade 3

Discussion

To the best of our knowledge, this is the first series reporting—albeit on a retrospective basis—such a dramatic and much higher than expected increase in severe late urinary sequelae in patients treated after radical prostatectomy with hypofractionated RT. This finding is even more surprising considering that all patients in the hypofractionated group underwent an IMRT technique, compared with only a minority in the CF cohort. Nevertheless, it cannot be entirely ruled out that part of this

Conclusions

These results seem to suggest that in the postprostatectomy setting, the unquestionable appeal of hypofractionation in terms of both logistic convenience and resource use advantages [1] is undermined by a significantly increased risk of severe late urinary toxicity. According to our results, an increase of approximately 10 severe genitourinary toxicities for every 100 patients may be expected within the first 5 yr after RT for patients treated with hypofractionated regimens compared with

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Platinum Priority – Prostate CancerEditorial by Mark K. Buyyounouski on pp. 1031–1032 of this issueHigher-than-expected Severe (Grade 3–4) Late Urinary Toxicity After Postprostatectomy Hypofractionated Radiotherapy: A Single-institution Analysis of 1176 Patients

Abstract

Background

Objective

Design, setting, and participants

Outcome measurements and statistical analysis

Results and limitations

Conclusions

Patient summary

Introduction

Section snippets

Patients and methods

Results

Discussion

Conclusions

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Eur Urol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

J Urol

Clin Oncol (R Coll Radiol)

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Platinum Priority – Prostate Cancer
Editorial by Mark K. Buyyounouski on pp. 1031–1032 of this issue
Higher-than-expected Severe (Grade 3–4) Late Urinary Toxicity After Postprostatectomy Hypofractionated Radiotherapy: A Single-institution Analysis of 1176 Patients