Tolerance doses for late adverse events after hypofractionated radiotherapy for prostate cancer on trial NRG Oncology/RTOG 0415

Abstract

Purpose/Objective: Hypofractionated radiotherapy (HRT) regimens for prostate cancer are emerging, but tolerance doses for late adverse events are scarce. The purpose of this study is to define dose-volume predictors for late gastrointestinal and genitourinary (GI and GU) toxicities after HRT in the multi-center NRG/RTOG 0415 low-risk prostate cancer trial (N=521). Material/methods: Treatment in the studied HRT arm was delivered as 70Gy at 2.5Gy/fraction with 3D-CRT/IMRT (N=108/413). At a median follow-up of 5.9 years, the crude late ≥Grade 2 GI and GU toxicities were 19% and 29%, respectively. For modeling, the complete HRT cohort was randomly split into training and validation (70% and 30%; preserved toxicity rates). Within training, dose-response modeling was based on dose-volume cut-points (EQD2Gy; bladder/ rectum: α/β=6Gy/3Gy), age, acute ≥Grade 2 toxicity, and treatment technique using univariate and multivariate logistic regression on bootstrapping (UVA and MVA). Candidate predictors were determined at p≤0.05, and the selected MVA models were explored on validation where model generalizability was judged if the area under the receiver-operating curve in validation (AUC validation) was within AUC training ±SD with p≤0.05, and with an Hosmer-Lemeshow p-value (p HL)>0.05. Results: Three candidate predictors were suggested for late GI toxicity: the minimum dose to the hottest 5% rectal volume (D5%[Gy]), the absolute rectal volume <35Gy, and acute GI toxicity (AUC=0.59-0.63; p=0.02-0.04). The two generalizable MVA models, i.e.. D5%[Gy] with or without acute GI toxicity (AUC validation =0.64. 0.65; p=0.01, 0.03; p HL =0.45-0.56), suggest that reducing late GI toxicity from 20% to 10% would require reducing D5%[Gy] from ≤65Gy to ≤62Gy (logistic function argument: 17+(0.24D5%[Gy])). Acute GU toxicity showed only a trend to predict late GU toxicity (AUC training =0.57; p=0.07). Conclusion: Uate GI toxicity, following moderate HRT for low-risk prostate cancer, increases with higher doses to small rectal volumes. This work provides quantitative evidence that limiting small rectal dose 'hotspots' in clinical practice of such HRT regimens is likely to further reduce the associated rates of GI toxicity.

COVID-19: hypofractionation in the Radiation Oncology Department during the “State of Alarm”: first 100 patients in a private hospital in Spain

“…Our attitude was to establish a better way to treat all patients who can benefit from radiotherapy; not to delay the onset of any patient whose deferral may worsen the prognosis of their disease; try to help the patient attend treatment as few times as possible and not increasing toxicity and maintaining the possibility of the best result. The hypofractionated treatments we indicated during the time of COVID-19 are supported mainly by international guidelines and phase III clinical trials [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19].…”

Refinement & validation of rectal wall dose volume objectives for prostate hypofractionation in 20 fractions

“…It should be also noted that the recent ASTRO, ASCO and AUA Evidence-based guideline on hypofractionated RT does not recommend non modulated 3DCRT techniques when delivering MHRT [27]. Therefore, unlike other Authors [9,17], we focused on patients treated with IMRT/VMAT only.…”

“…Dose-volume objectives are placed at planning on the rectum (or the rectal wall-RW) in order to control for (and possibly) limit its dosage. However, there are scarce data looking at the relationship between individual dose/volume metrics and late rectal toxicity in the setting of MHRT [9,[16][17][18] particularly regarding the 20fraction schedule that is widely supported by the available trials https://doi.org/10.1016/j.ctro.2020.01.006 2405-6308/Ó 2020 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.…”

Seven or less Fractions is Not the Standard of Care for Intermediate-Risk Prostate Cancer

“…By contrast, although many candidate structures, such as the whole bladder, bladder trigone and urethra, have been proposed for genitourinary toxicity [30e32], none has consistently been shown to predict toxicity. In the dosimetric analysis of RTOG 0415 [29], no correlation between bladder dose and physician-reported toxicity could be found. For erectile dysfunction, accumulating evidence suggests that dose to the penile bulb is correlated with long-term erectile dysfunction [33e35].…”

“…Gulliford et al [26] confirmed a relationship between the number of constraints 'missed' in the RT01 trial with clinician-reported toxicity. Thor et al [29] retrospectively analysed the randomised RTOG 0415 trial and found that restricting the minimum dose to the hottest 5% of the rectum to 62 Gy EQD2 (a/b 3 Gy) would reduce grade 2 þ RTOG toxicity from 20% (assuming the D5% was >65 Gy) to 10% [29]. Therefore, standard fractionation radiotherapy can now be optimised to minimise the risk of rectal sideeffects and, as shown in Ferreira et al [27] recently, if these constraints are respected, the chance of toxicity with conventional hypofractionation is low.…”