A Systematic Post-QUANTEC Review of Tolerance Doses for Late Toxicity After Prostate Cancer Radiation Therapy

Abstract

Purpose: The aims of this study were to systematically review tolerance doses for late distinct gastrointestinal (GI), genitourinary (GU), and sexual dysfunction (SD) symptoms after external beam radiation therapy (EBRT) alone and treatments involving brachytherapy (BT) for prostate cancer after Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) and ultimately to perform quantitative syntheses of identified dose/volume tolerances represented by dose-volume histogram (DVH) thresholds, that is, statistically significant (P ≤ .05) cutoff points between symptomatic and asymptomatic patients in a certain study.

Methods and materials: PubMed was scrutinized for full-text articles in English after QUANTEC (January 1, 2010). The inclusion criteria were randomized controlled trials, case-control studies, or cohort studies with tolerance doses for late distinct symptoms ≥3 months after primary radiation therapy for prostate cancer (N > 30). All DVH thresholds were converted into equivalent doses in 2-Gy fractions (EQD2_α/β) and were fitted with a linear or linear-quadratic function (goodness of fit, R²). The review was registered on PROSPERO (CRD42016042464).

Results: From 33 identified studies, which included 36 to 746 patients per symptom domain, the majority of dose/volume tolerances were derived for GI toxicity after EBRT alone (GI, 97 thresholds; GU, 8 thresholds; SD, 1 threshold). For 5 symptoms (defecation urgency, diarrhea, fecal incontinence, proctitis, and rectal bleeding), relationships between dose/volume tolerances across studies (R² = 0.93 [0.82-1.00]), and across symptoms, leading to a curve for overall GI toxicity (R² = 0.98), could be determined. For these symptoms, mainly rectal thresholds were found throughout low and high doses (10 Gy ≤ equivalent dose in 2-Gy fractions using α/β = 3Gy (EQD2₃) ≤ 50 Gy and 55 Gy ≤ EQD2₃ ≤ 78 Gy, respectively). For BT with or without EBRT, dose/volume tolerances were also mainly identified for GI toxicity (GI, 14 thresholds; GU, 4 thresholds; SD, 2 thresholds) with the largest number of DVH thresholds concerning rectal bleeding (5 thresholds).

Conclusions: Updated dose/volume tolerances after QUANTEC were found for 17 GI, GU, or SD symptoms. A DVH curve described the relationship between dose/volume tolerances across 5 GI symptoms after EBRT alone. Restricting treatments for EBRT alone using the lower boundaries of this curve is likely to limit overall GI toxicity, but this should be explored prospectively. Dose/volume tolerances for GU and SD toxicity after EBRT alone and after BT with or without EBRT were scarce and support further research including data-sharing initiatives to untangle the dose/volume relationships for these symptoms.

Fig 1.

Schematic of the study selection procedure. Altogether, authors of 23 different studies were contacted for additional/clarifying information in the search strategy step II. Of these, authors of 17 studies responded (74%).

Fig 2.

Identified DVH thresholds for the five GI symptoms after EBRT alone for which the quantitative synthesis was considered. Study-specific symptom rates are given next to the first (lowest dose) DVH threshold in each study. Each symbol is study-specific (exception: Rectal bleeding); open/closed symbols refer to ≥Grade 1/2; black dotted lines represent final fits (the associated R² is inserted in the legend). Color-coding: Anal Canal (red), Anorectum (blue), Anal sphincter (magenta), External anal sphincter (purple), Illiococcygeal muscle (brown), Rectum (black), and Rectal wall (green).

Fig 3A-E.

The 29 identified DVH thresholds for Rectal bleeding following EBRT alone (excluding the four anal canal thresholds; cf. Fig. 2), and the 25 DVH thresholds for ≥Grade 2 Rectal bleeding that were identified by QUANTEC [3] (QUANTEC studies marked with bright green boarder; different symbols for different sub-QUANTEC studies; subscript number refers to the reference list in [3]; subscript K: Koper et al Radiother Oncol 2004; 73:1–9; subscript Z: Zapatero et al Int J Radiat Oncol Biol Phys 2004; 59:1343–51). All 54 thresholds stratified with respect to A: OAR (Anorectum: blue; Rectum: black; Rectal wall: green; black dotted line: final fit for Rectal bleeding; grey dashed line: fit including the 25 QUANTEC thresholds). B: Rectal bleeding symptom cut-off. C: Rectal bleeding rate separated in five intervals. D: RT technique. E: Prescription dose level (EQD2₁₀) separated in five intervals (post-QUANTEC: the median value of all exploited prescription levels).

Fig 4.

Estimated COMT_DVHs for Defecation urgency, Diarrhea, Fecal incontinence, Proctitis, and Rectal bleeding following EBRT alone, and the fitted Meta DVH for overall GI toxicity based on the COMT_DVHs for each of these symptoms (black dotted line; dashed black lines: 95% Confidence Intervals). The majority of data for which all COMT_DVHs were derived stemmed from rectal doses followed by high anorectal doses (71%, 13%). The region below and above this Meta DVH suggests low and high risk, respectively, of developing overall GI toxicity, and the circles denote the two clusters of COMT_DVHs. The color-coding indicates the symptom-specific sensitivity, e.g., the tolerance doses for the most sensitive symptom Defecation urgency is red.