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

https://doi.org/10.1016/j.ijrobp.2018.08.015Get rights and content

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 (EQD2α/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.

Introduction

Over the past 3 decades, 2 major efforts have been conducted to better understand radiation therapy (RT) dose/volume tolerances for organs at risk (OARs) with the overall aim to limit the occurrence of severe late toxicity. The first consensus values were proposed in 1991.1 In 2010, the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) group presented evidence-based results made available from the accumulation of 3-dimensional (3D) treatment planning data.2 For prostate cancer, these efforts summarize dose/volume tolerances for OARs after external beam RT (EBRT) for commonly reported gastrointestinal (GI) and genitourinary (GU) toxicities and sexual dysfunction (SD).1, 3, 4, 5 However, dose/volume tolerances for distinct symptoms were typically not distinguished because these recommendations were based on toxicity scoring systems that combine symptoms (eg, by the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer6 and National Cancer Institute Common Terminology Criteria for Adverse Events7 systems). Furthermore, these QUANTEC reports on GI and GU toxicity and SD were derived for only the whole rectum, bladder, and penile bulb, respectively, and did not explicitly focus on dose/volume tolerances after treatments involving brachytherapy (BT).3, 4, 5

Since the publication of the 3 QUANTEC reports, dose/volume tolerances for late and distinct symptoms and other OARs have become available. The objective of this systematic review was to summarize dose/volume tolerances between distinct late GI and GU toxicities, SD symptoms, and relevant OARs after prostate cancer RT separately for EBRT alone and for BT with or without EBRT.

Section snippets

Search strategy

This systematic review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement,8 and protocol details were registered on PROSPERO (http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016042464). The PubMed database was scrutinized for full-text articles in English published up to December 31, 2017, focusing on studies reporting dose/volume tolerances for late toxicities only after prostate cancer RT. For GI toxicity and SD after EBRT alone, the

Results

A total of 168 full-text articles were identified, of which 33 fulfilled the inclusion criteria. Of these 33 studies, 22 concerned EBRT alone (n = 6313 treated between 1993 and 2014) and 11 concerned BT with or without EBRT (n = 3836 treated between 1995 and 2010; Fig. 1; Table 1, Table 2, Table 3; Tables E1 and E2, available online at https://doi.org/10.1016/j.ijrobp.2018.08.015). All studies presented with at least “fair” study quality (mean score ± standard deviation, 6 ± 1). The studies

Discussion

This systematic review was based on dose/volume tolerances for late and distinct RT-induced toxicities after prostate cancer RT from 10,149 patients and 33 studies. We identified 97 dose/volume tolerances, 8 dose/volume tolerances, and 1 dose/volume tolerance as quantified by DVH thresholds for GI, GU, and SD toxicity, respectively, in 13 OARs after EBRT alone. The corresponding numbers after BT with or without EBRT were 14, 4, and 2 in 4 OARs. An overall GI toxicity DVH curve based on

Conclusions

This systematic review provides evidence in support of rectal dose/volume tolerances after prostate cancer EBRT alone for defecation urgency, diarrhea, fecal incontinence, proctitis, and rectal bleeding within both the low- to intermediate-dose range (10 Gy ≤ EQD23 ≤ 50 Gy) and high-dose range (55 Gy ≤ EQD23 ≤ 78 Gy). The more sensitive symptom of defecation urgency implies that if its tolerance can be respected, the risk of development of other GI toxicities is low. Even though RT-induced

Acknowledgments

The authors acknowledge Konstantina Matsoukas at Memorial Sloan Kettering Cancer Center for conducting all initial literature searches. They thank all authors of individually published studies who clarified essential information on request.

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    This research was funded in part through National Institutes of HealthNational Cancer Institute Cancer Center Support Grant P30 CA008748 (M.T., A.J., and J.O.D.). Grants from the King Gustaf V Jubilee Clinic Cancer Foundation in Gothenburg, the Swedish Society for Medical Research, the Kamprad Family Foundation for Entrepreneurship Research & Charity, and the Research and Development Council of West Region County (Sweden) supported C.E.O.

    Conflict of interest: none.

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