Conventional Versus Hypofractionated Radiation Therapy for Localized or Locally Advanced Prostate Cancer: A Systematic Review and Meta-analysis along with Therapeutic Implications

doi:10.1016/j.ijrobp.2017.07.021

International Journal of Radiation OncologyBiologyPhysics

Volume 99, Issue 3, 1 November 2017, Pages 573-589

https://doi.org/10.1016/j.ijrobp.2017.07.021 Get rights and content

Purpose

A systematic review and meta-analysis were conducted to evaluate the therapeutic outcomes of conventional radiation therapy (CRT) and hypofractionated radiation therapy (HRT) for localized or locally advanced prostate cancer (LLPCa).

Methods and Materials

A total of 599 abstracts were extracted from 5 databases and screened in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Only phase III trials randomized between CRT and HRT in LLPCa with a minimum of 5 years of follow-up data were considered. The evaluated endpoints were biochemical failure, biochemical and/or clinical failure, overall mortality, prostate cancer-specific mortality, and both acute and late gastrointestinal (GI) and genitourinary (GU) (grade ≥2) toxicity.

Results

Ten trials from 9 studies, with a total of 8146 patients (CRT, 3520; HRT, 4626; 1 study compared 2 HRT schedules with a common CRT regimen), were included in the evaluation. No significant differences were found in the patient characteristics between the 2 arms. However, the RT parameters differed significantly between CRT and HRT (P<.001 for all). The use of androgen deprivation therapy varied from 0% to 100% in both groups (mean ± standard deviation 43.3% ± 43.6% for CRT vs HRT; P=NS). The odds ratio, risk ratio, and risk difference (RD) between CRT and HRT for biochemical failure, biochemical and/or clinical failure, overall mortality, prostate cancer-specific mortality, acute GU toxicity, and late GU and GI toxicities were all nonsignificant. Nevertheless, the incidence of acute GI toxicity was 9.1% less with CRT (RD 0.091; odds ratio 1.687; risk ratio 1.470; P<.001 for all). On subgroup analysis, the patient groups with ≤66.8% versus >66.8% androgen deprivation therapy (RD 0.052 vs 0.136; P=.008) and <76% versus ≥76% full seminal vesicles in the clinical target volume (RD 0.034 vs 0.108; P<.001) were found to significantly influence the incidence of acute GI toxicity with HRT.

Conclusions

HRT provides similar therapeutic outcomes to CRT in LLPCa, except for a significantly greater risk of acute GI toxicity. HRT enables a reduction in the overall treatment time and offers patient convenience. However, the variables contributing to an increased risk of acute GI toxicity require careful consideration.

Introduction

Hypofractionated radiation therapy (HRT) regimens for localized or locally advanced prostate cancer (LLPCa) have been compared with conventional radiation therapy (CRT) in a number of prospective phase III randomized clinical trials 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. The feasibility of exploring HRT regimens for LLPCa has been of interest, because these tumors are considered to have a fractionation sensitivity with low α/β values, similar to those of late-responding normal tissues. The α/β values for prostate cancer have been estimated by several investigators to range from 1 to 1.8 Gy, even lower than the adjacent late-responding normal structures, such as the rectum and bladder (α/β ≈ 3-5 Gy) 11, 12, 13, 14, 15.

HRT would, therefore, be expected to result in improved therapeutic outcomes compared with CRT. Fewer hospital visits for HRT would not only make it more convenient, especially for elderly patients, but also economically attractive (16). However, before HRT can be adopted as a standard of care for LLPCa, it is mandatory to assess the long-term therapeutic outcomes in terms of both the efficacy and the incidence of acute and late toxicity compared with CRT protocols.

To address this issue, a number of randomized trials between HRT and CRT have been performed either as single-institution or multicenter trials. Some of these studies were designed as noninferiority trials 1, 3, 4 and have now been reported with a minimum of 5 years of follow-up data 1, 2, 3, 4, 5, 6, 7, 8, 9. Although all these studies included LLPCa, differences were present in the patient population in terms of the T stage, Gleason score, pretreatment prostate-specific antigen level, risk category, use of androgen deprivation therapy (ADT), irradiated portals, and radiation therapy (RT) schedules (ie, total dose, dose/fraction, number of fractions, and overall treatment time [OTT]) in both regimens. The outcomes are usually reported as biochemical failure (BF), biochemical and/or clinical failure (BCF), overall survival, prostate cancer-specific survival, and early and late gastrointestinal (GI) and genitourinary (GU) toxicity.

It was desirable to synthesize the multiple studies to examine the therapeutic potential of HRT in LLPCa. The relatively large patient population enrolled in these trials, with a wide range of both patient characteristics and RT schedules, also provides an opportunity to explore possible predictive covariates that could significantly influence the clinical outcomes. The present study was performed to address these issues through a systematic review and meta-analysis of randomized trials between HRT and CRT for LLPCa.

Section snippets

Search strategy

The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (17) (Fig. 1). Five databases (ie, PubMed, Embase, Scopus, Web of Science, and the Cochrane library) were searched. The terms used were “prostatic neoplasms” (MeSH terms)” AND “radiotherapy” (MeSH terms) AND “hypofractionated” (all fields) AND “randomized controlled trial” (ptyp). The search was not limited to any date. The last search was performed on March

Study inclusion

A total of 9 randomized trials reported from 2005 to 2017 were finally considered 1, 2, 3, 4, 5, 6, 7, 8, 9. The CHHiP study (4) used 2 different HRT schedules (HRT₆₀, 60 Gy/20 fractions; and HRT₅₇, 57 Gy/19 fractions). These were compared against a common CRT arm (74 Gy/37 fractions). These 2 HRT arms (CHHiP HRT₆₀ and CHHiP HRT₅₇) were compared individually with the CRT arm in the present meta-analysis. Thus, 10 randomized comparative study arms between HRT and CRT were available for

Discussion

HRT schedules have been explored ever since the α/β for prostate cancer was estimated to be approximately 1.5 Gy in 1999 by Brenner and Hall (11). Thus, the various randomized trials for HRT versus CRT for LLPCa have been designed with varying time, dose, and fractionation schedules. These studies have now had a minimum follow-up period of 5 years, which allowed for a comprehensive evaluation and synthesis of their outcomes.

A meta-analysis of randomized controlled trials with escalated RT doses

Conclusions

The results of the present meta-analysis have reaffirmed HRT as a viable alternative for patients with LLPaC, because the therapeutic outcomes closely aligned with those of CRT. Furthermore, HRT could shorten the treatment duration, require fewer hospital visits, and reduce the costs for health care providers 16, 53. However, the incidence of acute GI toxicity might be greater than that with CRT and requires careful evaluation in future studies.

Acknowledgments

The authors acknowledge Nicci Lomax, Physicist, Kantonsspital Aarau, Switzerland for reviewing the rectal dose–volume constraints and Professor Michael Borenstein, Biostat, USA for his input on the meta-analysis. Partial fundings by Kelm Stiftung and Forschungsrat KSA, Switzerland is also acknowledged.