The report is a product of the VA/HSR Evidence Synthesis Program.

Hypofractionation Radiation Therapy for Definitive Treatment of Selected Cancers: A Systematic Review

Takeaway: This systematic review of randomized clinical trials found that for breast, prostate, or rectal cancer, hypofractionation results in similar overall and disease-free or progression-free survival, as well as most treatment-related harms, compared to conventional radiotherapy. The evidence is more sparse and less consistent for adults with other cancers

VA cares for an estimated 175,000 Veterans annually in their cancer treatment program. Radiation treatment for curative or definitive cancer therapy is an important and frequently used option. Radiotherapy requires balancing tumor cell destruction with limiting normal tissue damage. Hypofractionation is a treatment regimen in which the total dose of radiation is divided into larger doses per fraction (given once a day or less often), resulting in fewer fractions and shorter overall treatment durations compared to conventional radiotherapy. While hypofractionation has seen a marked increase in use over the last 20 years – in part due to advances in treatment technology – and has been recommended for certain cancers by the American Society for Radiation Oncology (ASTRO), it has not been universally adopted. The National VA Radiation Oncology Quality Task Force has been tasked with developing and establishing guidelines for VA and community clinicians who treat Veterans with cancer.

HSR&D’s Evidence Synthesis Program (ESP) Center located in Minneapolis, MN, responded to a request from the Task Force to conduct a systematic review on the comparative effectiveness of hypofractionation versus conventional radiotherapy for adults with breast, prostate, lung, rectal, head and neck, bladder, pancreas, and skin cancers. ESP investigators searched relevant articles in Medline and Embase from inception to January 5, 2022, supplemented by a review of systemic reviews identified through Cochrane and AHRQ databases. From this search, 106 publications were included, comprising 71 randomized controlled trials (RCTs) across five of the cancers of interest. Of the 71 RCTs, more than half (n=46) were rated low or had some concerns for risk of bias. No eligible trials were identified for bladder, pancreatic, or skin cancer.

Summary of Findings

Despite many randomized trials enrolling individuals with different cancers, evidence was limited regarding the comparative effectiveness and harms of hypofractionation versus conventionally fractionated radiotherapy for definitive (non-palliative) therapy. For individuals with breast, prostate, or rectal cancer, hypofractionation results in little to no difference in overall survival, or disease-free or progression-free survival versus conventional radiotherapy. Evidence was more limited for harms. Investigators found no data on cost or resource use. Results also showed:

• For individuals with small-cell lung cancer, hypofractionation may result in little to no difference in overall and progression-free survival over 15–36 months follow-up. Evidence is generally very uncertain regarding comparative treatment harms.
• For non-small cell lung cancer, evidence from one small RCT suggests that SBRT (stereotactic body radiation therapy) may result in little to no difference in overall survival versus conventionally fractionated radiotherapy through 36 months. Evidence is generally very uncertain regarding comparative treatment harms.
• For early stage glottic cancer (malignancy arising from the vocal cords and larynx), hypofractionation may result in little to no difference in overall and disease-free survival, and most harms.
• No RCTs evaluated bladder, pancreatic, or skin cancers.

Limitations

The search was limited to publications in English; as such, there may be relevant studies to the research questions that were missed. Other limitations are primarily due to existing data. Except for breast and prostate cancer, most other cancers had few trials, and they were generally small and short-term. No eligible studies were found for pancreatic, bladder, or skin cancers. Additionally, costs and resource use were not evaluated by eligible studies.

Implications

The National VA Radiation Oncology Quality Task Force will use the results of this systematic review to help develop and establish guidelines for VA and community clinicians who treat Veterans with cancer.

Future Research

RCTs of hypofractionation (moderate and ultra-hypofractionation) compared with conventional radiation therapy are needed for most of the cancers addressed in this review, with the possible exception of breast and prostate cancers. 

Effectively assessing differences in overall or disease-free survival likely requires large and longer-term studies. These requirements are especially important for assessing whether treatment effects vary by patient and tumor characteristics. However, such RCTs are costly, and the studied treatments may be outdated due to advances in diagnostic and treatment approaches. Therefore, it may be reasonable to first focus on important intermediate outcomes of effectiveness and harms. Further, factors that contribute to patient preferences and treatment burden – including cost, duration, sessions, and access – are relevant for influencing practice and policy decisions. More research focused on these outcomes will be needed.

Landsteiner A, Sowerby C, Ullman K, et al. Hypofractionation Radiation Therapy for Definitive Treatment of Selected Cancers: A Systematic Review. Washington, DC: Evidence Synthesis Program, Health Services Research and Development Service, Office of Research and Development, Department of Veterans Affairs. VA ESP Project 09-009; 2023.

To view the full report, go to: vaww.hsrd.research.va.gov/publications/esp/hypofractionation.cfm (Intranet only)

ESP is currently soliciting review topics from the broader VA community. Nominations will be accepted electronically using the online Topic Submission Form. If your topic is selected for a synthesis, you will be contacted by an ESP Center to refine the questions and determine a timeline for the report.

This Management e-Brief is provided to inform you about recent HSR&D findings that may be of interest. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. If you have any questions or comments about this Brief, please email CIDER. The Center for Information Dissemination and Education Resources (CIDER) is a VA HSR&D Resource Center charged with disseminating important HSR&D findings and information to policy makers, managers, clinicians, and researchers working to improve the health and care of Veterans.

This report is a product of VA/HSR&D's Evidence Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers –; and to disseminate these reports throughout VA.

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