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Prostate Cancer: Hypofractionated Radiotherapy’s Role in Post-operative Settings

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Hypofractionated external beam radiotherapy (EBRT) delivers the total prescribed therapeutic radiation dose in fewer, larger-dose fractions than standard radiotherapy dose schedules, accelerating treatment time.

Hypofractionated radiotherapy’s role in postoperative settings remains unclear and awaits outcomes from ongoing studies.

“The key advantages of moderate hypofractionation, owing to its shorter treatment courses, are lower cost and greater convenience for patients,” said Scott Morgan, MD, assistant professor of radiation oncology at the University of Ottawa in Canada.

Localized prostate cancer is particularly well-suited for hypofractionated radiotherapy because prostate tumors are intrinsically more radiosensitive than other nearby, healthy tissues.1 Larger radiation dose fractions with shorter overall treatment durations should therefore have a better effect on tumors than longer radiotherapy regimens with smaller daily doses, added Ronald C. Chen, MD, MPH, associate professor in the department of radiation at the University of North Carolina (UNC) at Chapel Hill and the UNC Lineberger Comprehensive Cancer Center.

“This idea is the basis for the research on hypofractionation in this disease,” Dr Chen said.

Fewer fractions of at least 2.5 Gy can yield better tumor cell death rates than conventional 1.8 to 2.0 Gy–range conventional radiation-dose schedules — and should do so without increasing toxicity to adjacent healthy, non-target tissues, agreed Thomas Zilli, MD, of Geneva University Hospital in Switzerland.

That expectation has been largely justified for primary radiotherapy.2

“There have been at least 9 randomized trials comparing conventional fractionation (8 to 9 weeks of radiation) vs moderate hypofractionation (4 to 5 weeks of radiation) in prostate cancer,” Dr Chen said. “These trials have essentially shown that moderate hypofractionation is similarly safe and effective as the conventional, much longer treatment courses.”

Four of these studies have been large, randomized, multi-center phase 3 clinical trials reported in 2016 and 2017 that demonstrated the non-inferiority of hypofractionated radiation regimens compared with conventional radiotherapy: the Prostate Fractionated Irradiation Trial (PROFIT), the Conventional vs Hypofractionated High-Dose Intensity-Modulated Radiotherapy for Prostate Cancer (CHHiP) trial, RTOG-0415, and the Hypofractionated vs Conventionally Fractionated Radiotherapy for Patients With Localized Prostate Cancer (HYPRO) trial.3-6

Moderate hypofractionation is delivered using intensity-modulated radiotherapy (IMRT). Following the recent clinical trial results, moderately hypofractionated IMRT is now considered a standard of care, Dr Chen said.

Stereotactic body radiation therapy (SBRT) is used to deliver “ultra-hypofractionation,” which can deliver radiation therapy even more quickly — in just 1 week, Dr Chen added.

“This is a promising technology and many prospective studies have shown that this seems to be safe and effective,” Dr Chen said. “There are several randomized trials ongoing at this time comparing SBRT to longer treatments using IMRT.”

Following publication of large, randomized clinical trials conducted in the United States, Canada, and Europe, the American Society for Radiation Oncology (ASTRO) created a task force, co-chaired by Dr Morgan, to develop an evidence-based clinical practice guideline about hypofractionated radiation therapy for localized prostate cancer, in collaboration with the American Society of Clinical Oncology (ASCO) and the American Urology Association (AUA).

Definitive ultra-hypofractionation can deliver the total therapeutic radiation dose in just 5 fractions, Dr Morgan noted. Results from single-arm trials of ultra-hypofractionation conducted to date are “very promising,” but the results of randomized trials in progress will be pivotal, Dr Morgan said.

Definitive ultra-hypofractionation can deliver the total therapeutic radiation dose in just 5 fractions, Dr Morgan noted. Early results are “very promising,” he added, though ultra-hypofractionation remains investigational.

Whereas the case for moderate hypofractionation is relatively strong, the evidence base for definitive ultra-hypofractionation for localized prostate cancer is, according to Dr Morgan, “substantially less mature at present. A number of large-scale randomized studies are under way but, to date, none have reported efficacy results. The literature at present consists largely of prospective single-institution and multi-institutional cohort studies.”

Yet now researchers are turning their attention to hypofractionated radiotherapy in the postsurgical setting.

Hypofractionated RT in the postoperative treatment of prostate cancer is “at a relatively early stage of evaluation,” Dr Morgan said.

“Hypofractionation in the postoperative setting is undoubtedly an appealing treatment strategy, with clear potential implications in terms of logistics and economies for the health care system,” Dr Zilli added. “Conflicting results have, however, been reported concerning long-term genitourinary late toxicity, limiting its current use in the real-world clinic.”

The randomized phase 3 NRG-GU003 trial ( Identifier: NCT03274687) may answer key questions in coming years about adjuvant hypofractionation toxicity and effects on patient quality of life.

“Most of the studies completed to date were single-arm trials of moderately hypofractionated post-prostatectomy RT conducted in single institutions,” Dr Morgan said. But NRG-GU003 is comparing moderately hypofractionated with conventionally fractionated radiotherapy in the postoperative setting.

The available evidence on acute toxicity is limited and contradictory — and even less is known about late toxicities involving local non-target tissues, or the long-term effects of adjuvant hypofractionated radiotherapy.7-9

“The major concern for postoperative hypofractionation remains late genitourinary toxicity,” Dr Zilli said. “In contrast to the definitive setting, genitourinary toxicity in the postoperative setting may [involve] a mix of different factors ranging from radiation-induced damage and urothelial repopulation to surgery-related damage to the bladder neck and urethra.”

Efficacy data are also immature. Little is known about survival outcomes, and even seemingly promising prostate-specific antigen changes, which are evidence of efficacy, should be interpreted with caution.

Findings from the SAKK 09/10 clinical trial ( Identifier: NCT01272050) may, according to Dr Zilli, provide a clearer picture about the role of dose escalation in the salvage setting.

“Biochemical control rates seem to be similar to standard fractionation,” he said. “Equivalence should, however, be prospectively confirmed. At the moment, even for standard fractionation, we lack clear evidence if dose escalation improves biochemical control and, eventually, survival outcomes.”

The above post is reprinted from materials provided by : Cancer Therapy Advisor

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