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‘Evidence is clear’: Moderate hypofractionation safe, effective for prostate cancer
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Moderate hypofractionation is a safe and effective alternative to standard hypofractionation for prostate cancer and should be considered during treatment discussions, according to a commentary published in The International Journal of Radiation Oncology Biology and Physics.
“The evidence is clear, the value to patients is obvious and the potential cost savings are substantial,” Justin E. Bekelman, MD, associate professor in the department of radiation oncology at Perelman School of Medicine and Leonard Davis Institute of Health Economics at University of Pennsylvania, and W. Robert Lee, MD, MEd, MS, radiation oncologist at Duke Health, wrote in the commentary. “It is time to use moderate hypofractionation for patients with intact prostate cancer.”
About one-third of men with prostate cancer undergo radiation, and it is the most common treatment approach for men older than 65 years. The standard approach consists of daily treatments that last up to 9 weeks. Moderate hypofractionation consists of 4 to 5 weeks of daily radiation treatments.
Three multicenter randomized trials that included a combined 5,537 patients with primarily low- or intermediate-risk prostate cancer showed the two approaches provided comparable cancer control. Physician-observed and patient-reported side effects also were similar between groups.
Age, race, disease severity and receipt of hormone therapy did not influence the results.
The lower number of radiation treatments creates a “win-win” for patients, payers and employers by reducing costs and allowing men to resume normal activities more quickly, Bekelman said.
HemOnc Today spoke with Bekelman about moderate hypofractionation, the advantages he believes it offers, as well as the concerns skeptics have expressed about this approach.
Question: Why do you think moderate hypofractionation is the right approach to prostate cancer treatment?
Answer: There have been 5,500 men who have gone through three different randomized trials. These studies — which included patients from the United States, Canada and Europe — have all shown consistent results. Shortened radiation for prostate cancer — a duration of 4 to 5 weeks — is equivalent for cancer care and is no more toxic than longer schedules. We can debate about which particular subsets of men we feel most comfortable to change practice in first, but the evidence at this point is clear through a median 5 years of follow-up. Importantly, all studies included patient-reported outcomes, and there were no clinically significant differences between mild hypofractionated and conventional fractionation schedules. Not only is there similar cancer care between the two regimens, but patients perceive the actual toxicity as very similar between a longer duration and shorter duration. This does not mean that we should only use moderate hypofractionation, but when we have two treatments like this, convenience for patients must enter the discussion.
Q: What concerns have skeptics expressed about this approach?
A: There are three main arguments against the adoption of moderate hypofractionation. The first concern is that there is not enough follow-up time to compare cancer control. There is a median follow-up of 5 years in these trials, but there is no relevant hypothesis in the scientific literature regarding radiobiological effectiveness that would suggest cure rates would diverge with extended follow-up. Therefore, I do not think this is a relevant argument.
Others say we need longer follow-up to monitor late toxicities. We do need longer follow-up, but we now have literature pointing to it. A study by Lieng and colleagues, published in Radiotherapy Oncology, examined longer-term outcomes of moderate hypofractionation. Toxicity at 8 years was low, tolerable and consistent with more extended hypofractionation for prostate cancer.
The last argument focuses on whether the doses are right and whether the moderate hypofractionation schedule should be compared with conventional hypofractionation schedules at higher doses. From a radiobiology point of view, one can argue the conventional arm doses used in the three different trials — although varied — represent the types of doses used in common practice. For this reason, I am not concerned.
Q: A similar debate occurred a couple years ago with breast cancer treatment. Is this a case of history repeating itself?
A: The interesting thing about the debate in breast cancer is that the initial trials in that disease gave pause for clinicians, even though local recurrence rates and cosmetic outcomes were similar in both groups. After the initial trials in breast cancer, adoption of the shorter radiation schedule was slow. Some argued clinicians were concerned that larger doses of radiation per fraction could lead to greater toxicity over time. However, even after investigators reported 12-year data in 2010, uptake of shorter radiation for whole-breast radiation did not accelerate.
We can learn from this experience in a couple ways. First, we should develop clear, high-quality practice guidelines on the safety and efficacy of moderate hypofractionation based on research. Second, we should begin to engage moderate hypofractionation as a new treatment paradigm. We should talk to our patients about the trials and introduce moderate hypofractionation techniques into our clinics. There is going to be a debate about which group of patients are most appropriate, but I bet there are at least some groups that are reasonable candidates for most clinicians.
Q: What should future research entail?
A: The three randomized trials already conducted in prostate cancer represent a comparison of moderate hypofractionation with conventional hypofractionation. These trials do not speak to ‘accelerated’ or ‘ultra’-hypofractionation external beam schedules for prostate cancer — those that can be completed in five treatments over 2 weeks. Those schedules are expected to be compared with mild hypofractionation in upcoming randomized trials. Over time, we should publish longer-term results from the hypofractionation randomized controlled trials to add to the body of evidence for the long-term safety and efficacy of this shorter treatment approach. – by Jennifer Southall
References:
Bekelman JE, et al. JAMA. 2014;doi:10.1001/jama.2014.16616.
Bekelman JE and Lee WR. Int J Radiat Oncol Biol Phys. 2017;doi:10.1016/j.ijrobp.2016.11.038.
Catton CN, et al. Abstract 5003. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.
Dearnaley D, et al. Lancet Oncol. 2016;doi:10.1016/S1470-2045(16)30102-4.
Lee WR, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2016.67.0448.
Lieng H, et al. Radiother Oncol. 2016;doi:10.1016/j.radonc.2016.10.017.
For more information:
Justin E. Bekelman, MD, can be reached at The University of Pennsylvania, 34th and Spruce streets, Philadelphia, PA 19104-6303; email: bekelman@uphs.upenn.edu.
Disclosure: Bekelman reports research support from NCI.