Expert Makes Case for Hypofractionation in Prostate Cancer

Howard M. Sandler, MD

Guidelines in development from the American Society for Radiation Oncology (ASTRO), American Society of Clinical Oncology (ASCO), and the American Urological Association (AUA) will soon support for the use of hypofractionation in patients with prostate cancer, explains Howard M. Sandler, MD.

“We’re finalizing our guidelines for hypofractionation, and we're going to strongly endorse the use of moderate hypofractionation in 28 or 20 fractions for most patients with prostate cancer,” said Sandler, who is chairman of the guidelines panel.

The 20-fraction schedule can be given over 4 weeks; however, Sandler says that he prefers hypofractionation in 28 fractions over 5.5 weeks.

Clinical trials such as CHHiP, PROFIT, and RTOG 0415 were integral in demonstrating the effectiveness of hypofractionation in select patients, he added, as they randomized men to hypofractionation of 20 and 28 fractions compared with standard fractionation.

OncLive: What developments have there been in the area of radiation oncology in prostate cancer?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Sandler, chair, Department of Radiation Oncology, Ronald H. Bloom Family Chair in Cancer Therapeutics, director, Samuel Oschin Comprehensive Cancer Institute, and professor of radiation oncology, Cedars-Sinai Medical Center, discussed the emergence of hypofractionation as a viable treatment approach for patients with prostate cancer.Sandler: One of the major trends in prostate cancer is a move toward hypofractionation. In treatment, we’ll use fewer radiation fractions than we used in the past. We would use up to 45 treatments over 9 weeks. That is a long time for individuals to come in every day for radiation therapy treatment. We are excited about the studies published in 2016 and 2017 that showed equivalent outcomes between dramatically shorter regimens and standard fractionation. The 2 regimens that were studied were 20 and 28 fraction regimens. Both studies were compared head to head with standard fractionation and were noninferior to one another.

Can you detail some of the trials that have demonstrated its success?

It's led to the widespread adoption of shorter and more convenient approaches without increasing side effects. It also reduces the overall healthcare expenditures in a patient’s treatment.Over 6000 patients have been randomized to moderate hypofractionation. The largest trial is the phase III CHHiP trial from the United Kingdom that randomized men to either standard radiation fractionation or 2 hypofractionation arms of either 20 or 19 fractions. The 19-fraction arm was inferior. There may not have been enough radiation in the 19-fraction approach, but the 20-fraction approach was the equivalent to standard fractionation.

Is moderate hypofractionation available everywhere, or only at select institutions?

Are there any predictive factors that determine a patient's response to the treatment?

Is there anything to keep in mind with regard to its safety profile?

Another important study is a Canadian study called PROFIT, which compared 2 arms of 20 fractions with a longer standard fractionation without hormonal therapy. Results showed complete equivalence between the 2 arms. Finally, there was a United States study that I participated in called RTOG 0415 that randomized men with low-risk cancer to the now standard 28-fraction approach. The study showed great safety and efficacy, and I've since adopted it. It's very similar to standard radiation. It does not require special equipment or special expertise to do moderate hypofractionation. Because it is a newer technique, it is the recommendation of the guidelines panel to use the same treatment techniques that were outlined in the publications that indicate the safety of moderate hypofractionation. Follow the “recipe,” and you can expect the same good results. Major organizations, such as ASTRO and ASCO, are going to endorse it and that will encourage its adoption. One of the factors that we looked at was patient eligibility. When we looked at the evidence that's been published, we didn’t find any subsets of patients who would not be eligible with one exception. If the radiation oncologist feels that a patient’s lymph nodes need to be treated in addition to the prostate, we don’t recommend the use of hypofractionation. None of the major studies included men who received lymph node radiation, so we don't know whether lymph node radiation is safe to do with hypofractionation. If that’s outlined in a patient’s treatment plan, they should be treated with standard fractionation. It's a very safe option, but I wouldn't call it any safer than standard fractionation. I would definitely call moderate hypofractionation a more convenient option because it can cut the treatment time in half. Patient satisfaction will be high. If you tell a patient that they can come to a radiation center half as often and still get good results, they will be very enthusiastic about it.

What advice would you like to give community oncologists about this soon-to-be recommended approach?

Can this approach be used in patients with oligometastatic disease, as well?

There was some concern about potential toxicity, and that is, in part, why these studies were done. These studies have shown no safety signals, and they have shown no efficacy concerns. It's a win for patients and physicians alike.Prostate cancer is a common treatment in radiation oncology departments. My advice to radiation oncologists is to start thinking about how you can incorporate the treatment into your practice. My advice to medical oncologists and urologic oncologists is to start talking about moderate hypofractionation with your patients. You might find that radiation oncology is a more attractive option for some patients when they realize it can be done in 4 or 5 weeks. The term “oligometastatic disease” came out of an influential editorial written by Samuel Hellman, MD, and Ralph R. Weichselbaum, MD, in the mid 1990s. It's their hypothesis that there is an intermediate stage between localized disease and widely metastatic disease in which patients may have limited metastatic disease and may benefit from additional treatment.

New imaging [techniques] like 18-F fluciclovine PET or prostate-specific membrane antigen-PET have made this very important today. These modalities can, for the first time, identify small-volume prostate cancer of 1 to 5 metastases. If a patient has more than 5 metastases, we call it standard metastatic disease. Otherwise, we now have the option to do metastasis-directed therapy with radiation or with surgery.

It has led to the hypothesis that we can delay time to hormonal therapy. If the Hellman and Weichselbaum hypothesis is true, we can potentially salvage patients by curing their oligometastatic disease. We are in the early stages of proving that hypothesis, and there's a lot of excitement about it.