Hypofractionated Radiation Recommended for Localized Prostate Cancer

Scott Morgan, MD, FRCPC

Scott Morgan, MD, FRCPC

A panel of experts has recommended hypofractionated radiation as an alternative to longer, conventional courses of radiation for men with earlystage prostate cancer who opt for external beam radiation therapy (EBRT) instead of other types of treatment or active surveillance.

The new guidelines from the American Society for Radiation Oncology (ASTRO), the American Society of Clinical Oncology (ASCO), and the American Urological Association (AUA) state that moderate hypofractionation confers similar outcomes for prostate cancer control, similar rates of late toxicity, and only a slight increase in acute gastrointestinal toxicity compared with conventional fractionation. This applies to low-, intermediate-, and high-risk groups, although the panelists noted that evidence beyond 5 years of patient treatment history is scant (Table).¹

Moderate hypofractionation was defined as 240 to 340 cGy per fraction compared with conventional fractionated EBRT of 180 to 200 cGy per fraction. The largest evidentiary base for treatment with moderate hypofractionation covered regimens of 6000 cGy delivered in 20 fractions of 300 cGy and 7000 cGy delivered in 28 fractions of 250 cGy, according to the guidelines.

The updated expert guidelines also state that ultrahypofractionation, an even shorter course of radiation, of 3500 to 3625 cGy in 5 fractions of 700 to 725 cGy, may be offered to patients in the low- to intermediate-risk range with prostate sizes less than 100 cm3; however, the recommendation is conditional, based on moderate quality of evidence and lower consensus among the panelists.

“Men who opt to receive hypofractionated radiation therapy will be able to receive a shorter course of treatment, which is a welcomed benefit to many men,” Scott Morgan, MD, FRCPC, assistant professor in the Division of Radiation Oncology at the University of Ottawa, Canada, and co-chair of the guideline panel, said in a release.² “When clinicians can reduce overall treatment time while maintaining outcomes, it’s to our patients’ benefit, as they can spend less time away from family and less time traveling to and from treatment.”

The 16-member expert panel reviewed data published from December 2001 through March 2017, including findings from 4 large, prospective, randomized clinical trials involving more than 6000 patients. The Society of Urologic Oncology, the European Society for Radiotherapy and Oncology, and the Royal Australian and New Zealand College of Radiologists have also endorsed the guidelines.

This is the first time ASTRO, ASCO, and AUA have issued a joint guideline regarding short-course radiation regimens. Results from several trials including CHHiP, PROFIT, and RTOG-0415 have shown that hypofractionation is a viable alternative to longer, conventional courses of radiation in terms of cancer control, toxicity, and quality of life.

“Conclusive evidence from several large, well-designed randomized trials now confirms that dose escalation can almost universally benefit men with early-stage prostate cancer who choose to manage their disease with external radiation,” Howard M. Sandler, MD, chair and professor of radiation oncology at Cedars-Sinai Medical Center, Los Angeles, California, and cochair of the guideline panel, said in the press release.²

“Significant advances in treatment planning and delivery have enabled oncologists to deliver more powerful, lifesaving doses of radiation in fewer visits and without compromising quality of life,” he added.

The expert panel states that physicians should offer moderate hypofractionation instead of conventional fractionation regardless of patient age, comorbidity, anatomy, and baseline urinary function. That recommendation includes patients with low- or intermediate-risk disease receiving EBRT to the prostate with or without radiation to the seminal vesicles and men with high-risk disease receiving EBRT to the prostate but not the pelvic lymph nodes.

However, experts advise that physicians should make sure patients are aware that there is limited follow-up beyond 5 years in the trials supporting these recommendations. Furthermore, moderate hypofractionation is associated with a small increased risk of acute gastrointestinal toxicity.

The recommendations support a hypofractionation schedule of 6000 cGy delivered in 20 fractions over 4 weeks or 7000 cGy in 28 fractions over 5.6 weeks. The strongest evidence supports 6000 cGy in 20 fractions of 300 cGy because this regimen was used in 2 different randomized trials and was tested in all risk groups, in both the presence and absence of androgen deprivation therapy.

One of those trials was CHHiP, the only study that directly compared hypofractionation regimens. In this trial, 3216 men were treated with radiation at 71 medical centers from October 2002 to June 2011. Patients were randomly assigned to conventional 7400 cGy delivered in 37 fractions over 7.4 weeks (n = 1065), 6000 cGy delivered in 20 fractions over 4 weeks (n = 1074), or 5700 cGy delivered in 19 fractions over 3.8 weeks (n = 1077). Time to biochemical or clinical failure was the primary endpoint. The critical HR for noninferiority was 1.208.³

At 5 years, the proportion of patients in the 6000 cGy group (90.6%; 95% CI, 88.5%-92.3%) who had biochemical or clinical failure was similar to that of the 7400 cGy group (88.3%; 95% CI, 86.0%-90.2%). The 6000 cGy group also proved to be noninferior to the 7400 cGy group (HR, 0.84; 90% CI, 0.68%-1.03%; P = .0018). Also, the 5700 cGy group had inferior cancer control compared with the 6000 cGy group, hence the expert panel’s preference for the larger overall dose.

Table. Panel Recommendations for Men With Localized PC Who Opt for EBRT¹

Ultrahypofractionation

The estimated cumulative incidence of grade ≥2 bowel adverse events (AEs) was 13.7% in the 7400 cGy group compared with 11.9% in the 6000 cGy group. Cumulative incidence of grade ≥2 bladder AEs was 9.1% versus 11.7%, respectively.The expert panel issued a conditional recommendation that men with intermediate-risk disease receive ultrahypofractionation. Because evidence is weaker than in low-risk disease, the panel encouraged more clinical trials. The experts recommended against the routine use of ultrahypofractionation in men with high-risk disease, also because of the paucity of high-quality evidence.

There are no efficacy and toxicity published data from randomized controlled trials comparing ultrahypofractionated and conventionally fractionated EBRT. However, results from prospective nonrandomized studies have shown ultrahypofractionation is safe for patients with prostate volumes ≤100 cm³ and with mild to moderate urinary symptoms at baseline.

The panel found data from 1 cohort study, 1 propensity-matched analysis, and 1 abstract comparing conventional and ultrahypofractionated regimens. Only 2 of those included efficacy data, both evaluating low-risk patients.

Musunuru et al conducted a single-institution cohort study of men treated at Sunnybrook Health Sciences Centre in Toronto, Canada, from January 2006 to December 2008. Patients were managed with active surveillance (n = 181), radical prostatectomy (n = 59), conventional EBRT (n = 66), low-dose-rate brachytherapy with iodine 125 (LDR; n = 192), or ultrahypofractionation (n = 84). The conventional regimen was 7600 cGy administered in 38 fractions over 7.5 weeks. The ultrahypofractionation regimen was 3500 cGy administered in 5 fractions of 700 cGy over 5 weeks.

At a median follow-up of 72.8 months, the biochemical disease-free survival rate (DFS) for ultrahypofractionation was 95.8% versus 92.1% for conventional EBRT.⁴

Image-Guided Radiation Therapy

Loblaw et al conducted a propensity-matched analysis comparing ultrahypofractionation with LDR and conventional fractionation for patients in a multi-institutional Canadian database. Investigators found a 6-year biochemical DFS of 85.9% for conventional fractionation and 100.0% for ultrahypofractionation for the matched patients (P = .045).⁵The panel unanimously recommended the use of image-guided radiation therapy (IGRT) for delivery of moderate or ultrahypofractionated EBRT. Although trial results evaluating the effect of IGRT on local control and/or reduced toxicity have been mixed, the expert panel concluded it is “central to the safe and effective delivery” of both types of hypofractionation.

Results from a phase II substudy of the CHHiP trial showed no significant difference in grade 2 bowel or bladder AEs in patients treated with or without IGRT. However, results published by Gill et al demonstrated a clear safety benefit associated with IGRT. Investigators collected acute toxicity data for 10 symptoms from 291 patients treated for prostate cancer from June 2006 to June 2009. Twenty-six were treated with non-IGRT and 265 were treated with IGRT. Gill et al evaluated 14,228 toxicity scores from 249 patients in the IGRT arm and 1893 toxicity scores from all 26 non-IGRT patients.⁶

The rates of grade ≥3 urinary frequency (23% vs 7%; P = .0188), grade ≥2 diarrhea (15% vs 3%; P = .0174), and grade ≥2 fatigue (23% vs 8%; P = .0271) were all lower in the IGRT arm.

“Image guidance and other advances in radiation therapy delivery have enabled radiation oncologists to treat prostate cancer with a therapeutic dose of radiation in a shorter treatment period than was previously possible,” Daniel Barocas, MD, associate professor in the Department of Urologic Surgery at Vanderbilt University Medical Center and guideline co-author, said in the statement.²

References

1. Morgan SC, Hoffman K, Loblaw DA, et al. Hypofractionated radiation therapy for localized prostate cancer: An ASTRO, ASCO, and AUA evidence-based guideline [published online October 11, 2018]. J Clin Oncol. doi: 10.1200/JCO.18.01097
2. New ASTRO/ASCO/AUA guideline for early-stage prostate cancer supports use of shortened courses of radiation therapy [news release]. American Society of Clinical Oncology. October 11, 2018. asco.org/about-asco/press-center/news-releases/new-astroascoaua-guideline-early-stage-prostate-cancer. Accessed November 4, 2018.
3. Dearnaley D, Syndikus I, Mossop H, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 2016;17(8):1047-1060. doi: 10.1016/S1470-2045(16)30102-4
4. Musunuru HB, Klotz L, Vesprini D, et al: Comparison of contemporary treatment options for early prostate cancer: A single institution series. Austin J Rad Onc & Ca. 2016;2(1):1-7. google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=2ahUKEwiqnfb0tbveAhWHjFQKHdtSDkcQFjAAegQIARAC&url=http%3A%2F%2Faustinpublishinggroup.com%2Fradiation-oncology-cancer%2Fdownload.php%3Ffile%3Dfulltext%2Fajroc-v2-id1018.pdf&usg=AOvVaw0DErTr7yulDeo9FUcRpp0O
5. Loblaw A, Pickles T, Crook J, et al: Stereotactic ablative radiotherapy versus low dose rate brachytherapy or external beam radiotherapy: Propensity score matched analyses of Canadian data. Clin Oncol (R Coll Radiol). 2017; 29:161-170. doi: 10.1016/j.clon.2016.10.001
6. Gill S, Thomas J, Fox C, et al. Acute toxicity in prostate cancer patients treated with and without image-guided radiotherapy. Radiat Oncol. 2011; 6:145. doi: 10.1186/1748-717X-6-145