It will come as no surprise to my readers that moderately hypofractionated IMRT (first-line radiation delivered in 20-26 treatments or fractions instead of the conventional 40-44 fractions) received strong endorsement from all of the major US organizations of physicians who treat prostate cancer. The American Society for Radiation Oncology (ASTRO), in collaboration with the American Society of Clinical Oncology (ASCO) and the American Urological Association (AUA) issued the new guidelines, which are also supported by the Society of Urologic Oncology (SUO), European Society for Radiotherapy & Oncology (ESTRO), and Royal Australian and New Zealand College of Radiologists.
A hypofractionation task force issued the new evidence-based guidelines. They divided their guidelines into two parts: (1) moderately hypofractionated IMRT (20-26 fractions); (2) ultrahypofractionated IMRT (4-5 fractions), usually called SBRT, SABR, SHARP, or CyberKnife (I will refer to it as SBRT). They strongly support moderate hypofractionation. They conditionally support SBRT, because of the moderate degree of evidence published by their cut-off date of March 31, 2017. They may revisit those guidelines after further review.
The following guidelines were strongly endorsed based on high quality evidence with strong consensus:
1A: Low risk men who refuse active surveillance should be offered moderately hypofractionated IMRT.
1B: Intermediate risk men should be offered moderately hypofractionated IMRT.
1C: High risk men should be offered moderately hypofractionated IMRT.
1D: Moderate hypofractionation should be offered regardless of patient age, comorbidity, anatomy, or urinary function. However, physicians should discuss the limited follow-up beyond five years for most existing RCTs evaluating moderate hypofractionation. *
1E: Men should be counseled about the small increased risk of acute gastrointestinal (GI) toxicity with moderate hypofractionation. Moderately hypofractionated EBRT has a similar risk of acute and late genitourinary (GU) and late GI toxicity compared to conventionally fractionated EBRT. However, physicians should discuss the limited follow-up beyond five years for most existing RCTs evaluating moderate hypofractionation.*
The following guidelines were strongly endorsed based on moderate quality evidence with strong consensus:
7A: Image guidance (e.g., fiducials, transponders, cone beam CT, etc.) should be used for both moderate hypofractionation and SBRT.†
8A: 3D-CRT should not be used with hypofractionation.§
The following guidelines were conditionally endorsed based on moderate quality evidence with strong consensus:
2A: 60 Gy in 20 fractions or 70 Gy in 28 fractions are suggested for moderate hypofractionation.
2B: No variation in treatment regimen by patient age, comorbidity, anatomy, or urinary function.
3A: Low risk men who refuse active surveillance should be offered SBRT
4A: The SBRT dose for low and intermediate risk men should be 35 Gy - 36.25 Gy in 5 fractions.**
4B: SBRT doses of 36.25 Gy in 5 fractions should not be exceeded outside of a clinical trial or registry.**
5A: At least two dose-volume constraint points for rectum and bladder should be used for moderate hypofractionation or SBRT: one at the high-dose end (near the total dose prescribed) and one in the mid-dose range (near the midpoint of the total dose).
The following guidelines were conditionally endorsed based on low quality evidence with strong consensus:
3B: Intermediate risk men should be offered SBRT, but should be encouraged to do so in a clinical trial or registry.**
3C: High risk men should be not be offered SBRT outside of a clinical trial or registry.
4C: Daily SBRT treatment is not recommended due to increased risk of toxicity.
5B: Normal dose/volume constraints used in the reference study should be adhered to for both moderate hypofractionation and SBRT
The following guideline was strongly endorsed based on low quality evidence with strong consensus:
6A: Planned target volume definition of the reference study should be adhered to for both moderately hypofractionated IMRT and SBRT.††
* While most of the hypofractionation trials did not report beyond 5 years of follow-up (see Table at this link), some did. The Archangeli et al. trial reported survival outcomes out to ten years. (I believe the guideline authors erred about this.) M.D. Anderson published an eight-year update after the close of the task force review. As we saw in our review of RTOG 0126, survival does not become a useful endpoint for perhaps 15-20 years for men with localized prostate cancer, and surrogate endpoints, such as 5-year recurrence-free survival or metastasis-free survival must be used instead. Kishan et al. proposed that for ultrahypofractionated regimens, 3-year PSA may be an excellent surrogate endpoint. The ProtecT clinical trial showed that adverse effects of radiation almost always show up in the first two years.
† For the disaster that can ensue when fiducials are not used with SBRT, see this link. The guidelines should state that intra-fractional motion tracking should be used with SBRT.
§ In the recently presented (not published in time for these guidelines) randomized clinical trial of ulrahypofractionated RT vs conventionally fractionated RT, they did use 3D-CRT in both arms. There was no difference in 5-year biochemical recurrence-free survival or 6-year toxicity.
** In a large, multi-institutional clinical trial (too late to make it into these guidelines), Meier et al. reported excellent 5-year oncological and toxicity outcomes using 40 Gy in 5 fractions. In SBRT dose escalation trials, both Zimmerman at UT Southwestern (reported here) and Zelefsky at MSKCC (I've heard from his patients) found that 45 Gy in 5 fractions gave excellent oncological and toxicity outcomes. The task force neglected the fact that prescribed doses are reported differently by different ROs. Alan Katz, for example, reports a prescribed dose of 35 Gy to the planned target volume (the prostate plus the margin around it), but the clinical target volume (the prostate itself) gets about 38 Gy, while the margin gets considerably less.
†† Smaller margins are possible when fiducials are used for intra-fractional tracking. Tighter margins cause less toxicity to organs at risk.
Sadly, the effect of hypofractionation on erectile function was seldom reported and was not part of the task force's analysis.
It is worth noting that conventionally fractionated IMRT became the standard of care without any comparative clinical trials. The longest running single institution dose-escalated IMRT trial (at MSKCC) had 10 years of follow-up on a small sample size (n=170). By contrast, Alan Katz is expected to report 10-year SBRT outcomes this year on 515 patients. The task force is holding SBRT to a higher standard that by this time next year, it should have the published results to meet.
While the task force endorsed moderate hypofractionation, we will have to see whether radiation oncologists (ROs) follow their guidelines. Because ROs are reimbursed by the number of fractions they give, they will be understandably reluctant to reduce the number of fractions. It remains to be seen whether insurance companies will enforce a limit. It is a clear benefit to the patient in terms of convenience and cost.