SBRT has excellent outcomes for intermediate risk patients

Stereotactic Body Radiation Therapy (SBRT, or sometimes SABR or SHARP or CyberKnife) has had excellent 7-year outcomes in an update of the consortium study. Amar Kishan presented the results of his analysis at the ASTRO meeting today.

The consortium consisted of

1 Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, USA
2 Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA
3 Flushing Radiation Oncology Services, Flushing, NY, USA
4 21st Century Oncology, Fort Myers, FL, USA
5 Department of Radiation Oncology, Georgetown University, Washington, DC., USA
6 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
7 Division of Genesis Healthcare Partners Inc., CyberKnife Centers of San Diego Inc., San Diego, CA, USA
8 Swedish Radiosurgery Center, Seattle, WA, USA.
9 Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON,
Canada.
10 Section of Radiation Oncology, Virginia Mason Medical Center, Seattle, WA, USA
11 Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
12 Department of Radiation Oncology, University of Michigan
13 Scripps Health, 11025 North Torrey Pines Road, La Jolla, CA, USA
14 Virginia Hospital Center, 1701 N. George Mason Dr, Arlington, VA, USA

The meta-analysis covers 2,142 low (n=1,185) and intermediate-risk men treated with SBRT between 2003 and 2012. Intermediate risk men were further subdivided into "favorable intermediate risk" (n=692) and "unfavorable intermediate risk" (n=265) per the NCCN definition.

After a median follow-up of 6.9 years, the 7-year biochemical recurrence-free survival was:

• low risk: 95.5%
• favorable intermediate risk: 91.4%
• unfavorable intermediate risk: 85.1%
• all intermediate risk: 89.8%

Low risk patients and some of the favorable intermediate risk patients would probably be diverted to active surveillance today. The 7-year intermediate risk biochemical recurrence-free survival compares favorably with (note: this is not a randomized comparison, which is the only valid way of comparing):

• Surgery: favorable intermediate risk (PSA=6.0, T1c, GS 3+4, 33% cancerous cores): 81% (mean of 5 and 10-yr Progression-free survival) (1)
• Surgery: unfavorable intermediate risk (PSA=6.0, T1c, GS 4+3, 67% cancerous cores): 53% (mean of 5 and 10-yr Progression-free survival) (1)
• Hypofractionated IMRT (5 year):  85% (2)
• Conventional IMRT (5 year): 85% (2)
• Low dose rate brachytherapy: favorable intermediate risk (avg of 5 and 10-yr): 87% (3)
• Low dose rate brachytherapy: unfavorable intermediate risk (5-year): 81% (3)
• Brachy boost therapy: unfavorable intermediate risk (10 year): 92% (4)

7-year metastasis-free survival was:

• low risk: 99.9%
• favorable intermediate risk: 98.3%
• unfavorable intermediate risk: 97.0%
• all intermediate risk: 98.0%

There were no prostate cancer-related deaths.

Use of ADT and higher doses (doses ranged from 33 Gy to 40 Gy in 4 or 5 treatments) did not affect recurrence.

Acute (within 3 months of treatment) toxicity was low:

• Urinary toxicity Grade 2: 8.8% Grade 3: 0.6%
• Rectal toxicity Grade 2: 3.2% Grade 3: 0.1%

Late-term cumulative toxicity was low:

• Urinary toxicity Grade 2: 9.4% Grade 3+: 2.1%
• Rectal toxicity Grade 2: 3.9% Grade 3+: 0.4%

Late-term grade 3 or greater urinary toxicity of 2.1% compares favorably to other radiation monotherapies reported in other studies. For example:

• Low dose rate brachytherapy: 7.6% (5)
• High dose rate brachytherapy (3 fractions):11% (6)
• Hypofractionated IMRT (70 Gy/28 fx): 3.5% (7)
• Conventionally fractionated IMRT: 2.3% (7)
• Brachy boost therapy: 19% (8)

Late-term grade 3 or greater rectal toxicity of 0.4% compares favorably to other radiation monotherapies reported in other studies. For example:

• Low dose rate brachytherapy: 0.8% (5)
• High dose rate brachytherapy (3 fractions):1% (6)
• Hypofractionated IMRT (70 Gy/28 fx): 4.1% (7)
• Conventionally IMRT: 2.6% (7)
• Brachy boost therapy: 9% (8)

This 7-year analysis on a large group of patients from multiple sites, should make intermediate risk patients comfortable in choosing SBRT, especially if they are favorable intermediate risk. For patients who are unfavorable intermediate risk, brachy boost therapy affords incomparable oncological control, but at the risk of much higher late term urinary and rectal toxicity.

ASTRO, ASCO, & AUA strongly endorse a shortened course of IMRT for primary therapy

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.

First randomized clinical trial of SBRT

In the first trial ever to randomly assign patients to extreme hypofractionation, primary radiation therapy delivered in just 7 treatments had the same effectiveness and safety as 39 treatments.

The results of the HYPO-RT-PC randomized clinical trial were published in The Lancet. There was an earlier report on toxicity. Details of the trial specs are available here. Between 2005 and 2015, they enrolled 1200 intermediate- and high-risk patients at 12 centers in Sweden and Denmark to receive either:

1. Conventional fractionation: 78 Gy in 39 fractions
2. SBRT (stereotactic body radiation therapy): 42.7 Gy in 7 fractions

The biologically effective dose is 19% higher for SBRT in terms of cancer control. The biologically effective doses are equivalent in terms of toxicity.

The patients were all intermediate (89%) to high risk (11%), defined as:

1. Stage T1c-T3a
2. PSA> 10 ng/ml 
3. Gleason score ≥7

80% of the men were treated with a technology called three-dimensional conformal radiation therapy (3D-CRT), which is seldom used for prostate cancer external beam therapy anymore at major tertiary care centers. It is never used for SBRT in the US because it is considered not precise enough, and too toxic. SBRT is usually delivered in 4 or 5 fractions in the US. CyberKnife and VMAT are the most common technologies in use, and use of sophisticated image guidance throughout each treatment is a common practice.

With follow-up of 1,180 patients for 5 years, they report biochemical recurrence-free survival of 84% in both arms of the study.

They also reported updated late-toxicity results. By 5 years after treatment:

• Grade 2+ urinary toxicity was 5% for conventional fractionation, 5% for SBRT - no significant difference.
• Grade 2+ rectal toxicity was 4% for conventional fractionation, 1% for SBRT - no significant difference.

Up until now, we've only had reports from clinical trials using SBRT (like this one) or conventional fractionation (like this one), and it could have been reasonably argued that SBRT results looked good because of selection bias. With this study, we now have Level 1 evidence of non-inferiority. This will not be surprising to those of us who have followed the randomized clinical trials of moderately hypofractionation vs. conventional fractionation (see this link). This will be hailed as a victory for patients who no longer have to endure and pay the high cost of 8 weeks of treatments. radiation oncologists, who are reimbursed by the number of treatments they deliver, probably will not be as thrilled.

Erectile Function after SBRT

Erectile function after radiation is of great interest to many men trying to decide between surgery and radiation, and to decide among the several radiation treatment options. Dess et al. reported the outcomes of men who received stereotactic body radiation therapy (SBRT), often known by the brand name CyberKnife.

Between 2008 and 2013, 273 patients with localized prostate cancer were treated at Georgetown University. All patients filled out the EPIC questionnaire at baseline, which includes several questions on erectile function. The authors focused on the question asking whether erections were firm enough for intercourse, irrespective of whether they used ED meds. A similar questionnaire, SHIM, was also used, but results were similar. Answers were tracked over time with analyses at 2 years and at 5 years. Importantly, the median age at baseline was 69 years. At 2 years:

• About half the men had functional erections at baseline
• Among those with functional erections at baseline, 57% retained potency
• The largest loss occurred by 3 months after treatment, with about 2/3 retaining potency at 3 months
• 2/3 retained potency at 3 months regardless of age
• Men under 65 suffered no further loss of potency, even after 5 years
• Men 65 and over continued to lose potency
• About half retained potency at 2 years
• About 40% retained potency at 5 years

The authors also looked at other causes of erectile dysfunction, including partner status, BMI, diabetes, cardiovascular disease,  depression, baseline testosterone levels, and baseline use of ED meds. None of those, except BMI, had a statistically significant effect in this patient population at 2 years post treatment.  Some gained importance by 5 years, but because they are age dependent, and also affect baseline ED, none except BMI were independently important after baseline function and age were accounted for. A few known risk factors for ED were not included: medications (e.g., beta blockers, testosterone supplementation, etc.), smoking, and substance abuse. Some of that data was collected and may be included in a subsequent analysis.

There is a source of statistical error called colinearity, which arises when 2 variables, like baseline potency and age, are substantially interlinked. Although they were independently associated with erectile function, there is considerable overlap, especially when patient age was over the median (69). It may be useful to separate the effect of one from the other. This is accomplished by using age-adjusted baseline erectile function in the same way that economists look at inflation-adjusted GNP. I hope the authors will look at this. As we saw, an analysis of brachytherapy utilizing a different technique showed that half of the loss of potency among men who had brachytherapy was due to aging.

The effect of age on potency preservation cannot be overemphasized. Undoubtedly, radiation can cause fibrosis in the penile artery, and fibrosis is worse in older men. But, contrary to a prevalent myth, those radiation effects occur very early. Following that early decline, the declines in potency are primarily attributable to the normal effects of aging (which include occlusion of the vasculature supplying the penis.) As we've seen in other studies, most of the radiation-induced ED will show up within the first two years, and probably within 9 months of treatment. This was shown for 3D-CRT in the  ProtecT clinical trial,  for brachytherapy, for SBRT, and for EBRT.

Looking at other reports of potency preservation following SBRT, the Georgetown experience (57% potency preservation) seems to be on the low end. There has only been one report of lower potency preservation: 40% at 3 years among 32 patients. An earlier report from Georgetown reported 2-year potency preservation at 79% at 24 months. Dr. Dess explained that the earlier report included men with lower potency at baseline. However, because baseline potency is highly associated with post-treatment potency, the outcomes should be in the other direction. The discrepant data are puzzling. At 38 months post treatment, Bernetich et al. reported potency preservation in 94% among 48 treated patients. Friedland et al.  reported 2-year potency preservation at 82%. Katz reported potency preservation of 87% at 18 months. Although, different patient groups may respond differently, it is difficult to understand why potency preservation was so much lower in the current study. These discrepancies argue for a more standardized approach to analyzing erectile function after treatment, and the present study makes a good start towards that goal.

Compared to other radiation therapies, SBRT fares well. Evans et al. looked at SBRT at Georgetown and two 21st Century Oncology locations and compared it to low dose rate brachytherapy (LDR-BT) and IMRT as reported in the PROSTQA study. At 2 years, among patients who had good sexual function at baseline, EPIC scores declined by 14 points for SBRT, 21 points for IMRT, and 24 points for LDR-BT( the minimum clinically detectable change on that measure is 10-12 points). There has been only one randomized trial comparing extreme hypofractionation to moderate hypofractionation. In that Scandinavian trial, they used an older technique called 3D-CRT, which would never be used today to deliver extreme hypofractionation (at least I hope not!). In spite of the outmoded technology, sexual side effects of of the two treatments were not different. In an analysis from Johnson et al. comparing SBRT and hypofractionated IMRT, the percent of patients reporting minimally detectable differences in sexual function scores was statistically indistinguishable in spite of the SBRT patients being 5 years older.

Dess et al. also looked at sexual aid utilization in a separate study on the effect of SBRT. They found:

• 37% were already using sexual aids at baseline
• 51% were using sexual aids at 2 years
• 55% were using sexual aids at 5 years
• 89% of users say they were helped by them at baseline, 2 years and 5 years
• 86% used PDE5 inhibitors only (i.e., Viagra, Cialis, Levitra or Stendra)
• 14% combined a PDE5 inhibitor with other sexual aids (e.g., Trimix, MUSE, or a vacuum pump)

Erectile function is well-preserved following SBRT, and seems to be as good or better than after IMRT, moderately hypofractionated IMRT, or LDR brachytherapy. Based on reports of a protective effect of a PDE5 inhibitor, patients should discuss their use with their radiation oncologist starting 3 days before radiation and continuing for 6 months after. High levels of exercise and frequent masturbation may have protective effects as well.

With thanks to Daniel Spratt and Robert Dess for allowing me to see the full texts of their studies

Questions to ask an SBRT doctor

SBRT doctor questions

1.     How many have you performed?

2.    How has your practice of SBRT changed over the years?

3.    What is your 5-yr freedom from recurrence rate for patients at my risk level? What proportion of your recurrences were local-only?

4.    What kind of urinary and rectal reactions can I expect? How long can I expect them to last? What medications or interventions do you typically give for that? Should I expect those symptoms to recur later?

5.     What is your rate of serious (Grade 3) adverse events? Do you see urinary strictures? Urinary retention requiring catheterization? Fistulas? Rectal bleeding requiring argon plasma or other interventions?

6.    What is the margin you will treat around the prostate? Is it less on the rectal side?

7.     What is the prescribed dose to the planned target volume?

8.    Do you work off a fused MRI/CT scan?

9.    What machine do you use (e.g., VMAT, CyberKnife, step-and-shoot, Tomotherapy, etc.)?

·      If CyberKnife: Do you use the IRIS or a new multileaf collimator?

·      Do you set a limit on “hot spots”?

10.  Do you use fiducials or Calypso transponders? Do you do transperineal placement of them?

o   What system do you use for inter-fractional tracking?

o   What system do you use for intra-fractional tracking?

11.   In my treatment plan, what do you identify as “organs at risk” and what dose constraints do you put on them?

o   What dose will my penile bulb receive?

12.  How long does each treatment take?

13.  How will I be immobilized during each treatment?

14.  Are there any bowel prep or dietary requirements?

15.  Should I avoid taking antioxidant supplements during treatment?

16.  In your practice, among men who were fully potent, what percent remained fully potent 3-5 years later?

o   Have any men retained some ability to produce semen?

o   What is your opinion of taking Viagra preventatively?

17.  Do you monitor side effects with the EPIC questionnaire?

o   In your practice, what percent of men experience acute urinary side effects?

o   In your practice, what percent of men experience acute rectal side effects?

o   In your practice, what percent of men experience late term urinary side effects?

o   In your practice, what percent of men experience late term rectal side effects?

18.  What kind of PSA pattern should I expect following treatment?

19.  What is the median PSA nadir you are seeing in your practice, and how long does it take to reach that, on the average?

20. In your practice, what percent of men experience biochemical recurrence?

o   What % of those have been local?

o   If there should be a biochemical (PSA) recurrence, what would the next steps be?

o   Have you ever used SBRT, brachy, or cryo for salvage after a local SBRT failure, and was that focal or whole gland?

21.  Are you open to email communications between us?