Can surgery+radiation+ADT provide equal outcomes to brachy boost therapy +ADT in high risk men?

As we saw (see this link) among men with Gleason 9 or 10, brachy boost therapy (BBT: external beam radiation with a brachytherapy boost to the prostate) was shown to provide better oncological outcomes (10-year metastasis-free survival and 10-year prostate cancer-specific mortality (PCSM)) compared to surgery (RP) or external beam radiation (EBRT) alone. Some researchers argue that the comparison was unfair. In that study, 43% of the RP patients received adjuvant or salvage radiation, and virtually all of the BBT patients received 1 year of adjuvant ADT. What if ALL of the RP patients were to receive radiation and ADT?

Tilki et al. did a retrospective study to answer that question. They looked at two groups of Gleason 9/10 patients treated at two institutions between 1992 and 2013:

• 559 men received RP+pelvic lymph node dissection (PLND) at the Martini-Klinik Cancer Center in Hamburg
• 88 received adjuvant EBRT
• 49 received adjuvant ADT
• 50 received both (called MaxRP)
• Median ADT duration - 8.6 months in 49 men with negative lymph nodes
• Median ADT duration - 14.5 months in 39 men with positive lymph nodes

• 80 men received BBT+ADT (called MaxRT) at the Chicago Prostate Center
• Median ADT duration - 6 months

After 5.5 years of median follow-up for MaxRT and 4.8 years of median
follow-up for those receiving RP, they found that the risk of PCSM compared to MaxRT was:

• 2.8 times greater for any RP (statistically significant)
• 0.5 times less for RP+adjuvant EBRT (not statistically significant)
• 3.2 times greater for RP+adjuvant ADT (statistically significant)
• 1.3 times greater for MaxRP (not statistically significant)

The 5-year PCSM was:

• 2% for MaxRT
• 22% for any RP (significantly higher than MaxRT)
• 4% for RP+adjuvant EBRT (not significantly different from MaxRT)
• 27% for RP+adjuvant ADT (significantly higher than MaxRT)
• 10% for MaxRP (not significantly different from MaxRT)

They computed a 76% chance ("plausibility index") that the PCSM was plausibly the same for MaxRT vs. MaxRP.

Kishan et al. supplied numbers from his study that are more directly comparable. They are shown in the table below.

Study	Tilki	Kishan
Sample size	BBT: 80 RP+EBRT: 88 RP+ADT: 49 RP+EBRT+ADT: 50	BBT: 436 RP+EBRT: 272 RP+ADT: 175
ADT duration (median)	BBT: 6 months RP (N1): 14.5 mos. RP (N0): 8.6 mos.	BBT: 12 months
Among RP,% N1	44%	17%
5-year % PCSM	RP (any): 22% BBT: 2%	RP (any): 12% BBT: 3%
Adjusted PCSM Hazard Ratio compared to BBT:	RP+ADT: 3.2 RP+EBRT: 0.5 (not sig.)	RP+ADT: 3.2 RP+EBRT: 2.0

We see that the two studies are really not comparable in some respects. The Kishan study was much larger, and was done among many of the top institutions. The Hamburg patients had a much higher percent of positive lymph nodes, and their mortality was twice as high as in the Kishan study. The Chicago patients only got half as much ADT vs. the Kishan study. Importantly, the Kishan study found that RP+EBRT had PCSM that was twice as high as BBT, while the Tilki study showed no statistically significant difference.

Another important aspect was not reported in either study - the toxicity of treatment. We know that surgery plus radiation has worse urinary and sexual side effects compared to surgery alone.BBT carries risk of higher late-term urinary side effects compared to EBRT alone.

Until we have a randomized clinical trial of BBT vs MaxRP, we will never have certainty, but for now, the Kishan study better reflects expected outcomes of these therapies at top institutions.

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.

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.

Brachy boost therapy and surgery extend survival about the same in high risk patients, but brachy boost does more

Two retrospective studies were published in the last week, and they had some similar findings, but some dissimilar things to say about which treatment is best for high risk prostate cancer. The three therapies they looked at were the combination of brachytherapy and external beam radiation (brachy boost therapy - BBT), external beam therapy alone (EBRT), and surgery (RP).

Kishan et al. reported on 1,809 men with Gleason score of 9 or 10 who were treated between 2000 and 2013 at 12 tertiary cancer care institutions (UCLA, Los Angeles VA, California Endocurie Therapy Center, Fox Chase, Mt. Sinai, Cleveland Clinic, Wheeling Jesuit University, University of Michigan, Johns Hopkins, Oslo University, William Beaumont Hospital, and Dana-Farber).

Patient characteristics:

• 639 were treated with radical prostatectomy (RP).
• 734 were treated with EBRT only.
• 436 were treated with BBT (BT was either low dose rate in 62% or high dose rate in 38%).
• All patients were Gleason 9 or 10 on biopsy.
• Pelvic LN involvement was discovered in 17% of RP patients ; 40% had positive surgical margins.
• RP patients were younger (61 years of age) compared to EBRT or BBT patients (68 years of age)
• RP patients were lower stage ( 87% clinical stage T1/T2) compared to EBRT (70% clinical stage T1/T2 ) or BBT patients (79% clinical stage T1/T2)
• RP patients had lower pre-therapy PSA (7 ng/ml) compared to EBRT or BBT patients (10 ng/ml)
• RP patients had lower percentage of Gleason score 10 (4%) compared to EBRT (6%) or BBT patients (9%)

Treatment specs

• Among the RP patients, 43% had adjuvant or salvage radiation therapy (68 Gy).
• Among radiation patients, about 90% had adjuvant ADT
• Median dose of EBRT was 74 Gy.
• adjuvant ADT continued for 22 months, median.
• Median equivalent dose of EBRT+BT was 92 Gy
• adjuvant ADT continued for 12 months.

Oncological outcomes

After a median follow-up of 4.2, 5.1 and 6.3 years for RP, EBRT, and BBT, respectively, the oncological outcomes (adjusted for age and disease characteristics) were as follows:

• The 10-year rates of distant metastases were
  • 46% for RP 
  • 44% for EBRT
  • 13% for BBT
  • Differences between BBT and the two others were statistically significant.


• The 10-year rates of prostate cancer-specific mortality (PCSM) were
  • 23% for RP
  • 26% for EBRT
  • 13% for EBRT + BT
  • Differences between BBT and the two others were statistically significant.


• The 10-year rates of all-cause mortality (ACM) were
• 32% for RP
• 39% for EBRT
• 31% for BBT
• None of the differences were statistically significant.
• There was a difference at 7.5 years in favor of BBT that vanished by 10 years.

In additional analyses, the authors looked at outcomes by duration of androgen deprivation for those receiving any kind of radiation. They found that ADT duration made no significant difference in detected metastases or PCSM within EBRT or BBT, and did not account for the difference between them. They also looked at radiation doses. EBRT patients who received <70 Gy had PCSM significantly worse than those who received ≥ 78 Gy. The rates of metastases did not differ. Notably, very few (11%) of the EBRT patients had both ≥ 78 Gy and ≥2 years of ADT, a combination that is now considered standard of care. Those that did had superior outcomes compared to RP. The use of LDR-BT or HDR-BT as part of BBT made no difference.

The authors conclude:

Among patients with Gleason score 9-10 prostate cancer, treatment with EBRT+BT with androgen deprivation therapy was associated with significantly better prostate cancer–specific mortality and longer time to distant metastasis compared with EBRT with androgen deprivation therapy or with RP.

In an analysis of the National Cancer Database, Ennis et al. reported on the overall survival of patients who were treated with RP, EBRT, and BBT for high-risk PC from 2004 to 2013. The database covers about 70% of all new prostate cancer patients treated in the US. The patient profile was:

• 24,688 patients treated with RP, at least at first
• 15,435 patients treated with EBRT
• 2,642 patients treated with BBT.
• All EBRT patients also had adjuvant ADT
• BBT patients may or may not have had ADT
• All were high risk by the NCCN definition: Either Gleason score 8-10, stage T3/4, or PSA≥20 ng/ml
• RP patients were younger (62 years of age) compared to EBRT (70 years of age) or BBT patients (67 years of age)
• RP patients were lower stage ( 89% clinical stage T1/T2) compared to EBRT (84% clinical stage T1/T2 ) or BBT patients (85% clinical stage T1/T2)
• RP patients had lower pre-therapy mean PSA (19 ng/ml) compared to EBRT (23 ng/ml) but the same as BBT patients (19 ng/ml)
• RP patients had lower percentage of Gleason score 8-10 (70%) compared to EBRT (78%) or BBT patients (73%)
• Comorbidities were similar among groups.
• The above risk factors as well as socioeconomic factors and year of diagnosis were used to adjust the raw data.
• It is unknown what percent of RP patients had adjuvant or salvage radiation.
• There was no data available on post-reatment metastases or prostate cancer-specific survival

Because surgery is sometimes aborted when pelvic LN cancer is discovered, they estimated the probability that patients had positive nodes, and included it as a risk factor. This would seem to double count those risk factors, but the authors say it had little effect. Based on their model, they estimated that the percent who had positive nodes was 10% of RP patients, 34% of EBRT patients, and 23% of BBT patients.

After a median follow-up of 36 months, the relative oncological outcomes (adjusted for age and other patient and disease characteristics), expressed as hazard ratios were as follows:

• RP: 1.0
• EBRT: 1.53 (i.e., 53% worse survival vs. RP)
• EBRT with < 79.2 Gy: 1.68
• EBRT with ≥79.2 Gy: 1.33
• BBT: 1.17 (not significantly different from RP)
• not different if ADT included
• no interaction between comorbidities and treatment effects

The authors conclude:

This analysis showed no statistical difference in survival between patients treated with RP versus EBRT plus brachytherapy with or without AD. EBRT plus AD was associated with lower survival. 

In an accompanying editorial, Ronald Chen discusses the problem of drawing conclusions about comparative effectiveness from this kind of registry data in the absence of clinical trial data. He points out that patient selection criteria are not completely reflected in comorbidity data. He believes that those who are selected for EBRT are just less healthy than those who can undergo anesthesia for surgery or brachytherapy. Other unmeasured confounders include burden of disease, and patient and physician preferences.

The two studies had similar conclusions, but tell us different things. They both found no effect of treatment on overall survival. Lest one walk away thinking it then doesn't matter, the experience of living with painful, crippling metastases and the experience of dying from prostate cancer are horrific in themselves. In the Kishan study among top institutions, there is greater confidence than in many studies that deaths due to prostate cancer could be distinguished from death from other causes. Still, overall survival is impaired in patients with cancer, even if the cancer itself isn't the ultimate cause of death.

Although several randomized clinical trials (RCTs) have demonstrated significant improvements in progression-free survival from BBT compared to EBRT, none have yet demonstrated improvements in overall survival. We saw this recently in the 2005 Sathya RCT. But the prostate cancer-specific mortality advantage of BBT has been confirmed in another study. In a recent analysis of the SEER database, PCSM was 40% higher among patients who had EBRT compared to those who had BBT.

Other than the lack of metastasis data and PCSM in the NCDB, there were other important differences between the two studies. In the Ennis study, only 25%-35% were gleason 9 or 10, whereas all were in the Kishan study. Other differences included the lack of comorbidity data in the Kishan study, and the lack of adjuvant/salvage radiation data in the Ennis study.

Prostate cancer-specific mortality rates were cut in half by BBT, and metastases were only a fraction compared to the other treatments. While this does not prove causality (only a randomized clinical trial can do that), it is highly suggestive that escalated dose can provide lasting cures. There may be good reasons why some high risk patients may have to forgo brachy boost therapy in favor of high dose EBRT or RP with adjuvant EBRT, but for most, brachy boost therapy will probably be the best choice. Patients who are treated with EBRT only, should receive a radiation dose of at least 79.2 Gy and two years of adjuvant ADT.

Sadly, a recent analysis of the National Cancer Database showed that utilization of brachy boost therapy for high risk patients has declined precipitously from 28% in 2004 to 11% in 2013. If a patient sees anyone other than the first urologist, he often only sees a single radiation oncologist who only informs him about IMRT. In most parts of the US, there is a dearth of experienced brachytherapists.

- with thanks to Amar Kishan for allowing me to see the full text.

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

Record 10-year SBRT study among low risk patients

Alan Katz has now published the study with the longest-running follow-up of any study of external beam radiation therapy for prostate cancer among low risk patients, in this case, using SBRT. 10-year follow-up among intermediate and high-risk patients will be presented at next year's ASTRO meeting. This study ties in longest length of follow-up with the Memorial Sloan Kettering (MSK) study of IMRT. IMRT involves 40-45 radiation treatments over the course of about 9 weeks; SBRT shortens the number of treatments to 4 or 5 over the course of about 11 days.

Focusing on their low risk cohort only, the Katz study has a distinct advantage over the MSK study in sample size:

• The Katz study started with 230 low risk patients and, because of later start dates and some loss to follow-up, had 57 evaluable low-risk patients who were tracked for 10 years.
• The MSK study started with 49 low risk patients and, because of later start dates and loss to follow-up, ended with only 2 patients tracked for 10 years.
• Median follow-up was 108 months for Katz and 99 months for MSK

The IMRT study used a prescribed dose of 81 Gy in 45 fractions. The Katz study used a dose of 35 Gy in 5 fractions on 42 patients and 36.25 Gy in 5 fractions on 188 patients (average = 36 Gy). The biologically effective dose for cancer control was 17% higher in the Katz study.

It is risky to compare SBRT and IMRT when patients are not randomized to treatment with one or the other. There has been such a randomized trial, and partial results have been reported (see this link). The median age was the same in both studies (69 years of age), and the same definitions for the low risk category, and for biochemical failure were used. To highlight some of the differences and similarities in outcome:

• 10-year biochemical disease-free survival was 94% for Katz vs. 81% for MSK
• 10-year distant metastasis free-survival was 98.4% for Katz and 100% for MSK
• No prostate cancer-related deaths at 10 years in either study

Late-term urinary and rectal side effects were infrequent and mild in both studies:

• Late-term urinary side effects:
• Grade 2: 9%, Grade 3: 3% in the Katz study
• Grade 2: 9%, Grade 3: 5% in the MSK study
• Late-term rectal side effects:
• Grade 2: 4%, Grade 3: 0% in the Katz study
• Grade 2: 2%, Grade 3: 1% in the MSK study

Of those who were previously potent before radiation, 56% were potent (sufficient for intercourse) 10 years later (median age 79) in both studies.

Other interesting outcomes of the Katz study included:

• Median PSA fell to 0.1 ng/ml after a median of 48 months
• 21% experienced a PSA bounce along the way.
• Cure rates were independent of whether patients received 35 Gy or 36.25 Gy
• Urinary toxicity was higher in the group that got the higher dose
• Rectal toxicity was no different in the two groups
• Patient-evaluated urinary and rectal function declined acutely but returned to baseline within a year
• Sexual function declined by 23% at 6-12 months, and continued to decline by 38% by 8 years. It is unknown what percent of that decline was age related (but see this link).

Looking at the higher local control rates of SBRT and HDR brachytherapy, Dr. Katz sees evidence that IMRT is sub-optimal in delivering biological effective dose. He also believes that no more than 35 Gy in 5 fractions is necessary to achieve that control, and that it would minimize side effects.

Of course, probably half of the low risk men in this study might have gone those ten years without needing any kind of treatment at all. But for those who may not want or may not be good candidates for active surveillance, SBRT is a low cost, low bother, low side-effect alternative that delivers high rates of long-term oncological control.

Amazingly, I still hear that there are insurance companies that will not cover SBRT because longer follow-up is needed. Dr. Katz had already reported the nine-year follow-up (see this link), and with this addition and the 10-year higher-risk update at ASTRO next year, it's hard to see what any objection might be.

Dr. Katz is to be congratulated for continuing to update his study for 10 years. It is a lot of work to follow up with so many patients, and collect and tabulate their reported outcomes. He is a radiation oncologist not associated with a large tertiary care facility that might have more resources at its disposal.

Revised ASCO/CCO brachytherapy guidelines

The publication of the ASCENDE-RT clinical trial (discussed here) has led to a revision in the brachytherapy guidelines (available here) issued by the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO). The guidelines are for patients who choose radical therapy rather than active surveillance. They based their guidelines only on randomized clinical trials that included brachytherapy as an option.  They exclude high dose rate brachytherapy (HDR-BT) as a monotherapy because it has not been proven in a randomized clinical trial.

Their guidelines suggesting which therapies are suitable are stratified by patient risk level:

Low Risk

• Low dose rate brachytherapy (LDR-BT) alone
• External Beam Radiation Therapy (EBRT) alone, or
• Radical prostatectomy (RP)

Intermediate Risk

For favorable intermediate risk patients (no Gleason score> 3+4, no more than half the cores positive, PSA<10, and stage<T2b):

• LDR-BT alone

For other intermediate risk patients:

• EBRT with or without androgen deprivation therapy (ADT) and a brachy boost (LDR-BT or HDR-BT) to the prostate.

High Risk:

• EBRT and ADT and a brachy boost (LDR-BT or HDR-BT)

They make the following qualifying statements:

• Patients should be counseled about all their management options (surgery, EBRT, active surveillance, as applicable) in a balanced, objective manner, preferably from multiple disciplines.
• Recommendation for low-risk patients is unchanged from initial guideline, because no new randomized data informing this question have been presented or published since.
• Patients ineligible for brachytherapy may include: moderate to severe baseline urinary symptoms, large prostate volume, medically unfit, prior transurethral resection of the prostate, and contraindications to radiation treatment.
• ADT may be given in neoadjuvant, concurrent, and/or adjuvant settings at physician discretion. It is noted that neoadjuvant ADT may cytoreduce the prostate volume sufficiently to allow brachytherapy
• There may be increased genitourinary toxicity compared with EBRT alone.
• Brachytherapy should be performed at a center following strict quality-assurance standards.
• It cannot be determined whether there is an overall or cause-specific survival advantage for brachytherapy compared with EBRT alone, because none of the trials were designed or powered to detect a meaningful difference in survival outcomes.

Neither the patient nor the doctor should take these to be their only options. ASCO/CCO only included options for which there is Level 1 evidence; that is, evidence from  randomized comparative clinical trials. Patients, doctors and insurance providers should make treatment decisions based on the full array of available clinical data, understanding that higher level evidence carries more weight.

Vessel-sparing IMRT spares erectile function

While either nerve-sparing surgery or radiation can cause erectile dysfunction, the probability for that for any given patient is always worse after surgery. The recent ProtecT randomized clinical trial removed any doubt of that, if there ever really was any. While nerve-sparing surgery was introduced by Walsh in 1982, there has been no similar breakthrough in IMRT radiation delivery - until now.

Effects of treatments on erectile apparatus

The mechanism of erectile function is complex, involving the brain, hormones, neurotransmitters, enzymes, and nitric oxide, just to mention a few vital components. Nerve impulses must travel from the brain, through the spine, along the nerve fibers that surround the prostate and then along its length down to the corpus cavernosa (the spongy tissue inside the penis from the penile bulb to the glans). Surgery, even nerve-sparing surgery, usually disrupts the signal that must innervate the penis. "Nerve sparing" is not an all-or-nothing technique. If the cancer has grown out into the neurovascular bundles, only some of the nerves may be spared. Take away too little, and the cancer is not cured; take away too much, and permanent erectile dysfunction is assured. Sometimes surgeons send frozen slices of tissue for pathological analysis before deciding how much to remove.

When radiation causes erectile dysfunction, the mechanism is very different. Nerves are relatively impervious to radiation; however, blood vessels and other endothelial tissue may be affected. The blood that supplies the penis comes to it through the "pudendal arteries" that flow downwards on either side of the prostate (in the "neurovascular bundle"). The blood enters the penis at the penile bulb (the part that extends inside the pelvis) and engorges the tissue of the corpus cavernosa. Radiation may cause an inflammatory reaction in the linings of the blood vessels and in the tissue of the corpus cavernosa. Over a period of months, the inflammation may result in scar tissue that restricts blood flow, and the impedes the ability of the spongy tissue of the corpus cavernosa to expand and contract elastically.

For years, there has been somewhat conflicting evidence about whether radiation's effect on erectile dysfunction can be mitigated by reducing the dose to the penile bulb (see this link). Consequently, radiation oncologists set a dose constraint for the penile bulb, but that was not a full solution. Many radiation oncologists have wondered whether the dose to the pudendal arteries and to the other parts of the corpus cavernosa could be  restricted to preserve erectile function without sacrificing oncological effectiveness. Innovations in MRI-based planning and super-precise (sub-millimeter) beam delivery have enabled that.

Vessel-sparing IMRT

Spratt et al. at the University of Michigan conducted a clinical trial on 135 patients treated between 2001 to 2009 to see whether "vessel sparing" IMRT could better preserve erectile function while achieving equal cancer control. As others have, they used a T2 MRI to delineate the contours of the penile bulb and corpus cavernosa. Their innovation was to use contrast-enhanced MRI-angiography to delineate the pudendal arteries that run near the prostate apex. The MRI images were fused with CT scan images and dose goals were set based on those. Intermediate and high risk patients were treated with low dose rate brachy (seed) boost therapy before they received IMRT; low risk patients received IMRT alone. A treatment margin of 1 cm was set for patients receiving IMRT only. It was lowered to 0.5 cm for those receiving brachy boost therapy.

Key patient and treatment characteristics included:

• Age = 63 (median)
• Baseline erectile function: IIEF score ≥ 16 (mild or no ED)
• Risk: Low - 39%, Intermediate - 53%, High -9%
• Gleason score: 3+3 - 44%, 3+4 - 33%, 4+3 - 13%, 8-10 - 9%
• Treatment: IMRT alone - 39%, brachy boost - 61%
• Dose: IMRT - 75.6-79.2 Gy, brachy boost - 110 Gy I-125 seeds + 45 Gy IMRT
• Pelvic dose: 45 Gy (high risk only)
• 6-month ADT: yes -33%, no - 67%

Potency preservation

During a median follow-up of 8.7 years, patients filled out questionnaires and doctors evaluated their erectile function at 2 years and 5 years. They were also queried about their use of erectile medicines and aids. Their responses were matched to the results of the PROSTQA study, matched for age, baseline potency, and other sexual risk factors. The percent of men who had erections firm enough for intercourse 2 years after treatment were:

• 78% if they had vessel-sparing IMRT
• 42% if they had conventional IMRT
• 24% if they had nerve-sparing prostatectomy

Other measures of erectile function at baseline, 2 years and 5 years included:

• No sexual aid use: 88%, 47%, 44%
• IIEF score ≥16 (no or mild ED): 100%, 70%, 67%
• High/very high confidence in getting and keeping an erection: 63%, 40%, 33%
• Potent without aids: 80%, 45%, 35%
• Potent with aids: 20%, 41%, 53%
• Impotent: 0%, 14%, 12%

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 EBRT. Perhaps the authors will make an attempt to separate the effect of patient aging in a future analysis. The University of Michigan should be able to accomplish this using their age-adjusted sexual domain EPIC scores.

It's worth noting that potency preservation was no different for those who had the brachy boost or IMRT only. It was better for younger men, men with higher baseline performance, and those who did not have adjuvant ADT.

Oncological outcomes

At 5 years, the biochemical recurrence-free survival for each risk group was:

• Low risk: 100%
• Intermediate risk: 100%
• High risk: 98%

At 10 years, the biochemical recurrence-free survival for each risk group was:

• Low risk: 100%
• Intermediate risk: 89%
• High risk: 88%

One could not ask for better outcomes!

Conclusion

It appears that vessel-sparing IMRT is a vast improvement over conventionally targeted IMRT in terms of preservation of erectile function, and based on this, should be adopted as standard practice for all patients who might benefit. Interestingly, potency preservation is similar to that reported for SBRT (see this link) and for high dose rate brachytherapy (see this link). That is not at all surprising because both of those therapies use much narrower margins than those used for IMRT, typically 2-3 mm vs. 10 mm for IMRT, and the biologically effective dose to the vascular tissue of the pudendal arteries are lower. With SBRT, intra-fractional motion is tracked, thus avoiding dose to nearby structures. With HDR brachytherapy, the gland is immobilized with catheters that prevent doses to the nearby vessels and organs. Hopefully, equally excellent results can be achieved with hypofractionated IMRT,  but that remains to be proved in future trials. With salvage IMRT, the entire prostate bed is treated, so I do not know if radiation to the pudendal arteries can be similarly avoided.

Anyone planning on having IMRT should forward a copy of this study to his radiation oncologist, and ask to discuss it at their next meeting. Of course, for men who are low risk, active surveillance will cause no erectile dysfunction and no loss of ejaculate.

For very high-risk patients, EBRT + BT is superior to surgery or EBRT only (Redux)

In August, Kishan et al. showed a preliminary analysis of oncological outcomes among Gleason score 9 and 10 patients treated with brachy boost therapy (EBRT+BT), external beam radiation therapy alone (EBRT) or surgery (see this link). Because of the limited sample size, some of the differences were not large enough to be statistically significant. Kishan et al. have now expanded their analysis to include 1,001 patients treated between 2000 and 2013, who were treated at several of the top institutions in the US: UCLA, Fox Chase, Cleveland Clinic, Mt. Sinai, and Wheeling Hospital. So far, only an abstract of the study has been presented at the GU Conference. The patient characteristics were as follows: 

• 324 were treated with radical prostatectomy (RP).
• 347 were treated with EBRT only.
• 330 were treated with EBRT + BT (BT was either low dose rate or high dose rate).
• All patients were Gleason 9 or 10 on biopsy.

Treatment specs

• Among the RP patients, 40% had adjuvant or salvage radiation therapy (68 Gy).
• Among radiation patients, 90% had adjuvant ADT
• Median dose of EBRT was 78 Gy.
• adjuvant ADT continued for 18 months, median.
• Median equivalent dose of EBRT+BT was 90 Gy
• adjuvant ADT continued for 12 months.

Oncological outcomes

After a median follow-up of 4.8, 6.4 and 5.1 years for EBRT, EBRT+BT and RP, respectively, the oncological outcomes were as follows:

• The 10-year rates of distant metastases were
  • 39.9% for RP 
  • 34.2% for EBRT
  • 19.7% for EBRT + BT
  • Differences between EBRT + BT and the two others were statistically significant.
• The 10-year rates of prostate cancer-specific mortality (PCSM) were
  • 20.3% for RP
  • 25.2% for EBRT
  • 14.1% for EBRT + BT
  • Differences between EBRT + BT and the two others were statistically significant.

The authors conclude:

Extremely dose-escalated radiotherapy offered improved systemic control and reduced PCSM when compared with either EBRT or RP. Notably, this was achieved despite a significantly shorter median duration of ADT than in the EBRT arm. 

Prostate cancer-specific mortality rates were cut in half by combining EBRT with a BT boost. While this does not prove causality (only a randomized clinical trial can do that) it is highly suggestive that escalated dose can provide lasting cures. There may be good reasons why some high risk patients may have to forgo brachy boost therapy in favor of high dose EBRT or RP with adjuvant EBRT, but for most, brachy boost therapy with ADT will probably be the best choice.

Sadly, a recent analysis of the National Cancer Database showed that utilization of brachy boost therapy for high risk patients has declined precipitously from 28% in 2004 to 11% in 2013. If a patient sees anyone other than the first urologist, he often only sees a single radiation oncologist who only informs him about IMRT. In most parts of the US, there is a dearth of experienced brachytherapists.