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

SpaceOAR hydrogel - is the difference worthwhile?

SpaceOAR hydrogel is spacer injected between the rectum and the prostate that increases their separation. This allows less radiation targeted at the prostate to hit the rectum. They published an interim 15-month report in 2015, and now Hamstra et al. have published their final report based on 3 years of follow-up.

The clinical trial was conducted at 20 participating institutions between 2012-2013 among patients who were to receive IGRT/IMRT as their first-line therapy for low- or intermediate-risk prostate cancer. Additionally, no more than 50% of biopsy cores were positive, ADT was not used, and prostates larger than 80 cc were excluded. The test was "single blinded:" physicians implanted the gel at the same time fiducials were implanted, but patients did not know if they received the spacer. All patients received 79.2 Gy of IMRT with 5-10 mm margins. 149 men were randomly assigned to the Spacer group. The Control group comprised 73 men.

While the researchers report physician-assessed toxicity data, they also collected patient-reported quality-of-life outcomes. Patient-reported outcomes are not subject to reporting bias, and are collected using well-validated questionnaires (EPIC). Patients did not know if they received the spacer. Patients filled out comprehensive questionnaires at baseline, 3 months after treatment, and then at month 6, 12, 15 and 36. On the EPIC questionnaires, a minimally important difference (MID) has been previously found to be a decline of 5 points, 6 points, and 11 points for rectal, urinary and sexual side effects, respectively. The researchers also reported the percent of patients whose quality-of-life scores declined significantly to a level that was at least twice as great (2X MID).

Acute toxicity

The change at 3 months compared to baseline represents the acute effects of radiation. This is the period of maximal deleterious effect of radiation on rectal and urinary quality of life. After 3 months, quality of life typically improves. The exception to this rule is sexual quality of life, which may continue to deteriorate, largely due to age (see this link).

At 3 months, the percent of patients who were bothered by any bowel-related side effect (moderate or big bother) was 9.4% among the Spacer group, and 5.7% among the Control group. The difference was not statistically significant. The only component (components included such morbidities of diarrhea, blood in stools, urgency, frequency, etc.) of bowel bother that was statistically significant was bowel pain, which was reported as a moderate or big bother by 6.8% of the Spacer group and none of the control group. The spacer made bowel pain worse rather than better.

Physician-reported grade 2 acute toxicity at 3 months was exactly the same (4%) for both the Spacer and the Control group. The spacer had no effect on any but the mildest acute toxicity.

Urinary scores were not significantly affected by the spacer. Among the Spacer group, 22.8% evaluated their urinary-related side effects as a moderate or big bother. Among the Control group, 17.1% evaluated it as a moderate or big bother. The difference between the two groups was not statistically significant, nor were any of the components of urinary function (e.g., pain, urgency, waking up to urinate, weak stream, frequency, etc.).

Bothersome sexual effects were also not significantly different between the Spacer and Control group, and at 3 months, were similar to baseline.

Late-term toxicity

At 36 months after treatment, 2.2% of the men in the Spacer group evaluated their bowel function as a big or moderate bother. This compares to 4.4% in the Control group -- not a statistically significant difference. None of the components of rectal bother were significantly better in the men who received the Spacer, although the scores were directionally better in almost every component. Quality of life in the rectal domain for both the Spacer and Control groups were close to their baseline values.

This low rate of bothersome rectal toxicity was confirmed by physician reports of rectal toxicity. Ignoring mild rectal side effects (i.e., grade 1, like blood spots on toilet paper or loose stool) that patients often do not bother to report to their doctors, we see that physician-reported grade 2 or higher rectal adverse events occurred in only 6% of patients, all in the Control group. Only one patient suffered a serious (grade 3) rectal injury in the Control group. It's worth noting that even this small number was an increase from the 15-month report. At 15 months, there was only one patient who had grade 2 or greater rectal toxicity. Late-term rectal toxicity is not a major issue with modern-day radiation.

Late-term urinary scores were not statistically significantly different for Spacer (4.4% big/moderate bother) and Control (8.9% big/moderate bother). Both were improved from baseline. The only component that was significantly worse was urinary frequency (18.2% vs 4.6%). It is unclear why any urinary side effects would be affected at all by a rectal spacer. It may be an artifact of the low sample size at 36 months - just 46 in the Control group, and 94 in the Spacer group.

There were no differences in overall sexual bother between Spacer and Control groups, or in any of its components. In the Control group, big/moderate sexual bother increased from 35.2% at baseline to 41.3% at 3 years. In the Spacer group, big/moderate sexual bother increased from 23.6% at baseline to 28.6% at 3 years. In both cases, sexual bother peaked at 1 year after treatment.

The following table shows the percent of patients in the Spacer and Control groups whose scores in each domain (rectal, urinary and sexual) declined by the minimally important difference (MID) or by at least twice the minimum (2x MID), which would be clinically significant to the patients.

*statistically significant difference between Control and Spacer with 95% confidence

We notice that the spacer moderated the declines in the rectal scores. There was a 16 percentage point improvement in late term rectal evaluations due to the spacer. However, we also saw that the relative decline was not very bothersome to the patients (96% did not find it even moderately bothersome).

What is perplexing here is why the urinary scores would have declined more without the spacer -the clinically notable difference (2x MID) was statistically significant.The dose received by the bladder and urethra was unaffected by the rectal spacer. There was also a rather sudden increase in both urinary and rectal MIDs at the 3-year mark. At all prior time points, there were no statistically significant differences between the Control and Spacer groups. Many respondents were lost to follow-up at 36 months (and over a third were lost) and data may become erratic as sample size gets small.

Is it worthwhile to treat all patients? 

The cost of the SpaceOAR hydrogel injection is about $2,500. IMRT patients should not expect any amelioration of bothersome acute rectal symptoms. A cost/value analysis depends upon which toxicity numbers one wants to focus upon.

1. Even if the difference were statistically significant (and it's not), only 2.2% would avoid bothersome late-term rectal symptoms by using the gel. So to spare one patient bothersome rectal symptoms, 45 patients would have to be treated at a cost of over $90,000. 
2. If we focus on the late-term toxicity improvement, 6% avoided late-term grade 2 or higher rectal symptoms by using a spacer. To spare one patient such symptoms, 17 patients would have to be treated at a cost of $42,500.
3. If we use the 2x MID difference as our guide, 16% would avoid low grade late-term rectal symptoms. So to spare one patient those symptoms, 6 patients would have to be treated at a cost of $15,000. 

Some would argue that even though the symptoms are relatively mild, late-term symptoms are often longer-lasting. Each patient has to decide for himself. Patients who are interested should obtain pre-approval from their insurance. It has been provisionally approved, but Medicare approval is expected in 2018.

Safety must be considered as well. The risks are not large, but neither are they non-existent. In addition to the dangers of anesthesia and infection, there is a small danger that the injection will penetrate the rectal wall or cause a rectal ulcer. Such dangers are small, and undoubtedly diminish with clinician experience.

Rather than treat all radiation patients, it would be much more efficient to identify the patient characteristics that increase the risk of late-term rectal toxicity. The presence of visceral fat, anatomic abnormalities, medications (e.g., anticoagulants and antihistamines), comorbidities (e.g., inflammatory bowel disease and diabetes), smoking, and the microbiome may play a role. There may also be a genetic component, like mutations in DNA repair genes, that renders a patient more susceptible to lasting damage from radiation. Further analysis may help explain why there was no benefit in terms of acute toxicity, and why even this small benefit took 3 years to show up. Dr Hamstra mentioned that analysis is ongoing, and they plan a follow-up presentation at ASTRO next year.

The researchers are to be congratulated on this very well executed randomized clinical trial. There are too few trials like this. In fact, Daniel Hamstra boasted:

"I think this is better than any other study ever performed for prostate cancer.  I know of no phase 3 trials testing a new technique or study which randomized patients and reported benefits for toxicity and QOL.  IMRT has not done it.  Image guided therapy has not.  Proton therapy has not.  Robotic surgery has not.  Nor has any surgical technique.  If you go back to the original Dutch 3D conformal trial published 15 years ago they showed reduced toxicity with 3D conformal RT as compared to 2D RT (but did not collect QOL).  So, this is really a landmark study in that it was randomized (and blinded in that the patients did not know which arm they were on until the end of the trial).

Note: Thanks to Daniel Hamstra for allowing me to read the full text, and responding to my questions.

9-year SBRT outcomes

Katz and Kang have posted their 9-year SBRT outcomes on 515 patients. This represents the longest tracking of SBRT outcomes -- just one year short of the IMRT tracking reported by Alicikus et al. on a starting cohort of 170 patients treated at Memorial Sloan Kettering Cancer Center.

The patients were treated between 2006-2010 using the CyberKnife platform.

• ·      324 were low risk, 139 intermediate risk, and 52 were high risk according to NCCN definitions.
• ·      70 patients received adjuvant ADT for up to one year.
• ·      158, all with Gleason score<4+3, received 35 Gy in 5 fractions.
• ·      357 received 36.25 Gy in 5 fractions
• ·      Median age was 69
• ·      Median PSA was 6.5 ng/ml

After a median followup of 84 months:

• ·      Oncological Control:

o   9-yr freedom from biochemical failure was:

§  95% for low-risk men

§  89% for intermediate risk men

§  66% for high-risk men

o   Median PSA nadir was .1 ng/ml

o   No difference in biochemical control for the lower vs. the higher radiation dose.

o   99.6% prostate cancer survival

o   86% overall survival

• ·      Toxicity:

o   Late rectal toxicity:

§  Grade 2: 4%

o   Late urinary toxicity:,

§  Grade 2: 9.5%

§  Grade 3: 1.9%

§  Grade 2 or 3: 6.9% for the lower radiation dose vs. 13.2% for the higher dose.

o   Patient-reported bowel and urinary quality-of-life (EPIC questionnaire) declined at one month then returned to baseline by 2 years. Sexual quality-of-life declined by 29% at last followup.

These are clearly excellent results for any kind of radical therapy. The authors conclude:

“These long-term results appear superior to standard IMRT with lower cost and are strikingly similar to HDR therapy.”

While it’s tempting to conclude that neither the higher dose of radiation, with its greater toxicity, nor the addition of ADT conferred any incremental benefit, that can only be proved with a randomized clinical trial. Until so proven, it must be understood as only a good hypothesis to be discussed by patients with their radiation oncologists. It is also worth noting that these reflect the outcomes of one very expert practitioner. There is an SBRT registry currently collecting data across many treatment centers.

The reported outcomes are nearly identical to those reported at 7 years (see this link and this link and this link), indicating very stable control and no additional late term toxicity with longer followup. In light of that, its low cost, convenience, and the fact that the standard of care, IMRT, has only one more year of follow-up on a much smaller sample size, it’s difficult to understand why some insurance companies still balk at covering SBRT for low and intermediate risk patients. Medicare does cover it.

LDRBT, IMRT and SBRT Quality of Life

Some of the leading lights in radiation oncology have collaborated on a study by Evans et al. of patient-reported quality of life (QOL) following various primary radiation treatments for prostate cancer. They analyzed three monotherapies (all without hormone therapy): low dose rate brachytherapy (LDRBT), intensity-modulated radiation therapy (IMRT), and stereotactic body radiation therapy (SBRT). It did not include high dose rate brachytherapy or proton therapy.

Because this study was so far-reaching in its scope and its findings, it is worth taking a close, detailed look at it. I will break it into three parts. In the first part, we’ll look at the basis of the study – how the study was designed and carried out, and what does it purport to tell us. In Part 2, we will look at some of the more important findings of the study. And in Part 3, we will discuss the implications and caveats of its findings, and draw conclusions.

PART 1. THE BASIS OF THE STUDY

The purpose of the study was to evaluate three primary radiation therapies – LDRBT, IMRT and SBRT – with respect to the patient-perceived side effects of those treatments, and to do so in a standardized and consistent manner. While this was a prospective study, it was not a randomized comparison, which is the gold standard for doing that. However, it does provide the doctor and patient with more information on what they can reasonably expect, across those treatments, than we’ve ever had before.

Data was provided by several of the top institutions in the US:

LDR or IMRT

Michigan (2 sites)

Mass General

Beth Israel Deaconess

MD Anderson

Cleveland Clinic

Washington University (St Louis)

SBRT

Georgetown

21st Century (2 sites)

The number of patients in the two-year follow up:

• ·        LDRBT: 243 patients
• ·        IMRT: 140 patients
• ·        SBRT: 272 patients

I don’t know how they selected which doctors and medical centers to include. In addition, the study was done with the assistance of the PROSTQA Study Consortium, a blue-ribbon panel of top researchers. They previously published much of this data on IMRT and LDRBT in 2008 (see this link). The SBRT data are new. Their results are a good indicator of outcomes from top practitioners at major treatment centers, and are not a good indicator of expected outcomes in community practice. I’m sure that many patients have favorite doctors whose work was not represented in this study, and they will argue that these results are not representative.

Because this was not set up as a randomized comparison of treatments, differences in patient selection may skew the results. Importantly, the LDRBT cohort is 5 years younger (65 years, median) than the other two groups (69 years, median). In all quality-of-life studies, younger patients do better. They are less likely to suffer deleterious effects of radiation, and they are more resilient in their recovery. Paralleling the difference in age at baseline, the baseline sexual QOL was best for LDRBT, and the baseline prostate symptom scores were best for LDRBT, followed by IMRT and SBRT.

The instruments they used to evaluate quality of life were EPIC-26 and SF-12. Patient-reported assessments have an advantage over physician-reported toxicity reports. The physician data depends on the patient to voluntarily tell the doctor about all adverse events, which is useful for highest grade events (3 or 4), but is less reliable for low grade events (1 or 2) that the patient might never bring to the doctor’s attention. Some men “tough it out,” some see their PCP instead (who may be more accessible), and some worry about even the most minor events. The survey instruments used here are standardized and validated, and guide the patient through a detailed assessment of the QOL issues that have been found to matter most. Patients filled them out at baseline, at 1-2 months, 6, 12, and 24 months. EPIC scores are based on scale of 0 (worst) to 100 (best). Although they also measured such qualities as general physical and mental status, and vitality/well-being, none of these were impacted by treatments.

IMRT and LDRBT patients were treated from 2003 to 2006; SBRT patients from 2007 to 2011. Contemporary best practice was observed as follows:

·        LDRBT: 144 Gy prescribed dose for I-125, US-guided, transperineal placement, I-125 or Pd-103 used, and 3-5 mm margins (more details here)

·        IMRT:76-79 Gy in 1.8-2.0 Gy increments, and 0.5-1.5 cm margins.

·        SBRT: 35-40 Gy in 5 fractions, fiducials or Calypso image guidance, and 3-5 mm margins.

There were two kinds of urinary problems that were measured: urinary incontinence (leakage, dribbling, control & pad use) and urinary irritation/obstruction (frequency, pain/burning, weak/incomplete). Bowel issues comprised urgency, frequency, leakage, bleeding and pain. The sexual domain comprised ability to have erections, their firmness, and frequency when needed; also, quality of orgasms and overall sexual function.

All of the study’s findings relate to how much patient evaluations changed compared to their baseline evaluations in the urinary, rectal and sexual quality of life domains. We expect that the radiation therapies that do the least damage will show the least deterioration in the patient perceptions in each domain.

Because the study was not randomized, and it did not attempt to match triplets of patients on their demographics and co-morbidities, we have the difficulty of comparing results in different kinds of patients. The analysis of patient characteristics across treatments revealed only one real glaring discrepancy – LDRBT patients were 5 years younger than the rest. The authors made some attempt to restore comparability by only looking at sexual scores among patients who were 60 years of age or older, but such analyses were limited in their published results. In my opinion, they ought to have computed age-adjusted scores in all domains. The failure to do so will compound the difficulties in interpreting results as they carry their tracking into the future when the aging of the study population has greater effects.

PART 2. DETAILED FINDINGS

In this part we’ll look at the results of their analysis. The authors did a great job of compiling a vast amount of information. Even so, in some cases, I wish more of the information had been presented (I was able to see the full text). Perhaps they will reveal more of the details in future analyses of this rich database.

Change from Baseline

The following table shows the EPIC score change from baseline after two years among patients having each kind of therapy. The last column shows, for reference, the minimum amount of change that has been found to be clinically important for that set of symptoms.

	LDRBT	IMRT	SBRT	Minimal Clinically Detectable Change
Urinary- irritative/obstructive	-6*	+2	0	5-7
Urinary - incontinence	-6*	-5*	-3	6-9
Bowel	-7*	-8*	-1	4-6
Sexual†	-24*	-21*	-14*	10-12

* Change is statistically significant

†Among those with scores over 60 at baseline (to help compensate for age-related differences).

Sexual status was the domain that was most affected by all the treatments. For LDRBT, it had the greatest deterioration. Deterioration in urinary and bowel scores were statistically significant and clinically meaningful in patients who had LDRBT. IMRT also had its greatest impact on sexual status, and not much different from LDRBT. Other than sexual status, only IMRT bowel scores deteriorated meaningfully; urinary status returned to near baseline. SBRT had the smallest change in sexual status, albeit large enough to be meaningful. Bowel and urinary status returned to baseline.

Minimal Clinically Detectable Change

The authors also looked at what% of patients suffered a minimal clinically detectable (MCD) change in each of those components of their quality of life over time. The typical pattern was a sharp increase at 1 or 2 months (acute effects). In all but sexual scores, that was followed by improvement. Predictably, urinary irritation/obstructive were most impacted, reaching about 90% at two months for LDRBT, and significantly better at all time points for IMRT and SBRT. The proportion who had MCD bowel symptoms and sexual symptoms was consistently more favorable for SBRT than for LDRBT or IMRT.

As a measure of the severity of symptoms, the authors looked at the % of patients who suffered an MCD increase of twofold or more over baseline after two years:

	LDRBT	IMRT	SBRT
Urinary (all)	45%	25%	18%
Bowel	25%	30%	11%
Sexual†	35%	33%	20%
None of the above	34%	40%	65%
All of the above	8%	7%	2%

In general, large clinical deteriorations in QOL were about twice as frequent for LDRBT compared to SBRT, with IMRT falling in the middle.

Symptom Severity over Time

As another measure of symptom severity, the table below shows the% change versus baseline in the proportion who rated their symptoms as moderate to severe, at 1-2 months and at 2 years:

	LDRBT		IMRT		SBRT
	2 mos.	24 mos.	2 mos.	24 mos.	1 mo.	24 mos.
Urinary (all)	+33%	+7%	+27%	+3%	+8%	-3%
Bowel	+14%	+6%	+16%	+6%	+7%	-2%
Erectile dysfunction†	+21%	+19%	+11%	+16%	+5%	+11%

† inability to have erections, among patients of all ages

Moderate to severe acute urinary and rectal side effects increased markedly for LDRBT and IMRT. For SBRT, they increased much less and returned to slightly better than baseline levels.

Keeping in mind that LDRBT patients were a median of 5 years younger than the other two groups, the increase in erectile dysfunction among LDRBT patients is troubling.  As we saw in a recent study, the deterioration occurs earlier than was previously thought. For SBRT, in contrast, there was only a +5% increase in erectile dysfunction severity at two months after treatment, but that increased to +11% by two years. Nevertheless, that was still lower than the other two therapies.

PART 3. DISCUSSION

In this section, we will make an attempt to explain the findings of the study and draw whatever conclusions we can from them.

We have seen a very consistent pattern across all the measures of QOL and in all of the domains: LDRBT patients did worst, SBRT patients did best, and IMRT patients were in between. Why should that be? Let’s examine a few hypotheses:

Patient selection/non-random

This was not a randomized comparative trial, so it is possible that the LDRBT patients selected were, for some reason, more prone to the damaging effects of radiation. This argument is weakened by the fact that they were 5 years younger, and their urinal, rectal and erectile function at baseline were better than in the other two groups.

Better practitioners not represented

Some of the top LDRBT practitioners like Peter Grimm, Michael Zelefsky, Brian Moran, and Gregory Merrick, to name a few, were not represented here. One could also argue in the other direction that some of the most experienced SBRT practitioners, like Christopher King, Alan Katz, and Debra Freeman, were not represented here. Their results might have increased comparative favorability of the SBRT results still further. However, the results do seem to be comparable to those reported by Katz and the 8-institution consortium.

Time of treatment

IMRT and LDRBT results were based on best practice in 2003-2006, while SBRT was based on patients treated in 2007-2011. There were technological improvements in both modalities since then that might make their outcomes more comparable to SBRT. As radiation technology continues to evolve, it becomes problematic to choose among them based on past performance.

Hypofractionation spares healthy tissue

Hypofractionation (SBRT or HDRBT) – radiation applied in fewer treatments (or fractions) – has been found to kill cancer cells more efficiently than normal fractionation (IMRT) or continuous fractionation (LDRBT). Because prostate cancer is especially susceptible to hypofractionation (technically, we say it has a low alpha/beta ratio of about 1.5), and because healthy nearby early-responding tissues are less susceptible (they have a higher alpha/beta ratio of about 10), healthy tissues are better spared by it.

A convenient measure for comparing the dose seen by nearby healthy tissues is something called the biologically effective dose (BED). We can compute for each modality the maximum BED experienced by nearby early-responding tissues that are responsible for acute side effects. With SBRT (7.5 Gy X 5 fractions), the BED to those tissues is 30% less than the dose from IMRT (1.8 Gy X 44 fractions). For LDRBT (144 Gy I-125 Rx dose), the maximum BED to those tissues is 56% greater than the dose from IMRT. ). Making comparisons solely on BED is problematic because LDRBT radiation is extremely short range, so a lower proportion of the bladder and rectum surface may be exposed to that maximum dose.

Dose constraints

Radiation oncologists set strict dose constraints for the bladder, urethra, rectum, and sometimes to the penile bulb, limiting the volume of those organs that receive potentially toxic doses. However, there is only so much that doses can be limited if they are to effectively kill the cancer in the prostate. I don’t know what dose constraints were set for the three modalities examined in this study. We can only assume that they used best practices.

Imaging

The imaging of the pelvic organs both in planning and in the application of radiation makes a large difference in toxicity. This is where SBRT shines. SBRT commonly uses a fused image of a CT and MRI with fiducials or transponders in place for planning. This helps to precisely predetermine, down to less than a millimeter, where all the beams will be directed. These practices can be used with IMRT as well. However, with IMRT, the images are aligned only once per session, whereas with SBRT, the images are aligned continually throughout the session. We recently saw how disastrous SBRT could be without intra-fractional motion tracking. LDRBT seed placement is commonly accomplished under ultrasound image guidance, using computerized intra-operative planning. The ultrasound can help the doctor see where the needles are going, but it can’t see the seeds well. Even stranded seeds tend to move, the prostate is moved by each needle insertion, and the prostate swells throughout the procedure, so that it is impossible to know where their final position will be. An image is obtained about a month later, after the swelling subsides, to check for major discrepancies in seed positions and to give an after-the-fact reading of the doses absorbed by organs at risk.

Late term effects

This study tracked patients for two years, which is long enough for most of the late-term side effects to show up. However, some will inevitably show up even later. Some tissues, particularly some in the bowel, are “late responding” to radiation damage. Late responding tissues are relatively more sensitive to the concentrated radiation of SBRT (they have an alpha/beta ratio of 3-5), so it is possible that SBRT’s advantage will decrease with longer follow up.

CONCLUSIONS

Although one can quibble over methodological issues in comparing the modalities, SBRT certainly provides excellent quality of life to treated patients. SBRT also is the most convenient of the treatments, requiring only five short visits, no intrusive procedures (other than fiducial placement), and no anesthesia. LDRBT is the winner on cost of treatment, with a $17,000 median Medicare reimbursement, followed by SBRT ($22,000) and IMRT ($31,000). However, a full cost analysis should also include the costs of managing the side effects of treatment, which seem to be much lower for SBRT and higher for LDRBT. Based on the findings of this study, and approximately equivalent oncological control for the 3 modalities in favorable risk patients, it is hard to justify IMRT. Availability is an issue: IMRT is available everywhere, while there is less access to excellent practitioners of SBRT (usually as CyberKnife®) and LDRBT. Some insurance still will not cover SBRT, although that is less often a barrier now.

An oft-heard argument against SBRT is that there’s not enough long-term data. SBRT is the youngest of the three modalities, used against prostate cancer since 2003. The longest-running SBRT study, has 7 years of follow up on 515 patients. For comparison, robotic prostatectomy has been used since 2000, and has never been proven superior to open surgery in a randomized comparative trial. IMRT, likewise, has never been evaluated in a comparative randomized trial, and in its current form, using dose escalation and precision IGRT techniques, was only begun in the mid-1990s. The longest-running IMRT study, at Memorial Sloan Kettering, has 10 years of follow up on 170 patients. LDRBT has been used, in some form, for over a hundred years. However, in its modern form with dose escalation and intra-operative planning methods, there are no studies older than 15 years that have any decisional value. I have often bemoaned the problem of “irrelevance” in long-term clinical studies: by the time we get the results, technology and practice have changed so much that the results have become irrelevant in making decisions among the best available therapies.

While this study raises the hypothesis that SBRT may be superior to IMRT and LDRBT, it is prudent for the patient to keep them all in his consideration set at least until the results of randomized comparative trials become available. This study should influence patients and clinicians to give serious consideration to SBRT.

Later this year, we will have the early results from Sweden of a randomized clinical trial of SBRT versus IMRT in intermediate-risk patients. There are several more comparative trials that are scheduled for completion in the coming years. If they confirm the results of this study, it will be difficult to justify IMRT as first-line therapy. Unfortunately, as far as I know, there are none planned comparing SBRT and LDRBT. There are few institutions that offer both modalities (Memorial Sloan Kettering is an exception), so randomization would be problematic.