Longer time between treatments reduces SBRT rectal toxicity.

There are many details of Stereotactic Body Radiation Therapy (SBRT) that may be optimized over the coming years. Among them is the optimum treatment schedule – how far apart should the treatments be spaced?

With radiation therapy of some rapidly growing cancers, there have to be multiple treatments each day. Prostate cancer is very slow growing in early stages, so the frequency of treatment is less a matter of oncological control, and more a matter of reducing toxicity.

Healthy tissue apoptosis or self-repair is thought to occur remarkable quickly after radiation, the self-repair half-life is less than two hours after treatment. This was the logic behind the treatment schedules devised for high dose rate (HDR) brachytherapy where there may be two or three treatments with only a break of several hours in between them. HDR brachytherapy has remarkably low levels of associated urinary, rectal and sexual toxicity in spite of the intense and frequent doses. It was originally thought that with SBRT, which is radiologically modeled upon HDR brachytherapy, the treatment schedule would not make much of a difference.

In a five-year follow-up study of 67 patients, King et al. found there was an increase in the most severe (Grade 3) late urinary toxicity from 3% in those treated every other day to 6% among those treated 5 days in a row, but the difference was not statistically significant, and the numbers were small. The differences were more marked in the lower grade late toxicity: Grade 1 and 2 urinary toxicity was 56% among those treated 5 days in a row and 17% if they were treated every other day. Low-grade late rectal toxicity was 44% on the everyday schedule but only 5% when treated every other day.

In a randomized clinical trial, Quon et al. studied the effects of two very different SBRT treatment schedules. They define acute toxicities as those appearing in the first 3 months following treatment; late term effects crop up later than 3 months, but usually appear within the first two years of treatment. Both acute and late-term effects are typically transient. This was an interim analysis. They randomly assigned 152 favorable risk men treated with SBRT (40 Gy across 5 treatments) at 3 Canadian centers to either of two arms:

1.      11 day arm - 5 treatments, every other day (excluding weekends), across 11 days

2.      29 day arm - 5 treatments, once per week, across 29 days

Patients self-evaluated their urinary, rectal and sexual function using the EPIC questionnaire. To help distinguish small differences, the researchers determined the% of patients whose EPIC scores increased (worsened) by half of a standard deviation or more from baseline – they labeled this a minimally clinically important change (MCIC). Their doctors also graded their urinary and rectal morbidities using RTOG/CTCAE 4.0 criteria. This interim analysis had a median of follow-up of 13.1 months. Table 1 below shows the toxicities and the MCIC for each group. It may be that not all Grade1 symptoms were reported by patients because they were expected, mild, and transient; also, some patients had mild symptoms at baseline, so I lumped together Grade 0 and Grade 1.

Table 1: Toxicity of shorter vs. protracted SBRT schedule

	11 day arm % of patients	29 day arm % of patients
Acute rectal toxicity
Grade 0/1	82	89
Grade 2	18	11
Grade 3	0	0
MCIC	90	75
Acute urinary toxicity
Grade 0/1	67	63
Grade 2	32	34
Grade 3	1	3
MCIC	96	75
Late rectal toxicity Grade 3	0	0
Late urinary toxicity Grade 3	1 patient	0

The study found :

·        Severe (Grade 3) toxicity was extremely rare

·        Acute toxicity was low (mostly, under Grade 2) in both arms.

·        Acute Grade 2 rectal toxicity was higher in the 11-day arm.

·        Acute Grade 2 urinary toxicity was not statistically different between arms.

·        MCICs, urinary and rectal, were lower (better) in the 29-day arm.

·        There were no differences between the two arms in sexual or hormonal effects.

·        So far, late toxicity has been low and not significantly different in both arms.

Although the authors defined MCIC to detect short-term decline in urinary and rectal function, King et al. (2013) found that those effects soon subsided, and there was a return to baseline function.

Grade 2 acute rectal symptoms were much higher in the 11-day Canadian arm compared to similar treatments at other institutions. This may be attributable to the higher dose used in the Canadian study. Acute Grade 2 urinary symptoms were significantly higher than the Katz study, but comparable to the Georgetown experience. Katz and Georgetown used lower doses (35/36.5 Gy vs. 40 Gy) and tighter treatment margins (2 mm vs. 5 mm) compared to the Canadian study.

Table 2: Toxicity reported in different SBRT studies: Canada, Katz, Georgetown

	Canada 11 day arm (40 Gy) % of patients	Katz (35 Gy) % of patients	Georgetown (35/36.25 Gy) % of patients
Acute rectal toxicity			(at one month)
Grade 0/1	82	96	95
Grade 2	18	4	5
Grade 3	0	0	0
MCIC	90
Acute urinary toxicity			(at one month)
Grade 0/1	67	96	64
Grade 2	32	4	35
Grade 3	1	0	0
MCIC	96
Late rectal toxicity Grade 3	0	0	0
Late urinary toxicity Grade 3	1 patient	0	0

Although spreading out treatments across 29 days instead of 11 days appears to reduce acute rectal toxicity, toxicity is nonetheless low grade. It is possible that small reductions in dose, or tighter treatment margins, may be made without sacrificing oncological control, and may be a better solution than spreading out the treatment intervals. Concerns about convenience may outweigh concerns about low-grade rectal toxicity for the patient, and such decisions are best left to a shared decision between patient and doctor.

Half of long-term erectile function (EF) loss after brachytherapy (BT) is due to aging.

One of the most important things we patients want to know about any treatment is what kind of potency we can expect afterwards. Urinary and rectal dysfunctions are often measured and reported by investigators, but sexual dysfunction is rarely reported or measured.

While there is at least some consensus on the use of the National Cancer Institute-defined common terminology criteria for adverse events (CTCAE 4.0) to grade urinary and rectal adverse events, there seems to be no consensus on how to measure sexual dysfunction. It is reported in a wide variety of different, non-comparable ways, if it is reported at all.

Several definitions are used in studies: IIEF/SHIM, EPIC-sexual status score, erection sufficient for intercourse, actual intercourse in the last month, and/or whether erection aids are needed or helpful. Often results are given among men who were previously potent or high-scoring only. Others report return to baseline function, where “return” may be defined as anywhere from within 1 point on IIEF/SHIM to any value within the population standard deviation.

From the patient’s point of view, we would love to have a nomogram that could predict our probability of potency after any given treatment. 

In 2011, Alemozaffar et al. (see The New Prostate Cancer InfoLink article) reported comparable figures on erectile function at two years after surgery (RP), external beam radiotherapy (EBRT), and brachytherapy (BT). They found that functional erection preservation could be predicted for each kind of therapy based on pre-treatment sexual function (EPIC scores), age, and a few other variables that varied with the type of treatment. However, there is a problem in the way they used baseline EPIC scores and age in their predictive model. The problem is that EPIC score is not independent of age - it is a function of age, especially in the age group studied. This problem, called covariance, violates a basic assumption of the model. The problem of covariance could have been fixed by using an age-adjusted EPIC score (much as we use inflation-adjusted constant dollars in economic analyses). The University of Michigan, which did the validation study, must have a validated file of EPIC scores by age for a random sample of healthy men. Those scores, expressed as a%, can become an indexing factor that will be divided into each respondent’s EPIC score according to his age.

We can easily see the “age problem” in the following table from the appendix (eTable3) of their study.

Percent of men with functional erections after 2 years

Age	RP	EBRT	BT
<50	55	100*	75*
50-59	43	52	67
60-69	27	39	44
70+	8*	30	24
Total	35	37	43
Median Age	60 years	70 years	66 years

* small sample size

Although the potency doesn’t seem to vary much between treatments in total (range 35% to 43%), it is only because the men who received EBRT and BT were older than the men who were treated with RP. Within every age group, potency preservation was higher with radiation.

Conventional wisdom is that radiation erodes potency slowly over time, while surgery affects potency at the beginning with some return over the first two years. The study only looked at potency at a single point in time, 2 years after treatment. This may obscure the long-term effect of radiation treatment on erectile function. This is more than just a technicality. As we measure potency after treatment for say 5 or 10 years, we want to be able to separate treatment effects from age effects. In the 60-75 age range that includes most treated patients, we expect potency to deteriorate naturally as we age, but what portion of that deterioration is because of the treatment?

Katz and Kang, in a 7-year follow-up study of quality of life following SBRT treatment, found that there was a brief early decline and recovery followed by a gradual long-term decline (see Figure 5). After 7 years, potency was about 67% of their original EPIC score. The authors point out: “In fact, potency preservation rates after SBRT are only slightly worse than what one would expect in a similar cohort of men in this age group, who did not receive any radiotherapy.” However, they made no attempt to separate the effects of treatment from the effect of natural aging.

In a new analysis of the erectile function after low dose rate (LDR) brachytherapy, Keyes et al. made the first such attempt to separate the impact of the two effects. They analyzed the erectile function of 2,929 favorable risk brachytherapy patients treated between at the British Columbia Cancer Agency between 1989-2012.

• ·      The men were categorized at the baseline visit by their doctors as having full (79%), partial (8%) or no (13%) erectile function. The men were re-categorized on follow-up visits by their doctors.
• ·      The men self-evaluated potency on follow-up visits using the Sexual Health Inventory for Men (SHIM) questionnaire.
• ·      All men in the study had at least 10 months of follow up and as long as 14.1 years (median 3.5 years).
• ·      44% had adjuvant ADT. It typically began 3 months before treatment and continued 3 months after, and was given to men with larger prostates or higher risk. It was rarely used after 2005.
• ·      The median age was 66 at treatment.
• ·      33% had hypertension, 10% had diabetes.
• ·      Expected erectile function by age without treatment was predicted in two ways:

o   1. The Massachusetts Male Aging Study (MMAS) predicts annual impotence rates of:

§  12.4 cases per 1000 for men 40-49

§  29.8 cases per 1000 for men 50-59

§  46.4 cases per 1000 for men 60-69

§  These were estimated in 5-year increments.

o   2. Baseline erectile function of men 5 years older was used as the level expected if there had been no treatment.

The authors report the following results:

• ·      There was a large decline in erectile function (EF) at the first (6 week) follow-up visit:

o   EF loss of 25-35% if they had no ADT. The authors attribute this to trauma and psychological factors rather than dose to erectile vasculature and structures.

o   EF loss of 80-85% if they had adjuvant ADT

• ·      The EF of those who didn’t have ADT continued to decline gradually.
• ·      The EF of those treated with adjuvant ADT rose back up to the level of the other men at the 2-year mark, and then similarly declined.
• ·      Among men fully potent at baseline, about 50% were fully potent at 5 years and an additional 10% were partially potent.
• ·      Among men fully potent at baseline, about 40% were fully potent at 7 years and an additional 15% were partially potent.
• ·      The following table shows potency by age group after 7 years.

Age Group	Percent with full EF after 7 years
<55	80
55-59	76
60-64	53
65-69	41
70-74	22
>74	13

• ·      About 30% of the fully potent men used PDE5 inhibitors.
• ·      Diabetes and hypertension significantly affected EF, radiation dose did not.
• ·      The following table shows actual and expected potency losses due to by age group.

Age group at 5 years post BT	EF loss* due to BT+age (percent)	EF loss due to age (avg expected)†	Loss due to age as% of total loss
<60	22	13	59
60-64	38	18	47
65-69	58	26	45
70-74	75	40	53
>74	93	55	59

* among those with normal EF at baseline

† average of MMAS and 5-year older EF in study cohort at baseline

• ·      About half of the long-term decline in EF was due to normal aging effects.
• ·      Most of the steep early decline is due to BT; most of the gradual later decline is due to aging.

This study goes a long way towards providing the data patients need to make a treatment decision. The patient wants to know, for each potential treatment, what his odds are of preserving functional erections at some future point in time. To build a database capable of answering his question, clinicians offering each treatment will have to collect the following data at baseline and follow-up visits:

• ·      EPIC score (age adjusted)
• ·      Age at treatment
• ·      Co-morbidities: cardiovascular disease, hypertension, diabetes, neuropathy, depression, hypogonadism
• ·      Medications: beta blockers, testosterone supplementation, ADT, opiates, adrenergics, etc.
• ·      Smoking
• ·      Substance abuse
• ·      Obesity
• ·      Married/sex partner

I am hopeful that someday clinicians will arrive at a consensus about collected the data, measuring and reporting potency. Patients can further this goal by letting their doctors know that this is important to them. Judging by how seldom reports like this are published, many doctors think it is not very important.

note: Thanks to Dr. Mira Keyes, Head of the Provincial Prostate Brachytherapy Program of the British Columbia Cancer Agency, Vancouver Cancer Centre for making the full text of the article available to me.