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.