Radiation treatment of men with inflammatory bowel disease (IBD)

A analysis of a tumor registry in Texas challenges the notion that men suffering from inflammatory bowel disease ought not have radiation therapy for prostate cancer.  Gestault and Swanson presented their findings at the recent ASCO Genitourinary Conference (Abstract 15). They searched a tumor registry and found 18 patients who suffered from inflammatory bowel disease (either Crohn’s disease or ulcerative colitis) and were treated with radiation between 2000 and 2010.

• ·      12 were treated with EBRT – either IMRT or 3D-CRT
• ·      6 were treated with low dose rate brachytherapy
• ·      22% were in remission before treatment
• ·      56% were taking a 5-ASA medication
• ·      17% were taking prednisone
• ·      6% were taking Remicade
• ·      6 patients (40%) had grade 1 diarrhea at baseline
• ·      2 had had an ostomy

After a median follow-up of 9.5 years:

• ·      4 patients (22%) had grade 1 diarrhea, none of higher grade
• ·      3 patients (17%) had grade 2 proctitis, none of higher grade

o   All of those had 3D-CRT, rather than IMRT

The authors conclude:

“Our findings suggest that IBD patients experience minimal toxicity with IMRT-based radiation therapy.”

While a study of 18 patients is far too small to draw any projectable conclusions, it does raise the interesting hypothesis that patients with IBD should not automatically be ruled out for primary radiation treatment. It might be prudent, however, to use a rectal spacer with such patients.

SpaceOAR hydrogel decreases rectal radiation dose, but is it worthwhile?

In April 2015, the FDA cleared Augmenix Corporation’s hydrogel spacer for use in the US, as announced in their press release. The rectal spacer has been used in Europe since 2010. There are several kinds of rectal spacers: hydrogel, hyaluronic acid gels, biodegradable balloons, and collagen.  They all entail injection of a biodegradable substance into the space between the rectum and prostate in order to reduce the radiation dose to the rectum. There have been several studies already published on its use with various kinds of radiation- IMRT, 3D-CRT, SBRT, protons, low dose rate brachytherapy, high dose rate brachytherapy, salvage radiation after primary prostatectomy, and salvage brachytherapy after primary radiation.

Approval was based on favorable results from a randomized clinical trial among 222 men in 20 centers. The study by Pierczonka et al. has now been published. The study design specs were:

• ·      222 men who received 79.2 Gy in 44 fractions
• ·      149 got fiducial markers plus the rectal spacer
• ·      73 got fiducial markers only (control group)

The results were as follows:

• ·      No spacer sensation following application.
• ·      Mild transient rectal events in 10%.
• ·      Average separation added was 12.6 mm.
• ·      Complete absorption by 12 months.
• ·      97% of the men with a rectal spacer had a reduction of more than 25% in the volume of the rectum that received 70 Gy.
• ·      100% of men with a rectal spacer met dose constraints.
• ·      92% of control group men met dose constraints.
• ·      Patient-reported bowel-related quality of life declined less for the rectal spacer group than for the control group at 6, 12, and 15 months.
• ·      There were no serious rectal adverse events. There were no differences in acute rectal toxicity whether the spacer was used or not. Adverse acute (earlier than 3 months) rectal events were noted in 34 percent of those who got the SpaceOAR gel, and 32 percent of those who did not — no difference.

So the hydrogel spacers were safe, well tolerated, and reduced the rectal dose somewhat. We note that the vast majority of radiation plans meet normal rectal dose constraints even without it. 

This confirms what we've seen in other studies about acute rectal toxicity. In a study from Germany last year, Uhl et al. reported acute GI toxicity of Grade 0 or 1 of 88%, and Grade 2 of 12%. In a recent study of an IMRT dose of 79.2 Gy by Michalski et al., Grade 0 or 1 GI toxicity was reported by 90% of patients, and Grade 2 by 10% – nearly identical to the results with rectal spacers.

As for late rectal toxicity (those that occurred between 3 and 15 months after treatment) there were only 5 cases of rectal symptoms (7 percent) at all in the group that did not have the spacer, and 4 of the 5 were mild — Grade 1 bleeding and urgency. It should be noted that Grade 1 symptoms are so mild that they are often not even reported, so I like to group Grade 0 and 1 together. There was only one serious rectal event (Grade 3 proctitis) in a man who did not get a spacer. There was a single late-term Grade 1 rectal adverse event in a man who got a spacer.

Confirming that finding, the Uhl et al. study reported no late GI toxicity of Grade greater than 1. This seems consistent with the statement in the Pierczonka et al. study also that there were no serious rectal adverse events. For a historical comparison, we can look to a 10-year study of men treated with 81 Gy IGRT/IMRT at Memorial Sloan Kettering Cancer Center, arguably among the best at this kind of therapy. Alicikus et al. reported late-term gastrointestinal toxicity of Grade 0 or 1 in 97% of patients, Grade 2 in 2%, and Grade 3 in 1%. So we see that severe late term rectal toxicity is not much of a problem using best practices of IGRT/IMRT even without a rectal spacer.

Late-term rectal events are not a serious problem with modern radiation techniques. Acute rectal adverse events are a much bigger problem, but the SpaceOAR gel did not help at all with that. 

I also notice very serious use of anesthesia with the rectal spacer, including general (36 percent), monitored (25 percent), local (31 percent), conscious sedation (6 percent) and other (11 percent). This increases the cost, and raises safety concerns (there were no anesthesia-related incidents), and limits the number of patients who are eligible for it. Antibiotic prophylaxis is required with it as well.

This raises the question: Is reducing the toxicity for 3% worth the cost of adding rectal spacers for all treated men? In Europe, the cost of a SpaceOAR gel injection was 1,700€ ($1,850). I think the decision about whether to use it should not be routine. It may have a very useful role in men with bowel inflammation, a history of rectal issues (hemorrhoids, for example), or anatomic abnormalities that make the rectal dosimetry problematic. There will always be that residual 1 or 2 percent who are sensitive to radiation for some reason, and who may benefit. I’m glad that there is this option for those few who may benefit from it.

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.