In several randomized clinical trials of external beam treatment of primary prostate cancer, we have seen that moderately hypofractionated intensity-modulated radiation therapy (HypoIMRT), accomplished in 12 to 26 treatments or fractions, is no worse than conventionally fractionated IMRT treatment (in 40 to 44 fractions). In a randomized clinical trial from Scandinavia, we recently saw that stereotactic body radiation therapy (SBRT, in 5 fractions) is no worse than conventional IMRT in quality-of-life outcomes, even using inferior technology. The missing piece of the puzzle is to answer the question of whether SBRT is any worse than HypoIMRT.
We don’t yet have a definitive answer (which would require a randomized clinical trial), but an analysis of pooled data from five different clinical trials suggests that SBRT is no worse and may be better than HypoIMRT in its urinary, rectal, and sexual outcomes. Johnson et al. pooled SBRT data from clinical trials among 534 men at three institutions (UCLA, Georgetown, and 21st Century Oncology) and HypoIMRT data from clinical trials among 378 men at Fox Chase Cancer Center and the University of Wisconsin. All patients were treated between 2002 and 2013 at those top institutions, with state-of-the-art equipment in the context of carefully controlled clinical trials. Because of this, all outcomes are probably better than those achieved in everyday community practice. The only significant difference in patient characteristics was that the SBRT patients were about 5 years older (69 years vs. 64 years of age for HypoIMRT). We expect older men to have more natural deterioration in urinary and sexual function.
The following table shows the percent of men receiving each treatment who suffered from at least the minimally detectable difference in patient-reported scores on validated quality-of-life questionnaires with respect to urinary, rectal, and sexual function. Numbers in bold italic typeface represent a statistically significant difference.
The data support the following conclusions:
- Urinary and rectal problems at 2 years were experienced by fewer of the men who had SBRT.
- Urinary and rectal problems improved after 2 years compared to 1 year post-treatment. For SBRT, they approached baseline values.
- Sexual issues did not improve at 2 years.
- While we expected the SBRT patients to experience greater deterioration owing to their age, the opposite occurred.
Why were the SBRT outcomes better?
SBRT is not just a high-dose-per-fraction version of IMRT, although it is that too. When the linear accelerator is delivering only 2 Gy per fraction, missing the beam target by a little bit is not likely to make much difference — it will average out in the long run. Because a geographic “miss” of the beam target has much greater consequence for SBRT, where the dose per fraction can be 8 Gy, much more care is taken to achieve pinpoint accuracy. This may include such steps as:
- Fiducials/transponders aligned within each treatment and not just between treatments
- Fast linear accelerators that minimize the time during which the prostate can move
- No treatment if the bowel is distended or the bladder is not full
- Tighter margins: as low as 0 mm on the rectal side and 2 mm on the front side; this compares to margins of 0.5 to 1 cm for IMRT
- Narrower dose constraints for organs at risk, including the bladder, rectum, urethra, femurs, and penile bulb
- More care taken to find a plan that optimizes prostate dose relative to organs at risk.
It is entirely possible that IMRT outcomes might be equivalent to SBRT outcomes if the same factors were incorporated into IMRT planning and delivery. But fractionation probably has an effect as well. To understand why, we must look at the radiobiology of prostate cancer.
Prostate cancer has been found to respond remarkably well to fewer yet higher doses of radiation. This is reflected in a characteristic called the “alpha/beta ratio” or α/β. The α/β of prostate cancer is very low, at about 1.5. It is lower, in fact, than that of surrounding healthy tissues. Many of those healthy tissues have an early response, which is responsible for acute toxicity, typically with 3 months of treatment (α/β = 10.0). Rectal mucosal tissue is an example. This means that a hypofractionated dosing schedule will kill relatively more cancer cells, while preserving more of the cells in the nearby organs.
There are fewer types of tissue in the pelvic area that have a delayed response to radiation, and those tissues, like nerve cells, tend to be radio-resistant. This is why late-term toxicity is relatively low. Some of the late-term effects we do see are due to cumulative responses to radiation, like the build-up of scar tissue and other reactive responses in vasculature, along the urethra, and in the rectum. Late responding tissue has an α/β of about 3.5
We can compare the biologically effective dose (BED) of the various dosing schedules to see the effect that hypofractionation would theoretically have in killing cancer cells and preserving healthy tissue.
So the kind of fractionation used in SBRT theoretically has about 35 percent more effective cancer-killing power than conventional fractionation, while its ability to generate acute toxic side effects is reduced by 25 percent, and its late-term side effects would be similar.
Why isn’t everyone who elects to have primary treatment with external beam radiation treated with SBRT?
It’s one thing to make predictions based on theory, but it’s quite another to determine whether it works as well in clinical practice. So far, non-randomized trials like the ones examined in this study have shown excellent oncological and quality-of-life outcomes for SBRT with up to 9 years of follow-up. We await the oncological results of randomized trials comparing SBRT to IMRT. The oncological outcomes from the randomized Scandinavian trial are expected any time now. There are several others that are ongoing.
With SBRT, the patient enjoys the obvious benefits of appreciably lower cost and a more convenient therapy regimen. Medicare and most (but far from all) insurance companies now cover SBRT. There is considerable resistance from radiation oncologists in private practice who would get reduced revenues, and would have to learn the new techniques and gain adequate experience in using them.
Note: This commentary was written by Allen Edel for The “New” Prostate Cancer InfoLink.
Filed under: Living with Prostate Cancer, Management, Treatment | Tagged: hypofractionated, IMRT, life, quality, radiation, SBRT, stereotactic |
THE "NEW" PROSTATE CANCER INFOLINK 
It seems the less side effects and cost the more the industry fights it.
Dear Gerald:
It also seems that the more some of us request actual proof that a new technique really is “better” than some of the older ones, the more many of the developers of the new technique resist seeking and providing such proof.
Medicine (for all sorts of reasons) tends to be highly resistant to change — just like a whole bunch of other things that profoundly affect people’s lives.
I think SBRT and hypofractionation are two cases where the developers, far from resisting providing proof, have welcomed it. Hypofractionation now has four large RCTs backing it. SBRT has myriad single institution studies, a few multiple institution studies, and a registry as well. It has one published RCT so far, with results expected from three in the next few years. By contrast, conventional IMRT has never had an RCT comparing it to the previous standard (3D-CRT). IMRT’s longest running single institution study, at MSKCC, was 10 years, but was considered standard-of-care from the start. Their study started with 170 patients, and ended with only 8 non-censored patients by the 10th year. Katz’s 9-year study had a much more robust sample size, with 515 patients. I expect he will publish 10-year outcomes within a year. Inexplicably, IMRT has been considered standard of care even without the proof that ought to have been required.