SBRT vs. moderate hypofractionation: same or better quality of life

We have seen in several randomized clinical trials of external beam treatment of primary prostate cancer that moderately hypofractionated IMRT (HypoIMRT) treatment (accomplished in 12-26 treatments or fractions) is no worse than conventionally fractionated IMRT treatment (in 40-44 fractions).  We recently saw in a randomized clinical trial from Scandinavia that SBRT (in 5 fractions) is no worse than conventional IMRT (see this link) in long-term quality-of-life outcomes, even though they used 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 5 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 3 institutions (UCLA, Georgetown, and 21^st 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 SBRT patients were about 5 years older (69 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 typeface represent a statistically significant difference.

	SBRT	HypoIMRT	Odds Ratio (adjusted)
Urinary	14%	33%	0.24
Rectal	25%	37%	0.66
Sexual	33%	39%	0.73

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.

(update: 4/11/2020) Kwan et al. reported on 78 patients randomized to SBRT (36.25 Gy in 5 weekly treatments) or moderate hypofractionation (70 Gy in 28 treatments). After at least 6 months of follow-up:

• there were no statistically significant differences in grade 2+ or grade 3 toxicities
• there were no minimally important differences in patient-reported quality of life on incontinence, irritative/obstructive urinary issues or bowel issues.

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 includes 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 0.5-1 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 (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 within 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 buildup 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.

	BED for cancer control	Relative BED for cancer control	BED for acute side effects	Relative BED for acute side effects	BED for late side effects	Relative BED for late side effects
80 Gy in 40 fractions	187 Gy	1.00	96 Gy	1.00	126 Gy	1.00
60 Gy in 20 fractions	180 Gy	0.96	78 Gy	0.81	111 Gy	0.89
40 Gy in 5 fractions	253 Gy	1.35	72 Gy	0.75	131 Gy	1.05

So the kind of fractionation used in SBRT theoretically has about 35% more effective cancer-killing power than conventional fractionation, while its ability to generate acute toxic side effects is reduced by 25%, 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.

Sexual function was no worse when fewer external beam radiation treatments were used

The HYPRO trial was designed to detect whether hypofractionation (fewer radiation treatments) was inferior to conventional fractionation. Their previous report looked at outcomes on late-term urinary and rectal function. Here, they report on sexual function outcomes.

To briefly recap, 820 intermediate/high risk patients were randomly assigned to one of two external beam radiation treatment protocols:

• Conventional fractionation: 78 Gy in 39 treatments
• Hypofractionation: 64.6 Gy in 19 treatments
• 39% had adjuvant hormone therapy lasting up to 6 months

It should also be noted that men were 71 years of age at the time of treatment.

After median follow-up of 37 months:

• Among those with partial or full erectile function at baseline, erectile dysfunction occurred in 34.4% among those who had hypofractionation and 39.3% among those who had conventional fractionation. The difference was not statistically significant.
• Orgasmic function among those who did not have hormone therapy was higher for the hypofractionation group. The difference was statistically significant.
• Overall, sexual function scores declined after treatment, but there was no difference between two treatments.

Two other randomized clinical trials also reported no difference in sexual function. Both the Fox Chase trial (see this link) and the M.D. Anderson trial (see this link) found hypofractionation made no difference in sexual outcomes. This should give some comfort to patients and radiation oncologists considering hypofractionation.

Hypofractionated radiation therapy using IMRT has a clear advantage

I was reticent to write about hypofractionation yet again after writing about it so often in the last year. See this link for my latest summary. In a sea of randomized trials demonstrating that hypofractionated radiation therapy (i.e., it is delivered in fewer treatments or fractions) was no worse in cancer control or in toxicity to conventionally fractionated (40-44 treatments), there was one study, the Dutch HYPRO study, where the toxicity was a bit worse. At the time (see this link), I speculated that that was because they included an older radiation technique called 3D-CRT rather than the IMRT technology that is now prevalent in the US. A new study from MD Anderson suggests that may indeed be the case.

Hoffman et al. presented the patient-reported outcomes of 173 men with localized prostate cancer who were treated at M.D. Anderson in Houston. They were randomized to receive either:

1. 75.6 Gy in 42 fractions (conventional fractionation) via IMRT
2. 72 Gy in 30 fractions (hypofractionation) via IMRT

The men filled out questionnaires at baseline, and at 2, 3, 4, & 5 years after treatment. Patients were probed on their urinary, rectal and sexual status. Patient-reported outcomes on validated questionnaires is a more reliable source of toxicity data because it does not rely on the patient volunteering information to the doctor or the doctor assessing or recording that information. Analysis of the two groups showed that:

• there was no difference with regard to rectal issues (urgency, control, frequency, or bleeding).
• there was no difference with regard to urinary issues (pain, blood in urine, waking to urinate at night, or leakage)
• there was no difference with regard to sexual issues (erections firm enough for intercourse)
• there were no differences at 2, 3, 4, or 5 years.

This should dispel any concerns that completing IMRT in less time may be more toxic. Just as with all forms of radiation, the technology has improved greatly over the years. In the hands of an experienced and careful radiation oncologist, there is no reason that external beam therapy cannot be completed in less time and at lower cost.

Why toxicity was higher with hypofractionation in Dutch trial

Aluwini et al. have published the toxicity outcomes of a randomized clinical trial (HYPRO) designed to test whether a hypofractionated external beam (EBRT) regimen compared to conventional fractionation. They will report on the oncological outcomes at a later date.

Between 2007 and 2010, 782 intermediate and high-risk patients were treated at 4 Dutch centers. About half were treated with the hypofractionated regimen, half with conventional dosing as follows:

• ·      Hypofractionation: 19 fractions of 3.4 Gy each
• ·      Conventional fractionation: 39 fractions of 2.0 Gy each
• ·      The relative biologically effective dose is 16% higher for the hypofractionated regimen.
• ·      Both groups were treated with conformal EBRT (3D-CRT and IMRT).

After a median followup of 60 months, the 3-year late-term toxicity outcomes were as follows:

• ·      Genitourinary toxicity, grade 2 or higher: 41% among the hypofractionated group vs. 39% for conventional fractionated.

o   Hazard ratio: 1.16 (Non-inferiority threshold: 1.11)

• ·      Genitourinary toxicity, grade 3 or higher: 19% among the hypofractionated group vs. 13% for conventional fractionated.

• ·      Gastrointestinal toxicity, grade 2 or higher: 22% among the hypofractionated group vs. 18% for conventional fractionated.

o   Hazard ratio: 1.19 (Non-inferiority threshold: 1.13)

• ·      Gastrointestinal toxicity, grade 3 or higher: 3% among the hypofractionated group vs. 3% for conventional fractionated.

Because the toxicity difference slightly exceeded the pre-established thresholds, the authors conclude that the hypofractionated regimen was not non-inferior to the conventionally fractionated regimen in terms of late term toxicity.

Because the hypofractionated regimen was a higher biologically effective dose, we might expect toxicity to be somewhat higher. Several recent major trials showed that hypofractionated IMRT was non-inferior to conventional fractionation in terms of both oncological control and late-term toxicity (see this link and this one, and this one). The lesson we learn from this study is that hypofractionation carries increased risk of toxicity. To avoid that, it is important to use well-planned IMRT or SBRT regimens. 3D-CRT is probably not the optimal platform for such treatment.

Patient compliance with radiation schedules

A new study by Ohri et al. (with additional information in the ASCO Post) found that for certain cancers, there was a 22% non-compliance rate at the Montefiore/Albert Einstein Cancer Center in NY. Non-compliant patients extended their total treatment time by about a week. The recurrence rate was 7% among compliant patients, but was significantly higher, 16%, among non-compliant patients. Now, the authors only looked at compliance with radiation schedules for head and neck, breast, lung, cervix, uterus and rectal cancers. Should prostate cancer radiation oncologists and their patients be concerned?

All cancers are different. It is impossible to generalize from one cancer to another. This is as true for radiation treatments as it is for medical treatments. Prostate cancer has some very unique characteristics that affect radiation treatments:

(1) Prostate cancer is very slow growing. For certain cancers like some head and neck cancers, the tumor growth is so fast that multiple radiations sessions must be scheduled each day (called hyperfractionation) in order to keep ahead of the high cancer cell repopulation rate. In fact, the repopulation rate increases as radiation progresses for such cancers. In contrast, even high-risk prostate cancers repopulate so slowly that delays of a few days to a week are insignificant. In fact, some treatment schedules for SBRT and HDR brachytherapy are a week apart with no apparent loss of efficacy.

(2) Prostate cancer responds to fewer, higher doses of radiation – hypofractionation. Prostate cancer has a peculiarly low radiobiological characteristic, called an alpha/beta ratio, which means it is killed more effectively by hypofractionated radiation. Two major randomized clinical trials have proved that shortened radiation schedules (20 fractions or 28 fractions) have equivalent effectiveness and no worse toxicity than the traditional fractionation of 40-44 treatments. The most extreme kinds of hypofractionation, SBRT and HDR brachytherapy, typically only need 4 or 5 treatments. Recent HDR brachytherapy protocols are using as few as 2 treatments. Therefore, patient compliance isn’t much of an issue. For cancers with a high alpha/beta ratio, more fractions with lower dose per fraction are needed to kill the cancer. Showing up every day for many weeks can be burdensome to the patient.

(3) Fatigue increases with the number of fractions, so reducing the number of prostate cancer treatments helps maintain vigor. With normally fractionated prostate radiation, fatigue peaks at 4-6 weeks after the start of therapy (See this link.). While fatigue scores increased a month after SBRT, it was not a clinically meaningful change (See this link.). Fatigue reported from prostate cancer radiation is less than from radiation to head and neck, alimentary and lung cancers (See this link.); therefore, non-compliance due to fatigue from radiation is probably less important for prostate cancer, particularly with hypofractionation. Other issues sometimes associated with extended fractionation include anxiety, nausea, lost days of work and financial burden. Ohri et al. found that compliance was worse among those of lower socio-economic class.

(4)    Prostate cancer’s alpha/beta ratio is much lower than the ratio attributable to healthy surrounding tissues – a therapeutic advantage. This means that prostate cancer cells are more efficiently killed by the hypofractionated regimen, but the healthy tissues of the bladder and rectum that respond quickly to radiation are not killed at all efficiently. So a total SBRT dose of, say, 40 Gy in 5 fractions, has much more cancer killing power than an IMRT dose of, say 80 Gy in 40 fractions, but less acute toxicity to healthy tissues.   This contrasts with other cancers where the alpha/beta ratio of the cancer is similar to that of nearby healthy tissues. In that case, the only way to mitigate damage to healthy tissues is to deliver the radiation in much smaller fractions, and allow time in between for sub-lethally damaged healthy tissues to self-repair. It doesn’t take long, only a few hours, but for practical purposes, treatments are a day apart.

(5) Prostate cancer is multi-focal in at least 80% of men. Tumors are almost always distributed throughout the entire prostate, so the entire organ is irradiated. This contrasts with many other cancers where there is a single large tumor growing in the organ, at least for a long time. For non-prostate cancers, it is rare for the entire organ to be treated.

(6) There are many important organs (including the bladder, rectum, penile bulb and femur) that fall, at least in part, within the radiation field. Prostate radiation requires sophisticated image-guidance and intensity modulation to treat the prostate and nothing else. Unlike radiation for other cancers where there are toxic effects due to treating the organ itself, there is almost no toxicity due to irradiation of the prostate itself (other than loss of seminal fluid). Discomfort from bladder and rectal toxicity arrives only towards the end or after the end of treatments, so there is little reason to discontinue or miss treatments.

(7) Unlike the other organ cancers that were treated in the study, the prostate is deep within the body. Higher energy X-rays are needed for that depth, and that spares closer-to-surface organs. Consequently, radiation burns of the skin rarely occur, and there is no discomfort associated with each treatment. There are exceptions in men who are hypersensitive to radiation, but burns, necrosis, and fistulas have rarely been reported.

There are some radiobiological considerations that are similar to other cancers that respond to radiation (not all of them do). Some cancer cells may self-repair sub-lethal damage to the DNA, and poor tumor-tissue oxygenation (hypoxia) may protect the tumor from radiation damage. For these reasons, it is important to deliver enough radiation to overcome the hypoxia and kill all the cancer cells. Dose escalation has improved the curative potential of radiation for prostate cancer.

An argument in favor of longer treatment regimens is that cancer cells are more vulnerable during certain phases of their cell cycle; therefore, there will be more opportunities to kill them over a longer treatment schedule. Another argument for longer schedules is that hypoxic protection of the tumor is worn away by the treatments, and subsequent growth of blood vessels around the tumor will re-oxygenate it, thus radio-sensitizing it. The greater local control we’ve seen with extreme hypofractionation suggests that it may elicit unique radiobiological mechanisms that might overcome hypoxia and cell cycle phase issues.

Because of prostate cancer’s low repopulation rate, higher quality of life during treatment, and with increasing use of hypofractionation (both moderate and extreme) there is no reason why patient compliance with prostate cancer treatment schedules should be a problem as it is for other cancers.

(Update 12/6/20) In the National Cancer Database, patient non-completion of SBRT for prostate cancer was 1.9% vs 12.5% for conventionally fractionated treatment.

Proton Hypofractionation

We have recently seen Level 1 evidence that IMRT hypofractionation (fewer, more intense treatments) is no worse than conventional fractionation. The same may hold true for proton therapy.

Proton therapy has come under fire because of its high cost and lack of proven benefit compared to photon IMRT. We are, therefore, interested in changes to the treatment protocol that may reduce costs and increase patient convenience, as long as efficacy and safety are not compromised. Vargas et al. reported the interim patient-evaluated quality-of-life scores of a small randomized pilot trial (NCT01230866) to determine whether proton therapy can be completed in just five treatments (similar to SBRT). Low risk patients were randomized to receive either:

• ·      38 RBE in 5 treatments (49 patients), or
• ·      79.2 RBE in 44 treatments (33 patients)

After 18 months median follow up:

• ·      Urinary, rectal, and sexual function scores were not different at 3, 6, 12, 18 or 24 months after treatment.
• ·      At 12 months, American Urological Association (AUA) Symptom Index Score was low, but slightly worse (8/35) for the hypofractionated therapy than for the conventionally fractionated therapy (5/35).
• ·      Scores remained low and equivalent for both groups in all other time periods.
• ·      There was no grade 3 or higher toxicity at any time in either group.

Kim et al. reported on a trial among 83 patients treated with five different fractionation schedules ranging from 60 CGE in 20 fractions to 35 CGE in 5 fractions. There was no significant difference in 4-yr biochemical failure for any of the treatment schedules within any risk group. Toxicity was low in all groups.

The low toxicity is certainly encouraging, and larger scale trials seem warranted based on this. In addition to the ongoing trial of the 5-treatment protocol, prospective patients may want to investigate the following (some include ADT for higher risk patients):

• ·      Loma Linda and Provision Center for Proton Therapy in Tennessee have ongoing clinical trials, (NCT00831623) and (NCT02198222), respectively, of a 20-treatment protocol .
• ·      MD Anderson is testing a 15-treatment protocol (NCT01950351).
• ·      The University of Florida is testing a mild hypofractionation schedule (NCT01368055).

Hypofractionation is non-inferior to conventional fractionation (redux)

It seems that several major randomized clinical trials of hypofractionation – fewer EBRT treatments at higher dose rates each – have all matured at the same time. While the Fox Chase Trial focused on patients with intermediate and high risk, RTOG 0415 only included men with low-risk prostate cancer.

Between 2006 and 2009, 1,115 low risk patients at about 300 sites in the US and Canada were randomly assigned to either hypofractionation or conventional fractionation:

• Hypofractionation: 70 Gy in 28 fractions (2.5 Gy per fraction)
• Conventional fractionation: 73.8 Gy in 41 fractions (1.8 Gy per fraction)
• The hypofractionated biologically effective dose is 15% higher.

Lee at al. report after a median follow up of 5.9 years:

• ·      7-year disease-free survival (DFS) was 76% for conventional RT, and 82% for hypofractionated RT.
• ·      Late grade 3 urinary toxicity was 2.6% for conventional RT, 4.1% for hypofractionated RT, and were not significantly different.
• ·      Late grade 3 rectal toxicity was 2.3% for conventional RT, 3.5% for hypofractionated RT, and were not significantly different.

This gives us Level 1 evidence that hypofractionated radiation is not inferior to conventionally fractionated radiation in either oncological outcomes or toxicity in low risk patients. Taken together with the CHHiP Trial and the Fox Chase trial, it will be hard to justify the added expense of a longer course of primary radiation therapy in any patient. Of course, this does not at all speak to whether even hypofractionated radiation is superior to active surveillance or to SBRT in low risk patients. Only time will tell if it is practice changing. Radiation oncologists who bill per treatment will naturally be resistant, while insurance companies may encourage hypofractionation.

Hypofractionation – no long-term effect on quality of life

Reducing the number of radiation treatments had no long-term differential effect on urinary, rectal or sexual quality of life, according to a study from Fox Chase Cancer Center that was recently presented at the ASTRO meeting.

These findings compliment their 2013 report of equivalent rates of cancer control from the two treatment schedules. Between 2002 and 2006, they randomly assigned 303 patients to either hypofractionation or conventional fractionation:

• ·      Hypofractionation: 70.2 Gy in 26 fractions (2.7 Gy per fraction)
• ·      Conventional fractionation: 76 Gy in 38 fractions (2.0 Gy per fraction)
• ·      High-risk patients received long-term adjuvant ADT; some intermediate risk patients received short-term ADT (there were no low risk patients).
• ·      Mean age was 67 years in both groups.
• ·      Patients evaluated their quality of life using the EPIC and IPSS questionnaires

The findings that were presented at ASTRO or included in a Medscape article about it were:

• ·      Urinary irritative symptoms declined by less than the amount considered to be minimally clinically detectable at both 3 years and 5 years, and were not different between the two groups.
• ·      Urinary continence symptoms declined by 7% at 3 years and by 9% at 5 years in the hypofractionated group. Compared to the conventionally fractionated group, it was significantly different at 3 years but not significantly different at 5 years. (The EPIC categories that are lumped together as “urinary incontinence” may not mean what most people mean by the term. It may include patient perception of any leaking or dribbling, as well as any pad use. The decline was large enough to be noticeable, but were not very large. The fact that they were not significantly different between the two groups at 5 years may speak to common age-related declines.)
• ·      Patients with poor baseline genitourinary function had worse quality of life outcomes with hypofractionated radiation than with conventionally fractionated radiation
• ·      Bowel symptoms declined by less than the amount considered to be minimally clinically detectable at both 3 years and 5 years, and were not different between the two groups.
• ·      Sexual function declined by a clinically detectable degree at both 3 years and 5 years, but was not different between the two groups.
• ·      Baseline function was an important predictor of long-term quality of life outcomes.

These findings echo the results just reported in the CHHiP trial in the UK. While caution is warranted among men with poor baseline urinary, rectal and sexual function, these two studies provide strong Level 1 evidence that hypofractionated radiation is not inferior to conventionally fractionated radiation. Most patients should be able to complete primary IMRT treatments in about 5 weeks rather than 8 weeks, and at considerably reduced cost.

Hypofractionated Radiation Therapy: Same results in less time

The largest yet randomized clinical trial comparing hypofractionated (fewer treatments or fractions) to normally fractionated IMRT has proved that oncological outcomes and late-term toxicities were the same for both treatment schedules.

The results of the CHHiP study were reported in an abstract by Dearnaly et al. delivered at the European Cancer Congress this week. There was also an interim toxicity analysis in 2012. There were 3,216 patients treated at 71 centers in the UK between 2002 and 2011. All patients were stage T1b-T3a, with <30% probability of seminal vesicle involvement. Patients were randomly assigned to one of three IMRT treatment schedules, for which I also show the relative biologically effective dose (BED) for oncological control compared to normal fractionation:

1.     74 Gy =2 Gy x 37 fractions (normal fractionation)

2.     60 Gy = 3 Gy x 20 fractions; relative BED: +4%

3.     57 Gy = 3 Gy x 19 fractions; relative BED: -1%

ADT began 3 months prior to the start of IMRT, and continued through treatment. The 2012 analysis showed that 93% of patients in each group received ADT.

Patient characteristics were as follows:

• ·      NCCN risk groups:

o   Low risk: 15%

o   Intermediate risk: 73%

o   High risk: 12%

• ·      Median age: 69 years
• ·      PSA: 10.1 ng/ml

After a median follow-up of 63.2 months, the 5-year progression-free (either biochemical or clinical) survival (PFS) rates were:

• ·      74 Gy: 88%
• ·      60 Gy: 91%
• ·      57 Gy: 85%

The difference in PFS for the 57 Gy vs. the 60 Gy schedule was statistically significant; the other differences were not statistically significant.

The toxicity outcomes reported as those with RTOG toxicity grades of 2 or higher were as follows:

• ·      Acute GI toxicity was lower with normal fractionation:

o   74 Gy: 25%

o   60 Gy: 39%

o   57 Gy: 38%

• ·      Acute GU toxicity was not significantly different among groups.
• ·      2-year GI toxicity was lower with hypofractionation in the 57 Gy group:

o   74 Gy: 4%

o   60 Gy: 3%

o   57 Gy: 2%

• ·      5-year GI toxicity was not significantly different among groups.

o   74 Gy: 1%

o   60 Gy: 2%

o   57 Gy: 2%

• ·      Neither 2-year nor 5-year GU toxicities were different among groups.

It is important to note that the normal fractionation schedule used in this trial (2 Gy x 37 fractions) is low compared to the current standard of care (2 Gy x 40 fractions), but was standard when this trial began in 2002. The 60 Gy schedule comes close to the current standard of care in terms of its biologically effective dose. Given this, it is not surprising that only the 60 Gy schedule achieved 5-year progression-free survival levels over 90%. The lowest dose schedule is on the steep part of the dose/response curve where even small increases in dose achieve large increases in cancer control.

While acute GI toxicity was higher at first with hypofractionation, the effect was transient, and had disappeared by 2 years. Lasting GI toxicity was negligible, and there were no differences at any time in GU toxicity.

Based on all this, the authors state, “Modest hypofractionated RT using 60Gy/20f appears effective and safe and may be recommended as a new standard of care.”

We should be clear that this is not SBRT; it is only IMRT with an accelerated dosing schedule. There are some important differences. SBRT typically uses doses of 6-8 Gy per fraction and just 4 or 5 fractions. Because of the extreme hypofractionation, it becomes critical to track prostate motion during each fraction and not just between fractions. Treatment margins are typically narrower with SBRT and may be as low as 0 on the rectal side. These differences are what make SBRT safe. In the current study, there was no allowance made for intra-fractional prostate motion and the margins were not altered, so it is not very surprising that rectal toxicity was higher at first, but it was perhaps surprising that there were no lasting differences.

We should also note a few similar randomized comparative trials in the last year. One, at Fox-Chase (n=333), looked at 76 Gy delivered in 38 fractions of 2 Gy each (normal fractionation) compared to 70 Gy delivered in 26 fractions of 2.7 Gy each (hypofractionated) among intermediate and high-risk patients. The 5-year biochemical and/or clinical disease failure rate was the same -- 21% for normal fractionation, 23% for hypofractionation -- and there was no difference in late term toxicity, except among men with compromised urinary function.

An M.D.Anderson study (n=203) compared the late toxicity of a normally fractionated schedule (76 Gy in 1.8 Gy fractions) to a hypofractionated schedule (72 Gy in 2.4 Gy fractions). As in the UK study, there were no differences in GU toxicity. There was an increase in GI toxicity in the hypofractionated group, although it was not statistically significant. Unsurprisingly, the authors found it was related to the volume of the rectum that received high doses.

A multi-institutional study from the Netherlands among intermediate and high-risk men (n=820) reported on the acute toxicity of a normally fractionated schedule (78 Gy in 2 Gy fractions) compared to a hypofractionated schedule (65 Gy in 3.4 Gy fractions). At 3 months, there was no difference in GI or GU toxicity. At 6 months, there was no difference in GU toxicity, but GI toxicity was higher in the hypofractionated group (42% vs. 31%).

We also saw recently (see: Can salvage radiation therapy be safely and effectively completed in less time?) that a shortened treatment schedule appeared to be safe and effective for salvage IMRT. However, this UK study is more compelling because it is a randomized comparative trial of great size.

The only impediment seems to be the higher rate of acute rectal side effects. The patient will have to decide if it is worth accepting those transient symptoms in exchange for the convenience of a 4-week treatment schedule. Given the lower rate of patient-reported adverse outcomes and the high rate of oncological control with SBRT, however, it would seem that the 10-day schedule (5 fractions, every other day) is a better alternative on all counts.