Questions to ask on a first visit for primary radiation therapy (IGRT/IMRT)

IGRT/IMRT Questions for Doctors

1. How many have you planned? 
2. How has your practice of IMRT changed over the years? 
3. What is your 5-yr freedom from recurrence rate for patients at my risk level? 
4. What proportion of your recurrences were local? (see this link) 
5. What kind of urinary and rectal reactions can I expect? 
• How long can I expect them to last? 
• What medications or interventions do you typically give for that? 
• Should I expect those symptoms to recur later? 
6. What is your rate of serious (Grade 3) adverse events? 
7. Do you see urinary strictures? 
8. Urinary retention requiring catheterization? Fistulas? 
9. Rectal bleeding requiring argon plasma or other interventions? 
10. What is the margin you will treat around the prostate? 
• Is it less on the rectal side? 
11. Will you include the pelvic lymph nodes? 
12. What about the seminal vesicles -proximal or entire? 
13. What are the prescribed doses to the planned target volumes? 
14. If applicable, in light of my unfavorable risk cancer: 
• do you think I need a brachytherapy boost to the prostate? (see this link) 
• do you think I need hormone therapy? For what duration?
15. In light of the 8 major randomized clinical trials on hypofractionation reported in the last year (see this link), do you recommend hypofractionation (fewer treatments) for me? 
16. Does your hospital do SBRT monotherapy for patients like me? Why not? 
17. Do you work off a fused MRI/CT scan for the plan? 
18. What machine do you use? (any brand of VMAT or Tomotherapy are good) 
19. Do you use fiducials or Calypso transponders? 
• Do you do transperineal placement of them? 
20. What system do you use for inter-fractional tracking? (cone beam CT or stereoscopic X-ray, probably) 
21. Is the alignment automated? 
22. In my treatment plan, what do you identify as “organs at risk” and what dose constraints do you put on them? 
• What dose will my penile bulb receive? 
23. Do you use angiography to locate and spare the pudendal artery? (see this link) 
24. How long does each treatment take? 
25. How will I be immobilized during each treatment? 
26. Are there any bowel prep or dietary requirements? 
27. Should I avoid taking antioxidant supplements during treatment? 
28. In your practice, among men who were fully potent, what percent remained fully potent 3-5 years later? 
29. Have any men retained some ability to produce semen? 
30. What is your opinion of taking Viagra preventatively? (see this link) 
31. Do you monitor side effects with the EPIC questionnaire? 
32. In your practice, what percent of men experience acute urinary side effects? 
33. In your practice, what percent of men experience acute rectal side effects? 
34. In your practice, what percent of men experience late term urinary side effects? 
35. In your practice, what percent of men experience late term rectal side effects? 
36. What kind of PSA pattern should I expect following treatment? 
37. What is the median PSA nadir you are seeing in your practice, and how long does it take to reach that, on the average?
38. If there should be a biochemical (PSA) recurrence, what would the next steps be? (they have to prove it’s local but not distant) 
39. Have you ever used SBRT, brachy, or cryo for salvage after a local IMRT failure, and was that focal or whole gland? 
40. Are you open to email communications between us?

Record 10-year SBRT study among low risk patients

Alan Katz has now published the study with the longest-running follow-up of any study of external beam radiation therapy for prostate cancer among low risk patients, in this case, using SBRT. 10-year follow-up among intermediate and high-risk patients will be presented at next year's ASTRO meeting. This study ties in longest length of follow-up with the Memorial Sloan Kettering (MSK) study of IMRT. IMRT involves 40-45 radiation treatments over the course of about 9 weeks; SBRT shortens the number of treatments to 4 or 5 over the course of about 11 days.

Focusing on their low risk cohort only, the Katz study has a distinct advantage over the MSK study in sample size:

• The Katz study started with 230 low risk patients and, because of later start dates and some loss to follow-up, had 57 evaluable low-risk patients who were tracked for 10 years.
• The MSK study started with 49 low risk patients and, because of later start dates and loss to follow-up, ended with only 2 patients tracked for 10 years.
• Median follow-up was 108 months for Katz and 99 months for MSK

The IMRT study used a prescribed dose of 81 Gy in 45 fractions. The Katz study used a dose of 35 Gy in 5 fractions on 42 patients and 36.25 Gy in 5 fractions on 188 patients (average = 36 Gy). The biologically effective dose for cancer control was 17% higher in the Katz study.

It is risky to compare SBRT and IMRT when patients are not randomized to treatment with one or the other. There has been such a randomized trial, and partial results have been reported (see this link). The median age was the same in both studies (69 years of age), and the same definitions for the low risk category, and for biochemical failure were used. To highlight some of the differences and similarities in outcome:

• 10-year biochemical disease-free survival was 94% for Katz vs. 81% for MSK
• 10-year distant metastasis free-survival was 98.4% for Katz and 100% for MSK
• No prostate cancer-related deaths at 10 years in either study

Late-term urinary and rectal side effects were infrequent and mild in both studies:

• Late-term urinary side effects:
• Grade 2: 9%, Grade 3: 3% in the Katz study
• Grade 2: 9%, Grade 3: 5% in the MSK study
• Late-term rectal side effects:
• Grade 2: 4%, Grade 3: 0% in the Katz study
• Grade 2: 2%, Grade 3: 1% in the MSK study

Of those who were previously potent before radiation, 56% were potent (sufficient for intercourse) 10 years later (median age 79) in both studies.

Other interesting outcomes of the Katz study included:

• Median PSA fell to 0.1 ng/ml after a median of 48 months
• 21% experienced a PSA bounce along the way.
• Cure rates were independent of whether patients received 35 Gy or 36.25 Gy
• Urinary toxicity was higher in the group that got the higher dose
• Rectal toxicity was no different in the two groups
• Patient-evaluated urinary and rectal function declined acutely but returned to baseline within a year
• Sexual function declined by 23% at 6-12 months, and continued to decline by 38% by 8 years. It is unknown what percent of that decline was age related (but see this link).

Looking at the higher local control rates of SBRT and HDR brachytherapy, Dr. Katz sees evidence that IMRT is sub-optimal in delivering biological effective dose. He also believes that no more than 35 Gy in 5 fractions is necessary to achieve that control, and that it would minimize side effects.

Of course, probably half of the low risk men in this study might have gone those ten years without needing any kind of treatment at all. But for those who may not want or may not be good candidates for active surveillance, SBRT is a low cost, low bother, low side-effect alternative that delivers high rates of long-term oncological control.

Amazingly, I still hear that there are insurance companies that will not cover SBRT because longer follow-up is needed. Dr. Katz had already reported the nine-year follow-up (see this link), and with this addition and the 10-year higher-risk update at ASTRO next year, it's hard to see what any objection might be.

Dr. Katz is to be congratulated for continuing to update his study for 10 years. It is a lot of work to follow up with so many patients, and collect and tabulate their reported outcomes. He is a radiation oncologist not associated with a large tertiary care facility that might have more resources at its disposal.

Vessel-sparing IMRT spares erectile function

While either nerve-sparing surgery or radiation can cause erectile dysfunction, the probability for that for any given patient is always worse after surgery. The recent ProtecT randomized clinical trial removed any doubt of that, if there ever really was any. While nerve-sparing surgery was introduced by Walsh in 1982, there has been no similar breakthrough in IMRT radiation delivery - until now.

Effects of treatments on erectile apparatus

The mechanism of erectile function is complex, involving the brain, hormones, neurotransmitters, enzymes, and nitric oxide, just to mention a few vital components. Nerve impulses must travel from the brain, through the spine, along the nerve fibers that surround the prostate and then along its length down to the corpus cavernosa (the spongy tissue inside the penis from the penile bulb to the glans). Surgery, even nerve-sparing surgery, usually disrupts the signal that must innervate the penis. "Nerve sparing" is not an all-or-nothing technique. If the cancer has grown out into the neurovascular bundles, only some of the nerves may be spared. Take away too little, and the cancer is not cured; take away too much, and permanent erectile dysfunction is assured. Sometimes surgeons send frozen slices of tissue for pathological analysis before deciding how much to remove.

When radiation causes erectile dysfunction, the mechanism is very different. Nerves are relatively impervious to radiation; however, blood vessels and other endothelial tissue may be affected. The blood that supplies the penis comes to it through the "pudendal arteries" that flow downwards on either side of the prostate (in the "neurovascular bundle"). The blood enters the penis at the penile bulb (the part that extends inside the pelvis) and engorges the tissue of the corpus cavernosa. Radiation may cause an inflammatory reaction in the linings of the blood vessels and in the tissue of the corpus cavernosa. Over a period of months, the inflammation may result in scar tissue that restricts blood flow, and the impedes the ability of the spongy tissue of the corpus cavernosa to expand and contract elastically.

For years, there has been somewhat conflicting evidence about whether radiation's effect on erectile dysfunction can be mitigated by reducing the dose to the penile bulb (see this link). Consequently, radiation oncologists set a dose constraint for the penile bulb, but that was not a full solution. Many radiation oncologists have wondered whether the dose to the pudendal arteries and to the other parts of the corpus cavernosa could be  restricted to preserve erectile function without sacrificing oncological effectiveness. Innovations in MRI-based planning and super-precise (sub-millimeter) beam delivery have enabled that.

Vessel-sparing IMRT

Spratt et al. at the University of Michigan conducted a clinical trial on 135 patients treated between 2001 to 2009 to see whether "vessel sparing" IMRT could better preserve erectile function while achieving equal cancer control. As others have, they used a T2 MRI to delineate the contours of the penile bulb and corpus cavernosa. Their innovation was to use contrast-enhanced MRI-angiography to delineate the pudendal arteries that run near the prostate apex. The MRI images were fused with CT scan images and dose goals were set based on those. Intermediate and high risk patients were treated with low dose rate brachy (seed) boost therapy before they received IMRT; low risk patients received IMRT alone. A treatment margin of 1 cm was set for patients receiving IMRT only. It was lowered to 0.5 cm for those receiving brachy boost therapy.

Key patient and treatment characteristics included:

• Age = 63 (median)
• Baseline erectile function: IIEF score ≥ 16 (mild or no ED)
• Risk: Low - 39%, Intermediate - 53%, High -9%
• Gleason score: 3+3 - 44%, 3+4 - 33%, 4+3 - 13%, 8-10 - 9%
• Treatment: IMRT alone - 39%, brachy boost - 61%
• Dose: IMRT - 75.6-79.2 Gy, brachy boost - 110 Gy I-125 seeds + 45 Gy IMRT
• Pelvic dose: 45 Gy (high risk only)
• 6-month ADT: yes -33%, no - 67%

Potency preservation

During a median follow-up of 8.7 years, patients filled out questionnaires and doctors evaluated their erectile function at 2 years and 5 years. They were also queried about their use of erectile medicines and aids. Their responses were matched to the results of the PROSTQA study, matched for age, baseline potency, and other sexual risk factors. The percent of men who had erections firm enough for intercourse 2 years after treatment were:

• 78% if they had vessel-sparing IMRT
• 42% if they had conventional IMRT
• 24% if they had nerve-sparing prostatectomy

Other measures of erectile function at baseline, 2 years and 5 years included:

• No sexual aid use: 88%, 47%, 44%
• IIEF score ≥16 (no or mild ED): 100%, 70%, 67%
• High/very high confidence in getting and keeping an erection: 63%, 40%, 33%
• Potent without aids: 80%, 45%, 35%
• Potent with aids: 20%, 41%, 53%
• Impotent: 0%, 14%, 12%

As we've seen in other studies, most of the radiation-induced ED will show up within the first two years, and probably within 9 months of treatment. This was shown for 3D-CRT in the ProtecT clinical trial,  for brachytherapy, for SBRT,  and EBRT. Perhaps the authors will make an attempt to separate the effect of patient aging in a future analysis. The University of Michigan should be able to accomplish this using their age-adjusted sexual domain EPIC scores.

It's worth noting that potency preservation was no different for those who had the brachy boost or IMRT only. It was better for younger men, men with higher baseline performance, and those who did not have adjuvant ADT.

Oncological outcomes

At 5 years, the biochemical recurrence-free survival for each risk group was:

• Low risk: 100%
• Intermediate risk: 100%
• High risk: 98%

At 10 years, the biochemical recurrence-free survival for each risk group was:

• Low risk: 100%
• Intermediate risk: 89%
• High risk: 88%

One could not ask for better outcomes!

Conclusion

It appears that vessel-sparing IMRT is a vast improvement over conventionally targeted IMRT in terms of preservation of erectile function, and based on this, should be adopted as standard practice for all patients who might benefit. Interestingly, potency preservation is similar to that reported for SBRT (see this link) and for high dose rate brachytherapy (see this link). That is not at all surprising because both of those therapies use much narrower margins than those used for IMRT, typically 2-3 mm vs. 10 mm for IMRT, and the biologically effective dose to the vascular tissue of the pudendal arteries are lower. With SBRT, intra-fractional motion is tracked, thus avoiding dose to nearby structures. With HDR brachytherapy, the gland is immobilized with catheters that prevent doses to the nearby vessels and organs. Hopefully, equally excellent results can be achieved with hypofractionated IMRT,  but that remains to be proved in future trials. With salvage IMRT, the entire prostate bed is treated, so I do not know if radiation to the pudendal arteries can be similarly avoided.

Anyone planning on having IMRT should forward a copy of this study to his radiation oncologist, and ask to discuss it at their next meeting. Of course, for men who are low risk, active surveillance will cause no erectile dysfunction and no loss of ejaculate.

Less treatment regret with SBRT and when patients are fully informed at UCLA

There is growing recognition that the patient's satisfaction or regret with his treatment decision is more than just a matter of whether he is happy with the oncological outcome. Satisfaction/regret is the product of many variables, including how well he understood his options, his interactions with his doctors, the side effects he suffered and when he suffered them, his expectations about the side effects of treatment, and cultural factors.

Shaverdian et al. explored the issue of treatment regret with patients treated at UCLA with three kinds of radiation therapy: Intensity Modulated Radiation Therapy (IMRT), Stereotactic Body Radiation Therapy (SBRT), and High Dose Rate Brachytherapy (HDR). Questionnaires were sent to 329 consecutive low or favorable intermediate risk patients treated from 2008 to 2014 with at least one year of post-treatment follow-up. There was a high (86%) response rate. The number of responses were:

• IMRT -  74 patients
• SBRT - 108 patients
• HDR  -   94 patients

Patient characteristics were similar across treatments. The only significant differences were:

• HDR patients were a median of 5 years younger
• IMRT patients disproportionately African- American and Asian-American
• Length of follow-up was longer for IMRT patients
• HDR patients were more likely to be taking medication for erectile dysfunction.

Decision-making process

Those that chose IMRT spent less time making their decision. The percent that spent less than a month making their decision was:

• IMRT: 47%
• SBRT: 31%
• HDR:  12%

Although most patients felt they had learned enough about the treatment options before making their decision, those who chose IMRT were least likely to say so:

• IMRT: 83%
• SBRT: 91%
• HDR: 86%
• 11% of the IMRT patients wished they had learned more about active surveillance.

There was widespread agreement that they had worked mutually with their doctors to arrive at a decision.

• IMRT: 85%
• SBRT: 91%
• HDR: 84%

Treatment regret

The percent who felt that they would have been better off with a different choice was least for SBRT:

• IMRT: 19%
• SBRT: 5%
• HDR: 18%
• This rate of treatment regret for IMRT and HDR is similar to the rate expressed for surgery (see this link).

Of those who expressed treatment regret, the biggest reason for it (36%) was because they could have had better sexual function. 72% of those with treatment regret would have chosen active surveillance if they had it to do over again.

 
After correcting for patient characteristics, the factor most associated with treatment regret was whether they had learned enough about other treatments. Those with treatment regret were 53 times as likely (odds ratio) to say that they had not learned enough. The next biggest factor predicting treatment regret was whether the long-term side effects were worse than expected (odds ratio = 42). Expectations and the disappointment of those expectations have a large impact on treatment regret. Those who chose IMRT were 11 times more likely to have treatment regret than those who chose SBRT, and those choosing HDR were 7 times more likely to experience treatment regret compared to SBRT. The table below shows the odds ratio for all statistically significant factors.

	Relative impact on treatment regret  (odds ratio)
Decision-Making Factors
Learned enough about treatments	53
Mutually worked with physicians	16
Doctors fully informed me	11
Side Effects
Short-term side effects worse than expected	8
Long-term side effects worse than expected	42
Bowel function	8
Sexual function	5
Urinary function	5
Treatment
IMRT vs SBRT	11
HDR vs SBRT	7
HDR vs IMRT	1

While IMRT was the highest cost treatment, it also gave the lowest value to the patient. Conversely, SBRT, the lowest cost treatment, provided patients with the highest value. To increase value to patients, doctors must assure that patients are fully informed about all their treatment options, and the side effects that they may reasonably expect. Patients should be encouraged to take their time investigating options, especially active surveillance.

All patients in this study were treated at UCLA, which has a policy of fully informing patients of all their options and expected outcomes. It is impossible to entirely separate the effect of superior patient counseling on the part of the physician from the superior treatment outcomes as the reasons for increased patient satisfaction. Perhaps if this questionnaire were used across multiple institutions those effects could be distinguished. Because UCLA is a nationally-renowned tertiary care center, these results are not at all applicable to what goes on in the community setting. If expanded, we would like to see comparisons with other treatment modalities: surgery (robotic and open), low dose rate brachytherapy, active surveillance, proton beam therapy, hypofractionated IMRT, and focal ablation therapies. It would also be instructive to compare the value attached to adjuvant treatment modalities (e.g., brachy boost therapy and hormone therapy) given to patients with more advanced disease and in the salvage setting. It is a good start, however, and provides a validated questionnaire by which treatment centers can assess their performance and set goals for improvement. We would love to see this "report card" expanded nationally.

Questionnaire

For those who have been treated and would like to see how your treatment falls on the treatment regret questionnaire, I've copied it below. It may also be useful for those who have not yet been treated to help assure you minimize your treatment regret.

Prostate Cancer Patient Voice Questionnaire

This questionnaire is designed to better evaluate your treatment experience so that we can continue to improve the quality of the care we provide. To help us get the most accurate measurement, it is important that you answer all questions honestly and completely.

Name: _______________________________________

Today’s Date (please enter date when survey completed): Month ________ Day_______ Year________

Question 1:
What is the highest level of education you have received? 
a) Less than high school
b) Graduated from high school
c) Some college
d) Graduated from college 
e) Postgraduate degree

Question 2:
How much time did you think about your diagnosis and treatment options before deciding on your treatment?
a) Less than 1 month 
b) 1-2 months
c) 2-4 months
d) 4-6 months
e) Over 6 months

Question 3:
Do you believe you learned enough about the different treatment approaches for treating prostate cancer before undergoing treatment? (circle all that apply)

1. a)  Yes
   
2. b)  No, I wish I had learned more about intensity
   modulated radiation therapy (IMRT)
   
3. c)  No, I wish I had learned more about stereotactic body
   radiation therapy (SBRT)
   
4. d)  No, I wish I had learned more about brachytherapy
5. e)No, I wish I had learned more about active surveillance
6. f) No, I wish I had learned more about surgical treatments
7. g) Other (please specify): _______________________ ___________________________________________

Question 4:
How true or false has the following statement been for you? “I felt that I worked with my doctors to mutually decide on the best treatment plan for me.”
a) Definitely false
b) Mostly false
c) Neither true nor false 
d) Mostly true
e) Definitely true

Question 5:
During the past 4 weeks, how much of the time have you wished you could change your mind about the kind of treatment you chose for your prostate cancer? 
a) None of the time 
b) A little of the time 
c) Some of the time 
d) A good bit of time 
e) Most of the time

f) All of the time

Question 6:
How true or false has the following statement been for you during the past 4 weeks?
“I feel that I would be better off if I had chosen another treatment for my prostate cancer.”
a) Definitely false
b) Mostly false
c) Neither true nor false 
d) Mostly true
e) Definitely true

Question 7:
If you do have regret about your treatment, which one of the following most accurately describes the reason why you have regret?

1. a)  I could have had fewer urinary symptoms with another treatment.
   
2. b)  I could have had fewer rectal symptoms with another treatment.
   
3. c)  I could have had better sexual function with another treatment.
   
4. d)  I could have had a less costly treatment.
   
5. e)  I could have had another more effective treatment.
   
6. f)  I could be better off now without having had any active treatment.
   
7. g)  Other (please specify): _______________________ ___________________________________________
   

Question 8:
If you do have regret about your treatment, which one of the following most accurately describes the treatment you now wished you had received?

1. a)  I would rather have had surgery (robotic or open prostatectomy).
   
2. b)  I would rather have had stereotactic body radiation therapy (SBRT).
   
3. c)  I would rather have had Brachytherapy.
   
4. d)  I would rather have had Intensity Modulated Radiation Therapy (IMRT).
5. e) I would rather have gone forward without active treatment (Active Surveillance).
6. f) Other (please specify):__________________________________________________________________

Question 9: 
This question asks about the short-term side effects. While undergoing treatment, were the short-term side effects you actually experienced less than or more than you had originally expected?
a) The side effects I actually experienced were exactly as I had expected.
b) The side effects I actually experienced were significantly less than I had expected. 
c) The side effects I actually experienced were slightly less than I had expected.
d)  The side effects I actually experienced were slightly more than I had expected.
e)  The side effects I actually experienced were significantly more than I had expected.

Question 10: 
This question asks about the long-term side effects. After completing treatment, were the long-term side effects you actually experienced less than or more than you had originally expected?

1. a)  The side effects I actually experienced were exactly as I had expected.
   
2. b)  The side effects I actually experienced were significantly less than I had expected.
   
3. c)  The side effects I actually experienced were slightly less than I had expected.
   
4. d)  The side effects I actually experienced were slightly more than I had expected.
   
5. e)  The side effects I actually experienced were significantly more than I had expected.
   

Question 11:
How strongly do you agree or disagree with the following statement? 

“Based on my experience, I believe my doctors fully informed me about possible side effects before I started treatment.”
a) Strongly disagree
b) Disagree
c) Neither agree nor disagree 
d) Agree
e) Strongly agree

Question 12:
Overall, how big a problem have your urinary, bowel, and sexual functions been for you during the last 4 weeks? (circle one number on each line) 

             (0) No problem  (1)Very small problem (2)Small problem  (3)Moderate problem (4)Very big problem 
Urinary function  0 1 2 3 4 
Bowel function    0 1 2 3 4 
Sexual  function   0 1 2 3 4 

note: Thanks to Dr. King for allowing me to review the full text.

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.

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.