Showing posts with label therapy comparison. Show all posts
Showing posts with label therapy comparison. Show all posts

Monday, January 30, 2017

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.

Saturday, January 7, 2017

What should focal therapy be compared to and how does it compare?

In a recently published randomized trial of a new kind of focal ablation therapy for prostate cancer that was widely misinterpreted in mainstream media, the authors wrote:
"A pivotal comparative study was therefore necessary, but was challenging to design in a manner that would be acceptable to both patients and clinicians and in which the same primary outcome [histologically confirmed progression of cancer] could be assessed for the intervention and the comparator. We had three options for the comparator: surgery, radiotherapy, or active surveillance. For the first two options, a primary outcome that could be applied to both the experimental group and the control group proved difficult to find. Surgery (radical prostatectomy) would not be suitable for a biopsy-based outcome because there would be no prostate from which to take a biopsy. Radiotherapy would be amenable to a protocol-required biopsy, but the histological outcome would be confounded by the necessary neoadjuvant and adjuvant androgen suppression that constitutes the standard of care. Therefore, active surveillance was the only comparator that could reasonably be used over the intended time frame [2 years] of the study.
This is an odd statement, indeed. They rejected surgery as a comparator because salvage treatment is usually given before it is possible to obtain histological (biopsy) confirmation of spread to the prostate bed. This is reasonable. They rejected comparison to radiation because it is difficult to interpret a biopsy on tissue in which the cancer has been shrunk by androgen deprivation. However, all patients were low-risk patients who would almost never receive neoadjuvant or adjuvant androgen deprivation along with their radiotherapy, at least not in the US. Perhaps this is or was standard of care in Europe. That left them with active surveillance as a comparator, but the kind of active surveillance and patient selection for it bears closer examination.

Active surveillance as practiced at the time (2011-2013) in those European centers of excellence was different in some important respects from active surveillance as currently practiced in US centers of excellence. In the US, a confirmatory multiparametric MRI (mpMRI) is often given within a year of the first biopsy, and biopsy cores are obtained from any suspicious areas. The authors state that their study began before this practice became prevalent in Europe. In spite of that, all patients who received focal ablation were given an mpMRI before therapy, while none of the men on active surveillance received it. Certainly, many of the men in the active surveillance cohort had undiagnosed higher grade cancer, and should not have continued on active surveillance. It is impossible to say that any of the cancers progressed in the 2 years on active surveillance, or whether they were simply reclassified because the two repeat biopsies found the cancer that was always there, and which might have been found earlier had the received an mpMRI as the ablation cohort did.

The authors further state:
"The European Medicines Agency agreed that we could reasonably exclude very low-risk patients. Therefore, lower and upper thresholds of risk (defined by Gleason score and tumour burden) were set, below and above which men were excluded.
So "very low risk" prostate cancer patients, who make up most of the patients in active surveillance programs in the US, and all of them in some programs (e.g., Johns Hopkins), were excluded. Focal therapy is compared here to higher risk active surveillance patients than is typical in the US.

Patient selection was also atypical in that no more than 3 positive cores were allowed, and the length of cancer in any one core had to be between 3mm and 5mm. Men with very small (<25 cc and very large (>70 cc) prostates were excluded.

Progression was deemed to have occurred if any of several criteria were met:
  1. Gleason pattern≥4
  2. > 3 positive cores
  3. Cancer core length > 5 mm
  4. PSA>10 in 3 consecutive measurements
  5. stage T3 discovered
Only the first 3 had a significant effect. It should again be emphasized that many active surveillance programs now recommend radical treatment if a biopsy shows predominant Gleason pattern 4. Under such programs, many, if not most, in their active surveillance cohort would not be deemed to have progressed. This is especially true when mpMRIs are used early to rule out predominant pattern 4.

The procedure

The kind of focal therapy used here (called TOOKAD soluble vascular photodynamic therapy) involves treating the patient under general anesthesia with an intravenous injection of a photosensitizing chemical, called padeliporfin. Optical fibers were inserted transperineally with one end at the tumor to be ablated and the other end attached to a near-infrared laser that delivered an energy dose of 200 J/cm. I believe the authors err when they characterize this as "non-thermal." The operation took about 2 hours, and patients stayed overnight in the hospital. The catheter was removed the next day.

Retreatment was allowed if the 12-month biopsy indicated residual cancer. It's important to keep this in mind when looking at the oncological outcomes. 32% received another treatment on the contralateral side. 6% received retreatment after 12 months. There is no analysis provided showing the toxicity among men who received multiple treatments compared to those who only received a single treatment.

Oncological outcomes

After 2 years of follow-up among the men who received up to two treatments of the focal photodynamic therapy (PDT):
  • 28% progressed, mostly with higher Gleason grade
    • 58% progressed or were reclassified in their active surveillance cohort
  • 51% had a positive biopsy
    • 86% had a positive biopsy in their active surveillance cohort
The European PRIAS study of active surveillance found that only 23% had progressed within 2 years, which was even less than the 28% progression rate found here with focal treatment, but PRIAS comprised patients who were very low risk only. In the Klotz study of low-risk patients, 30% progressed in 5 years - about the same as progressed in 2 years here with focal therapy. (See this link.)

Since this is only with 24 months of follow-up, we can conclude that 30% were able to avoid radical treatment for 2 extra years. (Update 6/2018: Even after 4 years of follow-up, the difference was maintained at about 30%). But if the active surveillance group had been initialized with mpMRI detection, it's not clear that this benefit would persist.

It's also worth noting that 52% had no evidence of disease in one active surveillance study on a confirmatory biopsy (see this link), similar to what was seen here with focal treatment. The apparent remission rate was about 40% even using mpMRI-targeted biopsy (see this link). These are much higher than the apparent remission rate of 14% in this active surveillance cohort, again calling into question how active surveillance was defined here. With treatment with Proscar or Avodart, the apparent remission rate has been found to be 54% (see this link), which is equal to that observed here with focal therapy. Could the same rate of apparent remissions be achieved simply by taking a pill?

Morbidity

Side effects of treatment, while seldom serious enough to warrant intervention other than re-catheterization for a period of time, did occur. One in three patients suffered some kind of toxicity from the treatment. Most were low grade (grade 1 or 2) and transient. The ones that occurred significantly more in the treated cohort were (cumulative incidence within 2 years):

  • Erectile dysfunction 38%
  • Blood in urine 29%
  • Painful urination 26%
  • Urinary retention 17%
  • Perineal pain 16%
  • Urinary urgency 11%
  • Urinary tract infection 11%
  • Urinary incontinence 10%
  • Urinary frequency 10%
  • Ejaculation failure 8%
  • Prostatitis 6%
  • Inguinal hernia 4%
  • Rectal hemorrhage 4%

There was one case of anaphylactic shock due to the anesthesia. Three men had urinary retention serious enough to require surgical intervention.

Would these men have been better off with radical therapy? We can look at these results side-by-side with some toxicity outcomes of SBRT treatment. The table below shows the highest incidence of side effects reported by both studies. I chose this Georgetown study because they gave 2-year outcomes and because they included Grade 1 toxicity - often only grade 2 or higher toxicity is reported. As with focal therapy, almost all of the side effects were mild (grade 1) and acute, occurring within the first month of treatment, and returning to baseline within 2 years. Potency retention was 79% at 2 years. Similar to focal ablation, only 1% had any serious (grade 3) toxicity. However, none were life-threatening.


In the SBRT study, there were no biochemical failures in the first two years among the low risk and intermediate risk patients in the study. This compares to 51% with evidence of disease, and 28% with higher risk prostate cancer already in the first 2 years for the focal therapy, even with retreatment in some.

It should be clear to patients that the benefits of focal therapy depends on what it is compared to. This analysis should also alert patients to be wary of media hype. For a discussion of the unresolved issues in focal ablation, see this link.

(update 2/2020) FDA Rejects TOOKAD for low-risk prostate cancer

The FDA oncologic drugs advisory committee rejected Steba Biotech's new drug marketing application. The decision may be revisited after Steba presents the results of a longer-running trial expected in 2025. In a Medpage interview, Patrick Walsh, on the committee, said:

"I think most of these patients [treated with TOOKAD] won't be told that at 2 years half of the men will still have cancer and in 28% it will be progressing."





Monday, December 5, 2016

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 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 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.



Wednesday, September 28, 2016

Toxicity equal for SBRT and conventional external beam radiation


There has been some question as to whether the toxicity of delivering very high doses of external beam radiation per treatment (or fraction) in fewer fractions (called “extreme hypofractionation” or SBRT) would be high compared to conventional dose rates per fraction. While SBRT practitioners have reported very low toxicity rates (see table in this link), there has always been some doubt because there may have been some bias in how patients were selected in the various studies.

The HYPO-RT-PC trial was the first trial ever to randomly assign patients to one kind of radiation or the other. Between 2005 and 2015, they enrolled 1200 intermediate-risk patients in Scandinavia to receive either:
  1.  Conventional fractionation: 78 Gy in 39 fractions
  2. SBRT: 42.7 Gy in 7 fractions

The biologically effective dose is 19% higher for SBRT in terms of cancer control. The biologically effective doses are equivalent in terms of toxicity.

There were a few differences from some US practices:
  • “Intermediate risk” was defined as one or two of the following 3 risk factors:

  1. Stage T1c-T3a (T3a is a high risk factor in the commonly used US definition)
  2. PSA> 10 ng/ml (PSA> 20 ng/ml is a high risk factor in the commonly used US definition)
  3. Gleason score ≥7 (Gleason scores greater than 7 are a high risk factor in the commonly used US definition)

  • 80% of the men were treated with a technology called 3D-CRT, which is seldom used for external beam therapy anymore at major tertiary care centers. It is never used for SBRT in the US because it is considered not precise enough, and too toxic.
  • SBRT is usually delivered in 4 or 5 fractions in the US. CyberKnife and VMAT are the most common technologies in use, and use of sophisticated image guidance throughout each treatment is a common practice.

The toxicity results are based on 866 patients who had 2-year follow-up results. There were some differences in acute toxicity:
  • Acute urinary toxicity was 27.6% for the SBRT group and 22.8% for the conventional fractionation group, but the difference was not statistically significant.
  • Acute rectal toxicity was 9.4% for the SBRT group and 5.3% for the conventional fractionation group. The difference was statistically significant, but narrowed by 3 or 6 months.

Neither physician-reported toxicity nor patient-reported late-term toxicity differed by the fractionation schedule they received. By two years:
  • Late-term urinary side effects were reported by 5.4% of the SBRT group and 4.6% of the conventional fractionation group. The difference was not statistically significant.
  • Late term rectal side effects were reported by 2.2% of the SBRT group and 3.7% of the conventional fractionation group. The difference was not statistically significant.
  • Impotence was reported by 34% of both groups, up from 16% at baseline.
  • Patient-reported bother from urinary, rectal and sexual side effects were not different.

Given their use of the largely outmoded 3D-CRT technology, it was not surprising that acute toxicity would be elevated. I’m frankly surprised that late-term toxicity was not higher for SBRT.

They plan to present their findings on oncological outcomes at a future time.

Saturday, September 17, 2016

Patient-reported outcomes from ProtecT - the first randomized trial comparing surgery, radiation, and active surveillance

While there were no differences in 10-year mortality when patients were randomized to surgery (RP), external beam radiotherapy (EBRT), and active surveillance (AS) (see this link), the side effects patients suffered from those treatments differed markedly. Johnson et al. have published the patient-reported outcomes of the ProtecT trial in the New England Journal of Medicine (see this link).

In the ProtecT trial, all participants (or actually 85% of them) filled out a series of validated questionnaires (EPIC and others) that probed issues of urinary function, rectal function, sexual function, and general health. I will ignore the overall health, vitality and mental status questions for now. Suffice it to say that they did not differ among therapies, nor were they very much affected by them. Questionnaires were filled out before the biopsy (the baseline), and at 6 and 12 months after randomization, and annually thereafter until 6 years from the initial biopsy.

What is especially interesting is seeing how equivalent patients (they are equivalent because they were randomized to the 3 treatments) did over the 6 years after receiving each treatment. This means that, for the first time, the side effect profiles are completely comparable (well, almost) and almost without bias.

Some messy data

I say "almost" because there was some switching of treatments that did occur. 22% of the men did not get the therapy they were originally randomized to, and they self-selected some other therapy or no therapy. However, in the analysis they are treated as if they got therapy that they were originally intended to get. Strange, huh?

In addition, they may have received salvage therapy after biochemical failure, and 55% of those assigned to AS did get a radical therapy eventually. So for each intended therapy:
  • Among those 291 men who started on AS but got radical treatment: 49% had surgery, 33% had radiation as specified, and 18% had another kind of radiation or HIFU
  • Among those 391 men who started on RP, 14 (4%) had adjuvant or salvage radiation, and 1 went on lifelong androgen deprivation therapy (ADT) within a year.
  • Among those 405 men who started on EBRT,  3 had salvage RP, 14 (3%) went on lifelong ADT, and 1 had HIFU.
Whether men had the assigned therapy or not, and irrespective of any other therapy they had, they are included with the group they were originally assigned to. It's messy.

Fortunately, there's hope in sight. In one of the Appendices (Section S3), they added the note:
"In future analyses, we intend to present patient-reported outcomes according to treatment received and an economic evaluation including assessment of therapies received for treatment impacts, as well as details about the reasons for change of management in the active monitoring arm to further inform individual and clinical decision-making"

That will give us a much truer picture of the side effects associated with the treatments they actually received.

The treatments

RP was open and nerve sparing. While most men now have robotic surgery rather than open surgery, it seems to make little difference, except for some higher incidents of issues arising during the operation (see this link).

AS did not have required follow-up biopsies, so their side effects may be a little better than on contemporary AS programs. Biopsy complications are never long-lasting anyway.

EBRT was different from contemporary standards. The dose was lower (74 Gy vs. 80 Gy), so there may have been fewer complications due to dose. They used an older delivery technique (3D-CRT vs IMRT) which had higher rates of side effects. And it was given together with short term (3-6 months) of ADT, which would certainly increase the early sexual side effects. ADT is seldom given to favorable risk patients today.

note: all of the patient-reported outcomes include the effect of whatever remedies they used to treat them.

1. Urinary Adverse Outcomes

a. Incontinence

This was a big issue for RP, of course, but not for AS or EBRT. The percent using one or more pads per day is one commonly used measure. As one can see in the following table, incontinence was highest at the 6-month time point, but had gotten somewhat better by the end of the first year. 20% were incontinent by the end of two years, with little improvement from that point.

For EBRT, incontinence peaked at 5% at 6 months. Remember, this was 3D-CRT - a technology that has greater toxicity than the IMRT predominantly in use now. It hovered around 3-4% thereafter.

For AS, incontinence also peaked at 4% at 6 months, and stayed at that level for the next couple of years. From then, it steadily rose to 8% by the end of the 6 year study. Remember that for the purposes of this trial, men were still included in the AS cohort whether they were eventually treated or not. By 6 years, more than half the men had been treated, primarily with surgery.

Table 1. Incontinence: The percent who used one or more pads per day

Time point
AS
RP
EBRT
Baseline
0%
2%
0%
6 months
4%
46%
5%
1 year
4%
26%
4%
2 years
4%
20%
4%
3 years
5%
20%
3%
4 years
7%
17%
4%
5 years
7%
17%
3%
6 years
8%
17%
4%


b. Urinary Irritation/Obstruction

The researchers examined the question of whether urination become more difficult or more frequent after therapy. One way to look at this is a set of questions on the EPIC questionnaire asking about urinary frequency and retention. On that questionnaire, a score of 100% means that function is perfect in that regard, no issues whatever.

On this dimension only EBRT had a clinically detectable effect, and it was only at the 6 month mark. EPIC score dropped from 93% to 84%. After that, it returned quickly to baseline levels.

Table 2. Urinary Irritation/Obstruction EPIC scores, where 100% would be the best possible score.

Time point
AS
RP
EBRT
Baseline
93%
92%
94%
6 months
92%
89%
84%
1 year
93%
93%
93%
2 years
92%
93%
93%
3 years
91%
93%
93%
4 years
91%
94%
93%
5 years
92%
94%
93%
6 years
92%
94%
93%

2. Rectal Adverse Outcomes

The researchers asked the trial participants about their bowel function at baseline and after treatment. There were no discernable effects of AS or RP. Bowel function among the men enrolled for EBRT declined by 6 months (from a score of 93% to 86%). Thereafter, bowel function scores returned to near baseline levels. Other than the 6 month time point, there were no significant differences among the 3 treatments.

Table 3. Bowel function EPIC scores, where 100% would be the best possible score.

Time point
AS
RP
EBRT
Baseline
92%
91%
93%
6 months
91%
92%
86%
1 year
92%
93%
90%
2 years
92%
93%
90%
3 years
92%
93%
91%
4 years
92%
93%
91%
5 years
92%
93%
90%
6 years
92%
92%
91%

3. Sexual Adverse Outcomes

This is one of the few trials that asked men detailed questions about their sexual function at baseline and for 6 years thereafter. One of the key measures of sexual function is the ability to have erections firm enough for intercourse. At baseline, about two-thirds of these 62 year old men (range 50-69), some with other comorbidities like diabetes, cardiovascular disease, and smoking, had suitable erectile function. 

None of the questionnaires asked about perceptions of penile shrinkage in length and girth, climacturia (urination at orgasm), or Peyronie's (abnormal penile curvature), which are often symptoms that affect sexual function post-prostatectomy. Nor do they ask about how the loss of ejaculate has affected sex. That is a certainty with surgery, a near-certainty after radiation, and is not affected by AS. Their definition of erectile function includes the effect of any erectile function aids (e.g. ED meds, injections, pumps, or implants) they may have been using.

For those randomized to RP, erectile function was reduced to 12% at 6 months (remember: they all had nerve-sparing surgery). It recovered somewhat to as much as 21% at 3 years but did not recover beyond that. At every time point, their erectile function was significantly worse than the other treatment cohorts.

For the AS cohort, erectile function declined by 6 months and continued to deteriorate thereafter as they elected to have radical therapies, predominantly surgery. 11% of this cohort had already elected to have radical treatment by the 6-month mark.

For the EBRT cohort, erectile function had dropped to a minimum value of 22% at 6 months. This may be largely attributable to the fact that all of the men in the EBRT cohort had 3-6 months of ADT. It is unknown how much, if any, of their testosterone came back after that and how long it took to recover. Erectile function snapped back a bit post-ADT, getting as high as 38% at 1 year, and declined to 27% by 6 years. Again, this was based on the 3D-CRT technology, and is below the rates usually seen for this age group with IMRT, brachytherapy, or SBRT.

Table 4. Erectile function - the percent who had erections firm enough for intercourse

Time point
AS
RP
EBRT
Baseline
68%
65%
68%
6 months
52%
12%
22%
1 year
49%
15%
38%
2 years
47%
19%
34%
3 years
41%
21%
34%
4 years
37%
20%
32%
5 years
35%
20%
27%
6 years
30%
17%
27%


Myths Exploded by this study:

Myth #1: The side effects end up about the same for surgery or radiation

That's clearly not true for incontinence or erectile function, It is true for urinary irritation and rectal function, which are at baseline levels and similar in all cohorts at 6 years.

Myth #2: With surgery, you get the side effects all at once and steadily recover; with radiation, the side effects come on steadily and may hit you many years later.

What we've seen here belies that myth. There is some recovery of continence up to two years later, but not thereafter. After radiation, incontinence was a minor symptom (except to those who had it, of course), but it did not increase over the years. Urinary irritation/obstruction increased at 6 months for EBRT, but returned to baseline permanently thereafter. Rectal function scores also permanently returned to baseline levels after the 6-month time point.

Myth #3: Over time, erectile function is about the same for surgery and radiation. 

As we've just seen, erectile function is much worse after surgery, and it never recovers much beyond 2 years. It is worth tracking this myth down to its source. I have even heard John Mulhall, the eminent Memorial Sloan Kettering sex specialist quote this myth.

I believe this myth started with the PROSTQA study published in 2008. Until the ProtecT trial, it was our best source of patient-reported outcomes after the various treatments. The patients were not randomly assigned, however, and differed markedly in their characteristics. Those characteristics, especially age, varied greatly with the treatments they chose. In the following table, hidden in an appendix (all the good stuff is usually back there), we can extract the following table:

Table 5. Percent with preserved erectile function sufficient for intercourse 2 years after treatment, broken down by age at treatment 



Age
RP
EBRT
BT
<50
55
100*
75*
50-59
43
52
67
60-69
27
39
44
70+
8*
30
24
Total
35
37
43
Median Age
60 years
70 years
66 years

small sample size

Although the potency doesn’t seem to vary much between treatments in total (range 35% to 43%), it is only because the men who received EBRT and BT were older than the men who were treated with RP. Within every age group, potency preservation was higher with radiation.

There are other differences between the two studies, such as: 
• this table only includes men who were potent before therapy, which would exclude about a third of men in the ProtecT trial. This would lower all the percentages in Table 5 relative to Table 4. 
• ProtecT included only men in the 50-69 age range, while half of the findings in ProstQA came from men treated with radiation over the age of 70. 
• Finally, ProtecT didn't yet report erectile function according to the therapy or therapies they actually received.

It is gratifying to see these myths shattered. Patients are the beneficiary.