The first randomized clinical trial comparing active surveillance, surgery and external beam radiation tells us little :-(

This was supposed to be HUGE! The first clinical trial ever where patients were randomly assigned to active surveillance (AS), radical prostatectomy (RP) or external beam radiotherapy (EBRT). The results were published in The New England Journal of Medicine (see this link). They started signing up men in the UK in 1999 and continued recruitment for 10 years. By 2009, they screened over 82,000 men for prostate cancer and found 1,643 men with newly diagnosed localized prostate cancer who were willing to be randomized to initial treatment with AS, RP or EBRT, about a third in each. They then followed them for a median of ten years to see how well they did with each therapy. Imagine the effort involved! Sounds good so far -- what could go wrong?

The bottom line was that all 3 therapies did about the same in preventing death. AS was found to cause higher rates of disease progression and metastases. We will explore why below.

There were several problems that arose.

1. They planned to detect mortality differences, but couldn't.

They thought there would be more deaths in the ten years of follow-up, but almost all the men defied those expectations. That's partly because of all the great new life-prolonging drugs that became available in the 21st century; drugs like docetaxel, Xtandi, Zytiga, and Xofigo. Also, in a clinical trial, patients are very closely diagnosed, treated, and monitored. They get far better care than the average patient in community practice. There were only 17 prostate-cancer related deaths

Men also survived longer because of progress in treating other diseases. But most of all, men lived longer because they frequently visited doctors as part of the study, during which they were  closely monitored for other illnesses. There were only 152 deaths from all other causes, only 9% of the total sample size. Men were 50 to 69 years of age  (62 years median) at the start of the study and were tracked for 10 years. On average, based on US actuarial tables, about 18% should have died from all causes. So the mortality rate was half of what was expected. On the average, men in the UK live two years longer than men in the US - not enough to account for the difference.

No worries. Instead of looking for mortality differences, the researchers had a secondary objective to look for differences in disease progression and rates of metastases. Those are excellent surrogate endpoints. But...

2. The intended treatment wasn't always what patients wound up doing

Although men were randomized to one of the 3 therapies, a lot of the men apparently changed their minds, as was their right. The authors of the study analyzed everything based on the intended treatment at the time they were randomized. This is how they said they would analyze the data, and they stuck with the plan. The switching that occurred was as follows:

• Of the 545 men randomly assigned to AS,  482 (88%) stayed with it at least for 9 months. The rest decided to have surgery, radiation, no therapy, or dropped out.
• Of the 553 men randomly assigned to RP, 391 (71%) did have surgery within the first 9 months following randomization. Most of the remainder switched to AS, the rest to radiation or other treatment, and a few chose no treatment or dropped out.
• Of the 545 men randomly assigned to EBRT, 405 (74%) did have EBRT within the first 9 months following randomization. Most of the remainder switched to AS, the rest to surgery, other treatment, no treatment or dropped out.
• In all, 22% of the men did not have the therapy they were originally randomized to, yet they are including in the analysis as if they did. It is unknown how this may have skewed the findings.

3. Their AS protocol was nothing like contemporary protocols.

     a. Inclusion criteria were much less restrictive

In contemporary AS protocols, almost all men are in the "low risk" category. "Low Risk" means they are stage T1c or T2a, their Gleason score is 6, and their PSA is less than 10. Some of the more restrictive AS programs, like Johns Hopkins, also include the "Epstein criteria." That means there were no more than 2 positive cores, no more than 50% cancer in any positive cores, and the PSA density must be less than 0.15 ng/ml/g. For the first time this year, NCCN included AS as an option for men with Gleason score 3+4 if no more than half the cores were positive, but only if they were otherwise low risk.

In the ProtecT trial, the only inclusion criterion was that the men had to have localized prostate cancer. See this link for their protocol. This means that they allowed men who were higher stage (T2b and T2c), higher grade (Gleason score ≥ 7), and higher PSA (PSA could be as high as 10-20 ng/ml). In fact, they previously reported that, among the AS cohort:

• 10% had an initial PSA between 10 and 20 ng/ml
• 22% had an initial Gleason score≥ 7 (2% were GS 8-10)
• 25% had a clinical stage of T2 - they do not break that into subcategories, presumably most were T2a

So, many of those higher risk men would have been screened out of a contemporary AS program. The authors did not analyze this higher risk subgroup to tell us how many of the 33 cases of metastases or 112 cases of clinical progression were among them, but they do report (Table 2) that of the 8 prostate-cancer deaths in the AS group, 5 were among men with Gleason score ≥ 7 at diagnosis (vs. 2 each for RP and EBRT). The remaining 3 deaths among those diagnosed as Gleason 6 was similar to the number for RP (3) and EBRT (2). It seems that all extra deaths were attributable to higher Gleason scores in their AS program.

     b. Monitoring of men on AS was below contemporary standards.

In contemporary AS protocols, there is always a confirmatory follow-up biopsy within a year of the first screening biopsy. The repeat biopsy schedule varies from that point on, and may be every year, as it was originally at Johns Hopkins. Some AS protocols utilize mpMRI to search for suspicious areas and only biopsy as suspicion arises, others implement a biopsy schedule that may vary depending on the findings of the last biopsy. Some do TRUS biopsies, some do mpMRI-targeted biopsies, some combine the two, and some do follow-up transperineal template-mapping biopsies. But all good AS programs include follow-up biopsies.

In the ProtecT trial, patients were screened for a high PSA (> 20 ng/ml), emergent symptoms, or a 12-month PSA increase ≥ 50%. So those who had a form of prostate cancer with a low PSA output (such as some of those with predominant Gleason pattern 5) would never be discovered until symptomatic metastases occurred. I don’t know what percent ever got a second biopsy.

We recently saw what happened in Göteborg when there was no pre-determined biopsy schedule: 54 out of 474 men (11%) failed on AS. They used a similar monitoring system as the ProtecT trial: quarterly, and then semi-annual PSA tests, and re-biopsy at the discretion of the doctor.

I sometimes talk to patients who get periodic PSA tests and claim they are on active surveillance. They are putting themselves in danger. Time and again, PSA kinetics have been rejected as a sole indicator of progression for very good reasons, mainly (1) PSA is affected by many non-cancer causes, and (2) some of the most virulent prostate cancer cells put out very little PSA. There is no substitute for confirmatory and follow-up biopsies.

Let's put perspective just how egregious a difference it is when active surveillance does not include follow-up biopsies. Current estimates are that one in three TRUS-guided biopsies (12 through the rectum) will miss a higher grade of cancer. So, if one biopsy failed to detect a higher grade cancer with odds of 33%, then the odds of missing it on two biopsies is (.33) squared, etc. As the following table shows, the odds of missing the higher grade cancer with annual biopsies for ten years is about 1 in a hundred-thousand.

Biopsy	Odds of missing higher grade in ALL the biopsies
1st	33%
2nd	11%
3rd	4%
4th	1%
5th	0.4%
6th	0.1%
7th	0.04%
8th	0.01%
9th	0.005%
10th	0.001%

Now, at Johns Hopkins, for example, it was their active surveillance policy to have annual biopsies, and they used the Epstein criteria discussed above. After 15 years of follow-up, the metastasis-free survival rate was 99.4%. Laurence Klotz at Sunnybrook in Toronto has the longest running trial of active surveillance in North America. They allowed some patients as high as favorable intermediate risk, and while there was always a confirmatory biopsy in the first year, their biopsy schedule was not as rigorous as Johns Hopkins. After 20 years, of follow-up, they report metastasis-free survival of 97.2%. In the ProtecT trial, there were 33 men out of the 545 men in the AS cohort - 6.1% had already been diagnosed with metastases after only 10 years of follow-up. The outcomes of the AS cohort are very out-of-line compared to active surveillance programs that have more rigorous selection criteria and monitoring protocols.

Selection criteria	Biopsy schedule	Active Surveillance Program	Follow-up	Metastasis-free survival
Strictest: Epstein protocol	Annual	Johns Hopkins	15 years	99.4%
Less strict: favorable risk only	Confirmatory and periodic thereafter	Sunnybrook	20 years	97.2%
Any localized regardless of PSA or grade	none	ProtecT	10 years	93.9%

4. Their EBRT protocol was below today's standards.

In the years prior to 1999 when they were planning this study, there were very different radiation therapies in place than have now become standard of care. This is a problem with all long-term clinical trials involving radiation technology. By the time we get the results, they are irrelevant because the technology and understanding has progressed so much. For an expanded discussion of this issue, see this link.

They used an older technology (3D-CRT) to deliver only 74 Gy in 37 treatments while adding 3-6 months of hormone therapy before and during treatment. Now, with IGRT/IMRT technology, the patients would safely receive about 80 Gy. Low and favorable risk patients probably do not benefit from adjuvant ADT -- it adds sexual side effects without adding to cancer control in most of them. Some have questioned whether the increase is justified for low or intermediate risk patients (see this link), but, as we saw, 10 years is not long enough to judge that, and there is no consequence to the higher dose in terms of side effects. It is entirely possible that the low dose they gave patients only delayed progression but did not cure the cancer.  If that is true, we may see the EBRT outcomes deteriorate when they present their planned 15-year follow-up.

ProtecT was a vast and expensive undertaking. It will probably never be repeated, and there isn't likely to ever be a US equivalent. Sadly, we can't learn very much from their current analysis of this major study, although it may yield more fruit with some subsequent analyses.

Better cancer control with radiation vs. surgery in high-risk patients

Researchers at the University of Alabama at Birmingham assigned high-risk patients to receive either external beam radiation therapy with androgen deprivation therapy (RT+ADT) or to receive surgery (RP) with or without adjuvant/salvage radiation. RT+ADT was the clear winner. It’s not a randomized trial, and it is small and retrospective, but it’s worthy of note nonetheless.

Baker et al. reported on 121 patients treated between 2001 and 2014 who were diagnosed with Gleason scores ≥8 (on either biopsy or pathology). 71 patients received RT+ADT according to the following protocol:

• ·      75-77 Gy in 40-42 fractions or 70 Gy in 28 fractions
• ·      All received pelvic lymph node radiation
• ·      Almost all (96%) received ADT for 24 months
• ·      1 patient received adjuvant docetaxel

50 patients who had life expectancies ≥ 10 years, no serious comorbidities, and whose prostate were considered resectable, were offered radical prostatectomy instead of radiation. All patients were seen by both a urologist and a radiation oncologist. Of the 50 RP patients:

• ·      76% also had pelvic lymph node dissection
• o   8±6 lymph nodes were sampled
• o   18% had positive lymph nodes
• ·      88% had adverse pathology: positive margins, seminal vesicle invasion, or extraprostatic extension
• ·      74% were stage T3 at pathology (vs. 4% pre-RP)
• ·      84% were GS≥8 at pathology (vs. 63% pre-RP)
• ·      44% received adjuvant radiation
• ·      24% received salvage radiation
• ·      Those with positive lymph nodes received salvage pelvic radiation
• ·      1 patient received adjuvant docetaxel

After average followup of 74 months for those who originally received RT+ADT and 60 months for those who originally received RP, the 5-year biochemical failure rate was:

• ·      7% for those originally receiving RT+ADT
• ·      42% for those originally receiving RP

The 5-year detection of distant metastases was:

• ·      2% for those originally receiving RT+ADT
• ·      8% for those originally receiving RP

The 5-year use of salvage (permanent) ADT was:

• ·      8% for those originally receiving RT+ADT
• ·      34% for those originally receiving RP

While the researchers did not report on toxicities, it is safe to say that those who received original RP suffered worse toxicities. This is true not only because surgery carries greater risk of incontinence and impotence, but also because 68% of those who originally received surgery received radiation on top of that, and half of those men received ADT with their adjuvant/salvage radiation. Adjuvant/salvage radiation has a worse toxicity profile compared to primary radiation.

The results in favor of initial radiation therapy are particularly impressive because radiation patients in this study had more progressed disease at the time of treatment. They had higher Gleason scores, higher stage, and higher risk of lymph node involvement. They were also considerably older. The results are all the more impressive because the amount of radiation given was low by today’s best practice standards, and because combination therapies of external beam radiation with a brachytherapy boost to the prostate have been proven superior to external beam monotherapy in randomized clinical trials. If anything, the selection bias and treatments in this study should have favored those who were initially surgically treated.

On the other hand, it’s been demonstrated that the limited pelvic lymph node dissection of the surgery patients given in this study is often inadequate to detect the full extent of involvement. They note that they have recently changed their protocol to include extended pelvic lymph node dissection (ePLND) on high-risk RP patients. Sometimes ePLND not only detects the extent of involvement, but may also clear the area of cancer without the need of salvage nodal radiation.  Two additional caveats are that the difference in definitions of biochemical failure and the two years of ADT may affect relative outcomes. However, it is hard to imagine that the long-term effects would enough to change conclusions given the magnitude of the difference.

While this is not the large-scale prospective randomized trial of RT vs. RP that we would like to see, the large variance in outcomes should be considered by anyone trying to decide between radiation and surgery for a high-risk diagnosis.

9-year SBRT outcomes

Katz and Kang have posted their 9-year SBRT outcomes on 515 patients. This represents the longest tracking of SBRT outcomes -- just one year short of the IMRT tracking reported by Alicikus et al. on a starting cohort of 170 patients treated at Memorial Sloan Kettering Cancer Center.

The patients were treated between 2006-2010 using the CyberKnife platform.

• ·      324 were low risk, 139 intermediate risk, and 52 were high risk according to NCCN definitions.
• ·      70 patients received adjuvant ADT for up to one year.
• ·      158, all with Gleason score<4+3, received 35 Gy in 5 fractions.
• ·      357 received 36.25 Gy in 5 fractions
• ·      Median age was 69
• ·      Median PSA was 6.5 ng/ml

After a median followup of 84 months:

• ·      Oncological Control:

o   9-yr freedom from biochemical failure was:

§  95% for low-risk men

§  89% for intermediate risk men

§  66% for high-risk men

o   Median PSA nadir was .1 ng/ml

o   No difference in biochemical control for the lower vs. the higher radiation dose.

o   99.6% prostate cancer survival

o   86% overall survival

• ·      Toxicity:

o   Late rectal toxicity:

§  Grade 2: 4%

o   Late urinary toxicity:,

§  Grade 2: 9.5%

§  Grade 3: 1.9%

§  Grade 2 or 3: 6.9% for the lower radiation dose vs. 13.2% for the higher dose.

o   Patient-reported bowel and urinary quality-of-life (EPIC questionnaire) declined at one month then returned to baseline by 2 years. Sexual quality-of-life declined by 29% at last followup.

These are clearly excellent results for any kind of radical therapy. The authors conclude:

“These long-term results appear superior to standard IMRT with lower cost and are strikingly similar to HDR therapy.”

While it’s tempting to conclude that neither the higher dose of radiation, with its greater toxicity, nor the addition of ADT conferred any incremental benefit, that can only be proved with a randomized clinical trial. Until so proven, it must be understood as only a good hypothesis to be discussed by patients with their radiation oncologists. It is also worth noting that these reflect the outcomes of one very expert practitioner. There is an SBRT registry currently collecting data across many treatment centers.

The reported outcomes are nearly identical to those reported at 7 years (see this link and this link and this link), indicating very stable control and no additional late term toxicity with longer followup. In light of that, its low cost, convenience, and the fact that the standard of care, IMRT, has only one more year of follow-up on a much smaller sample size, it’s difficult to understand why some insurance companies still balk at covering SBRT for low and intermediate risk patients. Medicare does cover it.

How long is long enough? Length of follow-up on clinical trials for primary treatments

Many of us are faced with the difficulty of choosing a primary therapy based on data from clinical trials with follow-up shorter than our life expectancy. How can we know what to expect in 20 or 30 years? This is quite apart from the fact that most published studies only tell us how the treatment worked for a chosen group of patients treated by some of the top doctors at some of the top institutions – they never predict for the individual case that we really want to know about; i.e., “me.” The issue of length of follow-up is particularly problematic for radiation therapies, although it may be too short for surgery and active surveillance studies as well. How can we make a reasonable decision given the uncertainty of future predictions?

I may have missed some studies, but the longest follow-up studies I have seen for each primary therapy treatment type are as follows:

• HDR brachy monotherapy - 10 years (CET/Demanes)
• HDR brachy+EBRT - 15 years (Kiel, Germany)
• IMRT - 10 years (MSKCC)
• LDR brachy monotherapy - 12 years (UWSeattle & Mt. Sinai)*
• LDR brachy+EBRT - 25 years (RCOG)
• Protons- 10 years (Loma Linda)
• SBRT - 9 years (Katz)
• Robotic RP - 10 years (Henry Ford Hospital, Detroit)
• Laparoscopic RP - 10 years (Heilbronn, Germany)
• Open RP - 25 years (Johns Hopkins)
• Active Surveillance - 20 years (Toronto)

*Mt. Sinai published a study with longer follow-up (15 years); however, all patients were treated from 1988 to 1992, before modern methods were used, and such results are irrelevant (see below) for decision-making today.

On a personal note, I was treated at the age of 57 and had an average life expectancy of 24 years, possibly more because I have a healthy lifestyle and no comorbidities. So there were no data that could help me predict my likelihood of cause-specific survival and quality of life out to the end of my reasonably expected days. What's more, the therapies with the longest follow-up (open RP, brachy boost) also have the highest rates of serious side effects. With my low-risk cancer, there seemed little need to take that risk with my quality of life.

While we may be tempted to wait for longer follow-up, (1) we don't always have that luxury, and (2) there very likely will not be any longer follow-up. Not only is follow-up expensive, there are also the problems of non-response, drop-outs, and death from other causes. The median age of patients in radiation trials is typically around 70, so many will leave the study. The 10-yr Demanes study, for example, started with 448 patients, but there were only 75 patients with 10 years of follow-up. The “10-year” study of IMRT at MSKCC started with 170 patients, but only 8 patients were included for the full ten years! After the sample size gets this small, we question the validity of the probability estimates, and there is no statistical validity in tracking further changes. (It is worth noting that IMRT became the standard of care without longer term or comparative evidence.)

An even bigger problem is what I call irrelevance. Technological and medical science advances continue at so brisk a pace that the treatment techniques ten years from now are not likely to resemble anything currently available (another argument for active surveillance, if that's an option). Dose escalation, hypofractionation, IGRT technology, intra-operative planning, VMAT, variable multi-leaf collimators, on-board cone-beam CT, and high precision linacs - all innovations that have mostly become available in the last 15 years - have dramatically changed the outcomes of every kind of radiation therapy, and made them totally incomparable to the earlier versions. Imagine shopping for a new MacBook based on the performance data of the 2000 clamshell iBook. By the time we get the long-term results, they are irrelevant to the decision now at hand.

What we want to learn from long-term clinical trials are the answer to two questions: (1) Will this treatment allow me to live out my full life? and (2) what are the side effects likely to be? To answer the first question, researchers look at prostate cancer-specific survival. It’s not an easy thing to measure accurately – cause of death may or may not be directly related to the prostate cancer. We usually look at overall survival as well. For a newly diagnosed intermediate risk man, prostate cancer survival is often more than 20 years, so we can’t wait until we have those results to make a decision. Taking one step back, we look at metastasis-free survival, but that is often over 15 years. Sometimes there is clinical evidence of a recurrence before a metastasis is detected (e.g., from a biopsy or imaging). More often, the only timely clue of recurrence is biochemical – a rise in PSA over some arbitrary point. That point is set by consensus. Researchers arrived at the consensus after weighing a number of factors, especially its correlation with clinically-detected progression. Biochemical recurrence-tree survival (bRFS), or its inverse, biochemical failure (BF), is the most commonly used surrogate endpoint.

We might be comfortable if outcomes seem to have reached a plateau. For some of the above studies, we are able to look at some of the earlier reported biochemical failure rates compared to those measures reported at the end of the study (ideally broken out by risk group).

• ·      In the Demanes Study, the 10-year results are virtually unchanged from the 8-year results.
• ·      In the Kiel study of HDR brachy boost, the 5-, 10- and 15-year BF was 22%, 31%, and 36%.
• ·      In the RCOG study of LDR brachy boost, the 10-, 15-, 20- and 25-year BF was 25%, 27%, 27%, and 27%
• ·      In the Mt. Sinai study of LDR brachy, the 8- and 12-yr BF was 12% and 10% for low risk; 19% and 16% for intermediate risk; 35% and 36% for high-risk patients.
• ·      In the MSKCC study of IMRT, the 3-, 8- and 10-yr BF was 8%, 11%, and 19% for low risk; 14%, 22% and 22% for intermediate risk; 19%, 33% and 38% for high risk patients.
• ·      In the Katz SBRT study, the 5- and 7-year BF was 2% and 4% for low-risk, 9% and 11% for intermediate-risk, and 26% and 32% for high-risk patients.
• ·      For comparison, the 5- 10- 15- and 25- year recurrence rates for prostatectomy at Johns Hopkins were 16%, 26%, 34% and 32%.

For most of the therapies, HDR & LDR brachy monotherapy, LDR brachy boost therapy, and SBRT, the failure rates remained remarkably consistent over the years. However, for surgery and IMRT, failure rates increased markedly in later years. Most of us can’t wait 25 or more years to see if a therapeutic option remains consistent or not, and for radiation, the results would almost assuredly be irrelevant anyway.

Ralph Waldo Emerson is misquoted as saying, “Build a better mousetrap, and the world will beat a path to your door.” An important criterion for decision-making when there is only limited data is our answer to the question: Is this a better mousetrap? Arguably, robotic surgery was only an improvement over open surgery, and not an entirely new therapy requiring separate evaluation. It has never been tested in a randomized comparison, and I doubt we will ever know for sure. Arguably, IMRT was simply a “better mousetrap” version of the 3DCRT technique it largely superseded and didn’t need a randomized comparison to prove its worth. Was HDRBT monotherapy just an improvement over HDRBT+EBRT? Was SBRT just an improvement over IMRT, or should we view it as a variation on HDRBT, which it radiologically resembles by design? There are no easy answers to any of these questions. However, as a cautionary note, I should mention that proton therapy was touted as more precise because of the “Bragg peak effect,” yet in practice seems to be no better in cancer control or toxicity than IMRT.

There is also the problem of separating the effect of the therapy from the effect of the learning curve of the treating physician. Outcomes are always better for patients with more practiced physicians. The learning curve has been documented for open and robotic surgery, but less well documented for radiation therapies. Patients treated early (and perhaps less skillfully) in a trial are over-represented in the latest follow-up, and there may be very little follow-up time on the most recently (and perhaps more skillfully) treated patients.

So when do we have enough data to make a decision? That comfort level will vary among individuals. I was comfortable with 3-year data based on choosing a theoretically “better mousetrap”, and many brave souls (thank God for them!) are comfortable with clinical trials of innovative therapies. In the end, everyone must assess for himself how long is long enough. For doctors offering competing therapies and for some insurance companies, there never seems to be long enough follow-up. I suggest that patients who are frustrated by those doctors and insurance companies challenge them to come up with concrete answers to the following questions:

• ·      What length of follow-up do you want to see, and why that length?
• ·      What length of follow-up was used to determine the standard of care?
• ·      Do you need to see prostate-cancer specific survival, or are you comfortable with an earlier surrogate endpoint?
• ·      What is the likelihood of seeing longer term results, and will there be any statistical validity to them if we get them?
• ·      Have outcomes reached a plateau already?
• ·      What evidence is there that toxicity outcomes change markedly after 2 years?
• ·      Will the results still be relevant if we wait for longer follow-up?
• ·      Is the therapy just a “better mousetrap” version of a standard of care?
• ·      Are my results likely to be better now that there are experienced practitioners?

LDRBT, IMRT and SBRT Quality of Life

Some of the leading lights in radiation oncology have collaborated on a study by Evans et al. of patient-reported quality of life (QOL) following various primary radiation treatments for prostate cancer. They analyzed three monotherapies (all without hormone therapy): low dose rate brachytherapy (LDRBT), intensity-modulated radiation therapy (IMRT), and stereotactic body radiation therapy (SBRT). It did not include high dose rate brachytherapy or proton therapy.

Because this study was so far-reaching in its scope and its findings, it is worth taking a close, detailed look at it. I will break it into three parts. In the first part, we’ll look at the basis of the study – how the study was designed and carried out, and what does it purport to tell us. In Part 2, we will look at some of the more important findings of the study. And in Part 3, we will discuss the implications and caveats of its findings, and draw conclusions.

PART 1. THE BASIS OF THE STUDY

The purpose of the study was to evaluate three primary radiation therapies – LDRBT, IMRT and SBRT – with respect to the patient-perceived side effects of those treatments, and to do so in a standardized and consistent manner. While this was a prospective study, it was not a randomized comparison, which is the gold standard for doing that. However, it does provide the doctor and patient with more information on what they can reasonably expect, across those treatments, than we’ve ever had before.

Data was provided by several of the top institutions in the US:

LDR or IMRT

Michigan (2 sites)

Mass General

Beth Israel Deaconess

MD Anderson

Cleveland Clinic

Washington University (St Louis)

SBRT

Georgetown

21st Century (2 sites)

The number of patients in the two-year follow up:

• ·        LDRBT: 243 patients
• ·        IMRT: 140 patients
• ·        SBRT: 272 patients

I don’t know how they selected which doctors and medical centers to include. In addition, the study was done with the assistance of the PROSTQA Study Consortium, a blue-ribbon panel of top researchers. They previously published much of this data on IMRT and LDRBT in 2008 (see this link). The SBRT data are new. Their results are a good indicator of outcomes from top practitioners at major treatment centers, and are not a good indicator of expected outcomes in community practice. I’m sure that many patients have favorite doctors whose work was not represented in this study, and they will argue that these results are not representative.

Because this was not set up as a randomized comparison of treatments, differences in patient selection may skew the results. Importantly, the LDRBT cohort is 5 years younger (65 years, median) than the other two groups (69 years, median). In all quality-of-life studies, younger patients do better. They are less likely to suffer deleterious effects of radiation, and they are more resilient in their recovery. Paralleling the difference in age at baseline, the baseline sexual QOL was best for LDRBT, and the baseline prostate symptom scores were best for LDRBT, followed by IMRT and SBRT.

The instruments they used to evaluate quality of life were EPIC-26 and SF-12. Patient-reported assessments have an advantage over physician-reported toxicity reports. The physician data depends on the patient to voluntarily tell the doctor about all adverse events, which is useful for highest grade events (3 or 4), but is less reliable for low grade events (1 or 2) that the patient might never bring to the doctor’s attention. Some men “tough it out,” some see their PCP instead (who may be more accessible), and some worry about even the most minor events. The survey instruments used here are standardized and validated, and guide the patient through a detailed assessment of the QOL issues that have been found to matter most. Patients filled them out at baseline, at 1-2 months, 6, 12, and 24 months. EPIC scores are based on scale of 0 (worst) to 100 (best). Although they also measured such qualities as general physical and mental status, and vitality/well-being, none of these were impacted by treatments.

IMRT and LDRBT patients were treated from 2003 to 2006; SBRT patients from 2007 to 2011. Contemporary best practice was observed as follows:

·        LDRBT: 144 Gy prescribed dose for I-125, US-guided, transperineal placement, I-125 or Pd-103 used, and 3-5 mm margins (more details here)

·        IMRT:76-79 Gy in 1.8-2.0 Gy increments, and 0.5-1.5 cm margins.

·        SBRT: 35-40 Gy in 5 fractions, fiducials or Calypso image guidance, and 3-5 mm margins.

There were two kinds of urinary problems that were measured: urinary incontinence (leakage, dribbling, control & pad use) and urinary irritation/obstruction (frequency, pain/burning, weak/incomplete). Bowel issues comprised urgency, frequency, leakage, bleeding and pain. The sexual domain comprised ability to have erections, their firmness, and frequency when needed; also, quality of orgasms and overall sexual function.

All of the study’s findings relate to how much patient evaluations changed compared to their baseline evaluations in the urinary, rectal and sexual quality of life domains. We expect that the radiation therapies that do the least damage will show the least deterioration in the patient perceptions in each domain.

Because the study was not randomized, and it did not attempt to match triplets of patients on their demographics and co-morbidities, we have the difficulty of comparing results in different kinds of patients. The analysis of patient characteristics across treatments revealed only one real glaring discrepancy – LDRBT patients were 5 years younger than the rest. The authors made some attempt to restore comparability by only looking at sexual scores among patients who were 60 years of age or older, but such analyses were limited in their published results. In my opinion, they ought to have computed age-adjusted scores in all domains. The failure to do so will compound the difficulties in interpreting results as they carry their tracking into the future when the aging of the study population has greater effects.

PART 2. DETAILED FINDINGS

In this part we’ll look at the results of their analysis. The authors did a great job of compiling a vast amount of information. Even so, in some cases, I wish more of the information had been presented (I was able to see the full text). Perhaps they will reveal more of the details in future analyses of this rich database.

Change from Baseline

The following table shows the EPIC score change from baseline after two years among patients having each kind of therapy. The last column shows, for reference, the minimum amount of change that has been found to be clinically important for that set of symptoms.

	LDRBT	IMRT	SBRT	Minimal Clinically Detectable Change
Urinary- irritative/obstructive	-6*	+2	0	5-7
Urinary - incontinence	-6*	-5*	-3	6-9
Bowel	-7*	-8*	-1	4-6
Sexual†	-24*	-21*	-14*	10-12

* Change is statistically significant

†Among those with scores over 60 at baseline (to help compensate for age-related differences).

Sexual status was the domain that was most affected by all the treatments. For LDRBT, it had the greatest deterioration. Deterioration in urinary and bowel scores were statistically significant and clinically meaningful in patients who had LDRBT. IMRT also had its greatest impact on sexual status, and not much different from LDRBT. Other than sexual status, only IMRT bowel scores deteriorated meaningfully; urinary status returned to near baseline. SBRT had the smallest change in sexual status, albeit large enough to be meaningful. Bowel and urinary status returned to baseline.

Minimal Clinically Detectable Change

The authors also looked at what% of patients suffered a minimal clinically detectable (MCD) change in each of those components of their quality of life over time. The typical pattern was a sharp increase at 1 or 2 months (acute effects). In all but sexual scores, that was followed by improvement. Predictably, urinary irritation/obstructive were most impacted, reaching about 90% at two months for LDRBT, and significantly better at all time points for IMRT and SBRT. The proportion who had MCD bowel symptoms and sexual symptoms was consistently more favorable for SBRT than for LDRBT or IMRT.

As a measure of the severity of symptoms, the authors looked at the % of patients who suffered an MCD increase of twofold or more over baseline after two years:

	LDRBT	IMRT	SBRT
Urinary (all)	45%	25%	18%
Bowel	25%	30%	11%
Sexual†	35%	33%	20%
None of the above	34%	40%	65%
All of the above	8%	7%	2%

In general, large clinical deteriorations in QOL were about twice as frequent for LDRBT compared to SBRT, with IMRT falling in the middle.

Symptom Severity over Time

As another measure of symptom severity, the table below shows the% change versus baseline in the proportion who rated their symptoms as moderate to severe, at 1-2 months and at 2 years:

	LDRBT		IMRT		SBRT
	2 mos.	24 mos.	2 mos.	24 mos.	1 mo.	24 mos.
Urinary (all)	+33%	+7%	+27%	+3%	+8%	-3%
Bowel	+14%	+6%	+16%	+6%	+7%	-2%
Erectile dysfunction†	+21%	+19%	+11%	+16%	+5%	+11%

† inability to have erections, among patients of all ages

Moderate to severe acute urinary and rectal side effects increased markedly for LDRBT and IMRT. For SBRT, they increased much less and returned to slightly better than baseline levels.

Keeping in mind that LDRBT patients were a median of 5 years younger than the other two groups, the increase in erectile dysfunction among LDRBT patients is troubling.  As we saw in a recent study, the deterioration occurs earlier than was previously thought. For SBRT, in contrast, there was only a +5% increase in erectile dysfunction severity at two months after treatment, but that increased to +11% by two years. Nevertheless, that was still lower than the other two therapies.

PART 3. DISCUSSION

In this section, we will make an attempt to explain the findings of the study and draw whatever conclusions we can from them.

We have seen a very consistent pattern across all the measures of QOL and in all of the domains: LDRBT patients did worst, SBRT patients did best, and IMRT patients were in between. Why should that be? Let’s examine a few hypotheses:

Patient selection/non-random

This was not a randomized comparative trial, so it is possible that the LDRBT patients selected were, for some reason, more prone to the damaging effects of radiation. This argument is weakened by the fact that they were 5 years younger, and their urinal, rectal and erectile function at baseline were better than in the other two groups.

Better practitioners not represented

Some of the top LDRBT practitioners like Peter Grimm, Michael Zelefsky, Brian Moran, and Gregory Merrick, to name a few, were not represented here. One could also argue in the other direction that some of the most experienced SBRT practitioners, like Christopher King, Alan Katz, and Debra Freeman, were not represented here. Their results might have increased comparative favorability of the SBRT results still further. However, the results do seem to be comparable to those reported by Katz and the 8-institution consortium.

Time of treatment

IMRT and LDRBT results were based on best practice in 2003-2006, while SBRT was based on patients treated in 2007-2011. There were technological improvements in both modalities since then that might make their outcomes more comparable to SBRT. As radiation technology continues to evolve, it becomes problematic to choose among them based on past performance.

Hypofractionation spares healthy tissue

Hypofractionation (SBRT or HDRBT) – radiation applied in fewer treatments (or fractions) – has been found to kill cancer cells more efficiently than normal fractionation (IMRT) or continuous fractionation (LDRBT). Because prostate cancer is especially susceptible to hypofractionation (technically, we say it has a low alpha/beta ratio of about 1.5), and because healthy nearby early-responding tissues are less susceptible (they have a higher alpha/beta ratio of about 10), healthy tissues are better spared by it.

A convenient measure for comparing the dose seen by nearby healthy tissues is something called the biologically effective dose (BED). We can compute for each modality the maximum BED experienced by nearby early-responding tissues that are responsible for acute side effects. With SBRT (7.5 Gy X 5 fractions), the BED to those tissues is 30% less than the dose from IMRT (1.8 Gy X 44 fractions). For LDRBT (144 Gy I-125 Rx dose), the maximum BED to those tissues is 56% greater than the dose from IMRT. ). Making comparisons solely on BED is problematic because LDRBT radiation is extremely short range, so a lower proportion of the bladder and rectum surface may be exposed to that maximum dose.

Dose constraints

Radiation oncologists set strict dose constraints for the bladder, urethra, rectum, and sometimes to the penile bulb, limiting the volume of those organs that receive potentially toxic doses. However, there is only so much that doses can be limited if they are to effectively kill the cancer in the prostate. I don’t know what dose constraints were set for the three modalities examined in this study. We can only assume that they used best practices.

Imaging

The imaging of the pelvic organs both in planning and in the application of radiation makes a large difference in toxicity. This is where SBRT shines. SBRT commonly uses a fused image of a CT and MRI with fiducials or transponders in place for planning. This helps to precisely predetermine, down to less than a millimeter, where all the beams will be directed. These practices can be used with IMRT as well. However, with IMRT, the images are aligned only once per session, whereas with SBRT, the images are aligned continually throughout the session. We recently saw how disastrous SBRT could be without intra-fractional motion tracking. LDRBT seed placement is commonly accomplished under ultrasound image guidance, using computerized intra-operative planning. The ultrasound can help the doctor see where the needles are going, but it can’t see the seeds well. Even stranded seeds tend to move, the prostate is moved by each needle insertion, and the prostate swells throughout the procedure, so that it is impossible to know where their final position will be. An image is obtained about a month later, after the swelling subsides, to check for major discrepancies in seed positions and to give an after-the-fact reading of the doses absorbed by organs at risk.

Late term effects

This study tracked patients for two years, which is long enough for most of the late-term side effects to show up. However, some will inevitably show up even later. Some tissues, particularly some in the bowel, are “late responding” to radiation damage. Late responding tissues are relatively more sensitive to the concentrated radiation of SBRT (they have an alpha/beta ratio of 3-5), so it is possible that SBRT’s advantage will decrease with longer follow up.

CONCLUSIONS

Although one can quibble over methodological issues in comparing the modalities, SBRT certainly provides excellent quality of life to treated patients. SBRT also is the most convenient of the treatments, requiring only five short visits, no intrusive procedures (other than fiducial placement), and no anesthesia. LDRBT is the winner on cost of treatment, with a $17,000 median Medicare reimbursement, followed by SBRT ($22,000) and IMRT ($31,000). However, a full cost analysis should also include the costs of managing the side effects of treatment, which seem to be much lower for SBRT and higher for LDRBT. Based on the findings of this study, and approximately equivalent oncological control for the 3 modalities in favorable risk patients, it is hard to justify IMRT. Availability is an issue: IMRT is available everywhere, while there is less access to excellent practitioners of SBRT (usually as CyberKnife®) and LDRBT. Some insurance still will not cover SBRT, although that is less often a barrier now.

An oft-heard argument against SBRT is that there’s not enough long-term data. SBRT is the youngest of the three modalities, used against prostate cancer since 2003. The longest-running SBRT study, has 7 years of follow up on 515 patients. For comparison, robotic prostatectomy has been used since 2000, and has never been proven superior to open surgery in a randomized comparative trial. IMRT, likewise, has never been evaluated in a comparative randomized trial, and in its current form, using dose escalation and precision IGRT techniques, was only begun in the mid-1990s. The longest-running IMRT study, at Memorial Sloan Kettering, has 10 years of follow up on 170 patients. LDRBT has been used, in some form, for over a hundred years. However, in its modern form with dose escalation and intra-operative planning methods, there are no studies older than 15 years that have any decisional value. I have often bemoaned the problem of “irrelevance” in long-term clinical studies: by the time we get the results, technology and practice have changed so much that the results have become irrelevant in making decisions among the best available therapies.

While this study raises the hypothesis that SBRT may be superior to IMRT and LDRBT, it is prudent for the patient to keep them all in his consideration set at least until the results of randomized comparative trials become available. This study should influence patients and clinicians to give serious consideration to SBRT.

Later this year, we will have the early results from Sweden of a randomized clinical trial of SBRT versus IMRT in intermediate-risk patients. There are several more comparative trials that are scheduled for completion in the coming years. If they confirm the results of this study, it will be difficult to justify IMRT as first-line therapy. Unfortunately, as far as I know, there are none planned comparing SBRT and LDRBT. There are few institutions that offer both modalities (Memorial Sloan Kettering is an exception), so randomization would be problematic.