Showing posts with label long term results. Show all posts
Showing posts with label long term results. Show all posts

Monday, September 11, 2017

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.

Wednesday, September 28, 2016

5-year SBRT trial: high cancer control, low toxicity

(9/10/2018)
Meier et al reported the results of a 5-year multi-institutional trial, (also reported at the 2017 ASTRO meeting), finding that SBRT had high rates cancer control and low toxicity.

This was a prospective clinical trial in which all 21 institutions treated 309 patients according to the same protocol. The institutions were community, regional and academic hospitals across the US. All patients were low (56%) or intermediate risk (44%). Of the 137 intermediate risk patients,  61% were favorable and 39% were unfavorable intermediate risk. The treatment was:
  • 40 Gy in 5 treatments to the prostate
  • 36.25 Gy to the seminal vesicles in intermediate risk patients
  • No concurrent or adjuvant androgen deprivation therapy was allowed.
At five years after SBRT treatment, the following oncological outcomes were reported:
  • 97.1% had no biochemical progression; that is, no increases in PSA to over 2 ng/ml from the lowest value achieved 
      o 97.3% for low risk patients, compared to 92.3% for IMRT historically
      o 97.1% for intermediate risk patients, compared to 91.3% for IMRT historically
           - 100% among favorable intermediate risk
           - 93.1% among unfavorable intermediate risk

By five years after SBRT treatment, the late toxicity outcomes were reported:
  • No grade 3 (serious) rectal side effects
  • Grade 2 rectal side effects in 2%
  • Grade 3 (serious) urinary side effects in 4 of the 309 patients (1.3%)
  • Grade 2 urinary side effects in 38%

These are certainly excellent outcomes, and are in-line with or better than retrospective SBRT studies that have previously been reported. So far, the longest running SBRT single institution study has been reported by Alan Katz (see this link). I’ve heard that a ten-year update is in the works. That will be as long and larger than the longest running IMRT trial.

SBRT is about half the cost of IMRT, and at only 5 treatments, is certainly a lot less bother for the patients. It has excellent outcomes even without adjuvant ADT in unfavorable intermediate risk patients. With large long-term studies now available, it is difficult to understand why some insurance companies still don’t cover it.

Thursday, September 15, 2016

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.

Tuesday, August 30, 2016

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.

Monday, August 29, 2016

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?

EBRT with 2 years of ADT better than 4 months in patients treated for locally advanced prostate cancer

It will come as no surprise that long-term ADT improved outcomes among men treated for locally advanced prostate cancer with external beam radiation. While this study is largely irrelevant now because a more recent study, DART 01/05 (discussed here), proved much the same thing with dose-escalation, this study also included pelvic lymph node treatment and has a median of 20 years of follow up.

The final results of RTOG 0902 were reported at the recent ASTRO meeting by Lawton et al. and in a news release. In this multi-institutional study, 1,992 patients were treated between 1992 and 1995. They were all high risk (T2c-T4) with no detectable distant metastases and PSA<150. All patients ere treated according to the following protocol:
  • ·      44-46 Gy to the pelvic lymph nodes
  • ·      65-70 Gy to the prostate
  • ·      The short-term ADT group (STADT) received 4 months of flutamide and goserelin, starting 2 months before EBRT.
  • ·      The long-term ADT group (LTADT) received 24 additional months of goserelin.

At 15 years after treatment:
  • ·      Disease-free survival was 16% for the LTADT group vs. 10% for the STADT group, and was statistically significant.
  • ·      PSA increase was 45% for the LTADT group vs. 61% for the STADT group, and was statistically significant.
  • ·      Local progression was 13% for the LTADT group vs. 23% for the STADT group, and was statistically significant.
  • ·      Distant metastases rate was 17% for the LTADT group vs. 26% for the STADT group, and was statistically significant.
  • ·      Disease-specific survival was 10% higher for the LTADT group vs. the STADT group, and was statistically significant.
  • ·      Overall survival was 30% for the LTADT group vs. 27% for the STADT group, and was not statistically significant.
  • ·      No difference in urinary toxicity and minimal difference in bowel toxicity between the two groups.

While all the survival numbers are very low in both groups, it should be recalled that the radiation dose received back then was well below the dose now considered curative. Also, most of such men would now be diagnosed at a much earlier stage of disease progression. There was a clear benefit to long-term compared to short-term androgen suppression, and DART 01/05 proved that the benefit was still true with dose escalation in high-risk patients.

Antiandrogen therapy enhances outcomes of salvage radiation


Two years of antiandrogen therapy improved survival in patients treated with salvage radiation. This report represents an update with over 12 years of median follow up. The results with 7 years of follow-up were previously reported here.

The results of the randomized clinical trial RTOG 96-01 were presented by Shipley et al. at the recent ASTRO meeting and reported in a press release. Between 1998 and 2003, 761 patients were treated at multiple sites across the US and Canada. All patients had biochemical recurrence and either stage pT2 with a positive margin or stage pT3, without lymph node involvement or metastases. All patients received 64.6 Gy of EBRT in 1.8 Gy increments (36 fractions), and either 24 months of bicalutamide (150 mg) or a placebo. After 12.6 years median follow up, the antiandrogen had the following effects:
  • ·      Reduced tumor progression and the incidence of local re-growth
  • ·      Reduced rate of metastases from 23% to 14%
  • ·      Reduced death from PC from 7.5% to 2.3%
  • ·      Improved overall survival at 10 years from 78% to 82% (p=.04)
  • ·      GI or GU toxicity were low and similar in both arms.
  • ·      Gynecomastia was common with bicalutamide.

While the salvage radiation dose delivered in this study falls short of the 70 Gy now considered adequate, it does provide evidence of a survival benefit linked to added hormone therapy. Another randomized clinical trial, GETUG AFU-16, proved that even a short course of ADT significantly improved progression free survival when used with salvage radiation, but longer follow up will be necessary to prove a benefit in prostate cancer survival. RTOG 96-01 proves that prostate cancer specific survival is indeed improved by the combination of hormone therapy with salvage radiation, although the benefit may be limited to those with lower PSA and negative margins.