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). Seventy-one (71) patients received RT + ADT according to the following protocol:
- 75 to 77 Gy in 40 to 42 fractions or 70 Gy in 28 fractions
- All received pelvic lymph node radiation
- Almost all (96 percent) received ADT for 24 months
- 1 patient received adjuvant docetaxel
Fifty (50) patients who had life expectancies ≥ 10 years, no serious comorbidities, and whose prostates 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 percent also had pelvic lymph node dissection
- 8±6 lymph nodes were sampled
- 18 percent had positive lymph nodes
- 88 percent had adverse pathology: positive margins, seminal vesicle invasion, or extraprostatic extension
- 74 percent were stage T3 at pathology (vs. 4 percent pre-RP)
- 84 percent were GS≥8 at pathology (vs. 63 percent pre-RP)
- 44 percent received adjuvant radiation
- 24 percent received salvage radiation
- Those with positive lymph nodes received salvage pelvic radiation
- 1 patient received adjuvant docetaxel
After an average (mean) biochemical follow-up of 74 months for those who originally received RT + ADT and 60 months for those who originally received RP,
- The estimated 5-year biochemical failure rates were
- 7 percent for those initially receiving RT + ADT
- 42 percent for those initially receiving RP
- The estimated 5-year rates for detection of distant metastases were
- 2 percent for those initially receiving RT + ADT
- 8 percent for those initially receiving RP
- The 5-year use of salvage (permanent) ADT was
- 8 percent for those originally receiving RT + ADT
- 34 percent 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 percent 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 disease that had progressed further 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 2 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.
Editorial note: This commentary was written for The “New” Prostate Cancer InfoLink by Allen Edel.
Filed under: Diagnosis, Management, Risk, Treatment | Tagged: ADT, androgen, deprivation, outcome, radiation, surgery |
THE "NEW" PROSTATE CANCER INFOLINK 
While the sitemaster would agree with Allen that this study is “worthy of note”, he really thinks that it is high time that both the urology community and the radiation oncology community got past their self-interested desires to base patient treatment decisions (and patient information) on this type of retrospective analysis of long-term follow-up data from highly selected groups of patients.
We need a major, preplanned, prospective registry study if we are ever to get beyond this type of information. We will never succeed in executing a randomized clinical trial of surgery vs. radiation in high-risk patients. However, in such a registry one would have carefully established criteria for inclusion in specific patient subsets and we can now insist on certain very specific, standardized treatment criteria that would include (for example) ePLND for any high-risk patient undergoing surgery and pre-agreed time on ADT for patients being treated with radiation therapy.
If the radiation oncology and the urology community wants to deliver real value for patients, then one of the critical value criteria is whether specific forms of therapy are better or worse, in general, for specific categories of prostate cancer patient. The study by Baker et al. is one more study that some in the radiation oncology community will use to bolster their beliefs while many in the urology community will criticize for a whole bunch of possible reasons (reasonable and unreasonable). From no perspective at all is this actually particularly helpful to the patient community.
One of the features of this study that interested me was its collaborative nature — both urologists and radiation oncologists were seen by all patients, and only the better candidates were offered surgery. Both kinds of specialists co-authored this study.
It is extremely difficult to do a randomized clinical trial of this in the US — few patients would agree to be randomized. Registries have their problems as well: they are still subject to selection bias, and best practices evolve over time. Unlike clinical trials, registries do not and never should, hold all variables constant — standards of care change as we learn from clinical trials, and treatments within registries change according to evolving best practices.
Around the world, those getting radical radiation have always been and probably will always be more progressed in their disease — registries will not change that. Within this study, radiation doses started low with conventional fractionation, but moved to a hypofractionated, more optimal dose. That was probably made possible by their shift from 3D-CRT to IMRT. While PLND was used at that time rather than ePLND used there now, one can imagine other changes in surgical best practice over time. Using new kinds of imaging now, we are better able to detect cancers with Gleason score ≥ 8 and to detect infected lymph nodes. A registry doesn’t change any of that. The University of Alabama at Birmingham is an NCCN hospital that treated all patients according to best practices as far as was known at the time.
So the patient today is left to decide about his current day treatment based on the results of sometimes outmoded practices. This will always be true, and we want it to be true — otherwise, there is no progress. We have to resign ourselves to that fact and use studies like this one, warts and all, to inform our decisions, but not to make our decisions for us.
Worth noting but very flawed. The use of 24 months of ADT in 96% of the patients doing RT is probably/likely the primary reason for the differential in statistics. This is also an option on the surgical side, though I seldom see it used. But perhaps we’d see far less positive margins in the RP patients if they all started with neoadjuvant ADT. I concur that we need a much more solid use of a statistical database of a size large enough to actually be able to use the data.
Tony,
The authors note: ‘Dorff et al. reported that, upon completion of a 24-month course of ADT, testosterone levels normalized at a median time of 11.7 months. Median duration of ADT in the RT group of our study was 24.3 months. Thus, we would expect to see an increased number of biochemical failures around the 36-month time point if ADT was “silencing” BF. However, this was not observed in our results, which had a median follow-up of 67 months for patients treated with RT + ADT. Additionally, numerous prospective studies have demonstrated the survival benefits of RT + ADT compared to RT monotherapy. It is likely that RT + ADT truly results in superior biochemical and metastatic control versus RP and is not simply a byproduct of temporary PSA suppression in the setting of GS ≥ 8.’
I think you’re right that based on SWOGS9921, adding 2 years of androgen suppression to RP would probably have reduced the 5-year biochemical failure rate. But other studies demonstrated that the suppression of biochemical failure was temporary with such treatment — there was no difference in overall survival (which is why it is not standard of care). This contrasts with the findings of DART 01/05, which demonstrated a real survival difference by adding 2 years of ADT to RT. Because original RT patients in this study were 10 years older, and the limited length of follow-up, overall survival could not be used as a comparable endpoint, although incidence of metastases was used.
In this study, 18 of the 34 patients who received RP and adjuvant/salvage RT also received adjuvant ADT. So the original RP group had the opportunity to extend their time to biochemical failure and time to metastasis using both radiation and androgen deprivation, whereas the patients receiving RT + ADT originally had no salvage treatments.
Allen,
I have an issue with the thread title. We at SWOG have all agreed that comparing RT with ADT against RP alone or with salvage ADT is imperfect. And this is very obvious. Perhaps if 96% of RP patients started out with ADT we could compare but this isn’t a great study strategy. It’s very important to note that the lesser morbidity with RT + ADT is age dependent. Younger versus older is a critical decision making criterion.
Since DART 01/05, there can be no doubt that in high-risk men, ADT should always be given along with IMRT. At the same time, adjuvant ADT has never demonstrated a survival benefit with RP. The benefits of ADT with IMRT in high-risk men were not age-dependent in DART 01/05, and should be included in all cases, according to NCCN. In fact, they list it as the top option for high-risk patients with “category 1” level of evidence. NCCN does not include ADT as a recommended option along with surgery + PLND.
What they looked at in this single-institution, retrospective, non-randomized study was current best practices beginning with radiation compared to current best practices beginning with surgery in high-risk men. The best practices for each at the time are described in detail in the narrative. I agree that best practices always evolve, which renders many long-term studies obsolete by the time results are in. Studies like this are nonetheless useful to aid the patient in considering his options, but do not make the decision for him.
One last note, of the 96% of men treated with the combination approach, it’s probably safe to say that anywhere from 50% to 76% of these men likely had no benefit from the ADT or had very little benefit. As good as the note is, it is still a very sad testament that most of these men were heavily over-treated with ADT. You and I discussed DART elsewhere and that was a better trial that the Baker et al. paper, but it too was overloaded with over-treatment.
I agree with you that many of the men might have done just as well without ADT, but which ones? So far, we have no biomarkers for identifying them.