The term “debulking” denotes the radical treatment (via prostatectomy or radiation therapy) of the cancerous prostate — lmost always in newly diagnosed patients — after distant metastases have been discovered. This first randomized clinical trial of debulking with external beam radiation found that there was no overall survival benefit.
Boevé et al. reported the outcomes of 432 men with bone metastases at 28 centers in the Netherlands from 2004 to 2014. The patients had received no previous treatments. They all had PSA levels > 20 ng/ml at the start of treatment and were under 80 years of age. They were randomized to receive either:
- Lifelong ADT (an LHRH agonist, starting with 4 weeks of an anti-androgen)
- Lifelong ADT + external beam radiation therapy (EBRT)
The EBRT dose was 70 Gy (35 treatments of 2 Gy each) or 57.8 Gy (19 treatments of 3.04 Gy each), which are biologically equivalent. No whole pelvic radiation or brachy boost therapy was given.
After 47 months median follow-up, the median overall survival was:
- 45 months in the group that received ADT + EBRT
- 43 months in the group that received ADT only
The difference was not significant
The authors also looked at survival differences based on:
- Number of bone metastases (15)
- PSA at diagnosis (≥ 60 ng/ml or < 60 ng/ml)
- Gleason score
- Clinical stage
- Age
- Performance status
- Painful bone metastases
None of these factors made any significant difference to survival.
The time to PSA progression was slightly longer among those who received EBRT (15 months vs. 12 months), but the statistical significance vanished after correction for patient characteristics.
These disappointing results conflict with several retrospective database analyses. This once again illustrates that only prospective randomized clinical trials can prove a causal relationship, and that observational studies are confounded by the vagaries of patient selection, i.e., patients who receive debulking in actual clinical practice are the ones who would do better anyway. It is worth noting that a similar thing had occurred with breast cancer. Several retrospective studies had suggested that resection of the breast tumor plus axillary lymph nodes increased survival even when distant metastases were detected. However, Badwe et al. reported that when women were prospectively randomized to that treatment or no such treatment, there was no survival difference.
Because this trial began over a decade ago, it does not include radiation doses now considered to be curative (around 80 Gy). Nor does it include brachy boost therapy, which was shown to be superior to EBRT alone in high-risk patients in the ASCENDE-RT randomized clinical trial. It is also unknown what effect whole-pelvic radiation or metastasis-directed therapy might have had, or whether prostatectomy with or without extended pelvic lymph node dissection (ePLND) may have increased survival.
This clinical trial began before CHAARTED, STAMPEDE, and LATITUDE clinical trials proved that early treatment with ADT + docetaxel and ADT + abiraterone improves survival in newly diagnosed metastatic men. It is unknown what effect debulking may have in men pre-treated with those systemic therapies.
Many of these unknowns are being explored in current clinical trials. The recently announced randomized clinical trial of debulking (at M. D. Anderson and other centers) will allow for debulking with either EBRT or surgery. This small clinical trial in Canada allows for debulking with surgery or with HDR brachytherapy (or SBRT in some patients), SBRT to metastases, together with intermittent ADT ± chemotherapy. This four-arm clinical trial in Europe allows for debulking with radiation therapy and for treatment with ADT + docetaxel or with ADT + docetaxel + abiraterone. This clinical trial in Germany randomizes patients to radical prostatectomy + ePLND + best systemic therapy (BST, based on the judgment of the treating physician) or to BST alone.
Because radiation and prostatectomy have adverse effects, this study should make patients cautious about the value of any kind of debulking outside of a clinical trial.
Editorial note: This commentary was written by Allen Edel for The “New” Prostate Cancer InfoLink.
Filed under: Diagnosis, Living with Prostate Cancer, Management, Treatment | Tagged: debulking, primary, prostatectomy, radiation, therapy, trial, tumor |
THE "NEW" PROSTATE CANCER INFOLINK 
It is to be hoped that the three large, randomized, prospective, clinical trials described by Allen Edel in this commentary will finally resolve the issue of whether debulking of the primary tumor is or is not beneficial in the treatment of men with newly diagnosed, metastatic prostate cancer.
Allen,
Thanks for posting this. I’m focusing on that now obsolete radiation dose of 70 Gy (or SBRT equivalent) — versus the modern dose of ~80 Gy, in men who already had metastatic disease and therefore were likely to have had more serious cancer in the prostate itself; dose inadequacy could have negated the potential advantage of debulking. After all, we saw a substantial improvement in progression-free survival and in survival when non-metastatic patients received the higher dose. I know you mentioned dose inadequacy as a possible explanation for the lack of success, but at this point, lacking information from the ongoing trials you noted, debulking is still a good bet for metastatic patients as I see it with my layman’s eyes.
Some physicians who treat a lot of prostate cancer, like Dr. Nick Vogelzang, have rather strongly advocated debulking. I’m curious what they would say about this interesting trial that you report.
Dear Jim:
If all you have ever seen are donkies, and someone who seems to be an expert tells you they are “horses”, why wouldn’t you believe them? … Until of course you actually see a horse!
All that Allen (and I) are currently saying is that we will all be a lot wiser when we have data from better trials that use current standards of care … and that in the interim one would be wise to acknowledge the fact that there are no data from any randomized clinical trials that support debulking. As Allen accurately observed, the surgical breast cancer community was shocked when debulking was shown to have no benefit in the treatment of metastatic breast cancer.
I would like to add the MSKCC surgical debulking trial.
I agree with the report of what this trial found and the question it raises about debulking – essentially what you are posting.
What I’m saying is that we now know that radiation dose makes a huge difference for many patients with intermediate- and high-risk prostate cancer, with a dose of 70 Gy specifically known by a number of trials to be inadequate for many patients, and that we now have reason to suspect that dose inadequacy could therefore be causing the results of this trial to be negative rather than positive.
For patients whose disease is already systemic and for their doctors who must make decisions in the near future whether to debulk the cancer with the attendant side effects and no assured benefit, there is no option to wait for trial results. Rather, they need to use whatever far-from-perfect evidence and logic suggest and reach a decision. I’m convinced that electing to debulk the cancer for systemic patients is a reasonable choice in 2018, as is choosing to forego debulking, which is what I did, with strongly suspected systemic/micro metastatic disease, between late 1999 until I had radiation in 2013.
Thanks for the post Allen.
I will bring it with me to discuss at SWOG this coming Friday in Chicago. This trial started even before TAX327 results showing survival benefit with docetaxel + prednisone were released. I like the last paragraph for the discussion, “Considering the outcomes of the current trial and the retrospective literature, local treatment of the prostate in patients with primary bone mPCa should not be performed outside clinical trials. Future trials should evaluate the impact of local treatment in patients with oligometastatic disease and by use of modern imaging modalities.” I believe this is spot on. I think all who do consider cytoreductive therapies for stage IV prostate cancer should do so in trials and S1802 meets the criteria of that statement.
I also note the following differences to the SWOG trial:
1. PSA <20 ng/ml;
2. Patients needed to be randomized within 8 weeks after diagnosis.
S1802 only deals with hormone-sensitive men; 8 weeks would typically not be enough time to tell if these patients were hormone sensitive. Additionally, if they were they would certainly have PSA values under 20 at the time of treatment. S1802 also excludes any patients with a rising PSA after SST.
Jim:
You are missing the point entirely. They should call SWOG and see if they could be enrolled in this trial.
Tony: You reversed the sign — it only included men whose PSA was > 20 ng/ml at the time of diagnosis, not after treatment began. It is not a difficult bar for men with bone mets who haven’t been pre-treated. 8 weeks is certainly enough for ADT’s impact to be felt; that’s how long ROs allow ADT to do its magic before starting EBRT.
Tony,
Of course I respect your opinion, as well as Sitemaster’s and Allen’s, but do you have a reason for thinking we would not likely see the same improvement in debulking that employed a modern radiation dose (around 80 Gy) that we saw for primary therapy with that modern dose versus the older dose level?
From my viewpoint, the use of a lower dose in this study – 70 Gy or the equivalent hypofractionated dose, the dose(s) associated with much lower success for primary therapy – created a huge hole in interpreting the value of debulking based on this study. To me it’s kind of like using PLCO results to assess active surveillance – really spurious.
Concerns with the Debulking Trial for Metastatic Prostate Cancer Patients Run by MD Anderson (https://clinicaltrials.gov/ct2/show/NCT03678025)
Thanks Allen for pointing out this trial.
The recently announced randomized clinical trial of debulking (at M. D. Anderson and other centers) will allow for debulking with either EBRT or surgery. However, it will do it with only a single ADT agent allowed. I see this as a problem, though probably it will just increase noise in the study and not totally undermine ability to achieve an answer. Hopefully. Maybe.
To me, the two avoidable problems are (1) ruling out combined or sequential ADT therapy and (2) losing patients who have a problem with their single allowed ADT agent. I realize, at this point after trial launch, that there is likely not a way to avoid these problems, but I’m describing them in the hopes that some correction may still be possible. Pending comments here, I plan to communicate with the principal investigator.
Why are only one systemic therapy agent and no sequential ADT allowed (applies to both arms of the study)? From my viewpoint, published records of medical oncologists with practices solely devoted to prostate cancer have already demonstrated, with the aid of impressive monitoring and meticulous records, that some patients benefit from combined or sequenced ADT agents. (I was on three simultaneous ADT agents — Lupron, an antiandrogen, and a 5-alpha-reductase inhibitor, intermittently for 14 years through the spring of 2014.) In this day of rapidly evolving know-how, more widely-accepted research, published while this study is under way, may support a combination approach, and that could pose a temptation issue for patients and an ethical issue for the trialists.
Some patients on antiandrogens, while a small proportion of all patients on the antiandrogens that may be used in this study, will show liver injury as monitored by liver function tests, which are standard care for use of antiandrogens. Known solutions are to switch to another ADT agent, or to see if they will respond to a countermeasure such as ursodiol. If they must switch to a second ADT agent, does that kick them out of the trial? I assume they would be permitted to use a drug like ursodiol to see if they could continue with an antiandrogen.
Tolerability of many of the ADT agents listed can be so poor that the patient needs to be switched to another agent. For instance, the effects of an LHRH agonist, such as Lupron, are intolerable for a small percentage of patients, even with countermeasures, which are often not employed. Similarly, for older antiandrogens, flutamide, which ideally is dosed every 8 hours, is inconvenient and tends to cause diarrhea, and with nilutamide there is a substantial risk of night blindness, which affects driving. Bicalutamide is clearly superior to both, including regarding its effectiveness against prostate cancer, but the list allows both of these older antiandrogens. Should a patient need to switch, I’m wondering if he would be kicked out of the study. (Why are flutamide and nilutamide included in the list of acceptable drugs as they are clearly inferior to bicalutamide?)
Why are enzalutamide and apalutamide not permitted? I’m glad to see that abiraterone acetate is allowed, even though it would have to be used “off label” (due to androgen sensitivity in this population, like enzalutamide and apalutamide) but the trial cries for adjustment to permit enzalutamide and apalutamide; I suspect they gained FDA approval too late during the trial planning process. Along this line, why is testing for splice variant AR-V7 not required for patients on abiraterone acetate (would also apply to are enzalutamide and apalutamide)? These days, is it not malpractice to fail to test for AR-V7 if the patient is not responding to these drugs, or even better, before starting treatment? And if the patient tests positive, why should he be lost to the trial instead of being allowed to switch to another agent? The whole issue in this paragraph is really important as these drugs have created a huge buzz in the metastatic survivor community; I suspect a lot of patients will be given one of them as their single ADT agent permitted by the trial.
An additional issue is the critical matter of adequate androgen suppression; in other words, will an ADT agent be used that really works for each patient? Why is there no induction period to determine adequate suppression of testosterone? (To me, adequate means about 20 or lower, not 50, but the research community seems oblivious to the compelling research-based rationale for the lower level.)
Why is there no provision for assessing adequate suppression of DHT (would like 5 or lower), as some men continue to run a high DHT despite adequate suppression of T?
Why is information on enzalutamide and apalutamide use pre-entry not collected?
The eligibility protocol states: “STEP 2 RANDOMIZATION: PRIOR/CONCURRENT THERAPY CRITERIA: Patients must not be planning to receive docetaxel after randomization.” Why, in view of CHAARTED and related studies, is chemo (including cabazitaxel as well as docetaxel) ruled out for this population of metastatic cancer? Just doesn’t make sense! What would make sense is to limit the trial population to patients with the lower metastatic burden that does not benefit from early chemo.
This is an interesting group, as only patients with a relatively low PSA for metastatic patients are eligible: “STEP 2 RANDOMIZATION: CLINICAL/LABORATORY CRITERIA: Patients must have a testosterone < 50 ng/dL within 28 days prior to randomization.”
I am hopeful that the fairly large size of the trial will enable success despite what looks like needless elimination of some enrolled patients.
Jim,
I don’t think anyone knows if the results would have been better with 80 Gy. It’s possible but unproven. I totally agree with Mike’s assessment that the best “debulking” trial results would have the most current standards of care in place and the Boeve et al. trial does not meet those criteria. As I stated earlier, this trial was started before the TAX327 results were reported and in no way measures other novel treatment options such as what we proved with CHAARTED, LATITUDE, and STAMPEDE (as Allen correctly points out). These trials all showed improved outcomes in their own right. Adding the debulking using modern standards of care is the premise behind SWOG S1802.
Allen,
Yes sir — I typed the sign backwards. Worth noting that Boeve et al. only used bicalutamide as a “flare reduction” tool and discontinued its use after 4 weeks. I’m not sure that would have had any impact, but most men treated later would have stayed on the AR until disease progression.
Dear Jim:
I simply do not have the time to address all of these comments. Some of them have already been discussed by Allen and Tony. Others address issues that are simply not possible in the context of a clinical trial.
You need to remember that trials like this are designed to build on data from prior, proven, level 1 trials (i.e., CHAARTED, STAMPEDE, and LATITUDE) and not on pure speculation from results in small numbers of patients that have never been validated in clinical trials. Also, trials like this have to limit options or they would require so many patients as to be impossible to allow for all the variations.
Trials like these are also carefully designed to allow for patient drop outs (which can occur for all sorts of possible reasons, far beyond the ones you call attention to).
Tony:
I don’t agree that most men stay on bicalutamide after the danger of testosterone flare is over. Most men I speak to use it only temporarily.
Sitemaster:
I’m working on another comment, but I wanted to briefly say thank you again for the awesome work you do to keep us informed and help us think through issues. Frankly, I don’t see how you even have time to do what you do.
A Recent Retrospective Finnish Study of Debulking — Higher Dose Radiation Plus ADT — in a Group of Consecutive Metastatic Men
Tony and Sitemaster (and fellow readers),
Thanks for your responses. I will now communicate with the point of contact and PI.
Regarding ~80 Gy vs. 70 Gy: Tony, clearly there is no definitive proof, but I find evidence, especially the Finnish study described below, and logic compelling. I’m basing this on trials that demonstrated the marked superiority of the higher dose vs. lower dose in clinical trials for men who were not metastatic, including trial evidence from Memorial Sloan-Kettering Cancer Center, and on the Finnish study with impressive results versus what we are used to seeing in this population. In essence, the trials showed us that the lower dose simply did not wipe out all the cancer of the prostate in many patients, while the higher dose did. By extension, that would also apply to metastatic men, and the Finnish trial is “corroborating evidence” (a common phrase these days). This all suggests that for a hefty proportion of men with metastatic cancer treated with lower dose radiation, you still have a cancer “mother ship”, and for men with metastatic disease, it is likely that that mother ship is armed with aggressive cancer capable of metastasizing. In contrast, the men treated with the higher dose of radiation no longer harbor a viable cancer mother ship — generally.
The following is kind of an opinion piece on what I would like to see in a debulking trial, based on a Finnish trial. For anyone who reads the whole thing, thanks! I am going to recommend this study, which is available in full online, to metastatic patients I encounter who are deciding whether to debulk their cancer with radiation or surgery to the prostate. To me, pending clinical trial results and interpretation, this is evidence that debulking is effective, at least for radiation at a higher dose plus ADT and expert management!
This discussion led me to studies of higher dose radiation plus ADT for metastatic patients, and I came across this Finnish study, by Joensuu et al., published in December 2016, which is a non-randomized retrospective analysis for consecutive men with high-risk, high-volume aggressive prostate cancer (all with bone metatases; half with pelvic nodal metastases; many with other metastases). I really like their approach to ADT, actually ADT plus, which is what I feel should be the approach to systemic therapy in prospective studies/ trials:
“Systemic therapies. The treatment strategy was the same for every patient in this fairly homogenous patient group: instead of using androgen deprivation alone we strived to use several different treatments to reduce the number of cancer cells in the body as low as possible, prior to initiation of radiation therapy.”
This included, for instance, use of chemotgherapy if PSA stopped declining. Rather than a protocol with a flat-footed list of acceptable agents and limitations on their use, the Finnish trial was more like what clinical practice should be: adjusting therapy to the individual patient to achieve a result, in this case a declining PSA if possible.
I also really liked the use of a dose of 150 mg of bicalutamide –- instead of 50 mg — in these metastatic men; this increased dosing is covered in the discussion section and is consistent with what I have seen for years advocated by the medical oncologists I like to follow. And I liked the non-use of the weaker and more problematic older antiandrogens flutamide and nilutamide; I’m thinking Finland, with its long periods of darkness, would not be too fond of the night blindness associated with nilutamide.) I liked the routine use of bone mineral density protection (BMD) with one of the usual agents.
With this overall strategy, systemic therapy is a “best individual result” protocol rather than treatment per an authorized list with restrictions. (Figure 4 gives the algorithm for this approach.) There was some pelvic dosing based on imaging. AMEN! The radiation dose was 78.2 Gy for 44 of the 46 patients, which nearly matched my own 78 Gy with pelvic dosing of 46 Gy (at least 45 Gy in the study). Radiation before 2009 was IMRT, but it was changed to VMAT RapidArc. “Radiopharmaceuticals” (variations involving samarium, radium, and lutetium) were used depending on tumor burden. Amen! Some bone metatases were also targeted with radiation, based on imaging. Amen! Dosing outside the prostate was determined by advanced imaging results, an approach which I love.
If I were reviewing this approach as a protocol for the CDMRP’s Prostate Cancer Research Program, I would give it an A+ and recommended it as a model. I love the outstanding flexibility that this approach would have as a protocol, and it looks achievable in practical operational terms in a trial. To me this would be the ideal for a patient-centered approach in a protocol as contrasted with a data-point driven approach. (By the way, the study uses ug/L as the unit of PSA, where 1 ug/L = 1 ng/mL, the typical US units.)
SUCCESS: Median progression-free survival in this high-risk challenging population was 3 years. Median overall survival was 8 years, at which point it abruptly fell to about 37% and flattened out through the 11 year point. As the authors put it:
“The OS in this patient series was 81% at 5 years and median survival was 8.1 years. Both figures compare favorably to concurrent series reported for the same group of high-risk patients with poor prognosis. In both CHARTEED and STAMPEDE studies, the OS of patients with metastatic PCa was about 50% at 5 years (6, 24).”
These results from the Finnish study strike me as impressive results in this population of men with life-shortening prostate cancer! Tolerability was also impressive. (I was also interested in this note about the synergy of radiation and ADT:
“Of note, Tarish et al. reported that castration mediates radiosensitization by impairing DNA-double-strand repair (25).”
I knew the concept but not the detail.)
Thank you FINLAND!!!
Dear Jim:
Again respectfully … with regard to what was very clearly a non-randomized pilot study in a highly self-selecting group of patients (see below) by the Finnish team of Joensuu et al. …
I would argue (strongly by the way) that this study doesn’t for one moment show that a higher dose of radiation therapy at the time of initial tumor debulking necessarily had anything to do with the patients’ overall survival. It seems much more likely to me that it was based on the extremely aggressive way that other therapies were used over time as the patients progressed.
The authors themselves point out that, with regard to radiation therapy:
“The main difference [from data from other studies with only about a 50% overall survival benefit] compared to our approach appeared to be that we also irradiated bone oligometastases and patients received radiopharmaceuticals if they had widely disseminated bone metastases. In general, the practice of irradiation of oligometastases seems to be increasing in popularity.”
I would agree with that.
I would also note that the study provides little to no data on the overall assessment of the patients’ quality of life. The only data on tolerability relates to the tolerability of radiation therapy within the first 2 years of the study. It does, however, note that two of the patients were cytopenic at the time of their deaths, and given the treatments received over time, that is not exactly a surprise.
Finally. the authors are also very clear that:
“All patients were treated according to the same principles, although scheduling and many details were adjusted individually in an adaptive manner.”
In other words, this was not a “trial” at all. It was — as the authors clearly state — a retrospective analysis of data from a highly adaptable treatment protocol in a relatively small series of 45 patients who were willing to and able to undergo what has to have been an extremely time-consuming series of assessment and treatments over an average period of less than 5 years (median follow-up was 4.38 years and mean follow-up was 4.63 years).
I would also point out that all these patients were being treated at the Docrates Cancer Center, which, as I understand it, is a private cancer center in Helsinki, and so all of the patients going there are self-selecting and affluent enough to afford the services offered. This is by no means a randomly selected group of men with metastatic prostate cancer.
Please understand that I am not criticizing the study. My point is that you are almost certainly over-generalizing the applicability of the outcomes seen in a study like this. My bet is that if one got data from a similar group of men all treated over time at — for example — the Royal Marsden Hospital in Sutton, one might be able to see very similar outcomes, but again, it would not be representative of what is actually available to 90% of the population of the UK (because in that case the Royal Marsden is probably the only institution in the UK that gets access to every single one of the newest methods to treat prostate cancer as soon as the become available for clinical trial — including to my certain knowledge things like abiraterone acetate, enzalutamide, PARP inhibitors, you name it).
Creation of a practically executable clinical trial to test out which of the multiple unusual forms of treatment used in the Finnish study actually contributed to the extended survival of these patients would require a whole new STAMPEDE-type adaptive trial over about 20 years and at a similar cost. By comparison, what the S1802 trial is doing is trying to set some ground rules for what all the new things in such a massive new adaptive trial should be compared to as a baseline.
Allen,
On your comment about the use of bicalutamide. Back in 2006 when I was diagnosed, the standard of care was referred to as ADT2 which consisted of Lupron and Casodex 50 mg. Other testosterone suppressions were not uncommon but Casodex was always administered as part of the protocol. I was on it for 28 months. It wasn’t until expanded use of abiraterone acetate that I saw a change, but still most men started ADT2 and then progressed, which is when bicalutamide was dropped and new second-line hormone drugs were used. But until that time when refractory progression was determined bicalutamide was dropped to intermittent use, many times dose-escalated to 125 mg. The exception to ADT2 was ADT3 which consisted of Lupron + Casodex adding a 5-ARI drug like finasteride or dutasteride.
Today, my case would likely have started with bicalutamide, then a Lupron depot, then dropping bicalutimade in exchange for Zytiga. I wonder if Chuck Maack would like to check in on this as he was the most prolific patient writer about it at the time.
Jim,
Again, sorry for slow reply. I agree with Mike’s assessment. I’ll just add the note that the S1802 outlines dosage at 80 Gy for standard IMRT delivery or even higher with SBRT.
Thanks to all who have participated.
Tony-
It may be that the standard of care for mCRPC was ADT2 in 2006, although I doubt it because there was even less info back then. In any case, ADT2 is not currently the standard of care. Here’s what NCCN says:
“• Antiandrogen monotherapy appears to be less effective than medical or surgical castration and is not recommended.
• No clinical data support the use of finasteride or dutasteride with combined androgen blockade.
• Patients who do not achieve adequate suppression of serum testosterone (less than 50 ng/dL) with medical or surgical castration can be considered for additional hormonal manipulations (with estrogen, antiandrogens, LHRH antagonists, or steroids), although the clinical benefit remains uncertain. The optimal level of serum testosterone to effect “castration” has yet to be determined.”
And…
“Medical or surgical castration combined with an antiandrogen is known as combined androgen blockade. No prospective randomized studies have demonstrated a survival advantage with combined androgen blockade over the serial use of an LHRH agonist and an antiandrogen.394 Meta-analysis data suggest that bicalutamide may provide an incremental relative improvement in OS by 5% to 20% over LHRH agonist monotherapy, but a clinical trial is necessary to test this hypothesis.412,413 However, others have concluded that more complete disruption of the androgen axis (with finasteride, dutasteride, or antiandrogen added to medical or surgical castration) provides little if any benefit over castration alone.414“
Clinical Trial Evidence of a Survival Benefit for Combined ADT for Prostate Cancer – NCCN is Mistaken!
Allen, in your comment of October 12 at 3:57 PM, you quoted the NCCN as follows: “No prospective randomized studies have demonstrated a survival advantage with combined androgen blockade over the serial use of an LHRH agonist and an antiandrogen.394” That statement by the NCCN is simply false!
Check this rather large, Phase III, randomized, double-blind placebo-controlled trial from way back in 1989 with the weaker antiandrogen flutamide plus leuprolide, which is of course an LHRH agonist, and see also this more detailed abstract. Results are described in the first abstract as follows:
“Six hundred three men received leuprolide in combination with either placebo or flutamide, and were followed for a minimum of 5 years. The 303 patients randomly assigned to receive leuprolide and flutamide had a longer progression-free survival and an increase in the median length of survival compared with the 300 patients receiving leuprolide plus placebo. Differences between the treatments were particularly evident for men with minimal disease and good performance status.”
The patients in this trial had previously untreated D2 cancer. Here are key lines from the second abstract:
“The 303 men receiving androgen blockade with leuprolide and flutamide demonstrated a longer progression-free survival (16.9 vs. 13.9 months, P = 0.039) and an increased median length of survival (35.0 vs. 27.9 months, P = 0.035). In the subgroup of men with minimal disease and good performance status, the advantages of maximal androgen blockade were more pronounced. It is concluded that combined androgen blockade with leuprolide and flutamide was more effective than leuprolide alone for patients with metastatic cancer of the prostate.”
In 2009 a Japanese team found a significant survival advantage for bicalutamide plus an LHRH agonist, as reported for their Phase III, double-blind, randomized, placebo-controlled trial of 205 patients. The key lines in the results part of the abstract are:
“At a median follow-up of 5.2 years, a significant overall survival advantage was observed in favor of CAB over LHRH-A monotherapy (Cox regression analysis: hazard ratio, 0.78; 95% confidence interval, 0.60-0.99; P = 0.0498; log-rank test: P = 0.0425). The difference in cause-specific survival between the 2 groups was not significant. The achievement of a prostate-specific antigen (PSA) nadir concentration < or = 1 ng/mL was a prognostic factor for improved survival. More patients attained PSA nadir concentrations < or = 1 ng/mL with CAB compared with patients who received LHRH-A monotherapy (81.4% vs 33.7%; P < .001).”
There is also a group of non-randomized studies that document an improvement using combined blockade versus an LHRH agonist alone, or bilateral orchiectomy, or the estrogen drug known as DES. Here is an example, a 1988 Canadian study.
Frankly, while the NCCN clearly does good work, it is a “committee”, and I sometimes suspect that its recommendations revert to what the “lowest common denominator” in their group dynamics will support. Some of this evidence of the superiority of combined blockade has been available for decades; in fact, it played a key role in my own decision to adopt combined blockade (later shifting to triple blockade) as my own strategy for a once life-threatening case. Yet the myth of non-advantage continues to this day.
I am mystified why the NCCN does not recognize that there is respectable, Phase III, randomized, double-blinded, large and reasonably long-follow-up evidence of the advantage of combined blockade.
When Antiandrogen Monotherapy May Be Wise (The NCCN’s View Notwithstanding)
Allen,
In your comment of October 12 at 3:57 PM, you quoted the NCCN as follows: “Antiandrogen monotherapy appears to be less effective than medical or surgical castration and is not recommended.” I’m sure most of us would generally agree with this, but it is a broad brush approach that is inappropriate for some patients, especially quite elderly patients.
Doctors with large practices devoted solely to prostate cancer patients, many of them with advanced cases, have the following view of use of an antiandrogen as monotherapy: generally an antiandrogen is inferior to LHRH agonist or antagonist therapy. However, it is sometimes best, especially when quality of life, which is especially an issue with elderly patients, is as or more important than control of the cancer. I particularly remember Drs. Charles “Snuffy” Myers and Dr. Mark Scholz expressing this view. Dr. Myers has commented that use of an LHRH agonist, LHRH antagonist, or bilateral orchiectomy in an elderly man, especially a man aged 80 older, can quickly put him in a nursing home because he no longer has the testosterone he needs to function adequately. In his recent (2018) book, The Key to Prostate Cancer, Dr. Scholz wrote that “Casodex is about two-thirds as effective as Lupron but with one-third the side effects” (p. 332). He added that, “In higher doses (three pills per day [150 mg total]), Casodex is almost as effective as Lupron” (p. 332). Casodex achieves this without decreasing testosterone and thereby fosters a better quality of life.
Jim:
I wouldn’t generalize from what Snuffy Myers and Scholz does to other doctors. On the other hand, it is certainly permissible to modify NCCN standard-of-care based on clinical judgment. The most suitable hormone therapy has to be decided on a case-by-case basis. Many men over 80 with mCRPC are under-treated or over-treated — i.e., given just hormone therapy when more aggressive therapy (like ADT + Zytiga or chemo) might add significantly to survival and QOL, or given hormone therapy when no survival increase is expected from it. When there are significant comorbidities in an elderly man, it is hard to see why watchful waiting wouldn’t be the best approach.