Deferred or immediate initiation of ADT in patients with PSA-only relapse


Abstracts of all papers to be presented at the upcoming annual meeting of the American Society of Clinical Oncology (ASCO) were made available for pre-meeting review yesterday. A paper on the appropriate timing of initiation of androgen deprivation therapy (ADT) was featured by ASCO in its related news conference.

The paper by Garcia-Albeniz et al. (see abstract no. 5003, to be presented on Sunday, June 1) was specifically discussed in an article in an issue of The ASCO Post that was also published yesterday. And it is important for readers to appreciate that, after more than 60 years of using various forms of androgen deprivation to treat advanced prostate cancer, we still have no really good evidence that allows us to ascertain when ADT should be initiated in men with a rising PSA after first-line or second-line treatment for any form of asymptomatic prostate cancer. As the authors note in the abstract of their paper, ASCO’s own guidelines state only that,

… the critical issue is to determine whether there is benefit and how large it is for starting ADT while patients are asymptomatic.

The data presented in this paper are based on study of available information about 2,022 men enrolled in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry. All 2,022 patients had an initial clinical stage of  cT3aN0M0 or lower, were treated by either radical prostatectomy or some form of radiotherapy and had an evident, biochemical, PSA-only relapse (i.e., a PSA of > 0.2 ng/ml after radical prostatectomy or three rising PSA levels after radiation therapy, with each PSA determination being month apart). Patients were excluded from the analysis if they had received ADT for any reason in the 12 months before their relapse; if they had evident metastatic disease based on a CT scan or bone scan; if they had clear symptoms suggesting progressive disease; or if they received any treatment other that ADT for their biochemical relapse (such as salvage radiation therapy after an unsuccessful radical prostatectomy).

The 2,022 patients were assigned to one or other of two groups:

  • Group A was considered to be an “immediate” strategy group, in which patients had been started on ADT within 3 months (a grace period) of PSA relapse.
  • Group B was considered to be a “deferred” strategy group of patients who initiated ADT 2 or more years after PSA relapse or when they presented with metastasis, symptoms or a short PSA doubling time.

Here are the core findings of the study:

  • The average (median) age of the 2,022 eligible patients was 69 years (range, 63 to 74 years)
  • 33.8 percent of patients had a Gleason score of > 7.
  • 31.8 percent of patients had been given radiation therapy as their primary treatment.
  • The average (median) time from primary treatment to PSA relapse was 27 months (range, 14 to 51 months).
  • After relapse, patients were followed a median of 53.2 months.
  • The hazard ratio (HR) for all-cause mortality for men in Group A as compared to men in Group B was 1.06.
    • This HR corresponds to a survival difference at 5 years of –5.5 percent.
  • The HR for prostate-cancer specific mortality for men in Group A as compared to men in Group B was 1.48.
    • This HR corresponds to a 5-year survival difference of –5.6 percent.

Garcia-Albeniz et al. draw the following conclusion:

Our study suggests little or no survival benefit … for immediate ADT initiation compared with deferred ADT initiation (at clinical progression or at least two years after PSA relapse) among prostate cancer patients with PSA-only relapse.

Now this finding is hardly revolutionary, but it does confirm something that has been known for a very long time … Immediate initiation of ADT does not offer a significant survival benefit for an awful lot of men who relapse after first- or even second-line therapies.

For many patients who relapse after first-line therapy, even though they are asymptomatic, the fact that their PSA is rising can become a driving force suggesting the need for immediate treatment. That reaction is entirely understandable … but not always sensible. The key question remains the unanswered one in the ASCO guideline: does the potential benefit of immediate ADT outweigh the potential risks for an individual patient? ADT is not exactly a benign form of treatment, and the earlier one starts it the longer one may have to live with the consequences of the side effects (and the risk for early initiation of castration resistance).

These data from the CaPSURE registry are helpful … but they don’t in any way resolve the problem. That would require a massive, potentially multi-arm, prospective clinical trial. And such a trial would take a decade or more to carry out. It may not even be feasible for all sorts of reasons — starting with the cost!

So what to do?

The “New” Prostate Cancer InfoLink is of the opinion that immediate initiation of ADT is probably correct and justifiable in certain subsets of men who undergo biochemical relapse after first- or second-line treatment:

  • Asymptomatic men with a PSA doubling time of ≤ 6 months (or possibly even ≤ 12 months)
  • Men with evident metastatic disease based on a CT scan or bone scan and a PSA doubling time of ≤ 12 months
  • Men with evident symptoms suggesting progressive disease

Conversely, men who don’t meet these criteria may well benefit (in terms of their quality of life and their potential for long-term survival) from deferring initiation of ADT until they do meet one of these criteria.

Having said that, we appreciate that this is a controversial issue and that individual patients will see these data and the related suggestions in different ways. What is critically important for all patients to appreciate, however, is that — for the majority of such patients — there is no good evidence that early initiation of ADT is associated with a really significant overall or prostate cancer-specific survival benefit compared with deferred ADT. It is therefore important for each patient to discuss this topic very seriously with his doctors before making the individual decision to initiate ADT. For all too many patients, the risks and the complications associated with early initiation of ADT may well exceed any definable benefit.

25 Responses

  1. Interesting. I just got a 23.5 mg Lupron shot after my PSA had risen from 0.1 to 0.2 to 0.3 at 2, 5, and 8 months respectively, post-RP, in preparation for IMRT which will commence in a couple weeks. I’m Gleason 9 stage pT3bN0M0 and had read that there was a progression-free survival benefit, albeit not huge, to hormone therapy + salvage radiation therapy. I didn’t want to leave anything on the table so I decided to try Lupron to see how I handled it. So far so good!

    Bob

  2. The more interesting analysis for me is whether there was a difference in outcomes for higher versus lower Gleason scores and stages — or if this was even analysed.

    I posed the same question with respect to another study published in the past week in the Journal of Urology, where I only read teh abstract. It found no difference between LDR brachytherapy, LDR brachytherapy + IMRT and LDR brachytherapy + IMRT + hormone therapy as primary interventions.

    It is noteworthy that two studies come out in the same week questioning the value of HT. There are several studies suggesting that radiation + neo-adjuvant hormone therapy are superior for primary intervention so I find the second study puzzling.

    My gut suggests that the results could well be sensitive to the original aggressiveness (Gleason score) and stage. The results based on the consolidated sample may be less meaningful.

  3. I never looked at the abstract — a friend who I met with tonight and who finds himself in this exact boat after HDR + IMRT + HT about 5 years back, pointed out that June Chan, Matt Cooperberg, and Peter Carroll are all on the study. I may well write them tomorrow to ask if they segmented by Gleason grade and/or stage.

    rd

  4. Dear Sitemaster Mike,

    “The HR for prostate-cancer specific mortality for men in Group A as compared to men in Group B was 1.48.”

    Does this mean that the men in Group A (the “immediate” strategy) had a 48% lower cancer-specific survival? This would be very curious, and is in strong contrast to, for example, the findings of Matsumoto and colleagues, reporting about the MP70-03 prospective trial:
    Optimal timing of hormonal therapy for prostate-specific antigen recurrence after radical prostatectomy”.

  5. Dear Rick:

    There is no doubt that the Devil is in the details. I think the key point here, as with the question of whether to treat or to monitor low-risk disease, is that we all need to develop a better understanding of which patients have a high probability of benefit from early intervention and which patients have a very low probability of benefit but a significant probability of harms. This will take time to tease out … but in the meantime we need to get away from the assumption that everyone will benefit from these types of treatment, regardless of individual characteristics.

  6. Rick: Re e-mailing Carroll et al. … Ask them to send you a PDF copy of the actual paper and then forward a copy to me please.

  7. Dear Frank:

    Look at the conclusion of the abstract to the Matsumoto paper. It states as follows:

    “The findings indicated that for high-risk patients (Gleason score ≥8 and PSA-DT <6 months), salvage HT for BCR after PSA nadir (< 0.2 ng/mL) should be started before the PSA level exceeds 1.0 ng/mL, otherwise there is a significant risk of subsequent biochemical progression after HT. Meanwhile, the induction of salvage HT could be delayed in non-high-risk patients.

    I have deliberately highlit the final sentence. It seems to me that Matsumoto et al. actual agree with the information above. If you look at their figure alone, you are missing a key point about their presentation at the AUA.

  8. Dear Mike,

    Yes, I read the conclusion of the Matsumoto paper, but this is not the point. Still wondering where the 48% (cancer specific) survival disadvantage in early ADT patients comes from? This is a significant number which does not correlate with study data published up to date referring the early/late ADT question!

  9. Dear Frank:

    With respect it is absolutely the conclusion that is the point. You can’t make the sort of direct comparison you are trying to make without taking account of all sorts of details about how the two studes were done. And we don’t have all those details — although we do have some.

    So … for example … we have no idea why the decision was taken, in any of the men in the CaPSURE study, to initiate ADT early or late. All we know is that it happened. It is a registry study. Conversely, the Matsumoto study was done in Japanese men, and there are a lot of data suggesting that the development and progression of prostate cancer in Japanese men who live in Japan is really rather different to the development and progression of men living in America (probably for all sorts of reasons but specifically including things like diet and lifestyle over a 40- to 50-year period).

    Furthermore, the Matsumoto graph you refer to implies that in their study, if they divided the high-risk patients and the low-risk patients each into two groups based on PSA levels at time of initiation of ADT, there was a survival benefit for the men who had ADT given earlier. But we don’t have comparable data for the CaPSURE study, so we can’t compare apples to apples.

    I understand that the two studies appear to show some different effects. It would be lovely if detailed data from all studies like these were directly comparable, but they just aren’t. That’s why it is the general conclusions that are important and not the detailed differences, which can be affected by 1,001 factors that are specific to the individual studies.

  10. Dear Mike,

    Don’t focus too much on this Matsumoto paper, because there is so much more in the literature, e.g., a Cochrane Database analysis by Nair et al.:

    “Early androgen suppression may provide a small but statistically significant improvement in overall survival at 10 years.”

    From Lancet Oncology by Messing:

    “Early ADT benefits patients with nodal metastases who have undergone prostatectomy and lymphadenectomy, compared with those who receive deferred treatment.”

    All this is in sharp contrast to a 48% disease-specific survival loss.

    And if Japanese men do have some advantages during their ADT treatment, then it might be beneficial for us to adopt some parts of their lifestyle!?

  11. Dear Frank:

    I sincerely think you are missing the point. There is a high level of agreement among experts that early ADT is very appropriate for selected patients with strong continuing indicators for high-risk disease following first-line treatment. This would most certainly include patients with nodal metastases at time of surgery; men with Gleason 8-10 disease at surgery; etc. Any sign that such men have a rising PSA post-surgery is an indicator for further treatment. There is also an increasingly strong agreement among experts that early ADT is not appropriate among men with lower-risk disease: those with lower Gleason scores at surgery, but particularly those with slowly increasing PSA levels and long PSA doubling times (e.g., of 18 months and longer) after first-line treatment.

    This is in complete agreement with the findings of the Cochrane report. The reason that early ADT “may provide a small but statistically significant improvement in overall survival at 10 years” is because the men who are benefitting are a small subset of the whole: the men with higher-risk disease.

    With regard to the benefits of the (historic) Japanese lifestyle … It is well understood that, back in the 1980s and early 1990s, the risk for prostate cancer was far lower among Japanese men who lived in Japan than it was among Japanese men who had emigrated to America. It is also evident that as the Japanese have started to adopt more Westernized lifestsyles, that risk for prostate cancer in Japan appears to be rising. If you could persuade Americans (and the Japanese) to re-adopt the Japanese diet and lifestyles of the early 20th Century, there is little doubt in my mind that we would see a decline in risk for prostate cancer by something like 2060 … but (a) Good luck with that project and (b) Do remember that it takes 40+ years to develop prostate cancer and so it would take 40+ years to reverse an epidemiological trend of this type.

  12. Everything I’ve read says there’s a progression-free survival advantage but not a overall survival advantage for pT3b guys with Gleason 8-10 disease having ADT + SRT post-RP and the earlier ADT is introduced the better. I’m not sure I get why a PFS advantage doesn’t translate into an OS advantage, however.

  13. Bob:

    There are lots of possible reasons why PFS benefits may no translate into OS benefits. Exactly why it may or may not be observable in individual patients of specific groups of patients, however, is extraordinarily hard to determine. This probably reflects our still very limited knowledge about the ways in which different subtypes of prostate cancer progress at a biological level.

  14. I just looked at that study abstract again and spotted another potential built-in bias!

    The sample is taken from men who had radical prostatectomy and radiation. However, if they had had ADT within 12 momths of their PSA starting to climb, they were excluded.

    32% of the sample had radiation. If they had any Gleason grade 4 at the time of diagnosis, they should have gotten ADT at the time of treatment — anywhere from 3 to 24+ months, so those men with intermediate- or high-risk disease whose PSA climbed within 12 months of completing treatment were excluded.

    While we do not know for sure, that could well have biased the sample to men radiated with 3+3 Gleasons who never had ADT. If so, it would explain why deferring ADT made no difference for many in that group.

    rd

  15. Rick:

    Dear Rick, that isn’t a “bias”. It was a decision built into the study design — and for good reason.

    And there is no absolute requirement that men being treated with radiation therapy who have any amount of Gleason 4 disease have to get any period of ADT together with radiation therapy. That is still a controversial issue — even within the radiation oncology community — particularly if the patient has only a small amount of Gleason 3 + 4 disease

  16. Sitemaster:

    Is there or isn’t there agreement that ADT before and during SRT (and maybe after) has a meaningful PFS benefit for high-risk guys like me with Gleason 4 + 5 = 9, SVI, EPE, a positive surgical margin, a 4-month PSADT, and 5 months of biochemical recurrence?

    Bob

  17. Dear Bob:

    I think that the vast majority of clinicians would agree that someone with your characteristics would be wise to have some period of ADT in combination with salvage radiation therapy. There is no concrete agreement, however, on exactly how long that period should be.

    My entirely personal view is that 18 months of ADT (in total) would be a minimum period, started 3 or 4 months prior to actual radiation. Others might well still consider 3 years in total to be the minimum period acceptable.

  18. Mike:

    I am not sure why that is not a bias. While the researchers may have recognized it in designing the study, that does not preclude bias.

    As we both know, there are many studies suggesting that results are improved by adding HT to initial radiation for men with intermediate- and high-risk disease. I have not checked the ASTRO protocols but adding HT is fairly common practice albeit influenced by the amount of G4 cancer suspected.

  19. Sitemaster:

    I’ve actually been advised to start my IMRT/IGRT only a few weeks after my Lupron shot; I got the 22.5 g shot last Wednesday and am having a pelvic MRI and IMRT simulation tomorrow. Whether or not I get one or more additional shots is still to be decided. It depends to a large extent on how I react to the current shot, I guess. I wish there was better data on how many shots are necessary. My next PSA is in 4 months. PSAs post-RP have been 0.1, 0.2 and 0.3 at 2, 5, and 8 months, which I am told are not awful considering my pathology. The belief is that the prostate cancer is still near the positive margin. I hope the MRI shows that!

    Bob

  20. Dear Bob:

    Medicine (contrary to popular expectations) is still just as much an “art” as it is a science. I would agree with your doctors that your PSA data “are not awful” considering your pathology, but I also realize that that is not necessarily an entirely comforting message.

    With regard to the timing, staring your IMRT/IGMT “a few weeks” after your first shot of Lupron might be 4 to 8 weeks, which is probably fine. Whether the MRI can tell anyone anything with real accuracy about the presence of cancer close to where the positive surgical margin was is much harder to know. There are an awful lot of potential variables that could affect the results of an MRI scan like that and therefore the interpretability of the scan data.

  21. Dear Rick:

    “Bias” is predicated on the idea that either the researchers didn’t understand that the way they designed their study had consequences as to how the data needed to be interpreted or they did understand that and designed the study in such a way as to take advantage of that effect in order to achieve a result that they were seeking.

    I don’t see any sign of either of these factors. (Nor do I believe that people like Matt Cooperberg or Peter Carroll would do such a thing). The researchers in this case were very open about the fact that they had excluded a subset of patients (and they had a good reason for doing this). Does this affect the applicability of the result (in that you can’t apply in to the subset of patients they excluded)? Well sure it does! Almost all trials have inclusion and exclusion criteria that affect how the results can be interpreted, but that doesn’t mean there was “bias”.

  22. Mike — I am sure you are correct given the quality of the researchers. Let’s wait to see if the PDF calls the readers’ attention to a subtle but significant distortion in the population rather than letting them impute it.

  23. I’d like to point out that published version of this research appeared in the May issue of the European Journal of Cancer.

    The criterion for “deferred ADT” seems to have changed a bit in the published version. There is no 2-year threshold. Patients were assigned to the deferred strategy if “they initiated ADT when they presented with metastasis, symptoms or a short PSA doubling time.”

    I haven’t seen the full text. There are so many confounding factors, I really wonder how they were accounted for. Just to state the obvious, patients could have chosen “immediate” ADT because of adverse factors such as adverse surgical pathology or short PSA doubling time, and that would have tended to nullify any advantage of early ADT.

  24. So now after PSA has climbed again to 0.7 from 0.4, 0.1 and < 0.1 ,after stopping Lupron after 6 months, I'm off to Sand Lakes Imaging to try to find the source of the rising PSA. An 18 PET/CT scan 6 weeks ago found nothing. I’ve been advised by Dattoli to start ADT (Casodex, Lupron, Avodart) after the scans no matter what they disclose. Then maybe more IMRT — possibly to nodes. But what if no prostate cancer is discovered by more scans? I certainly don’t want radiation again unless it’s necessary and of course not to the prostate bed, which has already received 68.2 Gy! Should I just get scans periodically until metastases are found or start blasting the nodes “just in case”?

  25. Bob:

    That’s really not a question we can help you to answer. We can’t give that sort of medical advice. That’s between you and your doctors.

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