Primary ADT in treatment of elderly men with organ-confined prostate cancer

One really has to wonder whether we are still treating elderly men, initially diagnosed with organ-confined prostate cancer, with first-line or “primary” androgen deprivation therapy ADT)! And if we are, why on Earth is that?

In a new paper by Dell’Oglio et al. in European Urology Focus, the authors set out to study the patterns of survival and mortality of men diagnosed with organ-confined prostate cancer in their 80s and 90s and treated with primary ADT. We should be clear that such treatment is not suggested or recommended in any clinical guidelines. However, as will be shown below, the paper by Dell’Oglio et al. is based on men diagnosed and treated between 1991 and 2009, so whether these data are really relevant to what is happening today, in 2017, is open to considerable question.

The life expectancy of the average 80-year-old man in America today (i.e., a man born on August 7, 1937) is 8.7 years. Similarly, the life expectancy of the average 90-year-old (i.e. a man born on August 7, 1927) is only 4.3 years. Thus, if you are diagnosed with a truly organ-confined form of prostate cancer after age 80, your chances of dying of prostate cancer are pretty small — unless the cancer has a Gleason score of 8 to 10.

Dell’Oglio et al. used data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database, to identify 14,785 patients in their 80s and 90s who were treated with  primary ADT for organ-confined prostate cancer between 1991 and 2009. They then used the data from these patients to study the 10-year overall mortality, prostate cancer-specific mortality, and other-cause mortality rates for these patients.

Here is what they found:

  • 80 percent of the deaths of these patients were due to non-cancer causes.
  • 20 percent were stated to be due to prostate cancer.
  • The 10-year overall survival rates among the 14,785 patients were
    • 15.4 percent for all patients
    • 19.9 percent in the patients aged 80 to 84 years at initiation of treatment
    • 3.1 percent in the patients aged ≥ 90 years at initiation of treatment
    • 18.7 percent in the patients with a Charlson comorbidity index of 0
    • 11.5 percent in the patients with Charlson comorbidity index of ≥ 2
  • The 10-year prostate cancer-specific mortality rates among the 14,785 patients were
    • 16.4 percent for all patients
    • 15.5 percent in the patients aged 80 to 84 years at initiation of treatment
    • 19.7 percent in the patients aged ≥ 90 years at initiation of treatment
    • 19.2 percent in the patients with a Charlson comorbidity index of 0
    • 13.3 percent in the patients with Charlson comorbidity index of ≥ 2
  • The 10-year other-cause mortality rates among the 14,785 patients were
    • 68.2 percent for all patients
    • 64.6 percent in the patients aged 80 to 84 years at initiation of treatment
    • 77.2 percent in patients in the patients aged ≥ 90 years at initiation of treatment
    • 62.1 percent in the patients with a Charlson comorbidity index of 0
    • 75.2 percent in in the patients with Charlson comorbidity index of ≥ 2

And it has to be said that even these numbers seem high (for the prostate cancer-specific mortality rates), which could reflect the fact that many of these patients may not have really had organ-confined prostate cancer at time of diagnosis at all. After all, if any of them had a PSA of 50 ng/ml or higher and a Gleason score of 7 to 10, the chances are very high that they had either node-positive or micrometastatic prostate cancer — even if this wasn’t visible on a bone scan at that time.

On the basis of these data, the authors conclude that:

These figures question the rationale for [primary] ADT in elderly men with organ-confined [prostate cancer].

Now let us be very clear. ADT is a perfectly reasonable form of therapy for an elderly man with prostate cancer when he needs it — usually as palliative therapy to manage any risk for bone pain associated with metastatic disease. And there are always going to be exceptions to every general rule. But …

ADT alone is not going to cure such patients. When it works well, it may be able to put patients into remission for extended periods of time. However, the earlier one starts ADT in such patients, the earlier they are at risk for development of castration-resistant prostate cancer that may lead to their deaths.

Current guidelines suggest that the most appropriate way to manage such patients should be focused on optimizing their individual life expectancy, their general state of health, and their quality of life. Younger and healthier 80-year-olds with higher-risk forms of organ-confined prostate cancer and a reasonable life expectancy of 10+ years may well still be good candidates for some form of radiation therapy (with or without a short course of ADT). Any 80- or 90-year-old with low- or very low-risk organ-confined prostate cancer should just be monitored (regardless of his age). And an 80- or 90-year-old with a life expectancy of < 10 years who is  diagnosed with any form of organ-confined prostate cancer should also just be monitored, with the understanding that he can be treated with ADT should this become necessary (i.e., managed on watchful waiting). Giving ADT to 80- to 90-year-old men who don't actually need such treatment for palliative reasons is going to significantly impact their quality of life while not providing any meaningful benefit in terms of their overall survival.

One can only hope that when we can get data on the treatment of 80- to 90-year-old men from 2010 to 2017, we will see that there has been a major drop in the use of primary ADT as a first-line treatment for organ-confined prostate cancer.

4 Responses

  1. Kind of ADT Used for 80+ Patients is Not Covered in the Abstract, and Matters!

    Thanks for this report. The subject study contributes to the field not by its results but by drawing attention to the issue of ADT in quite elderly men. (I’m saying “quite” elderly because I’m 74, and clearly not “elderly” despite some wrinkles, use of a pill-organizer for more than a decade, and being an AARP member for more than two decades.)

    However, the abstract of this study does not indicate the kind of ADT used, which is critical for such elderly patients aged 80 and older. As a veteran of primary ADT from December 1999 through April 2014 for a once life-threatening case (hopefully curative radiation plus ADT in 2013), I have watched developments in ADT closely, and the kind of ADT matters a lot for elderly patients according to doctors who used a lot of primary ADT for such patients (as well as younger patients) over the past decades and up to the present.

    Essentially, ADT that eliminates testosterone produced in the testes causes serious side effects in many, if not a majority, of such elderly patients, per these doctors. While younger men generally tolerate such ADT fairly well (like me), it reportedly puts many elderly patients in a nursing home or a lot closer to needing one. I was about to inform one such patient in our UsTOO group about that when his wife told me he had just had an orchiectomy, so I said nothing, knowing it would not help. He experienced the all-too-typical difficulties associated with losing all testosterone so late in life and stopped attending our group. He passed on not too long after that.

    I believe it is highly likely that the ADT used in this study was mainly the kind that is so harmful to such patients, likely either medical (LHRH-agonists at that time – Lupron and Zoladex) or orchiectomy. I believe that because that was the popular approach at the time the patients were treated, while combined, triple, and antiandrogen only blockade (+/- a 5-ARI drug: finasteride or dutasteride) were considered investigational. In contrast, the medical oncologists I have followed for years favored, during this period (and now), a much milder form of ADT: an antiandrogen (such as flutamide or bicalutamide during that period, or an antiandrogen plus a 5-alpha reductase inhibitor. I’ve heard expert medical oncologists state that the milder approach has only 20% of the side effects of the other version (the one eliminating testicular testosterone) while providing about 80% of the benefit in cancer control. That is often sufficient for men of 80 years and older. Moreover, for non-metastatic patients, a dose of just 50 mg per day (my dose) versus 150 mg is often favored when cancer control is not a dominant issue.

    Therefore, I wish the authors had not concluded that “These figures question the rationale for PADT in elderly men with organ-confined PCa.” I wish they had looked into the kind of ADT and were able to state that “These figures question the rationale for PADT that eliminates testicular testosterone in elderly men with organ-confined PCa, but more research is needed on milder forms of ADT.”

    What we need is a study of antiandrogen and antiandrogen plus 5-ARI ADT in patients aged 80 and older. I did a probe of PubMed and did not find studies that focused on that age group; my search string — prostate cancer AND antiandrogen monotherapy AND elderly NOT radiation NOT (LHRH-agonist OR castration) NOT tamoxifen – yielded 35 results with a filter for “clinical trial”, but none focused on the 80 and older group. Adding a filter for “80 and over: 80+ year” reduced the list to 15 items, but none of the abstracts of the relevant papers mentioned such an age grouping. It looks like the subject study may be unique in drawing attention to an area that has value for a lot of doctors and their patients.

  2. Does Earlier ADT Shorten Lifespan, Especially in Elderly Men?

    This was real for me even though I was not elderly when the issue confronted me. Whether earlier ADT shortened life, or at best did not extend life, faced me back in 2000 when I had the choice of moving from ADT to a long-shot try at a cure for my then life-threatening case with a 5-year prognosis from respected doctors, so I cannot help being influenced by my own experience. I consulted with doctors on both sides of the issue, examining studies they marshalled in support of their views. It looked to me like single agent ADT (then an LHRH agonist like Zoladex or Lupron, or orchiectomy) led fairly rapidly in 1.5 to 2.5 years to castration-resistant cancer even in patients with more favorable cases than mine, and that combined intermittent blockade that added an antiandrogen worked better but with ever-decreasing vacation times (from the LHRH agonist and antiandrogen) before castration resistance set in within a few years. In contrast, intermittent ADT3 (then an LHRH agonist, plus an antiandrogen, plus a 5-ARI drug) looked like a potentially more effective regimen. My single case is of course anecdotal, but it was clear that intermittent ADT3 was still working well for me by the time I ended it in 2014 in my fourth cycle, that cycle 18 months long on the drugs, in support of an attempt at a cure with radiation in 2013.

    Therefore, based on informal studies and some published work as well as my own experience and shared experience from some fellow survivors on ADT, I doubt the generality of the statement that “… However, the earlier one starts ADT in such patients, the earlier they are at risk for development of castration-resistant prostate cancer that may lead to their deaths ….” In other words, while that may be true for elderly patients, I doubt it can be generalized to the whole body of patients eligible for well-done ADT.

    However, the statement is worth study for the elderly group because they are not well suited for LHRH agonists or antagonists that eliminate testicular testosterone (addressed in earlier comment), and these drugs are the core of combined blockade and ADT3. We need to find out the extent of risk of castration-resistance in elderly men on just an antiandrogen or antiandrogen plus a 5-ARI drug, and whether such therapies lessen, extend, or make no difference in survival for elderly patients.

    Moreover, this ideally would be done not as a stand-alone but in a context where other emerging therapy combinations, such as advanced imaging, genetic testing, lifestyle modification, active surveillance, focal therapy, and oligometastatic radiation or surgery, as well as modern radiation to the primary site, could be employed in assessing and dealing with the cancer for this elderly group. Also, life expectancy, co-morbidities considered, is likely an important variable in assessing effectiveness.

  3. Dear Jim:

    You appear to be missing the entire point of the article, which is that most men of 80 or 90 years of age will never need ADT at all if they have been diagnosed with organ-confined disease, and that those who do need will be a very small fraction of those patients (probably no more than about 10% — if that).

    The question of what type of ADT to give to that very small subset of patients is apposite, but it would be very hard to conduct a study to evaluate this, for all sorts of reasons. However, in most elderly patients of this type “less is more”.

  4. Dear Jim:

    You are confusing actuality and probability.

    The sentence reads as follows: “However, the earlier one starts ADT in such patients, the earlier they are at risk for development of castration-resistant prostate cancer that may lead to their deaths.”

    If you don’t start on ADT, you can’t be at risk for castration-resistant prostate cancer until you do start ADT.

    Could you die sooner from metastatic prostate cancer if you didn’t start ADT when your cancer was metastatic? Yes! Of course. But we aren’t talking about men with metastatic disease. We are talking about men with organ-confined prostate cancer! Why would you want to increase your risk for castration-resistant prostate cancer when your disease was organ-confined? Then you would have no effective therapy to manage bone pain when you actually needed it!

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