Colorectal cancer among prostate cancer patients treated with ADT

As if it wasn’t long enough already, the list of adverse events “associated with” the use of androgen deprivation therapy (ADT) in the treatment of prostate cancer is growing. Some of these adverse events are common and well understood and widely observed in randomized clinical trials (loss of libido, erectile dysfunction, hot flashes, breast tenderness, loss of energy and strength). Others have been reported based on large, retrospective cohort analysis (metabolic syndrome, type II diabetes, cardiovascular problems). And then there are the ones reported by smaller numbers of patients  (loss of mental acuity, inability to focus or concentrate, depression) that can be devastating when they do occur.

Gillessen et al. have now added to the list of possibilities.

They used the the linked Surveillance, Epidemiology, and End Results (SEER)–Medicare database to identify 107,859 men diagnosed with prostate cancer between 1993 and 2002. Follow-up data on these patients were available through 2004. They used these data to identify men who had a diagnosis of colorectal cancer as a second primary cancer, and they then assessed the potential influence of ADT on the occurrence of colorectal cancer in this cohort of patients.

They report the following results:

  • Unadjusted incidence rates of colorectal cancer were …
    • 6.3/1,000 person-years in prostate cancer patients who had an orchiectomy (surgical castration)
    • 4.4/1,000 person-years in prostate cancer patients treated with an LHRH agonist (medical castration)
    • 3.7/1,000 person-years in prostate cancer patients who did not receive any ADT; 95% confidence interval [CI] = 5.3 to 7.5), followed by men who had GnRH agonist therapy (; 95% CI = 4.0 to 4.9), and men who had no androgen deprivation (; 95% CI = 3.5 to 3.9).
  • After adjustment for patient and prostate cancer characteristics,  compared to no use of ADT, the hazard ratios (HRs) for colorectal cancer in these patients was …
    • 1.31 in men using LHRH agonist therapy for 25 months or longer
    • 1.37 in men treated by orchiectomy

The authors conclude that, “Long-term androgen deprivation therapy for prostate cancer is associated with an increased risk of colorectal cancer.” An associated editorial by Lin and Giovannucci, published in the same issue of the Journal of the National Cancer Institute states that, “an elevated risk of colorectal cancer may be an additional consideration to weigh in the risk vs. benefit profile” of ADT when used to treat men with prostate cancer. Those are both fair comments … so long as we carefully note the use of the terms “associated with” and “may.” There is no definitive claim of a cause and effect relationship by the athors or the editorialists. Indeed, in their editorial, Lin and Giovannucci are careful to note that there could be all sorts of other reasons why some men with prostate cancer went on to get colorectal concer that have no direct relationship to the use of ADT. They could, for example, have been less physically active, spent less time outside, and therefore had low levels of vitamin D. These are all factors known to be associated with an increased risk for colorectal cancer.

No one has ever suggested that ADT is a benign form of treatment for prostate cancer. It was initially developed as a method to palliate the pain and suffering of men with extensive, metastatic forms of the disease. And many have suggested that it has been massively over-used in the past 15-20 years as a tool to “palliate fear” in men with a rising PSA after the failure of first- and second-line therapies or as a first-line therapy for some men long before there was any evidence of metastatic disease.

The “New” Prostate Cancer InfoLink has long considered that ADT needs to be used selectively, in men who have the potential to gain significant benefit from use of this type of hormone manipulation, because they have clearly advanced forms of prostate cancer. Furthermore, such patients should be carefully informed and advised of established methods that can be used to manage the known complications of ADT. And, in addition, intermittent hormone therapy as opposed to continuous hormone therapy should be considered seriously under all circumstances to minimize risk from long-term complications of ADT.

Unfortunately there is no long-term, prospectively complied database that allows us to document the time-related complications of ADT with care and accuracy. When you mess in a major way with someone’s  endocrine system (which ADT very definitely does), consequences are inevitable. This was probably acceptable in the men with extensive metastases and severe pain for whom this form of hormonal therapy was originally intended. Today’s prostate cancer patients are a very less advanced set of men, and they may be on ADT for as long as two or three decades. We owe it to these patients to be more astute in when to use such therapies, with what intent, and for how long at a time. 

Conversely, we need to be careful not to over-stress the possible risk for colorectal cancer. If Gillessen et al. are correct in their estimation, the relative increase in risk in risk for colorectal cancer in prostate cancer patients being treated with an LHRH agonist (as compared to men receiving no ADT) certainly appears to be 30-40 percent. However,  the absolute increase  in risk is 0.7/1,000 patient-years — which equates to 7 cases in every 1,000 men receiving ADT for 10 years. It isn’t negligible … but it also isn’t an enormous increase in their risk when the base rate is 37 cases/1,000 prostate cancer patients followed for 10  years who had no ADT. The risk associated with orchiectomy may or may not be higher, but orchiectomy is a much less common form of treatment for prostate cancer today than it was back in the early to mid 1990s.

4 Responses

  1. As you say “ … many have suggested that it has been massively over-used in the past 15-20 years as a tool to “palliate fear” in men with a rising PSA after the failure of first- and second-line therapies or as a first-line therapy for some men long before there was any evidence of metastatic disease.

    Can we assume that none of the 107,859 men diagnosed with prostate cancer between 1993 and 2002 in this study had any primary treatement and, specifically, radiation therapy?

  2. Terry:

    No … That assumption would be completely incorrect.

    These men could have received ADT at any time in the course of their treatment … and for any reason from the desire to reduce the size of the prostate prior to surgery or radiation to palliation of pain in men with advanced metastatic disease.

  3. I’m disappointed that this study was published and that it drew added attention with an associated editorial, even though the latter at least raised some of the obvious confounding issues. My strong impression is that the study tells us very little about the relationship of prostate cancer and colorectal cancer except that the pair occurs with low frequency. Here’s a shocking, equally insightful relationship: increasing duration of androgen deprivation therapy is associated with increasing age. I’ll bet that it’s statistically significant. You can take that to the bank!

    Sitemaster, I don’t know how you produce so many excellent articles, but a mistake did creep into this one: the first bullet, third empty circle, should match 3.7 with the CI range of 3.5-3.9; the paragraph should end with “and in men who had an orchiectomy (; 95% CI = 5.3 to 7.5). However, that adjustment does not diminish my concern with the study.

    To me the likely most prominent confounder is the pattern of therapy decisions in the period studied. Back then, and probably continuing today, ADT was reserved predominantly for patients who were not considered eligible for the typical therapies (almost always surgery or radiation). Such men were typically distinctly older and less healthy, as has been noted in many studies. As such, they would be somewhat more prone to the constellation of other health conditions that attend aging, including colorectal cancer.

    I’m glad the vitamin D connection was mentioned in the article (and in the editorial). I suspect that radiation would also be more associated with colorectal cancer for the same reason: proportionately greater numbers of men treated by radiation who were older and less healthy, though likely younger and healthier, overall, than the ADT group. I’m very glad the article also mentioned the tiny incidence of colorectal cancer that served as the basis for the relative rankings; knowing the absolute incidence is often a key fact in an analysis. Its mention it here should go a long way toward eliminating concerns among readers.

    I would like to stand up for ADT. It has been a fine therapy for my challenging case, and my experience has heightened my awareness of certain key points. While there has been some increase in awareness of cardiovascular and insulin-related side effects of ADT recently, even among the medical oncologists specializing in prostate cancer, those experts knew of the side effects before 2000. Moreover, they had a pretty good idea of their incidence, time of onset, and range of severity, but even more important, they had found ways to minimize them. What we are seeing frequently is that researchers are apparently stumbling onto these side effects and thinking they have something fresh and little understood, when the contrary is fortunately the case.

    If anyone would like a list, countermeasures for loss of libido, reduced erectile function, hot flashes, breast tenderness, loss of energy and strength, metabolic syndrome, type II diabetes, cardiovascular problems, mental function, depression and bone density could be provided. So many physicians and researchers present these potentially real issues as inevitable, serious, persistent, and unmanageable when in fact that is often not the case. I regret that this study will provide further weight on the side of lack of knowledge regarding ADT.

    By way of a real world truth check, may I brag for just a moment about my fasting lipid results from late September, in the fifth month of my third vacation from ADT, after completing a total of 69 months of ADT over three cycles: HDL 84, LDL 78, total cholesterol 174, trigs 60. My fasting glucose was also well into the middle of the range. Of course one person’s experience does not indicate what is likely, but it does prove what is possible. Basically, as an 11th year survivor, in this third extended vacation period from the heavy duty drugs, I am enjoying the same quality of life and good health I had in the years before I was diagnosed, in fact better in some respects, except for a touch of challenging prostate cancer. (I’ve even regrown a respectable amount of hair in the male pattern baldness areas!)

    The medical oncologists specializing in prostate cancer would likely take strong exception to the suggestion that men wait to start ADT until symptoms of metastatic disease appear. While that approach has been advocated by Dr. Patrick Walsh and others, the oncologists consider it dangerous. They judge that the ADT drugs are most effective when the disease has developed less momentum, when it is not yet metastatic. As an 11th year non-medically educated survivor of a challenging case who has closely followed ADT developments, I agree with them.

    My impression is there is nearly a consensus among the medical oncologists expert in ADT favoring intermittent ADT, where possible, rather than continuous blockade. Thanks for giving intermittent ADT a nod.

  4. Excellent document and Sitemaster comments!

    I am a 7-year intermittent ADT suvivor, with manageable side effects. Hope to change, when available, to one of the new hormonal treatments.


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