Is Gleason pattern 5 resistant to adjuvant androgen deprivation therapy?

In a research study synthesis published in European Urology, Anthony D’Amico raises the hypothesis that androgen deprivation therapy (ADT) is most effective with Gleason pattern 4, but has lesser or no effect when prostate tumors include Gleason pattern 5. However, all of the studies he draws upon used hormone therapy adjuvant to radiation therapy.

He looked at five randomized clinical trials that attempted to find the optimal duration of adjuvant ADT in high-risk or locally-advanced men. He noticed that the trial that had the lowest proportion of Gleason 8 to 10 disease (19 percent) — that is, there was a relatively higher proportion of Gleason 3 + 4 and 4 + 3s — showed a significant survival benefit to extended (36-month-long) ADT compared to short duration (6-month-long) ADT. On the other end of the spectrum, the clinical trial that had the highest proportion of Gleason 8 to 10 (60 percent), including at least 20 percent with pattern 5, showed no improvement in survival whether ADT was used for 36 months or 18 months. Two other clinical trials with 24 percent and 35 percent Gleason 8 to 10 showed no benefit to longer duration ADT. One clinical trial with 25 percent Gleason 8 to 10 did show a benefit to longer duration ADT, but D’Amico conjectures that they probably included more Gleason 4 + 4s in the mix.

D’Amico believes that there is biochemical justification for his hypothesis: because Gleason pattern 5 is most likely to lead to castrate resistance, conventional ADT is more likely to fail when it is present. However, it is one thing to say that tumors that exhibit pattern 5 are also more likely to have castrate-resistant cells; it is quite another thing to claim that pattern 5 is itself castrate resistant. I haven’t seen any studies that would substantiate the latter claim.

D’Amico seems to ignore that all the studies he cites used ADT and radiation taken together. In fact, ADT is thought to improve the efficacy of radiation in three ways:

  1. It radio-sensitizes the cancer to radiation.
  2. It kills off any surviving hormone-sensitive cancer cells.
  3. The increase in antigens from the killed cancer cells evokes an immune response.

While he is quite right that the ADT may allow the castrate-resistant cells to survive, it is hoped that those cells will at least be weakened by the ADT and will be killed off by adequate doses of radiation.

The other effect he ignored in his analysis is radio-resistance. That is, it is quite likely that the reason that advanced tumors with a lot of Gleason pattern 5 may not succumb to increasingly longer duration of ADT is not because of hormone resistance, but because higher doses of radiation (in conjunction with hormone therapy) may be necessary. This is why brachytherapy boost therapies consistently outperform even dose-escalated IMRT in high-risk men.

Taking a closer look at some of the studies he cites as evidence leads to more doubt about his inferences. DART 01/05 GICOR looked separately at high-risk and intermediate-risk patients. Survival improved significantly for high-risk men receiving longer duration ADT, but not for intermediate-risk men receiving longer ADT. Unless all the high-risk patients were Gleason 4 + 4, this argues against D’Amico’s hypothesis.

Similarly, RTOG 9202 looked at the subcategory of men with Gleason score 8 to 10. Ten-year overall survival was 45 percent among those who received long-term ADT, but only 32 percent among those who got short-term ADT. At the same time, there was no overall survival benefit in the total “locally advanced” cohort that included Gleason 7s. Once again, it’s difficult to see how this substantiates his hypothesis.

Confounding the analysis as well is the fact that three of the studies included whole pelvic radiation, while two of the studies excluded patients who were found to have cancerous lymph nodes.

While several studies have failed to prove a benefit to adding ADT to radiation in low-risk and favorable intermediate-risk men, D’Amico’s “hand waving” analysis cannot lead to any valid conclusion about the relative effect of ADT on Gleason pattern 4 or 5. There is no question that the presence of any Gleason pattern 5 increases risk markedly and all treatments are apt to be less successful. We hope that D’Amico’s conjecturing will not lead to any changes in adjuvant ADT use in patients with Gleason pattern 5 receiving radiation therapy. It is certainly a testable hypothesis, but there are no data in the studies he cites to support that.

The valid issue his essay does raise is the importance of collecting more detailed Gleason pattern data. The traditional grouping together of Gleason scores of 8 to 10 obscures the data needed to properly analyze the effect of pattern 5. The new Epstein groupings don’t help very much either because Group 4 includes Gleason scores 4 + 4, 3 + 5 and 5 + ; and Group 5 includes 4 + 5, 5 + 4 and 5 + 5. There is a “very high risk” NCCN category that includes anyone with primary Gleason pattern 5 (i.e., 5 + 3, 5 + 4, and 5 + 5). There is still much to learn about its optimal treatment; however, it will be difficult to accrue large studies on this relatively rare risk group in the US.

Editorial note: This commentary was written for The “New” Prostate Cancer InfoLink by Allen Edel.


7 Responses

  1. I would love to see more statistics broken down by Gleason score and stage. My husband, who is 58 and diagnosed as Gleason 10 in 12/12 at biopsy has to have totally different stats than the mean age of 73 and Gleason 8 to 10 than most studies I’ve seen report results for. It would be nice to have a more extensive database where you can search by Gleason, stage, treatment, age, etc., like the one at the Yana website. Thanks for keeping us updated.

  2. Mary:

    Alas, men like your husband are actually very rare, and so accumulating the data on such patients would only be possible if we had a standardized national database here in America (like they do in, for example, Sweden). That’s not likely to to happen in my lifetime.

  3. I had seven Gleason 9s, an 8, and three Gleason 7s (11/12) with a relatively low PSA of 5.7. Three months of Lupron/Casodex and my PSA dropped to 0.2. Currently in the midst of 45 sessions of radiation therapy and after 6 months of ADT have decided that I’ll take one more 3-month shot and that’s it. In all probability it’ll take 6 months or more to get back my T levels. If 9 weeks of RT plus over a year without T can’t cure this, then it can have me. Living on Lupron is a living hell; effectiveness be damned, I want as normal a life as possible for as long as possible.

  4. Len,

    That is, of course, entirely your decision. The study with the highest radiation dose, DART 01/05 GICOR (referenced above), proved there was a significant survival advantage to 28 total months of ADT compared to 4 total months. However, only you can decide if the extra 10 points or so of survival is worthwhile. Keep in mind, however, that if the disease progresses to metastatic, you will most likely need ADT permanently for pain palliation.

  5. Len:

    Another thing you could look into is using a very different type of hormonal therapy — with estrogen patch therapy as opposed to LHRH agonist therapy.

    I know of no data on the use of estrogen patch therapy in combination with radiation therapy as a form of first-line treatment for high-risk disease like yours, but if you really just can’t deal with the side effects of the ADT (and some men can’t) then this is at least another option.

  6. What those studies don’t tell you is the negatives of long-term ADT. Stay on it 28 months and you might not see T levels restored for 28 months, if ever. Then there is bone loss, and other elevated risks. As effective as treatments have become, I think there is still some missing link that better defines high-risk prostate cancer. You read of guys with two Gleason 7s that have bone metastases and lymph node invasion. How can I be off the charts with Gleason 9s and no metastases? How can I see PSA drop 96% after 3 months of ADT? After a DRE my oncologist said my prostate is small and can’t feel anything remarkable. He calls me a paradox. I think the real answer is Gleason and PSA don’t completely tell the story.

  7. Dear Len:

    Most experienced clinicians, advocates, and patients are only too well aware that Gleason scores and PSA levels “don’t completely tell the story”. Indeed, they are far from telling the whole story for an individual patient. Several years ago now, the Prostate Cancer Foundation and some of the researchers they support announced that they had (by then) been able to identify at least 25 subtypes of prostate cancer based on the genetic make up of individual tumor types. On top of that you have to take into account the immunological make-up of the individual patient as well.

    The management of progressive prostate cancer is, consequentially, very challenging — for the patient and often for his physicians as well.

    The other issue is that most experienced clinicians, researchers, patients, and advocates are acutely aware of the multiple side effects that can and do occur for men who are on long-term ADT. Published data on these go back decades. The problem is that they don’t occur consistently in all patients — by any manner of means! Although the vast majority of patients will see their PSA levels reduced and their serum T levels drop down to < 50 ng/ml, that is only a part of the story. Some men will have hot flashes that are so bad that they simply cannot stay on therapy. … Many men will experience a truly minimal range of side effects. … Some men will start to experience mental function effects within as little as 6 months. … From that perspective you are not a paradox at all. You are one more man on an extended spectrum of responses to ADT. You need to become your own advocate and work with your doctor to find the most acceptable way to stay on an appropriate form of therapy so as to extend your life (assuming you want to do that). You might find this recent book by Richard Wassersug et al. to be helpful. Dr. Wassersug is a prostate cancer researcher as well as a patient and he has a very detailed understanding of the differing types of ADT and how the can affect different patients.

    I understand your anger and your sense of frustration. However, it is an illusion to think that we are “really good” at managing progressive prostate cancer. We aren’t. The tools that are currently available work really well for some men and appallingly badly for others. But a really good doctor will work closely with a polite but strong-willed patient to manipulate his therapy to optimize the clinical benefit and minimize the adverse effects of treatment to the greatest degree possible.

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