Should we debulk the primary tumor in some men with metastatic prostate cancer?


Back in the 1980s, it would never (well, probably nearly never) have crossed anyone’s mind to carry out any type of primary tumor-debulking treatment on any patient who was newly diagnosed with evident, metastatic prostate cancer. Indeed, the vast majority of men who were found to have positive surgical lymph nodes at the time of surgery would be sewn right back up without any attempt to actually carry out surgery. (The group at the Mayo Clinic was perhaps the only prostate cancer group in the world that was completing surgery on men with positive lymph nodes at that time.)

In recent years, the idea of debulking the primary tumor (also known as cytoreductive surgery) by giving radical prostatectomies to men with node-positive forms of prostate cancer has become more common. And now we are seeing exploratory studies of the role of cytoreductive radical prostatectomy (CRP) in men who are diagnosed with limited amounts of evident metastatic disease.

Heidenreich et al., in Aachen, Germany, recently conducted a pilot study of CRP in a series of 23 men (Group A) who had  biopsy-proven prostate cancer, a relatively low level of metastasis to the bones (i.e., fewer than three “hot spots” on a bone scan), no visceral metastasis, and no extensive lymph node metastasis. All 23 patients had also had a high-quality, initial response to androgen deprivation therapy (ADT) prior to their surgery (i.e., their PSA level dropped to < 1.0 ng/ml after neoadjuvant ADT and prior to the surgery). The research team compared the outcomes from the men in Group A to the outcomes among as similar group of 38 men (Group B) who had metastatic prostate cancer that was treated by ADT alone, without local therapy. However, this was only a case-control trial and not a randomized, controlled trial.

Here are their study findings:

  • Average (mean) patient ages were
    • 61 years (range, 42 to 69 years) for the men in Group A
    • 64 years (range, 47 to 83 years) for the men in Group B
  • Patients in Groups A and B were similar with respect to their initial PSA levels, biopsy Gleason scores, clinical stages, and their extent of metastatic disease.
  • Average (median) follow-up was
    • 34.5 months (range 7 to 75 months) for the men in Group A
    • 47.0 months (range 28 to 96 months) for the men in Group B
  • Average (median) time to onset of castration-resistant prostate cancer (CRPC) was
    • 40 months (range, 9 to 65 months) for men in Group A
    • 29 months (range, 16 to 59 months) for men in Group B
    • This difference of 11 months was statistically significant (p = 0.04).
  • Average (median) times to clinical progression-free survival (PFS) were
    • 38.6 months for men in Group A
    • 26.5 months for men in Group B
    • This difference of 12.1 months was statistically significant (p = 0.032)
  • Cancer-specific survival rates were
    • 95.6 percent among men in Group A
    • 84.2 percent for men in Group B
    • This difference was again statistically significant (p = 0.043).
  • Overall survival rates were similar between the two groups.
  • The percentages of patients who received palliative surgical procedures for locally progressing prostate cancer were
    • 0 percent of men in Group A
    • 29 percent of men in Group B

Heidenrich et al. conclude that:

  • Cytoreductive radical prostatectomy (CRP) “is feasible” in carefully selected patients with metastatic prostate cancer who respond well to neoadjuvant ADT.
  • Such patients have a relatively long life expectancy and CRP reduces not only the risk of locally recurrent prostate cancer but also the risk for further, local complications.
  • CRP might be an appropriate treatment option overall management of men with minimal metastases to bone at the time of initial diagnosis.

It does need to be emphasized that there was no sign of any significant difference in time to death from all causes between the two groups. Whether such a difference in survival might become evident in a larger group of men who had been randomized to ADT or ADT + CRP is a question that may be worth asking. Getting men to enroll in such a trial might be more difficult.

 

 

12 Responses

  1. If there was “no sign of any significant difference in time to death from all causes between the two groups”, then why would subjecting the men to that surgery be a good idea? Is it just on the off-chance that it might help? Or would it depend on the man’s age?

  2. Clara:

    I don’t think we necessarily know who would benefit enough to consider this type of tumor-debulking surgery as yet. That’s exactly why I emphasized this point.

    It seems likely that the men who are most likely to benefit would be the ones who were younger, with a lower metastatic load, and most especially those for whom it might alos be possible to debulk the metastases as well as the primary tumor through the use of targeted radiation therapy. There is a way to go before we could be sure than any specific subset of men might benefit enough from this type of treatment to make it worth the risks.

  3. Most interesting, and timely — I have been debating this very issue in the Inspire UsTOO forum, where it was questioned that Mayo had a bias to surgery in advanced/locally advanced prostate cancer.

    The man who started the thread was asking about a lymphadenectomy offered to him at Mayo post-RP, and post salvage radiation. I have never heard another institution offer that as an independent surgical option.

    Mayo does have several studies to support their “debulking” approach, some of which are referenced in this meta-study.

    Maybe it’s not such a bad thing ….. ???

  4. One other thing …. what might “palliative surgical procedures for locally progressing PCa” include … lymphadenectomy?

  5. Rick:

    Certainly minimally invasive lymphadenectomy would be one such possibility. There might be others too.

  6. I have heard quite a bit on this at Mayo but also I know a couple guys that were treated at Memorial Sloan-Kettering in the same manner — though they were both further progressed than the patients in this trial. I have little doubt that debulking may help some men. But we have a long way to go on how to identify them. The side effects of a debulking procedure can, in fact, have a huge negative quality of life impact on men that do not benefit from it. I would imagine that a radical prostatectomy on a metastatic case would mean wider more invasive dissections, and thus wider and more invasive morbidities. The Heidenreich et al. abstract makes no mention of this side of the discussion.

  7. Hi Rick and Sitemaster,

    I have often wondered why more patients dx’d with metastatic disease, most especially younger patients, did not attempt to de-bulk their cancer. I am aware of the disruptive nature of surgery but, since the genie is already out of the bottle …. I am not a doctor and this question is way above my pay grade.

    I was dx’d in 2005 and had open RP, salvage radiation, etc. … In 2013, I did seek out the people at the Mayo Clinic for consultation. I did this independent of advice from my primary care oncologist. The people at the Mayo Clinic did not in any way pressure me to have the surgery and I was surprised it was an option. They very patiently explained my options and the likelihood for success.

    My primary oncologists never discussed the possibility of such a course of action.

    In January 2013 I had extended pelvic lymph node dissection (ePLND) and as right retroperitoneal lymph node dissection (right RPLND). I made my choice more as a “Hail Mary” play since I was already CRPC (lymph node positive; no other known mets). My hope was to de-bulk my cancer with an attempt to establish a period of treatment-free remission.

    Had I been aware of this surgery as a treatment option I would have opted for the surgery earlier in my treatment regimen (my ePLND surgery was not minimally invasive and in fact was worse to recover from than my original RP). The surgery did not achieve the hoped-for outcome but it did provide me with valuable insight to the spreading of my cancer through my lymphatic system, which in turn helped me to better prepare for the future.

    I believe strongly that each patient is different — as is their disease. Patients should seek out other opinions during their treatment regimen similar to what they should do prior to first-line treatment.

    Bill

  8. I posted this thread on Inspire since it expands another recent discussion on that site — a couple of interesting personal testimonials have been posted.

    And thanks for your post Bill — always great to hear from you! Are you aware of any other US institutions that do late-stage lymphadenectomies? Did Mayo present any clinical evidence to support the procedure?

    Thinking of you, rd

  9. An 11-month difference in time to onset of CRPC, significant at p = 0.04 probably translates into a similar difference in time to death, once the study runs long enough.

    Indeed, a difference is emerging, at a significant level: “Cancer-specific survival rates were 95.6 percent among men in Group A, 84.2 percent for men in Group B. This difference was again statistically significant (p = 0.043).”

    However, the study did not run long enough to measure the difference in time to death at a significant level, Almost, but not quite.

  10. I would also point out that this is a very small study, and so the early death of a single patient in either arm of the trial would have a highly impactful effect on the statistical probabilities. One must be very cautious not to over-interpret data from a study of this size.

  11. Since the researchers are reporting medians and not means (averages) it is unlikely that a single early death would have much impact on the overall result. It is a technical point but one worth considering. I think a reasonable conclusion to draw from this study is that debulking delays progression by about a year, whether measured biochemically or in terms of the onset of castrate resistance. There is a small but nonetheless statistically significant evidence of extended prostate cancer-specific survival in this cohort, although not a significant difference in all-cause survival.

  12. Hi Rick,

    Dr. Karnes (Mayo) told me they had done about 40 procedures like mine and also let me know that someone (I can’t recall the surgeon’s name) at MSKCC was also doing the same procedure. No real research paper but something was in process and I believe they did subsequently release one. They were very upfront about the prospects for the outcome. My hope was we would find the cancer located in only one or two areas and be limited to a few nodes. What we found was cancer in 15 of 25 nodes removed. The cancer was widely dispersed in the the pelvic area. I was fairly young and able to deal with the physical stress of an extended surgical procedure. I knew it was a long shot but did feel it was my last chance to get off of treatment, at least for a while. I have significant side effects from ADT. My MSKCC oncologist had told me these side effects would most likely be amplified by the second-line treatment like Zytiga and Xtandi. I had just switched from intermittent to continuous ADT and was headed towards second-line treatment. I knew the odds but for me the gamble was worth the try. I would make the same decision again. It is very clearly not a path for everyone … but for the select patient it may be a serious consideration.

    Thanks

    Bill

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