Chatter about down-staging with ipilimumab prior to surgery

According to a report on WebMD, presumably based on media information provided by the Mayo Clinic, two patients with relatively advanced stages of prostate cancer treated with the investigational drug ipilimumab have been put into what appears to be complete remission. The article on WebMD actually states that, “Both patients were reportedly free of cancer after treatment with a combination of hormone therapy, an experimental immunotherapy, and surgery.” However, we should be careful about how we interpret this information.

The patients in question had been enrolled in a clinical trial at the Mayo Clinic. In this trial, they had been treated with hormone therapy to suppress their testosterone level and then with ipilimumab to see if it would delay progression of their prostate cancer. However, after a while, both patients (for their own personal reasons) decided to opt out of the trial and to have surgery for removal of their prostates — even though patients in the study were not initially considered to be candidates for surgery. Apparently, at least 5 patients showed such dramatic regressions in their cancers after the combination of hormone therapy and ipilimumab that that they left the trial in order to have surgery.

Detailed data on these 5 patients was presented at the annual meeting of ASCO a few weeks ago, and the abstract of that presentation is available on line. The full results of this study are still to be published, and the trial is ongoing.

What do we really know, so far, from the data available. Well here’s what we hope is a completely unbiased summary:

  • All 5 patients had apparently unresectable, locally advanced disease (stage T2c-T4) prior to treatment with androgen ablation + MDX-010 (ipilimumab)
  • All 5 patients had dramatic responses to androgen ablation + MDX-010 (ipilimumab) and subsequently underwent radical prostatectomy.
  • All 5 patients had negative margins at surgery.
  • Of the 5 patients, 2 exhibited dramatic and indisputable down-staging of their disease.
  • These 2 patients had originally presented with 80 percent of their biopsy cores involved with cancer, extraprostatic extension, seminal vesicle invasion, and bladder base involvement.
  • Both patients had clinical stage T4 disease at the time of diagnosis but pathological stage T2c disease after radical prostatectomy.
  • One patient has been free of disease with an undetectable PSA for 19 months following the radical prostatectomy and adjuvant radiation treatment.
  • The other patient is stated to be “free of cancer” post-surgery, but no information is available on time of follow-up.

In their ASCO abstract, Granberg et al. write that, “We have been able to demonstrate true down-staging of locally advanced prostate cancer with neoadjuvant AA + MDX-010 therapy.” That would appear to be a fair and honest comment.

Does this mean that every patient diagnosed with locally advanced prostate cancer should be trying to get hormone therapy + ipilimumab in an attempt to down-stage their cancer prior to surgery? Well — probably not.

The “New” Prostate Cancer InfoLink believes that a critical next step needs to be a small, multi-center clinical trial in which men diagnosed with well-defined cT3-4 prostate cancer are stratified by risk factor (PSA level or PSA velocity and Gleason score) and randomized to androgen deprivation therapy with or without ipilimumab. If their PSA drops by a predetermined amount, they should then have the choice of radical prostatectomy or radiation therapy delivered with curative intent. Such a trial might allow us to understand just how effective this treatment really is in down-staging patients and then offering curative therapy.

What the Mayo study has certainly shown is that there is a potential new hypothesis about down-staging, but that hypothesis needs careful testing.

In comments to WebMD, Dr. Eugene Kwon, one of the study’s leaders, freely admits that, “This occurred not because we as physicians and scientists were so brilliant, but because a patient’s wife re-crafted our thinking about what was achievable.”

Apparently, “Even though this patient had remarkable reduction in disease, we still did not think surgery would be beneficial,” Dr. Kwon is quoted as saying. “But in a two-hour, late-night phone conversation that became quite acrimonious, she demanded that we take her husband off the study and do surgery.”

For those readers who hadn’t noticed, patients (and/or their spouses) can become very difficult at times. In some cases, difficult patients can change the course of medicine. However, we are going to need more data to know whether this will prove to be the case in this particular situation.

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