Metastases, Not Death, New Benchmark in Prostate Cancer?

Pam Harrison

March 16, 2017

The primary endpoint of active surveillance (AS) trials should be reconsidered, a prostate cancer (PC) expert is arguing, because metastatic disease, not death from prostate cancer, is the more meaningful clinical endpoint to patients, and as such, it should serve as a benchmark against which different treatment protocols are compared.

Given the treatment-related toxicities associated with therapies that are used to prolong ― but not save ― life, the question arises as to whether the occurrence of metastasis as opposed to death should be used as the primary endpoint, writes Anthony D'Amico, MD, PhD, Brigham and Women's Hospital and the Dana Farber Cancer Institute, Boston, Massachusetts.

Dr D'Amico's opinion piece was published online February 27 in the Journal of Clinical Oncology.

"Specifically, there are some men who may gain 15 years with near-perfect health and then develop metastases that are initially minimally symptomatic, but later develop a significant decrement in health-related quality of life for some time due to clinically symptomatic progression of metastatic PC, before dying of a competing risk," he comments. "For these men, their overall quality-adjusted life-years may be higher than another patient who undergoes immediate treatment with radical prostatectomy and then develops severe urinary incontinence and impotence, despite living for the next 15 years free from PC recurrence."

Data From Recent Clinical Trials

To some extent, the question over metastases vs PC death as an endpoint has already been answered, given the results from recent clinical trials, he argues.

In the most recent study, the Prostate Testing for Cancer and Treatment (ProtecT) trial, the rate of death from prostate cancer at a median follow-up of 10 years was not significantly different between men with predominantly low- or intermediate-risk prostate cancer treated with either radical prostatectomy (RP), radiation (RT), or active monitoring (AM).

However, as Dr D'Amico points out, the risk for metastatic disease was more than twofold higher in men who underwent active monitoring compared to those treated with either surgery or radiation.

The men who developed metastatic disease (33 on AM vs 13 to 16 with immediate treatment) now face at least palliative intermittent androgen deprivation therapy (ADT), meaning castration, and its associated adverse effects "for the remainder of their lives," Dr D'Amico writes.

"[So] is it really considered a success if a man suffers recurrence with metastatic disease, which often means a painful bone fracture along with castration and all of its toxicities?" he asks.

Similarly, two other randomized trials found that the risk for metastases was significantly reduced in men who received treatment with surgery compared to those underwent watchful waiting (WW) or observation over long-term follow-up.

In the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) trial, for example, radical prostatectomy reduced the risk for overall survival by 29% compared with watchful waiting over a median of 13.4 years (P = .001).

Surgery also reduced the risk for prostate cancer-specific mortality by 44% (P = .001) as well as the risk for metastases by 43% (P < .001) compared to watchful waiting over the same follow-up period.

In the United States Prostate Cancer Intervention Versus Observation Trial (PIVOT) trial, surgery also reduced OS (P = .22), prostate-cancer specific mortality (P = .09), and metastases (P < .001) over a median of 10 years of follow-up compared with observation alone. The risk for metastases in the PIVOT trial was reduced by a factor of more than two, Dr D'Amico notes.

"What is remarkable about the ProtecT study findings is that despite having a control arm of AM as compared with WW and having much more favorable-risk disease characteristics compared with the men enrolled in the SPCG-4 and PIVOT studies, a more than two-fold and significant reduction (P =.004) in the occurrence of metastasis was observed in men randomly assigned to treatment compared with AM, which is similar to what was observed in both the SPCG-4 and PIVOT studies," Dr D'Amico emphasizes.

"Moreover, this increase in metastatic disease was observed after only a 10-year median follow-up, which is relevant to healthy men in their 50s and 60s, whose life expectancy exceeds 20 to 30 years, respectively," he adds.

Furthermore, not all men who develop metastatic prostate cancer will die of it, Dr D'Amico argues. There is often a very long interlude between the diagnosis of metastatic disease and death, during with men may well die of an unrelated cause.

Nevertheless, men with metastatic disease will almost invariably be treated for it, and as a consequence, they become subject to both the physiologic and psychological consequences of that treatment, he points out.

"Developing metastatic PC is a life-changing event for many men, which brings the fear of dying of PC into their daily life in addition to dealing with the lifelong adverse effects of treatment for metastatic PC," Dr D'Amico concludes.

"Therefore, I suggest consideration be given to making metastasis a benchmark for success for ongoing and planned studies of contemporary AS for men with favorable-risk PC and death from PC a secondary end point," he adds.

Patient Perspective

Asked for his opinion on the subject, Andrew Loblaw, MD, a radiation oncologist at Sunnybrook Health Sciences Center in Toronto, Ontario, agreed with Dr D'Amico that metastatic disease could be a viable endpoint for trials evaluating AS, especially from a patient's perspective.

"First of all, it's a really important event for patients when they go from localized disease to cancer that's spread elsewhere. That's a huge area of concern and distress," he told Medscape Medical News.

"So it's a really important 'bad milestone' for the patient," he added.

Dr Loblaw hastened to add that "all is not lost" when a man does develop metastatic disease, because there are many strategies today that work well both for men with hormone-sensitive disease as well as for those with castration-resistant disease, and patients can remain alive for many years and, in his view, have a reasonable quality of life over that time.

On the other hand, if trialists do design studies with metastatic disease as the primary endpoint, they need to ensure that the trial design takes into account not only the type of scans men receive and the tracer used to detect metastatic disease but also who reads those scans and how those scans are scheduled.

"Overall, metastatic disease is a very important endpoint for patients, but it would be very helpful for us as a trial community as well, because it'll be less costly for us to do our studies, and we'll get our answers earlier, which is really key," Dr Loblaw said.

"But there are extra steps that we'll need to take within these trials to make sure they are done properly, and we have to be aware of these steps so we can adjust and account for all the possible mitigating factors if metastatic disease is used as a primary endpoint."

Dr D'Amico has disclosed no relevant financial relationships. Dr Loblaw has financial ties with GlaxoSmithKline, Merck, Bristol-Myers Squibb, Novartis, Roche, Amgen, Astellas Pharma, Sanofi, Janssen Oncology, Elekta, and Paladin.

J Clin Oncol. Published online February 27, 2017. Full text

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