THE "NEW" PROSTATE CANCER INFOLINK

This week’s New England Journal of Medicine contains data from a fifth update to the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) trial of radical prostatectomy vs. watchful waiting in “early” prostate cancer. Survival data from this important trial were first reported by Holmberg et al. (in 2002) and subsequently by Bill-Axelson et al. (in 2005, in 2008, and in 2011). In addition, quality of life-related data have also been reported by Johansson et al. (in 2009 and in 2011) and by Bill-Axelson et al. (in 2013).

In this very latest update, Bill-Axelson and her colleagues report data at a total follow-up of 23.2 years since enrollment of the first patient in 1989. And it should be clearly stated, immediately, that the members of this research team, and their original 695 patients, all deserve enormous recognition for their dedication to this study over a total period that now exceeds 25 years.

Between 1989 and 1999, SPCG-4 enrolled and randomly assigned 695 men with “early” prostate cancer to watchful waiting or radical prostatectomy. However, we should promptly remind readers that these 695 patients were not what we would describe as “early stage” prostate cancer patients today. These patients were all diagnosed based on clinical symptoms — i.e., by digital rectal examination or as a consequence of other symptoms suggestive of prostate cancer that led to a biopsy. None of them were sent for a biopsy based on a PSA test and diagnosed as a consequence. The PSA test was not in use in Scandinavia at that time as a tool to assess risk for prostate cancer.

The primary endpoints of the SPCG-4 trial were death from any cause, death from prostate cancer, and the risk of metastases. Secondary endpoints included the initiation of androgen deprivation therapy (ADT).

Here are the core findings as of December 31, 2012 (at an average follow-up period of 13 years):

• 447/695 patients (64.3 percent) had died.
  • 200/347 patients (57.6 percent) in the radical prostatectomy group.
  • 247/348 patients (71.0 percent) in the watchful waiting group.
• 162/695 patients died of prostate cancer.
  • 63/347 patients in the radical prostatectomy group.
  • 99/348 patients in the watchful-waiting group.
  • The relative risk was 0.56 and the absolute difference was 11.0 percentage points.
• 8 men needed to be treated to prevent 1 prostate cancer-specific death.
• 1 patient died after surgery in the radical prostatectomy group.
• There was a relative reduction of 25 percent in the number of patients requiring ADT in the radical prostatectomy group compared to the watchful waiting group.
• The benefit of surgery with respect to death from prostate cancer was largest in
  • Men younger than 65 years of age (relative risk, 0.45)
  • Men with intermediate-risk prostate cancer (relative risk, 0.38).
• Radical prostatectomy was associated with a reduced risk of metastases among older men (relative risk, 0.68; P = 0.04).
• A large proportion of long-term survivors in the watchful waiting group have not required any palliative treatment.

The most insightful “general media” assessment of the data from this trial is probably provided in a report in The Boston Globe.

There is no doubt that in this large group of men, all initially diagnosed based on clinically evident risk for localized prostate cancer, long-term follow-up has demonstrated a substantial reduction in mortality after radical prostatectomy. However, one only has to read the abstracts of the papers on quality of life to realize that, whether treated by radical prostatectomy or watchful waiting, nearly half the men in this trial had serious quality of life issues over time.

From today’s perspective, when most men are being diagnosed with much earlier stage disease (i.e., negative DREs and no other clinical indication of a problem), based primarily on PSA levels alone, one has to ask how many such men are really good candidates for immediate surgery (or other forms of treatment). The fact that “a large proportion” of the 101 long-term survivors in the watchful waiting group of the SPCG-4 trial have never required any form of palliative treatment (at an average of 13 years of follow-up) clearly indicates that, even among these men, all diagnosed with clinical evidence of the possibility of prostate cancer, patients may survive for many years with no evidence of clinically significant progression of their disease.

Over the past 25 years, the SPCG-4 trial has provided us with enormous insight into the progression of prostate cancer in this particular set of patients. However, the question of how we apply the learnings from this trial to patients being diagnosed with early stage prostate cancer of low and intermediate risk today (particularly among men of > 65 years of age) remains a difficult one to resolve.

Some members of the surgical community have long argued that this trial is absolute proof of the value of immediate surgery in all men diagnosed with early stage prostate cancer. The “New” Prostate Cancer InfoLink has long taken a somewhat different position, which is that it is proof of

• A long-term survival benefit from radical prostatectomy in a subset of men diagnosed with clinical evidence of localized prostate cancer, most especially those of < 65 years of age
• A long-term benefit of freedom from metastasis in a less well-defined group of men enrolled into the trial (but possibly those initially diagnosed with intermediate-risk disease based on these most recent data)

We have not yet been able to read the full text of this latest paper from the SPCG-4 trial, but it would be fascinating to know the detailed diagnostic criteria (and the follow-up information) about the surviving men followed by watchful waiting who have never needed any form of palliative care. Could such data help us to better define men who are truly at minimal risk from progressive disease over a period of 15+ years? Have the SPCG-4 investigators been tracking relevant data from these men over time? Do they have access to the original biopsy specimens from these men to be able to study the genetic make-up of their tumors? Can we even tell why such men have not demonstrated evidence of significant clinical progression?

Filed under: Diagnosis, Living with Prostate Cancer, Management, Risk, Treatment | Tagged: outcome, radical prostatectomy, SPCG-4, surgery, watchful waiting |