Interpreting the latest prostate cancer study

Last week in NEJMAnna Bill-Axelson and colleagues published the latest findings from the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4).

METHODS: Between 1989 and 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy and followed them through the end of 2012. The primary end points in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) were death from any cause, death from prostate cancer, and the risk of metastases. Secondary end points included the initiation of androgen-deprivation therapy.

RESULTS: During 23.2 years of follow-up, 200 of 347 men in the surgery group and 247 of the 348 men in the watchful-waiting group died. Of the deaths, 63 in the surgery group and 99 in the watchful-waiting group were due to prostate cancer; the relative risk was 0.56 (95% confidence interval [CI], 0.41 to 0.77; P=0.001), and the absolute difference was 11.0 percentage points (95% CI, 4.5 to 17.5). The number needed to treat to prevent one death was 8. One man died after surgery in the radical-prostatectomy group. Androgen-deprivation therapy was used in fewer patients who underwent prostatectomy (a difference of 25.0 percentage points; 95% CI, 17.7 to 32.3). 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) and in those with intermediate-risk prostate cancer (relative risk, 0.38). However, radical prostatectomy was associated with a reduced risk of metastases among older men (relative risk, 0.68; P=0.04).

CONCLUSIONS: Extended follow-up confirmed a substantial reduction in mortality after radical prostatectomy; the number needed to treat to prevent one death continued to decrease when the treatment was modified according to age at diagnosis and tumor risk. A large proportion of long-term survivors in the watchful-waiting group have not required any palliative treatment.

About 23 years ago, the investigators randomly assigned Scandinavian men with early prostate cancer to receipt of surgery (prostatectomy) or no surgery (watchful-waiting). Those assigned to the surgery group were less likely to die after 23 years of follow-up. Being less likely to die doesn’t mean not dying. In fact, only one man in eight benefited from surgery in general and one man in four among those under 65.

Even though some men didn’t benefit from surgery, it’s not easy to tell in advance who those men would be. This is typical in medicine: more people get treated than will benefit because we can’t precisely target treatment to only those we know will benefit. In fact, those surgery “number needed to treat” (NNT) figures of eight in general and four under 65 are quite low. Lots of widely accepted therapies have higher NNTs.

So, is this a slam dunk for prostatectomy? Are the great debates about whether and how to treat prostate cancer over? Nope.

There are a number of other considerations. First, treatment comes with other effects besides potential mortality reduction (side effects and complications that impact quality of life). As Richard Lehman noticed, surgery

definitely decreases all-cause mortality, at the cost of a prevalence of erectile dysfunction of 84% in the radical-prostatectomy group at 12.4 years and 80% in the watchful waiting group; urinary leakage was reported in 41% and 11%, respectively.

(More on quality of life outcomes from prostate cancer treatment here.)

Second, the results of this study aren’t necessarily generalizable to a US population, as Richard Hoffman explained.

PSA screening became widespread in the US in the early 1990s—a decade before the first SPCG-4 publication. Perversely, the American way was to expend considerable resources to promote screening efforts to find cancers…before knowing whether these cancers could be successfully treated. [So,] the SPCG-4 results are not readily translatable to US practice. Only 5% of the study cohort had cancers detected by screening PSA—the rest either had symptoms and/or a palpable tumor. In the US, a substantial proportion of men with PSA-detected cancers have microscopic disease—which may never cause problems during a man’s lifetime. The US Prostate Cancer Versus Observation Trial (PIVOT) also evaluated surgery vs. watchful waiting. However, PIVOT, which mostly enrolled men with PSA-detected cancers, found no benefit for surgery. Post-hoc analyses suggested that only the small proportion of men with higher-risk cancers (based on PSA and the microscopic appearance of the cancer) seemed to have a survival benefit. This suggests that most men with PSA-detected cancers—the great majority of whom undergo aggressive treatment–will experience only the potential harms of treatment without any expectation of experiencing a prostate-cancer survival benefit.

(More on the PIVOT results here.)

Finally, the SPCG-4 study only compares surgery with watchful waiting, not to various forms of radiation therapy as well. Though the results certainly add to our body of knowledge about the long-term benefits (and harms) of prostatectomy relative to watchful-waiting, they do not, by themselves, answer all the questions patients or practitioners might have. It’s essential that the findings be interpreted in the context of the wider body of evidence, and in light of their limitations.

The prostate cancer screening and treatment debates will most certainly go on.


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