Extended follow-up in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG4), reported recently in The New England Journal of Medicine,¹ found that men with early-stage prostate cancer, particularly those under 65 years old, who were treated with radical prostatectomy had increased survival compared to those assigned to watchful waiting. But differences in how prostate cancer is detected and treated now, compared to the years 1989 through 1999, when these men were randomized to surgery or watchful waiting, may limit the study’s impact to informing discussion of the issue, stimulated by widespread coverage by major media, including The Wall Street Journal, the Los Angeles Times, The Boston Globe, and CNN.

Men who were younger than 65 years and had radical prostatectomy had a significant absolute reduction of 25.5 percentage points in overall mortality and 15.8 percentage points in death from prostate cancer, according to the study. There was no significant reduction in mortality among men aged 65 years or older at time of diagnosis.

“I don’t see these data having a major change in the uptake of surveillance or radical prostatectomy. I think they confirm what we already knew—older men are less likely to benefit from aggressive treatment,” H. Ballentine Carter, MD, said in an interview with The ASCO Post. Dr. Carter is Professor of Urology, Oncology, and Director, Division of Adult Urology, Brady Urological Institute, at Johns Hopkins Medicine in Baltimore. “In my opinion, it is just more evidence that active surveillance is a very reasonable option, especially for men over age 65 who have low-risk disease.”

Most Had Palpable Tumors

Of the 625 men in SPCG-4, 347 were randomly assigned to radical prostatectomy and 348 to watchful waiting. The mean age of men in both groups was 65, and the mean prostate-specific antigen (PSA) level was approximately 13 ng/mL. Most had T2 tumors. “Only 12% of the patients had nonpalpable T1c tumors at the time of enrollment in the study,” the investigators pointed out.

At 18 years, the cumulative incidence of death was 56.1% in the radical prostatectomy group and 68.9% in the watchful waiting group (a 12.7 percentage point difference, 95% confidence interval [CI] = 5.1–20.3). This corresponded to a 0.71 relative risk of death in the radical prostatectomy group (95% CI = 0.59–0.86, P < .001).

The cumulative incidence of death from prostate cancer at 18 years was 17.7% in the radical prostatectomy group and 28.7% in the watchful waiting group (an 11.0 percentage point difference, 95% CI = 4.5–17.5), which corresponded to a 0.56 relative risk of death in the radical prostatectomy group (95% CI = 0.41–0.77, P = .001).

Pre-PSA Era

The SPCG-4 trial was initiated before the era of PSA screening. “By contrast, the Prostate Cancer Intervention versus Observation Trial (PIVOT),² initiated in the early era of PSA testing, showed that radical prostatectomy did not significantly reduce prostate cancer-specific or overall mortality after 12 years,” the SPCG-4 authors noted.

“PSA screening profoundly changes the clinical domain of study,” they continued. “Among other considerations, the substantial additional lead time necessitates very long follow-up periods in the PIVOT trial to determine the effect of surgery as compared with observation. In the meantime, the SPCG-4 offers insight regarding the effectiveness of radical prostatectomy and the natural history of prostate cancer.”

In the SPCG-4 study, “only 5% of prostate cancers were detected with screening; three out of four had palpable disease; almost 50% had PSAs over 10 ng/mL; and one in three had a Gleason score above 6. So this is not a screen-detected group of people,” Dr. Carter noted.

‘Stratification Is Suspect’

“To assess the possible modification of the treatment effect, analyses were stratified according to the patient’s age at diagnosis (< 65 years vs ≥ 65 years) and tumor risk,” the study authors reported. Men with PSA levels < 10 ng/mL and a Gleason score < 7 or World Health Organization (WHO) grade 1 disease were considered low risk. Those with PSA levels ≥ 20 ng/mL or higher and Gleason scores > 7 were considered high risk. Men who did not meet criteria for either low or high risk were considered intermediate risk.

“The stratification is suspect because three out of four patients had palpable disease, and that is not what we are dealing with today. These are people who had disease more advanced than what we are detecting today. It doesn’t mean that it is not an informative trial. It is just not generalizable. If anything, it suggests that the results are the worst case scenario, for the control group anyway,” Dr. Carter said.

“If you look at the cumulative rates of death in men with low-, intermediate-, and high-risk disease in the control group that didn’t get treated, and then you look at the control group of the PIVOT trial, which is a PSA era trial, you will see that the low-risk cancers of yesterday are the intermediate-risk cancers of today. That is an important caveat, the point being that you can’t take the information from the low-risk cancers in the Scandinavian Prostate Cancer Group study and generalize that to the low-risk cancers of today, because with PSA screening, there is a lead time on average of a decade,” he continued.

“So I think what the Scandinavian Prostate Cancer Group study shows for men under age 65 is that those who are going to benefit the most are those with intermediate- or high-risk disease. I am not suggesting that men under age 65 with low-risk disease should never be treated. I am only suggesting that those with intermediate- or high-risk disease are the people who are more likely to benefit,” Dr. Carter explained.

The authors do note in their conclusion that their analyses according to tumor risk are “merely hypothesis-generating.”

Dr. Carter commented, “That’s exactly right, because it is not generalizable to today.”

Role of USPSTF Recommendation

In 2012, the U.S. Preventive Services Task Force (USPSTF) updated its prostate cancer screening recommendation against PSA-based screening and now “recommends against PSA-based screening for prostate cancer.”³ This is a grade D recommendation, meaning that there “is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.”

Asked if this could alter the PSA testing scenario once again, Dr. Carter replied, “No, I don’t think that is true. The only data we really have on changing behavior is from the 2008 USPSTF Grade D recommendation for men over age 75, and that didn’t change behavior at all—not one bit. So I don’t think that men are less likely to get PSA screened. We don’t have that information for after the 2012 USPSTF recommendation yet. But if the past is any indication of the future, that task force recommendation is not going to have any impact unless it impacts payment.”

Different Approaches

Differences in how prostate cancer is managed now, as compared with the time of the SPCG-4 trial, also involve surgical procedures and follow-up monitoring and treatment.

“The surgical approach then was very different from the surgical approach today,” Dr. Carter noted. According to the study design, “radical excision of the tumor was given priority over nerve-sparing surgery.”

In a quality-of-life assessment at a mean of 12.4 years, the SPCG-4 researchers found that the prevalence of erectile dysfunction was about the same for men in the SPCG-4 assigned to surgery (84%) or watchful waiting (80%), but urinary leakage was much higher in the surgery group—41% vs 11% in the watchful waiting group—as was distress from these symptoms. More modern surgical techniques and nerve-sparing procedures can mitigate effects of prostatectomy on erectile dysfunction and urinary incontinence, Dr. Carter noted, citing a study by Sanda et al.⁴

J. Leonard Lichtenfeld, MD, Deputy Chief Medical Officer of the American Cancer Society, commenting in Dr. Len’s Cancer Blog,⁵ noted that men in the watchful waiting cohort in SPCG-4 never received any curative treatment.

“That is a much different approach to watchful waiting than we currently recommend in the United States, where watchful waiting after a diagnosis of prostate cancer usually means offering curative treatment when the prostate cancer changes its behavior,” Dr. ­Lichtenfeld wrote.

“I think that is a very valid criticism,” Dr. Carter stated. “We are very carefully monitoring people who get periodic biopsies, periodic PSAs, digital exams, and now [magnetic resonance imaging].”

“About the best thing we can say about this study is it is applicable to men treated the way we used to treat prostate cancer,” Dr. Lichtenfeld’s blog concluded. “But considering how much better we understand and implement watchful waiting, this study should not be used to encourage surgery for every man diagnosed with prostate cancer.” ■

Disclosure: Drs. Carter and Lichtenfeld reported no potential conflicts of interest.

References

1. Bill-Axelson A, Holmberg L, Garmo H, et al: Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med 370:932-942, 2014.

2. Wilt TJ, Brawer MK, Jones KM, et al: Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 367:203-213, 2012.

3. Screening for Prostate Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 157:120-134, 2012.

4. Sanda MG, Dunn RL, Michalski J, et al: Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 358:1250-1261, 2008.

5. Lichtenfeld JL: It helps to know what watchful waiting really means in prostate cancer treatment. Dr. Len’s Cancer Blog, March 6, 2014. Available at www.cancer.org/aboutus/drlensblog.

In the News focuses on media reports that your patients may have questions about at their next visit. This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.