Prostate Cancer: 3 Years More After Surgery

Alexander M. Castellino, PhD

December 12, 2018

New longer-term data from a Scandinavian trial show that men with clinically detected prostate cancer who underwent radical prostatectomy lived an additional 2.9 years compared to patients who underwent watchful waiting.

The finding, from the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4), was published online December 13 in the New England Journal of Medicine.

In the SPCG-4, which was conducted from October 1989 through February 1999, patients with localized prostate cancer were randomly assigned to undergo watchful waiting or radical prostatectomy. Follow-up data were collected through 2017.

"It is pretty amazing that after 29 years since the study started, 20% of the men are still alive, and only 30% have died from prostate cancer," corresponding author Anna Bill-Axelson, MD, associate professor and consultant in urology at Uppsala University, Sweden, told Medscape Medical News. "Prostate cancer is a slow-growing tumor in most cases, and in order to benefit from radical prostatectomy, the patient needs to develop a lethal disease and be healthy enough not to die from something else," she added.

Men were eligible to be enrolled in SPCG-4 if they were younger than 75 years, had a life expectancy of more than 10 years, and had no other known cancer that was likely to shorten survival. In addition, their prostate-specific antigen (PSA) level had to have been <50 ng/mL, and they had to have had localized disease. "Within the era in which this study was conducted, most of these men would have been considered as intermediate risk," Anthony V. D'Amico, MD, from Brigham and Women's Hospital and the Dana-Farber Cancer Institute, Boston, Massachusetts, told Medscape Medical News when approached for comment.

Since the time of the study, multiparametric MRI arrived. "These data serve to raise awareness that before a man undergoes active surveillance or observation for low-risk prostate cancer, multiparametric MRI should be suggested in order to identify occult, grade 4 or higher prostate cancer, as these men are at increased risk for death if they are otherwise in good health and not treated," he added.

Bill-Axelson told Medscape Medical News that, in light of the fact that 70% of the patients did not die from prostate cancer, many would probably be candidates for active surveillance today. "The diagnostic work-up at that time was limited with only a few biopsies, so a large number were undergraded compared with today," she said. "MRI that is used today makes grading more accurate, but may also result in an upgrading that will result in overtreatment," she added. "The introduction of MRI is a paradigm shift," she said. It now makes all previous studies that were based only on biopsies somewhat difficult to interpret, she added.

Also approached for comment, Karim Fizazi, MD, PhD, of the Institut Gustave Roussy, Villejuif, France, highlighted the 26% reduction in the relative risk for death from any cause and the 45% reduction in the relative risk of dying from prostate cancer for the patients who underwent radical prostatectomy in SPCG-4. "Basically, this trial remains important indeed: it focused on patients with clinically detected localized prostate cancer (no more, no less) and clearly shows that these patients deserve a local treatment," he said. "On top of this, the median follow-up of 23 years is exceptional, and it is a tour de force," he added.

Fizzazi noted that the data are very clear for patients younger than 65 years. "For older men, the benefit of the local treatment is lower, and its use needs to be discussed, taking into account potential benefit vs potential harms, by assessing absolute age, comorbidities, and whether the cancer is aggressive or not," he said. "Very importantly, the data reported in this trial do not apply to men whose cancer was detected on PSA screening or MRI while they were asymptomatic," he added.

Details of the SPCG-4 Study Results

In the Scandinavian trial, 695 men with localized prostate cancer were randomly assigned to undergo either radical prostatectomy (n = 347) or watchful waiting (n = 348) from October 1989 to February 1999. After the first 2 years, patients underwent an annual follow-up examination. "No patient was lost to follow-up, and annual follow-up continued through 2017," Bill-Axelson told Medscape Medical News.

The median age at enrollment was 65 years. Only 12% of men had nonpalpable stage T1c tumors at inclusion. The mean PSA level was 13 mg/mL.

Median follow-up was 23.6 years (range, 20 days - 28 years); maximum potential follow-up was 29.3 years. A total of 85% of men in the treatment arm underwent radical prostatectomy; 15% in the watchful waiting group later underwent treatment with curative intent.

At 23 years, the cumulative incidence of death from any cause was higher in men who received watchful waiting, at 83.8%, vs 71.9% for the patients who underwent prostatectomy (absolute difference, 11.9%). With a hazard ratio (HR) of 0.74, the men who underwent prostatectomy were at a 26% reduced risk for death from any cause (P < .001).

The SPCG-4 investigators report that this endpoint (death from any cause) was significant for men younger than 65 years (HR, 0.62; 95% confidence interval [CI], 0.48 - 0.80) but not for those aged 65 and older.

The cumulative incidence of prostate cancer death was also higher for men who underwent watchful waiting, at 31.3%, vs 19.6% for those who underwent prostatectomy (absolute difference, 11.7%; HR, 0.55; P < .001)

Distant metastases were experienced by more men who received watchful waiting, at 43.3%, vs 26.6% for those who underwent prostatectomy (P < .001).

The benefits of radical prostatectomy with respect to prostate cancer death and distant metastases were also seen in men aged 65 years and older.

Of all histopathologic measures, only the presence of extracapsular extension was associated with a fivefold increased risk for death from prostate cancer.

The researchers note that per-protocol analyses, which took into account nonadherence to therapy, provided similar results as the intent-to-treat analyses.

Comparing Long-term Results Across Trials

In their article, Bill-Axelson and colleagues comment on how their trial results compare with those of others.

The Prostate Cancer Intervention Versus Observation Trial (PIVOT), which compared prostatectomy with observation, showed a relative risk reduction of 0.65 for death from prostate cancer after prostatectomy compared with observation at a follow-up of 19 years. This is similar to what was seen in the SPCG-4 trial after 10 years of follow-up, they note. However, the "absolute difference in risk was only 4 percentage points, reflecting the low baseline risk," they add. "Only long-term follow-up can reveal whether the PIVOT results will catch up with the SPCG-4 results after passing of the lead time associated with PSA testing or whether they will remain unchanged as a result of a substantial overdiagnosis of nonlethal prostate cancer," the researchers comment.

The Prostate Testing for Cancer and Treatment (ProtecT) study compared prostatectomy with active surveillance in men with PSA-detected prostate cancer. This study found a 0.63 relative risk for death from prostate cancer at 10 years after radical prostatectomy compared with active surveillance.

Because active surveillance entails curative treatment when such treatment is indicated, this trial in fact effectively compared immediate curative treatment with delayed curative treatment, Bill-Axelson and colleagues point out. The event rate was still low, with only 1% of men dying from prostate cancer in 10 years. That suggests "an even longer lead time and possibly a greater degree of overdiagnosis than in PIVOT," they comment. "The length of time for a more substantial benefit to occur even among men with more advanced tumors, as in our trial, highlights the importance of carefully selecting men who might benefit from curative treatment and not treating the small, low-risk tumors often diagnosed today, unless they show signs of progression during active surveillance," the SPCG-4 investigators write.

Unanswered Question

Given that in the SPCG-4 study, patients in the standard treatment arm received watchful waiting and not active surveillance, would active surveillance have made a difference had it been an option in this study? "It remains to be discerned if surveillance would lead to the same degree of increased risk of death from all causes," D'Amico said.

D'Amico pointed out that the ProtecT study — in which surveillance was the control arm — led to a doubling of metastatic rate in men with favorable-risk, low-risk, or intermediate-risk prostate cancer. This raises the concern that even active surveillance of occult or grade 4 prostate cancer may be associated with an increased risk for death from prostate cancer. "Therefore, multiparametric MRI is routinely recommended before placing men on active surveillance in order to minimize the risk for grade 4 discovery," he said.

Watchful Waiting and Active Surveillance: Still Appropriate for Some

Bill-Axelson told Medscape Medical News that watchful waiting is still used for men whose life expectancy is less than 10 years. "As in ProtecT at 10 years, less than 1% of men have died from prostate cancer, so in older men with low-intermediate-risk disease, this is still an option," she said. "With watchful waiting, which is what we studied in SPCG-4, no curative treatment is intended, only symptomatic treatment with hormones if the patient develops metastases," Bill-Axelson said. "This is still used in men with other diseases who have a short life expectancy," she added.

In active surveillance, curative treatment is postponed until the tumor shows signs of becoming more aggressive on repeat biopsy, while the cancer is still localized to the prostate, Bill-Axelson explained. "That is what should be used in all men with low-risk disease and favorable intermediate-risk disease to reduce overtreatment," she said.

In Sweden today, more than 80% of men with low-risk disease start on active surveillance, she added.

According to the Prostate Cancer Foundation (PCF), active surveillance protocols should include PSA testing, digital rectal examinations, and serial prostate biopsies. Ancillary radiologic and genomic tests are investigational but may have a role for patients with discordant clinical and/or pathologic findings.

The PCF recommends that patients be monitored regularly for signs of progression. It recommends that PSA testing and digital rectal examinations be performed once or twice a year, and that a repeat biopsy of the prostate be performed every 1 to 5 years. If there is evidence that the cancer is progressing, treatment may be warranted.

The foundation also notes that in men with low-risk prostate cancer who have been on active surveillance for 10 to 15 years after diagnosis, rates of the spreading of disease or of dying of prostate cancer are low. As an example, the PCF cites a Johns Hopkins study of the use of active surveillance. That study found that after 15 years, fewer than 1% of men had developed metastatic disease.

Current guidelines from the American Society of Clinical Oncology (ASCO) indicate active surveillance as the recommended option for most patients with low-risk prostate cancer. Active surveillance recommendations include follow-up biopsy at 6 to 12 months to confirm eligibility, then every 2 to 5 years.

Active surveillance is more controversial for intermediate-risk patients, who have a higher risk of developing metastatic disease, the ASCO guidelines note. These patients should be counseled regarding the higher risk of the cancer progressing without treatment, they add.

The study was supported by grants from the Swedish Cancer Society, the National Institutes of Health, the Karolinska Institute, the Percy Falk Foundation, and the Örebro County Council. Dr Fizazi has been or is on the advisory board of and/or a speaker for Amgen, Astellas, Bayer, BMS, Dendreon, Ipsen, Janssen, Takeda, Novartis, Sanofi. Dr D'Amico reported has disclosed no relevant financial relationships.

N Engl J Med. Published online December 13, 2018. Abstract

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