March 23, 2009 (Stockholm, Sweden) — Men with localized prostate cancer who were randomly assigned to receive radical prostatectomy in the Scandinavian Prostate Cancer Group (SPCG)-4 trial not only achieved superior survival, compared with men who were randomized to watchful waiting, they did so without sacrificing quality of life.
In fact, they scored slightly better in terms of anxiety, depression, well-being, and overall quality of life than men in the watchful-waiting group, said Lars Holmberg, MD, professor of cancer epidemiology at King's College London School of Medicine, in the United Kingdom, who was one of the SPCG-4 study authors.
Speaking here at the European Association of Urology 24th Annual Congress, Dr. Holmberg told delegates that the SPCG-4 investigators were surprised to find no difference in quality-of-life scores between the 2 study groups. "It is widely accepted that radical prostatectomy is associated with severe morbidity," he said. "But when we assessed quality of life, we found that it was actually slightly higher in the men who got the surgery. So we were wrong in our assumption that we would gain some years of life with radical prostatectomy at the cost of quality of life."
Long-Term Trial
The SPCG-4 trial has been ongoing since 1989, when it was launched to compare the effects of radical prostatectomy and watchful waiting on disease-specific mortality in Scandinavian men with locally advanced prostate cancer. For the next 10 years, until 1999, men from Sweden, Finland, and Iceland were randomly assigned to radical prostatectomy (n = 347) or to watchful waiting (n = 348). In 2005, after a median follow-up of 8.2 years, the investigators reported that men in the surgery group had lower rates of death from prostate cancer than men in the watchful-waiting group.
In August 2008, the investigators reported updated data (J Natl Cancer Inst. 2008;100(16):1144-1154) that showed that men in the surgery group continued to have decreased cancer-related mortality, compared with men in the watchful-waiting group.
The 12-year results showed that 12.5% of the surgery group and 17.9% of the watchful-waiting group had died of prostate cancer, for a relative risk reduction of about 35% and a 5.4% absolute risk reduction in disease-specific survival in favor of radical prostatectomy (P = .03). "This means that we need to operate on 19 patients to gain 1 life," noted Dr. Holmberg.
In addition, 19.3% of men in the surgery group and 26% of men in the watchful-waiting group had been diagnosed with distant metastases, for a 6.7% absolute risk reduction in favor of radical prostatectomy (P = .006).
"We had expected that the absolute difference in cumulative incidence of distant metastasis and prostate cancer death would increase with longer duration of follow-up, but there was no further increase after 7 to 9 years," said Dr. Holmberg.
In the men who were treated surgically, all but 1 of the deaths occurred in patients with extracapsulary extension in the radical-prostatectomy specimen.
Patients with a Gleason score of 2 to 6 had the lowest risk for recurrence.
Radical Prostatectomy Had Large Effect on Reducing Mortality
Radical prostatectomy had a large effect on reducing mortality in men younger than 65 years but had little or no effect in patients older than 65 years. But Dr. Holmberg cautioned against taking this finding as evidence of a lack of effect in elderly patients. "This was a subgroup analysis, which is always unstable. The finding represents a hypothesis that needs further investigation."
Prostate-specific antigen (PSA) kinetics were useless to guide treatment decisions for the watchful-waiting group, he added. "To use only PSA to follow watchful-waiting patients does not seem to be that safe. You would need to combine that with other more sophisticated methods of follow-up. People right now are experimenting with a series of biopsies and other methods."
In an interview with Medscape Oncology after his presentation, Dr. Holmberg said that the data from the quality-of-life analysis are very important.
He pointed out that the patterns of symptoms differ between the 2 groups, because the treatments are associated with vastly different adverse effects. For surgery patients, the adverse effects appear early, right after the surgery. But for watchful-waiting patients, the pattern is reversed. In those patients, symptoms increase as the disease burden increases, he said.
Increase in Symptoms Decreases Quality of Life
"People who have surgery learn to live with their symptoms afterward. They learn to use Viagra, they get support, and the symptoms tend to wear off. In contrast, patients in the watchful-waiting arm do not have many symptoms at the start but, as the disease grows, they get more and more symptoms. They also get many more hormonal treatments, which have side effects," Holmberg said.
Because SPCG-4 was begun before the era of PSA screening, the results may not be entirely generalizeable to the current population of prostate cancer patients. Dr. Holmberg admitted that the trial could not be started today, in the era of PSA testing, noting that the patients in SPCG-4 are not representative of the prostate cancer patients clinicians see today. "The tumors we saw in our study are larger tumors than you would expect to see in today's current screening situation. There were more T2 tumors."
Nevertheless, the study has yielded important and useful information, Dr. Holmberg said.
"I think our trial has actually shown that, even if the tumor is more advanced, it is worthwhile to do an operation, and we have data to show that it actually cures some patients. When we started the study, we doubted whether it was beneficial at all to intervene as early in the disease as this. There were no randomized studies at that time to tell us that, just indirect inferences."
An Important Study
Asked by Medscape Oncology to comment about the SPCG-4 study, Fritz Schröder, MD, from the Erasmus Medical Center, in Rotterdam, the Netherlands, called it an important study. "This is the only study that shows that radical treatment is better than watchful waiting. It shows a significant difference, which in absolute terms amounts to only about 5%, but it is still very relevant. The question is whether this finding will translate from statistical to clinical significance," he said.
The key to that question lies in the number of patients needed to treat in order to save 1 life. Dr. Schröder said that many of his colleagues will doubt whether it is worthwhile treating a patient with surgery when there are other treatments available that might also prolong life. But others will say that the evidence that radical prostatectomy saves lives clearly demonstrated in the study makes the choice for surgery compelling.
"My feeling is that this has to be discussed with the patient. It is not only up to the doctor to determine whether a 1 to 20 relation is adequate or acceptable. It is an ethical issue that has to be discussed with the patient," he said.
Dr. Schröder said that he found the results of the quality of life analysis encouraging. "The finding that there is no big difference between watchful waiting and active treatment reflects the fact that, although there are adverse effects in the sexual and micturition field, these are clearly not experienced as something very bad in the radical-treatment group. This is important."
He agreed with Dr. Holmberg's assertion to be very careful in interpreting the subgroup analysis that found less benefit for radical prostatectomy in patients older than 65 years.
"It is important to take this observation with a grain of salt. If I see a patient who is in excellent shape at 70 years old and I estimate that he could make it to 95 because his family history is very favorable, I would not hesitate to recommend aggressive treatment to the man, in spite of this suggestive subgroup finding."
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