Clinically Localized Prostate Cancer – Treatment or Active Monitoring

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 180,890 new cases of prostate cancer will be diagnosed in 2016 and over 26,000 men will die of the disease. The widespread use of PSA testing in the recent years has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer. The management of clinically localized prostate cancer that is detected based on Prostate Specific Antigen (PSA) levels remains controversial and management strategies for these patients have included Surgery, Radiotherapy or Active Monitoring. However, it has been proposed that given the indolent nature of prostate cancer in general, majority of the patients do not benefit from treatment intervention and many patients die of competing causes. Further, treatment intervention can result in adverse effects on sexual, urinary, or bowel function. The U.S. Preventive Services Task Force (USPSTF) has recommended that population screening for prostate cancer should not be adopted as a public health policy, because the risks appeared to outweigh benefits, from detecting and treating PSA-detected prostate cancer. Previously published trials evaluated the effectiveness of treatment, but they did not compare Surgery, Radiotherapy and Active Monitoring.

Prostate Testing for Cancer and Treatment (ProtecT) study is a prospective, randomized trial, which compared Active Monitoring, Radical Prostatectomy, and External Beam Radiotherapy, for the treatment of PSA-detected clinically localized prostate cancer. A total of 1,643 patients were randomly assigned to Radical Prostatectomy (N=553), Radiotherapy (N=545) or Active Monitoring (N=545). Patients in the Active Monitoring group were evaluated every 3 months for the first year, then every 6-12 months thereafter and radical treatment with curative intent was offered, based on changes in PSA levels. This is different from “watchful waiting”, which has no planned curative radical treatment on disease progression. The median age in this study was 62 yrs, the median PSA level was 4.6 ng/ml, 77% had tumors with a Gleason score of 6 and 76% had Stage T1c disease. The primary end point was prostate cancer mortality at a median of 10 years of follow-up, with prostate cancer-related deaths defined as deaths that were definitely or probably due to prostate cancer or its treatment. Secondary end points included all-cause mortality and the rates of metastases, clinical progression, primary treatment failure, and treatment complications.

At a median follow up of 10 years, prostate cancer-specific mortality was low at approximately 1% irrespective of treatment and all-cause mortality was also low at approximately 10%. However, higher rates of disease progression were seen in the Active Monitoring group (22.9 events per 1000 person-years) compared to the Surgery group (8.9 events per 1000 person-years) or the Radiotherapy group (9.0 events per 1000 person-years). This meant that patients assigned to Active Monitoring were significantly more likely to have metastatic disease than those assigned to treatment (P<0.001 for the overall comparison).

The authors in a companion article (N Engl J Med. DOI: 10.1056/NEJMoa1606221) focused on the patient-reported outcomes after Monitoring, Surgery and Radiotherapy over 6 years of follow up. Prostatectomy had the greatest negative effect on urinary continence and sexual function, whereas Radiotherapy plus neoadjuvant androgen-deprivation therapy had more of a negative effect on bowel function, urinary voiding and nocturia, although patients recovered some function over time. Approximately 44% of the patient’s who were assigned to Active Monitoring, did not receive radical curative treatment and were able to avoid these toxicities.

It was concluded that at a median follow up of 10 yrs, prostate cancer-specific mortality was low, irrespective of the treatment given, with similar efficacy outcomes but with a variable impact on quality of life. However, it should be noted that patients assigned to Active Monitoring were significantly more likely to have metastatic disease than those assigned to treatment. This in turn would warrant salvage treatment, which could result in toxicities as well. Further follow up, evaluating long term survival and the accompanying risk/benefits, will allow patients to make informed decisions, with regards to the treatment options, for clinically localized prostate cancer. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. Hamdy FC, Donovan JL, Lane JA, et al. for the ProtecT Study Group. September 14, 2016DOI: 10.1056/NEJMoa1606220