37 Early Stage Prostate Cancer: Controversies in Management
Prostate cancer is the second most common type of cancer in men around the world (1). It is a clinically heterogeneous disease, and the clinical course and aggressiveness of prostate cancer varies widely from patient to patient. This heterogeneity makes it difficult to implement evidence-based clinical practice guidelines to every single patient. As such, controversy has arisen over the management of prostate cancer. This chapter discusses the controversies surrounding prostate cancer screening, treatment strategies of localized prostate cancer, androgen deprivation treatment, and the role of proton therapy.
PROSTATE CANCER SCREENING
Case 1: A 48-year-old African American male presents for consultation about prostate cancer screening. One of his brothers was diagnosed with prostate cancer at the age of 60 years.
Question 1: Should he undergo prostate cancer screening?
Prostate cancer often grows slowly. The 5-year survival of patients with prostate cancer confined within the prostate and local spread is about 100% versus 29.3% for patients with distant metastasis (2). It seems reasonable that prostate cancer screening would be able to reduce morbidity and mortality in the subset of asymptomatic patients with aggressive localized prostate cancer. Unfortunately, prostate cancer screening is not well supported by data from randomized studies. 38Limitation in the design and differing results of randomized trials are to blame for lack of supportive data for screening.
Two large randomized trials were done to evaluate the effectiveness of prostate cancer screening. The European Randomized Study of Screening for Prostate Cancer (ERSPC) randomized 182,160 men between the ages of 50 and 74 to prostate-specific antigen (PSA) screening. Follow-up was truncated at 13 years for the 162,243 men in a prespecified core group between the ages of 55 and 69. The absolute rates of prostate cancer mortality were 0.43 versus 0.54 per 1,000 person-years. Forty-eight additional patients needed to be diagnosed to prevent one prostate cancer death. Although there are factors in this trial that biased results toward effects or no effects, the absolute benefit of prostate cancer screening was low (3).
In the U.S. Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial, 76,693 men between the ages of 55 and 74 were randomly assigned to annual screening with PSA and digital rectal examination (DRE) or to usual care. After 7 years of follow-up and longer-term follow-up, there was no reduction in the primary outcome of prostate cancer (4). The negative results of the PLCO trial may be confounded by the high rate of PSA testing in the control arm, a higher PSA cutoff for biopsy, and the substantial proportion of men with abnormal PSA and/or DRE results who had not undergone biopsy within 3 years following the positive screen.
Furthermore, a 2010 meta-analysis summarized results from six randomized trials. Screening with PSA with or without DRE compared to no screening did not reduce death from prostate cancer (5). In 2011, a Cochrane meta-analysis had similar findings (6). However, screening did significantly increase the probability of cancer diagnosis.
In addition to conflicting results regarding the efficacy of prostate cancer screening as shown in randomized trials, prostate cancer screening is associated with significant risks of biopsy, overdiagnosis, and treatment. However, once prostate cancer has advanced far enough to cause symptoms, it is generally no longer localized and is therefore incurable. As a result, it is important to discuss potential benefits and risks of prostate cancer screening with patients. More importantly, involving patients in the shared decision-making process and using a decision-making aid have been proven to decrease screening 39rate, increase screening satisfaction, and decrease decision conflicts in systemic reviews and randomized trials (7,8).
TREATMENT OF LOCALIZED PROSTATE CANCER
Case 2: A 55-year-old male was recently found to have a PSA of 8 ng/mL. No abnormality was detected on DRE. Prostate biopsies showed two positive biopsy cores with less than 50% involvement in any one core.
Question 2: What kind of treatment options can be offered to this patient?
Due to widely used prostate cancer screening, many men were diagnosed with clinically localized prostate cancer. The biggest concern is if the diagnosed prostate cancer is clinically significant enough to warrant medical treatment. Besides, selection for optimal treatment for the individual patient is often complicated and controversial due to underlying tumor heterogeneity. The treatment options include active surveillance, radiation therapy, and prostatectomy. In general, treatment planning needs to take into account the patient’s life expectancy, comorbidities, risk stratification of cancer, and preference. Based on baseline PSA, Gleason score, and the extent of prostate involvement, patients can be divided into very-low-, low-, intermediate-, high-, and very-high-risk groups. For patients with very-low-risk cancer and life expectancy less than 20 years, active surveillance is preferred. In patients with low-risk prostate cancer and life expectancy greater than 10 years, definitive therapy (radiation and prostatectomy) or active surveillance is acceptable (9,10). For patients with intermediate-, high-, and very-high-risk prostate cancer, definitive treatment (radical prostatectomy or radiation) is recommended. Side effects are different for each treatment. Radiation may be associated with gastrointestinal symptoms, urinary symptoms, and erectile dysfunction. Prostatectomy can result in urinary incontinence and erectile dysfunction. Although active surveillance does not cause the aforementioned side effects, it does induce significant stress and anxiety. As a result, patients on active surveillance often end up getting radiation therapy or prostatectomy. Oftentimes, the choice of treatment is left up to the discretion of clinicians in collaboration with patients.
40RADIATION TREATMENT: PROTON THERAPY
Case 3: A 75-year-old male presented with newly diagnosed prostate cancer. He has disease limited to one lobe of the prostate, a serum PSA 7 ng/mL, and a Gleason score of 4.
Question 3: Is this patient a candidate for proton therapy?
Because of the unique physical properties of heavy particles, a proton beam results in the majority of the energy being deposited at the end of a linear track, reducing the dose to normal tissues. Although many proton treatment centers have opened in recent years, there are no randomized trials that compare proton beam therapy with photon beam therapy or brachytherapy in men with clinically localized prostate cancer. A systematic review of the available evidence from the American Society for Radiation Oncology (ASTRO) on efficacy and toxicity concluded that outcomes were similar with proton beam therapy and intensity-modulated radiation therapy (IMRT), but did not demonstrate an advantage for the proton beam approach (11).
As mentioned earlier, controversy in management of prostate cancer stems from the underlying heterogeneity. Hopefully, these controversies might be resolved by tailoring treatment to the individual’s genetic makeup in the era of personalized oncology.