Prostate Cancer
William G. Nelson, H. Ballentine Carter, Theodore L. DeWeese, Emmanuel S. Antonarakis and Mario A. Eisenberger
Summary of Key Points
Incidence
• Prostate cancer is the most commonly diagnosed life-threatening cancer in men (241,740 cases and 28,170 deaths in 2012).
• Small prostate cancers are present in 29% of men between ages 30 and 40 and 64% of men between ages 60 and 70.
• The lifetime risk of a prostate cancer diagnosis is 1 in 6, and the risk of dying from prostate cancer is 1 in 35.
• Age, family history, diet and lifestyle, and ethnicity are risk factors for prostate cancer development.
Biological Characteristics
• Germline mutations in RNASEL and MSR1, encoding proteins that function in host responses to infection, appear responsible for some cases of hereditary prostate cancer.
• An inflammatory lesion, termed proliferative inflammatory atrophy (PIA), is an early precursor to prostate cancer.
• Somatic inactivation of GSTP1, encoding a carcinogen-detoxification enzyme, may initiate prostatic carcinogenesis by increasing the vulnerability of prostate cells to damage mediated by oxidant and electrophilic carcinogens.
• Gene fusions, involving TMPRSS2 and ETS family transcription factor genes, may contribute to the androgen dependence of prostate cancers.
• Defects in the functions of NKX3.1, PTEN, and CDKN1B are common in prostate cancer cells.
Screening, Diagnosis, and Staging
• Prostate cancer screening using specific antigen (PSA) testing reduces the risk of prostate cancer death but may also lead to overdiagnosis of non-life-threatening disease.
• Transrectal ultrasound (TRUS)-guided core needle biopsies are used to diagnose prostate cancer.
• Stage, histologic grade (Gleason score), and serum PSA levels are prognostic factors.
Primary Therapy
• Management options include observational strategies (watchful waiting and active surveillance), anatomic radical prostatectomy (with or without robot-assisted laparoscopic techniques), external beam radiation therapy, and brachytherapy.
• A progressive rise in the serum PSA after treatment indicates prostate cancer recurrence.
• Depending on the approach used, side effects associated with treatment of localized prostate cancer can include urinary, bowel, and sexual dysfunction.
• Salvage therapy for prostate cancer recurrences after initial treatment include external radiation after surgery, or include surgery, brachytherapy, or cryosurgery after external beam radiation.
Treatment of Advanced Disease
• Androgen suppression, most often accomplished via the use of luteinizing hormone–releasing hormone (LHRH) analogs or antagonists, with or without antiandrogens, is the most commonly used treatment.
• Side effects can include loss of libido, hot flashes, gynecomastia, loss of lean muscle mass and bone density, and the development of metabolic syndrome.
• Docetaxel and cabazitaxel chemotherapy improves the survival of men with progressive androgen-independent prostate cancer.
• Second-line treatments targeting the androgen-signaling pathway, including abiraterone acetate and enzalutamide, prolong survival of men previously treated with androgen suppression and taxane chemotherapy.
• Bisphosphonates and denosumab antagonize loss of bone density accompanying androgen deprivation, and reduce skeletal complications associated with metastatic prostate cancer progression.
• Sipuleucel-T, a dendritic cell vaccine, has shown a survival benefit in men with advanced prostate cancer. Other immunotherapies are under development in clinical trials.
1. A 73-year-old man with a serum PSA of 5.6 ng/mL and a history of hypertension and diabetes was subjected to transrectal ultrasound (TRUS)–guided prostate biopsy. Of 12 biopsy cores, prostate adenocarcinoma, Gleason 3 + 3 = 6, was seen in <50% of only one of the cores. Treatment options for this man should include
A External beam radiation therapy, given using an intensity-modulated radiation therapy (IMRT) approach, and androgen deprivation therapy (ADT)
C Radical prostatectomy, using robot-assistance, followed by adjuvant radiation therapy
2. A 61-year-old healthy man with no urinary symptoms has a serum PSA of 3.8 ng/mL and an unremarkable digital rectal examination (DRE). His PSA 1 year previously was 2.2 ng/mL, and a PSA test from 3 years ago was 0.7 ng/mL. Further evaluation should include
A Whole body 18FDG-PET/CT scan
B Treatment with dutasteride to determine whether the serum PSA falls
C Trans-rectal ultrasound (TRUS) with 12-core prostate biopsies
3. A 68-year-old man develops an asymptomatic rising serum PSA first detected 6 years after a radical prostatectomy for Gleason 3 + 4 = 7 prostate cancer. Imaging studies were without evidence for distant metastases. Watched for an additional 3 years, the PSA doubling time was estimated at 20 months and repeat imaging was without interval appearance of metastatic lesions. Appropriate treatment options include
4. A 57-year-old man with recurrent prostate cancer after a radical prostatectomy, complicated by bone and soft tissue metastases, suffers with cancer progression despite treatment with an LHRH analog and denosumab, manifest as a rising serum PSA, an increase in the size of measurable metastases, and the emergence of bone pain in the right pelvic region. Reasonable treatment options at this point include
5. A 72-year-old man with a serum PSA of 4.2 ng/mL presents after two sets of transrectal ultrasound (TRUS)–guided 12-core biopsies with findings of high-grade prostatic intraepithelial neoplasia (HG-PIN) on 2 of the cores collected a the second biopsy procedure. Treatment options should include
1. Answer: D. Low-risk prostate cancer in an elderly man with significant risk factors for cardiovascular disease may best be approached via an active surveillance approach.
2. Answer: C. A rise in the serum PSA from 0.7 to 2.2 ng/mL and then to 3.8 ng/mL, consistent with a PSA velocity > 0.75 ng/mL-year, should alert the physician to the possibility of prostate cancer. A prostate biopsy is needed to make the diagnosis, and to provide a Gleason score that can be used to direct further evaluation and treatment.
3. Answer: A. A rising serum PSA after a radical prostatectomy, in the absence of symptoms attributable to metastatic disease progression, with a PSA doubling time ≥15.0 months, pathological Gleason score ≤7, and time from prostatectomy to PSA recurrence >3 years portend a low probability of symptomatic metastatic progression. In this setting, the best course of action may be to avoid hormonal therapy until or if needed.
4. Answer: D. For symptomatic prostate cancer progression despite LHRH analog treatment, with bone pain, palliative radiation therapy, docetaxel chemotherapy, and abiraterone acetate are all reasonable treatment options.
5. Answer: E. HG-PIN is not an indication for treatment of any kind.
