I. What every physician needs to know.

Prostate cancer, an adenocarcinoma, is the second most common cause of cancer deaths among men, as well as the most common solid tumor in men, overall. In the past, serial serum PSAs and DREs were used as screening, but recently these tests have become controversial.

Diagnosis is based on prostate biopsy. Prognosis is multifactorial – dependent on the histological Gleason Score, serum PSA, and the clinical staging – categorizing localized cancer patients as low-, intermediate-, or high risk. The cure rates for localized prostate cancer range from 30-70% with appropriate therapy and 5-year survival rates are around 100%.

Androgen deprivation is the best initial therapy for metastatic prostate cancer. Most men develop resistance within 48 months, known as “castration-resistant” prostate cancer. Combination hormone and Docetaxel therapy is being considered as a treatment option as well. The next line of therapy consists of chemotherapy, immunotherapy, or androgen-modulation. Castration-resistant bone metastases can be treated with zoledronic acid and denosumab, a RANK-ligand inhibitor.

II. Diagnostic Confirmation: Are you sure your patient has prostate carcinoma?

A 12-core ultrasound or MRI guided prostate biopsy, performed by a urologist, is needed for the diagnosis of prostate cancer. After the diagnosis is made, the following is needed for appropriate staging of intermediate and high risk patients:

Computed tomography (CT) abdomen/pelvis with iv contrast or magnetic resonance imaging (MRI).
Bone scan.

A. History Part I: Pattern Recognition:

Most men with localized prostate cancer are asymptomatic, and are discovered after an abnormal DRE or an elevated serum PSA.

Men with prostate cancer may have their presentation masked with overlying benign prostate hyperplasia (such as urinary urgency/frequency, weak stream, and incomplete voiding), others may have dysuria, UTIs, or pelvic pain. Metastatic prostate cancer may present with acute kidney injury secondary to obstructive uropathy, lower extremity edema, bone pain, weight loss or spinal cord compression.

B. History Part 2: Prevalence:

Advancing age: Incidence in men age 65-75 is 35%, age 55-64 is 30%, age 45-54 is 10%, and age 35-44 is 1%.
In 2014, 233,000 new cases of prostate cancer were diagnosed and 29,480 prostate cancer related deaths were noted.
Family History: Men with a 1st-degree relative are two-times likely to develop prostate cancer, and men with two 1st-degree relatives are five-times likely.
Race: Highest worldwide incidence in African Americans. African-Americans have higher mortality and are diagnosed at a younger age than Caucasians.
Geographical: The highest risk for prostate cancer occurs in Scandinavia, while the United States and Europe have intermediate risk, and the risk for prostate cancer is lowest in Asia though risk in Asian men who immigrate to US increases to that of US men.

Genetic and environmental factors have been linked to prostate cancer. The HPC-1 gene on Chromosome 1 has been associated with familial prostate cancer. Environmental factors that render an increased risk include prostatitis, STDs, Western diet and androgens. Vitamin D may have a protective effect. Finasteride (PCPT Trial) and dutasteride (REDUCE Trial) have been shown to reduce rates of low-grade prostate cancer compared to placebo. These drugs cause erectile dysfunction and reduce PSA levels, but they have not been FDA approved for cancer prevention. Trials of Vitamin E and selenium showed no preventative benefit.

C. History Part 3: Competing diagnoses that can mimic prostate carcinoma.

Since the symptoms of prostate cancer over lap benign prostatic hyperplasia, it can be mistaken as prostate cancer. Prostatitis, BPH, recent transurethral catheterization, and a DRE can elevate serum PSA. Metastatic Paget Disease and other causes of pelvic adenopathy such as lymphoma should be considered.

Most commonly prostate cancer is adenocarcinoma, but can develop into other histopathological types, including transitional carcinoma, neuroendocrine carcinoma, small-cell carcinoma, signet-ring carcinoma, squamous cell carcinoma, as well as a sarcoma of the prostate.

D. Physical Examination Findings.

Digital rectal examination may reveal an abnormal prostate gland. Commonly, the gland may be hard and may have nodular characteristics or reveal a large tumor, which may be unilateral or bilateral. Due to anatomic limitations, anterior prostate tumors may be difficult to palpate by DRE.

E. What diagnostic tests should be performed?

Prostate biopsy. The only diagnostic test is the 12-core prostate gland biopsy. The biopsy is key for determining histological grading, which is used for risk stratifying and prognosis. Prostate cancer is heterogeneous in nature. The Gleason Score is reflected as two numbers – the first being the most prevalent tumor grade and the second being the second most common tumor grade. The sum of the tumor grades represents the overall Gleason Score.
Serum PSA. A serum PSA may be obtained for screening, appropriate staging of prostate cancer and to risk stratify for recurrence and remission. There has been controversy about utilization of PSA as a screening test especially in men younger than 55 years who are not high risk. The concern is over diagnosis and overtreatment of clinically unimportant prostate cancers. Hence, patient’s age, risk factors to develop prostate cancer, overall health and life expectancy, and patient preferences should be considered. The American Urological Association does not recommend screening in men >75 years or those with life expectancy of <10-15 years.
Clinical Stage. Determined by DRE or imaging, the stage is based upon how much of the prostate gland represents tumor. Local prostate cancer is staged T1-T3a. Stage T3b-T4, as well as pelvic lymph node involvement (N1) is considered locally advanced disease. Prostate cancer is considered metastatic when bone, visceral organs, or lymph nodes outside of the pelvis are involved.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Serum PSA can be utilized though remains controversial as described above. Usually serum PSA 4.0-10.0 ng/mL is concerning and may need further screening prior to biopsy. These patients should be sent to an urologist and have a repeat PSA to confirm. Note that PSA can be abnormally elevated BPH, prostatitis or after a recent DRE.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

No further imaging is required to establish the diagnosis. A Transrectal Ultrasound is primarily used to guide prostate biopsy.

The following imaging studies should be obtained when appropriate after the diagnosis of prostate cancer to evaluate extent of tumor, to reveal lymph node involvement, or uncover metastatic disease.

Bone scan – A technetium-99 radionucleotide bone scan should be considered for any patient with symptoms of bone involvement, a serum PSA > 20ng/mL, T2 stage and PSA >10 ng/mL, a Gleason Score of >8, or a clinical stage of T3-T4. Metastatic bone lesions are typically blastic in nature.
CT – A CT scan of the chest/abdomen/pelvis with IV contrast should be considered for patients with clinical stage T3-T4, or high concern for lymph node metastases.
MRI – Multiparametric MRI is being utilized to guide biopsies and to determine extent of local disease. MRI may be preferred for those patients unable to obtain a CT with IV contrast.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

PET scan is not recommended for staging or monitoring of prostate cancer.

ProstaScint, visualization of a monoclonal antibody to prostate specific membrane antigen by single photon emission CT, is not routinely recommended due to the high rates of false-positives and false-negatives. It has limited utility in detection of occult mets after prostatectomy.

III. Default Management.

A. Immediate management.

The most common emergent situations caused by prostate cancer are due to obstruction of the genitourinary tract; if prostate cancer is metastatic (usually involving the bone) malignant hypercalcemia or compression of the spinal cord can occur.

Malignant hypercalcemia: Patients may present with altered mentation or weakness. When hypercalcemia is confirmed, administration of IV fluids should begin, as well as an IV bisphosphonate (e.g. zoledronic acid) and subcutaneous or intramuscular calcitonin. Since the patient is at high risk for cardiac arrhythmias, ICU monitoring and telemetry is warranted.

Spinal cord compression: Patients may present with focal weakness, decrease in sensation, or incontinence. Complete a full neural examination including checking for saddle anesthesia and rectal tone. If compression is suspected administer IV steroids, obtain confirmatory imaging and consult neurosurgery and/or radiation oncology for definite management of decompression.

Genitourinary obstruction: Large prostate tumors, in addition to prostate cancer with concurrent BPH, can completely obstruct the bladder. A transurethral or suprapubic catheter should be placed to free the obstruction. Also, the tumor, or enlarged lymph nodes, may obstruct the ureters causing unilateral or bilateral hydronephrosis or hydroureter. In the setting of decreased urine output and possible acute kidney injury, a renal ultrasound should be obtained. If unable to relieve the obstruction, percutaneous external nephrostomy tubes may need placement by an interventional radiologist or urologist.

B. Physical Examination Tips to Guide Management.

Currently, there are no physical exams that are useful in the acute management of prostate cancer. For the chronic management of prostate cancer, regular DREs are recommended, which should be followed by the outpatient oncologist or urologist.

For a patient with urinary obstruction, urine output should be monitored for outflow return after catheterization, or for decrease, a sign of worsening renal function.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

No laboratory tests are recommended for prostate cancer and the acute response to therapy. During active surveillance or after surgery or radiation, serum PSA is monitored every 6-12 months and DRE every year to monitor remission and recurrence. If rising PSA is noted, a CT of the abdomen/pelvis should be obtained. If patient has new bone pain a bone scan should be performed.

In the setting of malignant hypercalcemia, serial calcium levels should be obtained to monitor adequate response to therapy.

D. Long-term management.

Management of Localized prostate cancer:

Categorized as low, intermediate and high risk which helps determine management:

Low risk: PSA < 10 ng/mL, and Gleason score 6, and clinical stage T1-T2a.

Low Risk: active surveillance (serum PSA every 6 months, plus DREs and repeat prostate biopsies every 12 months), Radical prostatectomy, brachytherapy, or external beam radiation therapy (EBRT). Studies have shown equivalent outcomes in remission and recurrence for all definite therapies. There have been recent advances to the radiation techniques leading to fewer bowel, bladder, and erectile dysfunction. Surgical candidates may undergo nerve sparing techniques leading to less erectile dysfunction.
Intermediate risk: a single feature of PSA 10-20ng/mL, or Gleason sum 7, or clinical stage T2b.

Intermediate Risk: Radical prostatectomy with pelvic lymph node dissection, brachytherapy, or EBRT plus 6 months of androgen deprivation therapy (ADT), consisting of a LHRH agonist (e.g., leuprolide) plus an anti-androgen (e.g., bicalutamide).
High risk: either PSA > 20 ng/mL, or Gleason score 8-10, or clinical stage T3a. High Risk: Radical prostatectomy with extended pelvic lymph node dissection, brachytherapy, or EBRT plus 2 years of ADT is more favorable than prostatectomy. Patients with only a few positive cores may be appropriate for prostatectomy but should also receive extended pelvic lymph node dissection. Prostatectomy patients should be counselled on multi-modal treatment because of the benefit from adjuvant radiation if positive surgical margins or seminal vesicle involvement is found.

Management of Locally Advanced Prostate Cancer:

External beam radiation with concurrent ADT for 2-3 years and radical prostatectomy with pelvic lymph node dissection for stage T3 without fixation to adjacent organs. If the patient is not a candidate for definitive local therapy, ADT alone is most appropriate.

N1 Lymph Node Positive: Radiation with immediate long-term ADT is most appropriate to improve 5-year and 10-year survival rates.

Management of Metastatic Prostate cancer:

Immediate ADT (benefit is equivalent to surgical castration) regimen including a LHRH antagonist plus an anti-androgen drug – the goal testosterone level is <50 ng/dL. An additional LHRH antagonist may be considered if the PSA rises. Surgical orchiectomy is a viable option to ADT.

Management of Metastatic Castration-Resistant: Depending on symptoms, treatment options include combination chemotherapy, immunotherapy, as well as hormonal therapy. Palliative relief from bone metastases is usually the goal of therapy, which can be accomplished with denosumab, a RANK ligand inhibitor, or zoledronic acid (the only bisphosphonate recommended) to suppress osteoclast activity.

After primary therapy (prostatectomy, brachytherapy or EBRT +/- ADT), serum PSA should be monitored every 3 months during the first year, then every 6 months during the second year, then annually – serum PSA should become undetectable after 4-8 weeks after prostatectomy and up to 12 months after radiation.

After radical prostatectomy, recurrence is defined as >.2 ng/mL. The “Phoenix Criteria,” according to the American Society for Therapeutic Radiology and Oncology define recurrence after radiation as the nadir PSA level plus 2 ng/mL.

E. Common Pitfalls and Side-Effects of Management.

The most common side-effects of both radical prostatectomy and radiation therapy are erectile dysfunction and bladder incontinence. Additional side effects from radiation therapy include diarrhea and rectal irritation, though newer techniques of radiation have reduced the side effect profile while increasing radiation dosages to the target site. Advances in surgical technique, such as nerve-sparring and robot assistance, have decreased the incidence of erectile dysfunction.

Metastatic prostate cancer is commonly complicated by involvement of the bone, including pathological fractures, bone pain, hypercalcemia, and spinal cord compression. Common side effects of zoledronic acid and denosumab are fatigue, myalgias, fever, anemia, elevated serum creatinine, hypocalcemia, hypophosphatemia and osteonecrosis of the jaw. Most metastatic prostate cancer will become castration resistant within 2 years and is invariably fatal.

Though most patients do not received chemotherapy, ADT is not completely benign. Patients can expect flushing, night sweats, fatigue, weakness, decreased libido, erectile dysfunction, and weight gain. Over time, patients may develop hypertension, dyslipidemia, insulin resistance, metabolic syndrome, osteopenia/osteoporosis, and are at increased risk for clinical bone fractures, cardiovascular events, and cerebrovascular events.

Patients on ADT should receive vitamin D and calcium supplements, and if osteopenia/osteoporosis develops, then a bisphosphonate should be initiated.

IV. Management with Co-Morbidities.

A. Renal Insufficiency.

Zoledronic acid should be dosed according to creatinine clearance.

B. Liver Insufficiency.

The anti-androgens nilutamide, flutamide, and bicalutamide should be avoided in moderate to severe impairment.

C. Systolic and Diastolic Heart Failure.

ADT increases risk of hospitalization and death from heart failure.

No change in standard management defined.

D. Coronary Artery Disease or Peripheral Vascular Disease.

ADT increases risk of myocardial infarction, coronary disease incidence, and risk of cardiac death.

No change in standard management defined.