Prostate Cancer

Prostate Adenocarcinoma

What every physician needs to know:

Prostate adenocarcinoma is the most common non-cutaneous cancer and the second leading cause of cancer death in men in the US, with an annual incidence of over 200,000 cases per year and an annual mortality of over 30,000 deaths per year.

Screening for prostate cancer (using digital rectal exam, and PSA) is controversial. While a large European randomized trial showed a decreased risk of prostate cancer mortality in men receiving PSA screening approximately once every 4 years, a US randomized trial did not demonstrate a reduction in prostate cancer mortality in men undergoing annual screening with digital rectal exam and PSA measurement.

Two agents (finasteride and dutasteride; both 5α-reductase inhibitors) have been shown to reduce the incidence of prostate cancer in placebo-controlled randomized trials. However, these drugs were not approved by the FDA for prostate cancer chemoprevention, due to concerns about toxicities as well as an increased detection of high-grade prostate cancers in men taking the 5α-reductase inhibitors.

Localized prostate cancer is curable in 30-70% of patients with appropriate local therapy. Selection of the optimal local therapy is guided by the clinical stage (determined by digital rectal exam), the Gleason score, and the serum PSA level. These parameters can be used to classify patients as having low-risk, intermediate-risk, or high-risk localized prostate cancer.

In men with recurrent prostate cancer after maximal local therapy as evidenced by a rising PSA alone without radiographic evidence of distant metastases, time to metastatic progression and overall survival may be prolonged and are most strongly influenced by the PSA doubling time. Management of these patients with biochemical recurrence is controversial and includes observation, androgen deprivation therapy, and clinical trial participation.

In men with metastatic prostate cancer, androgen deprivation therapy (ADT) is the most effective initial treatment, although a recent trial has demonstrated improved survival with the addition of docetaxel chemotherapy to ADT, particularly in men with high-volume disease. Nevertheless, most men develop resistance to androgen suppression within 12-48 months (median 18 months). When this occurs, the disease transforms to a new state known as castration-resistant prostate cancer, which is invariably fatal.

There are six FDA-approved treatment modalities for metastatic castration-resistant prostate cancer (mCRPC) that have resulted in survival improvements in such patients. These include two chemotherapy drugs (docetaxel and cabazitaxel), one therapeutic vaccine (sipuleucel-T), one radiopharmaceutical (radium-223 dichloride), and two androgen-modulating drugs (abiraterone and enzalutamide).

In patients with castration-resistant bone metastases, two osteoclast-inhibiting agents have gained FDA-approval for the prevention of skeletal related events: the bisphosphonate agent zoledronic acid, and the receptor activator of nuclear-factor kappa-B (RANK) ligand inhibitor denosumab.

Are you sure your patient has prostate cancer? What should you expect to find?

The majority of men with localized prostate cancer do not have any symptoms, and are often diagnosed from an abnormal digital rectal exam or elevated serum PSA level.

The other possible presenting symptoms in patients with localized prostate cancer can overlap considerably with those associated with benign prostatic hypertrophy (and are often caused by BPH rather than prostate cancer). These include urinary urgency, urinary frequency, weak urinary stream, urinary outflow obstruction, hematuria, dysuria, irritative voiding symptoms, urinary tract infections, or pelvic pain.

Men with more advanced disease who have bulky pelvic lymph node metastases may present with hydroureter/hydronephrosis, or lower extremity edema.

Men with bony metastases often present with bone pain, or rarely may present with signs and symptoms of spinal cord compression (lower extremity weakness, sensory loss, paralysis).

The diagnosis of prostate cancer is usually confirmed with a 12-core biopsy, most commonly performed using a transrectal approach with ultrasound guidance. This is usually performed by a urologist. At least 6 biopsy cores should be obtained from each prostate lobe (right and left).

Beware of other conditions that can mimic prostate cancer:

Prostate adenocarcinoma is by far the most common type of prostate cancer histology, and most of the information contained in this chapter relates to this histology. However, there are other rare cancer histologies that can be found in the setting of a prostate mass/enlargement.

These other unusual histologies include transitional carcinoma of the prostate, neuroendocrine carcinoma of the prostate, small-cell carcinoma of the prostate, signet-ring carcinoma of the prostate, squamous cell carcinoma of the prostate, and sarcomas of the prostate. These histologies portend a much poorer prognosis, and often require different treatment.

Cancers may also arise in other adjacent sites and invade into the prostate gland, mimicking conventional prostate adenocarcinoma. Examples of this include urothelial carcinoma of the prostatic urethra which invade into the prostate gland. Distant metastases to the prostate gland are extremely rare.

In addition, there are several types of prostate adenocarcinoma variants. The usual type of prostate adenocarcinoma is acinar adenocarcinoma which arises in the prostatic acini. Other adenocarcinoma histologies include ductal adenocarcinoma (which occurs in the major ducts and often projects into the urethra), and mucinous adenocarcinoma (which secretes abundant mucin). Although these adenocarcinoma variants are not necessarily treated differently from conventional acinar prostate adenocarcinoma, they usually portend an inferior prognosis.

If a patient presents with bone metastases with an occult primary tumor, evaluation of serum PSA may be helpful to aid in the diagnosis. In men, other cancers that may present with bone metastases include lung cancer, thyroid cancer, kidney cancer, and multiple myeloma.

One distinguishing feature between these other cancers and prostate cancer is that prostate cancer usually forms osteoblastic (rather than osteolytic) bone metastases. The diagnosis can be confirmed by a bone biopsy, and pathological material should be stained for PSA, Prostate-specific acid phosphatase (PSAP), and racemase. Alternatively, a prostate gland biopsy (which may be easier to obtain) may be taken.

Which individuals are most at risk for developing prostate cancer? Is there a role for prostate cancer screening?

Age

The risk of developing prostate cancer increases with advancing age. The incidence of prostate cancer in men aged 35-44 is 1%; the incidence in men aged 45-54 is 10%; the incidence in men aged 55-64 is 30%; and the incidence in men aged 65-75 is 35%.

Demography

The risk of prostate cancer is highest in Scandinavia, intermediate in the US and Europe, and lowest in east Asia. African-Americans are affected 30% more often than Caucasians, and are diagnosed at younger ages. Corrected for stage, African-Americans may possibly have higher mortality rates from prostate cancer.

Family history

Men with a first-degree relative (father, brother, or son) with prostate cancer have a two-fold increased risk of developing prostate cancer in their lifetime. Patients with 2 first-degree relatives with prostate cancer have a five-fold increased risk of developing prostate cancer.

Inherited DNA repair gene mutations

It is now appreciated that presence of a germline DNA repair gene mutation (particularly in the BRCA1, BRCA2 and ATM genes) is associated with an increased risk of both localized and metastatic prostate cancer. In a recent study, it was suggested that 12% of men with metastatic disease harbor a germline mutation in a DNA repair gene, compared to 5% among men with localized prostate cancer, and only 2% in the general population. The chance of harboring a germline DNA repair gene mutation increased further in men with a positive family history of prostate, breast, ovarian or colorectal cancers.

Dietary factors

The link between dietary factors and prostate cancer risk is controversial. Studies indicate that progression of prostate cancer may be more closely linked with dietary factors than prostate cancer initiation/incidence. For example, African-Americans, low consumption of tomato products (which contain lycopene) and high consumption of alpha-linolenic acid (found in vegetable oils, soybeans and walnuts) have been associated with higher incidence of prostate cancer.

Body mass index, low consumption of tomato sauce, high calcium intake, and high alpha-linolenic acid intake have all been associated with more advanced prostate cancer and prostate cancer progression. Eating cruciferous vegetables (broccoli, cauliflower, cole slaw, sauerkraut) may reduce the risk of advanced prostate cancer.

Sexual activity

One large prospective study of almost 30,000 men showed an association between high ejaculatory frequency (>21 ejaculations per month) and a decreased risk of prostate cancer. However, in that same study, there was no associated increased risk of prostate cancer for men with the lowest ejaculatory frequency category.

Retroviruses

Recent data have implicated a retrovirus called XMRV in prostate cancer genesis. Expression of this virus in the prostate, or presence of viral DNA or protein in the prostate, has been linked with high-grade tumors. Further confirmation of these findings is required before a viral etiology can be attributed to aggressive prostate cancer.

Inflammation

Chronic prostatic inflammation has been linked with high-grade disease. Several cohort studies and a meta-analysis have suggested a protective effect of daily aspirin intake on the risk of prostate cancer. In addition, statin drugs (HMG-CoA reductase inhibitors) may be associated with a reduction in the risk of high-grade prostate cancer. However, aspirin and statins are not used clinically for prostate cancer chemoprevention.

5α-reductase inhibitors

Two prospective randomized trials have shown a 20-25% risk reduction in prostate cancer incidence in men who were randomized to receive either daily finasteride or daily dutasteride compared to placebo. However, the use of finasteride and dutasteride as chemopreventive agents is not universally accepted, and the FDA has recently declined to approve either of these drugs as prostate cancer prevention agents.

Although both of these drugs appeared to decrease the incidence of low-grade prostate cancers, they seemed to have little impact on high-grade tumors (with a possible increased detection rate of high-grade tumors in patients taking dutasteride). Also, concerns over adverse events such as erectile dysfunction as well as reductions in PSA levels with these drugs have limited their generalized acceptance as chemopreventive agents.

Prostate cancer screening

Screening with PSA and DRE is controversial. Although screening results in increased prostate cancer detection and a stage migration towards earlier diagnosis, its effect on prostate cancer mortality is uncertain. Two large randomized trials have recently examined the role of prostate cancer screening on cause-specific mortality.

In the American (PLCO) trial that randomized 77,000 men to annual PSA and DRE or standard practice, prostate cancer was more commonly detected in the screened group but there was no appreciable difference in prostate-specific mortality between the groups after 7 years of follow-up.

However, in the European (ERSPC) trial that randomized 182,000 men to PSA screening at various intervals versus no screening, a 21% reduction in the risk of prostate cancer deaths was observed in the screened population after 13 years of follow-up. In that study, the number needed to screen to prevent one prostate cancer death was 781 men, and the number needed to treat with local therapy to prevent one cancer death was 27 men.

Based on these and other randomized studies, several screening guidelines have been formulated:

American Urological Association (AUA) guidelines

Men under the age of 40 should not be screened.

Men between the ages of 40 and 54 years at average risk should not be routinely screened; however, those at higher risk (e.g., positive family history or African American race) should have an individualized screening decision.

Men between the ages of 55 and 69 years should consider PSA screening based on personal values and preferences.

A routine screening interval of two or more years may be preferred over annual screening; however, intervals can be individualized based on baseline PSA level.

Men over the age of 70 years or those with less than a 10-15 year life expectancy should not have PSA screening, although some men over the age of 70 years in excellent health may consider screening.

American Cancer Society (ACS) guidelines

The ACS has now de-emphasized mass prostate cancer screening programs, while recommending a discussion of the pros and cons of PSA testing based on individual risk.

National Comprehensive Cancer Center (NCCN) guidelines

The NCCN has also adopted an individualized risk assessment model, stressing an informed discussion with patients about the advantages and disadvantages of screening starting at age 45 years. Annual to biannual testing in those with a PSA above the age-specific median (0.7 ng/mL for men age 40-49 years and 0.9 ng/mL for men age 50-59 years) is recommended, while a retest at age 50 is recommended for those below the median. Annual to biannual testing is recommended for all men with a PSA of more than 1.0 ng/mL.

U.S. Preventive Services Task Force (USPSTF) recommendations

The USPSTF recommends against PSA-based screening for prostate cancer regardless of age.

What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

Determining the initial treatment approach for prostate cancer depends on accurate classification into different risk-groups based on 3 diagnostic parameters:

• PSA level

• clinical stage

• Gleason score

Combinations of these 3 parameters allow classification of patients into high-risk, intermediate-risk, low-risk (and very low-risk) groups.

PSA level

A peripheral blood sample for measurement of serum total PSA should be performed in all patients. Knowing the prior history of PSA values may also help to determine the rate of change of PSA over time.

Gleason score

This is determined by a pathologist from prostate biopsy tissue. Before the selection of primary therapy, patients should undergo a 12-core transrectal ultrasound-guided prostate biopsy. The Gleason score is a measure of the tumor grade (degree of differentiation). Each biopsy core is evaluated for the presence (or absence) of cancer, and is then assigned a primary and secondary Gleason score if cancer is present.

The primary Gleason score (ranging from 1-5) reflects the tumor grade/differentiation which is the most prevalent in that biopsy specimen. The secondary Gleason score (also ranging from 1-5) reflects the tumor grade/differentiation that is the second most prevalent pattern.

The Gleason sum (ranging from 2-10: higher scores portend a more aggressive phenotype) is the most informative aspect of the Gleason score, and guides prognosis and treatment. If multiple biopsy cores are assigned a Gleason sum, the highest Gleason score should be used for determining prognosis and treatment options.

Risk stratification

Risk stratification (i.e. likelihood of cancer recurrence or persistence after appropriate local therapy) of localized prostate cancer based on PSA level, clinical stage, and Gleason sum. Risk of recurrence/persistence in each group respectively is: 1-2%; 5-10%; 15-20%; 30-40%.

• Very low-risk (1-2% risk of persistence/recurrence): PSA <10 ng/mL and Gleason sum <6, and clinical stage T1, and <2 positive cores (each with ≤50% cancer).

• Low-risk (5-10% risk of persistence/recurrence): PSA <10 ng/mL and Gleason sum <6, and clinical stage T1-T2a.

• Intermediate-risk (15-20% risk of persistence/recurrence): PSA 10-20 ng/mL or Gleason sum 7, or clinical stage T2b-T2c (2 or more of these features constitutes high-risk).

• High-risk (30-40% risk of persistence/recurrence): PSA >20 ng/mL or Gleason sum 8-10, or clinical stage T3a.

Locally advanced disease

Patients are considered to have locally advanced (as opposed to localized) prostate cancer if they have:

• Clinical stage T3b-T4: these patients are at very high risk of relapse after local therapy.

• Involvement of pelvic lymph nodes (N1 disease): these patients are sometimes considered to have metastatic disease.

Metastatic disease

Patients are considered to have distant metastatic disease (M1) if they have:

• Involvement of lymph node groups outside of the pelvis (e.g. retroperitoneal, inguinal, mediastinal, axillary lymph nodes).

• Involvement of bone or visceral sites (e.g. liver, lung).

Imaging studies

• Bone scan: Obtaining a radionuclide (technetium-99) bone scan should be considered in patients with PSA over 20 ng/mL, in patients with clinical stage T2 and PSA over 10 ng/mL, in patients with Gleason sum 8-10, and in patients with clinical stage T3-T4, or in those with symptoms.

• CT scan: Obtaining a CT scan of the chest/abdomen/pelvis with intravenous iodinated contrast should be considered in patients with clinical stage T3-T4, and in patients with a predicted risk of lymph node metastases above 20% (based on Partin Tables).

• MRI scan: Obtaining a pelvic MRI or dedicated prostate MRI may be considered in patients with clinical stage T3-T4. An MRI evaluation may be useful in confirming extraprostatic tumor extension, demonstrating presence or absence of seminal vesicle invasion, and evaluating pelvic lymph nodes for any suspicious features that may suggest lymph node involvement.

• PET scan: The use of PET imaging for the staging or monitoring of prostate cancer is not recommended.

• The use of ProstaScint scans is no longer generally recommended, due to unacceptably high false-positive and false-negative rates.

Molecular studies

Investigators are currently exploring the role of a novel fusion protein called TMPRSS2:ETS both as a diagnostic and prognostic biomarker. This fusion gene is found in up to 60% of primary prostate cancers. The fusion protein in regulated by androgens, directs transcriptional activity of DNA, activates oncogenic signals, and is not present in benign (non-malignant) prostate tissue. The utility of this fusion protein in guiding staging and prognosis is still undefined at present.

Staging

Clinical stage is determined by performing a digital rectal exam as well as imaging tests (and should not be confused with pathological stage which is determined using the prostatectomy specimen).

Table I. TNM Staging of prostate cancer.

What therapies should you initiate immediately (i.e, emergently)?

There are very few situations in which patients with prostate cancer require immediate or emergent treatment. Some examples are listed below:

Acute urinary obstruction

If patients have large-volume localized prostate cancer (or have prostate cancer in the setting of pre-existing BPH), they may present with complete bladder outflow obstruction caused by an enlarged prostate resulting in external compression of the bladder base or prostatic urethra.

The most important initial management of these patients involves placement of a urinary catheter to relieve the outflow obstruction. If it is impossible to place a trans-urethral catheter due to a severe obstruction, a suprapubic catheter may need to be inserted surgically.

Hydronephrosis

If there is extension of the prostate cancer to the bladder base, or if there are bulky pathological lymph nodes in the pelvis, this may result in unilateral or bilateral hydroureter and/or hydronephrosis.

In rare cases, patients may also demonstrate impaired renal function as manifested by a reduced creatinine clearance. Immediate management options for such patients may involve insertion of percutaneous external nephrostomy tubes (which are usually placed by interventional radiologists). If there is persistent ureteral obstruction, internal ureteric stents may be inserted at a later time (this procedure is often performed cystoscopically by a urologist).

Spinal cord compression

Compression of the spinal cord is an absolute emergency in all of oncology, but occurs more frequently in cancers that may predispose to bone metastases. Spinal cord compression may be caused by pathological compression fracture of a vertebral body, or may be due to epidural soft-tissue extension from a vertebral bone metastasis. Presenting clinical symptoms usually include back pain, lower extremity weakness/paralysis, sensory loss especially in the perineal area, urinary and/or fecal incontinence, or urinary retention.

Emergent management should include intravenous steroid administration (e.g. 16-100 mg dexamethasone bolus dose), followed by subsequent steroid administration every 4-6 hours (e.g. 4-10 mg dexamethasone). Definitive management of spinal cord compression should then ensue, and may involve surgical decompression (often performed by a neurosurgeon or orthopedic spinal surgeon), or external-beam radiation therapy (usually 20 Gy in 5 fractions, or 30 Gy in 10 fractions). Often, surgical decompression may be followed by post-operative external-beam radiation.

Hypercalcemia of malignancy

In patients with widespread bone metastases, malignant hypercalcemia may develop. However, this complication is rare among prostate cancer patients who usually have predominantly osteoblastic (rather than osteolytic) bone metastases. Initial management of malignant hypercalcemia involves fluid hydration (with isotonic sodium chloride solution) and administration of an intravenous bisphosphonate (e.g., zoledronic acid). Sometimes, calcitonin (which is given intramuscularly or subcutaneously) is used, but it becomes less effective after several days of use.

What should the initial definitive therapy for the cancer be?

Very low-risk

• Localized prostate cancer (PSA <10 ng/mL AND Gleason sum ≤6 AND stage T1 AND ≤2 positive cores each with ≤50% cancer)

Active surveillance is rapidly becoming the most popular approach for the management of patients with very-low risk prostate cancer, a disease state that may never result in morbidity or mortality from prostate cancer. This involves actively monitoring the course of the disease with the expectation to intervene if the cancer progresses. Active surveillance is especially attractive for men who have a limited overall life expectancy (<10 to 15 years).

This approach entails the following:

• PSA tests every 6 months

• Digital rectal exams every 12 months

• Repeat prostate biopsies every 1-2 years

Most studies show a less than 5% prostate cancer-specific mortality rate for men in this category who choose initial deferred therapy, particularly in those men with a PSA doubling time of over 3 years. About 25-30% of men in active surveillance cohorts will eventually progress to a higher risk group (due to an increase in PSA, Gleason sum, or clinical stage). However, a recent study demonstrates an increased risk of aggressive disease in African Americans with very-low risk prostate cancer, suggesting that active surveillance may not be a feasible option in this population. Additionally, it is not currently known whether deferred definitive therapy (i.e. radical surgery or radiation) results in inferior outcomes compared to immediate definitive therapy.

Low-risk

• Localized prostate cancer (PSA <10 ng/mL AND Gleason sum ≤6 AND stage T1-T2a)

In these patients, radical prostatectomy and radiation therapy are both excellent initial treatment options, and the choice of primary therapy may depend on patient age, medical comorbidities, complications of each treatment, and patient preferences.

Surgery

Radical prostatectomy is often performed retropubically using a lower midline incision, and in the past was also performed using a perineal approach (which has now become uncommon). Robotic-assisted laparoscopic prostatectomy (RALP) is currently the most common form of prostatectomy performed in the US.

Among the various treatment options for prostate cancer, only radical prostatectomy has been proven to confer a survival advantage over watchful waiting. After a median of 12.8 years of follow-up, a large randomized Swedish trial showed a 30% reduction in the risk of prostate cancer-related deaths in men undergoing radical prostatectomy compared to those undergoing watchful waiting.

Additional randomized studies have shown that the use of neoadjuvant or adjuvant androgen deprivation therapy does not improve progression-free survival, and therefore this approach cannot be routinely recommended.

The main complications of radical prostatectomy include urinary incontinence and erectile dysfunction. Although all men may experience urinary incontinence in the first few weeks or months after prostatectomy, most men do recover urinary control (in experienced centers, >90% of men report minimal or no long-term urinary problems).

The incidence of erectile dysfunction, which ranges between 20-80%, is reduced by performing a nerve-sparing radical prostatectomy, an approach that is most appropriate in men with small-volume disease. In carefully selected patients, the nerve-sparing procedure confers no greater risk of prostate cancer recurrence. Recovery of erectile function after prostatectomy is generally influenced by age (the younger, the better), pre-treatment erectile function (the stronger, the better), and the completeness of the nerve-sparing approach (bilateral sparing is better than unilateral).

Radiation therapy

Radiation therapy is another excellent primary treatment option for men with low-risk localized disease. In such patients, there is no additional benefit (and there might be a harm) from using adjuvant androgen deprivation therapy. The most common side effects with all forms of prostate radiation therapy include urinary incontinence, rectal irritation (diarrhea, bleeding), and erectile dysfunction.

3D conformal radiation therapy

Three-dimensional conformal external beam radiation therapy (EBRT) produces 3D representations of the prostate gland and designs highly tailored treatment portals creating a volume of high radiation dose that conforms to the shape of the prostate. This approach permits the use of radiation doses far higher than tolerable with traditional techniques resulting in fewer bowel and bladder complications. Using 3D conformal EBRT techniques, the optimal total radiation dose appears to be 75-78 Gy (delivered in 40-44 daily fractions of 180 cGy over 7-8 weeks).

Intensity modulated radiation therapy

Another approach known as intensity-modulated radiation therapy (IMRT) is rapidly becoming the modality of choice in academic institutions. This refinement of conformal therapy employs high non-uniform beam intensity and dynamic multileaf collimation to create even more precise dose distributions, permitting further dose escalations with reduced toxicity. With this methodology, radiation doses of 81-86 Gy have been given with minimal adverse events.

Brachytherapy

A third radiation modality includes brachytherapy, also known as interstitial radiotherapy. One advantage of this technique (whereby radioactive seeds are inserted into the prostate gland using a transperineal approach) is that the whole treatment can be administered in a single outpatient visit.

Two radioactive seed isotopes have been used successfully: iodine-125 and palladium-103. Brachytherapy is most appropriately used in patients with low-risk prostate cancer (and selected intermediate-risk patients); significant dose fall-off 2-3mm beyond placement of the seeds within the prostate gland limits the application of this method in patients with potential periprostatic or regional disease extension. Typical doses of 145 Gy for iodine-131 and 125 Gy for palladium-103 are utilized.

Intermediate-risk

• Localized prostate cancer (PSA 10-20 ng/mL OR Gleason sum 7 OR stage T2b-T2c)

In these patients, the most appropriate treatment options include radical prostatectomy with or without pelvic lymph node dissection, or radiation therapy combined with short-term (4-6 months) neoadjuvant/concurrent/adjuvant ADT.

Surgery

In men with intermediate-risk disease undergoing prostatectomy, pelvic lymph node dissection should be considered for those patients with an above 2% predicted probability of lymph node metastases. In addition, these patients may not be as appropriate for nerve-sparing prostatectomy or RALP. Once again, there is no role for neoadjuvant/adjuvant androgen deprivation therapy as an adjunct to prostatectomy.

Radiation therapy

In patients undergoing definitive radiation for intermediate-risk localized prostate cancer, a short course of ADT has been shown to improve outcomes. In theory, there may be some synergy between the apoptotic response induced by ADT and radiation therapy that may result in improved local tumor control. Also, because ADT shrinks the prostate and reduces prostate volume, this may reduce the number of target cancer cells while also allowing for more focused radiation therapy that may spare the rectum and bladder.

These theoretical benefits were borne out in a prospective trial that randomized patients with intermediate-risk disease to EBRT alone (70 Gy) or EBRT given together with 6 months of ADT. In that trial, after a median follow-up of 4.5 years, patients treated with combined EBRT and ADT demonstrated improved progression-free survival, prostate cancer-specific survival, and even overall survival compared to those receiving EBRT alone.

The survival benefit in that study was primarily confined to those men without cardiovascular comorbidities, illustrating the importance of carefully selecting men for combined therapy. These findings have been confirmed by a second study showing an improvement in 8-year survival rates in men receiving radiotherapy plus 4 months of ADT compared to those who received radiation alone.

ADT is most commonly administered in the form of a luteinizing hormone-releasing hormone (LHRH) agonist/antagonist, which may or may not be combined with an oral antiandrogen. Commonly used agents include:

LHRH agonists

• Leuprolide (Lupron) 22.5 mg IM every 3 months

or

• Goserelin (Zoladex) 10.8 mg SC every 3 months

Antiandrogen

• Bicalutamide (Casodex) 50 mg PO daily

High-risk

Localized prostate cancer (PSA >20 ng/mL OR Gleason sum 8-10 OR stage T3a)

In these patients, prostatectomy is generally a less favorable approach (but may be appropriate in selected individuals), and the majority of patients should receive radiation therapy combined with long-term (2-3 years) ADT.

Surgery

Because of the lower chance of achieving a complete surgical resection, and the higher incidence of extra-prostatic disease extension, the use of radical prostatectomy should be reserved for carefully selected patients and those that do not demonstrate signs of prostatic fixation on digital rectal exam. For example, a patient with a single core showing a Gleason score of 8 without any other high-risk features, may be an appropriate candidate for surgery. In these cases, an extended pelvic lymph node dissection is also warranted.

In addition, there are certain circumstances in which adjuvant post-operative radiation therapy may be indicated. To this end, three randomized trials have shown a benefit to early adjuvant radiation therapy in men with positive surgical margins, confirmed seminal vesicle invasion, or pathological extracapsular extension (the adjuvant radiation is usually offered several weeks following prostatectomy, after urinary continence is restored).

With a median follow-up of 12 years, the most mature study conducted by the Southwestern Oncology Group (SWOG) confirmed an improvement in metastasis-free survival and overall survival in such patients that received adjuvant radiation therapy. Other studies have confirmed the progression-free survival benefit of adjuvant radiation but not the overall survival advantage, although follow-up times are shorter. In addition, some studies seem to suggest that the largest benefit from adjuvant radiation may be in men who have a positive surgical margin after prostatectomy.

Radiation therapy

The most common approach for high-risk localized disease is administration of radiation therapy plus long-term neoadjuvant/concurrent/adjuvant androgen suppression. A large randomized study conducted by the Radiation Therapy Oncology Group (RTOG) in high-risk patients has demonstrated a benefit from long-term (2 years) ADT compared with short-term (4 months) ADT when added to radiation therapy in terms of prostate cancer-specific survival and overall survival.

A European Organisation for the Research and Treatment of Cancer (EORTC) trial also showed superior survival when 2.5 years of ADT were added to radiation therapy in patients with high-risk disease. However, there is an increased incidence of cardiovascular complications with long-term androgen ablation, especially in men older than 65 and in those with pre-existing cardiac risk factors.

Finally, additional evidence suggests that the use of ADT alone (without radiation) is insufficient therapy in these patients. This notion is supported by a multicenter randomized European trial enrolling high-risk patients showing that the combination of ADT and radiotherapy resulted in lower 10-year overall mortality and disease-specific mortality rates than seen with ADT alone.

Locally advanced prostate cancer (stage T3b-T4)

Management of patients with locally advanced disease should be performed in the setting of a multidisciplinary urological oncology clinic. Reasonable treatment options include external-beam radiation therapy (with or without brachytherapy) combined with long-term (2-3 years) ADT, radical prostatectomy plus pelvic lymphadenectomy in selected patients without fixation to adjacent organs, or ADT alone (only for men who are not eligible for any definitive local therapy).

Radiation therapy

Two RTOG trials and one EORTC trial provide strong evidence that immediate long-term (2-3 years) ADT in conjunction with external-beam radiation improves outcomes (relapse-free survival; distant metastasis-free survival; cancer-specific survival) compared to radiation therapy used alone in men with locally advanced prostate cancer.

This combination is therefore considered a standard-of-care for these patients. For men with locally-extensive prostate cancer, local failure remains a potential concern after EBRT, prompting investigators to seek alternative means to intensify therapy.

One strategy has been to deliver large fractions of radiotherapy using high-dose-rate (HDR) brachytherapy in combination with EBRT. The large interstitial fractions achieved using this approach deliver a high radiation dose to the prostate but spare normal tissues due to rapid dose fall-off outside the implanted volume.

Importantly, men with locally advanced disease are probably not good candidates for permanent brachytherapy implants (these patients have extracapsular extension and this localized therapy may not offer adequate dosimetric coverage of extraprostatic disease).

Surgery

Radical prostatectomy is only a reasonable option in the minority of patients with locally advanced prostate cancer and should not be offered to men with pelvic fixation of their prostate gland. One of the largest experiences with prostatectomy in this patient population comes from the Mayo Clinic and consists of over 1000 patients presenting with clinical stage T3 disease. In the series, the 15-year cancer-specific survival rate was 77%, and only 21% of patients experienced a local recurrence after prostatectomy. Finally, an extended pelvic lymphadenectomy is recommended in these patients.

Lymph node-positive (N1) disease

Surgery

It has been debatable whether any type of local therapy adds to the overall survival duration in patients with known pelvic lymph node involvement. Until recently, the standard approach had been to perform a frozen-section pathologic analysis on the pelvic lymph nodes recovered at the time of prostatectomy (prior to removal of the prostate), and to abort the procedure if this analysis revealed lymph node micrometastases.

However, some retrospective series from US-based centers have suggested a potential survival benefit in men who underwent radical prostatectomy despite the identification of regional lymph node micrometastases. Therefore, performing a completion prostatectomy in such cases appears to be a reasonable approach.

Studies investigating the benefit of ADT monotherapy in men with positive pelvic lymph nodes have revealed mixed findings. In a small Eastern Cooperative Oncology Group (ECOG) trial, men who had regional nodal metastases discovered during radical prostatectomy were randomly assigned to receive immediate post-operative ADT or to be followed until clinical disease progression.

At a median follow-up of 11.9 years, those receiving immediate ADT demonstrated a significant improvement in overall survival. However, the results of this trial have been called into question, and a meta-analysis conducted by ASCO resulted in a recommendation against immediate ADT for men with pelvic lymphadenopathy. More recently, a non-randomized observational study failed to show a survival benefit of early ADT compared to observation in men with node-positive prostate cancer.

Radiation therapy

There is also compelling data showing that long-term survival in patients with N1 disease may be achieved by combining radiotherapy with androgen deprivation. For example, a subset analysis of an RTOG trial showed that in node-positive patients, immediate androgen suppression plus radiation therapy resulted in 5 and 10-year cause-specific survival rates of 84% and 75% respectively.

In addition, data from the M. D. Anderson Cancer Center showed a benefit to pelvic radiation plus immediate ADT compared with ADT alone. Therefore, combined radiation plus long-term ADT may be a very reasonable option in node-positive men.

What other therapies are helpful for reducing complications?

The most significant and potentially dangerous complications arising in men with prostate cancer are the skeletal-related events (SREs), a constellation of bone complications associated with osseous metastases which include:

• pathological fractures

• severe bone pain

• hypercalcemia of malignancy

• spinal cord compression

• bone complications needing surgical intervention or focal radiation therapy.

SREs are most common in patients who have developed castration-resistant prostate cancer, because these bone metastases no longer respond to androgen-suppressive therapies. In these patients with castration-resistant bone metastases, two drugs have been FDA-approved for the prevention of SREs: the bisphosphonate agent zoledronic acid, and the RANK ligand inhibitor denosumab.

A recent trial demonstrated no benefit in decreasing SREs with zoledronic acid in the hormone-sensitive setting. In general, we administer bisphosphonates or denosumab only to patients with prostate cancer with skeletal metastases that have progressed after hormonal therapies.

Bisphosphonates

Bisphosphonates have become an integral part of the management of metastatic prostate cancer to the bones. These compounds reduce bone resorption by inhibiting osteoclastic activity and proliferation. Zoledronic acid (Zometa) is indicated for the treatment of patients with progressive castration-resistant prostate cancer with evidence of bone metastasis.

Other bisphosphonates have also been evaluated in patients with prostate cancer including pamidronate, alendronate, etidronate, ibandronate, and clodronate. However, their benefit has not been conclusively established in prospective randomized clinical trials and their use is generally not recommended.

Typical dosing of zoledronic acid is listed below:

• Zoledronic acid (Zometa) 4 mg IV every 4 weeks (dose adjustments for renal dysfunction–CrCl 50-60 mL/min: 3.5 mg; CrCl 40-49 mL/min: 3.3 mg; CrCl 30-39 mL/min: 3 mg).

It is recommended that patients take concurrent oral calcium supplements (1200 mg daily) and vitamin D supplements (400-800 units daily).

Side effects of zoledronic acid include fatigue, myalgias, fever, anemia, and mild elevations of serum creatinine. Hypocalcemia has also been described. In addition, dose-reductions are required for patients with impaired creatinine clearance or reduced glomerular filtration rates.

An unusual complication of zoledronate is the development of severe jaw pain associated with osteonecrosis of the mandibular bone. This is most frequently seen in patients undergoing dental work or in those with a history of poor dentition and chronic dental disease. Zoledronate and other bisphosphonates should not be administered to patients with these problems.

Denosumab

Interactions between tumor cells and the bone marrow microenvironment have been postulated as an important mechanism in the pathogenesis of bone metastasis. Tumor-associated cytokines have been shown to induce the expression of RANKL (receptor activator of nuclear-factor kappa-B ligand), which binds and activates RANK found on osteoclasts. Inhibition of RANKL has recently been the focus of much clinical research and represents an effective osteoclast-targeting strategy for patients with castration-resistant bone metastases.

Denosumab (Xgeva) is a fully human monoclonal IgG2 antibody with a very high affinity for human RANKL. In a pivotal multi-center phase III double-blind randomized study comparing denosumab against zoledronate for the prevention of skeletal-related events (SREs) in 1904 patients with bisphosphonate-naïve metastatic CRPC, men receiving denosumab (n=950) had an improved time to first SRE (20.7 vs 17.1 months, representing an 18% reduction in the risk of first SREs). Notably, there was no difference in overall survival or progression-free survival between the study arms.

Common toxicities of denosumab include fatigue, nausea, hypophosphatemia, hypocalcemia, as well as osteonecrosis of the jaw (2%). Therefore, denosumab is a reasonable alternative to zoledronate for prophylaxis against SREs in patients with metastatic CRPC and bone metastases.

One significant advantage of denosumab is that it does not require dose adjustment or monitoring for renal impairment, as does zoledronic acid. In addition, denosumab is given by subcutaneous injection rather than by intravenous infusion, can be administered in a matter of seconds, and does not require venous access. Usual dosing is as follows:

• Denosumab 120 mg SC every 4 weeks.

Palliative radiation therapy and radiopharmaceuticals

External beam radiation therapy is an effective treatment for controlling local pain associated with one or a small number of skeletal metastases. In general, a treatment regimen of 30 Gy delivered over 10 fractions results in rapid and durable local symptom control and may diminish the dependence on analgesics. Single high-dose palliative radiation therapy may provide equal palliation as well. These treatments are usually delivered by radiation oncologists.

In patients who have more extensive bone metastases causing diffuse pain in multiple skeletal sites, alternatives include wide-field irradiation (e.g. hemi-body irradiation) or systemic administration of radioactive bone-targeting radio-isotopes that can deliver therapeutic doses of ionizing radiation to widespread skeletal metastatic disease.

Radiopharmaceuticals used in this fashion include FDA-approved strontium-89 (Metastron), FDA-approved samarium-153 (Quadramet), and radium-223 (Alpharadin). These treatments are usually administered in nuclear medicine departments. Administration parameters are listed below:

• Strontium-89 50 microCuries/kg IV push over 2 minutes.

• Samarium-153 1 milliCurie/kg IV push over 1 minute.

  Both strontium-89 and samarium-153 can be re-administered as required for 1-2 additional doses separated by intervals of at least several weeks.

  The most significant toxicity of both of these agents is myelosuppression, which occurs in 40-60% of patients and may possibly limit the subsequent use of chemotherapy.

• Radium-223 50 kBq/kg (1.35 microCurie/kg) IV push over 1 minute every 4 weeks x 6 months.

What should you tell the patient about prognosis?

Localized prostate cancer

The prognosis for localized prostate cancer is excellent, and depends primarily on the serum PSA level at diagnosis, the clinical stage, and the Gleason grade. The goal of therapy is cure (through surgery and/or radiation), which is achieved in about 30-70% of patients, although outcomes for patients treated by conservative measures are also good. Cancer-specific survival rates for patients receiving optimal local therapy exceed 80% at 20 years. Even in men who are treated conservatively (without attempted curative therapy), 10-year cancer-specific survival rates exceed 90%.

Biochemically-recurrent prostate cancer

Although there are generally no curative therapies for men with biochemically-recurrent prostate cancer after local therapy, outcomes for these patients are also excellent. Prognosis is guided by two main clinical factors: the Gleason score at the time of diagnosis (the higher, the worse), and the PSA doubling time (the lower, the worse). Overall, median metastasis-free survival in these patients is about 10 years, and median overall survival is about 20 years (from the time of biochemical recurrence).

Metastatic prostate cancer

In patients with metastatic prostate cancer, the goals of therapy are palliative and focus on treatment or prevention of pain and other skeletal-related complications. Prognosis is primarily determined by the extent of metastases (the more, the worse), and by the location of metastases (visceral are worse). Overall, median survival with appropriate therapies in these patients is about 5-7 years.

Castration-resistant prostate cancer

In patients with metastatic castration-resistant prostate cancer (CRPC), the goals of therapy are palliative and focus on treatment of bone pain and other skeletal-related complications. CRPC is usually the fatal form of this disease. Prognosis is determined by several factors including PSA level, PSA doubling time, Gleason score, performance status, hemoglobin level, albumin level, alkaline phosphatase level, LDH level, presence of visceral metastases, and presence of pain. Overall, median survival in these patients with maximal therapy is about 2-3 years.

What if scenarios.

Small cell (or neuroendocrine) carcinoma of the prostate

A rare but important disease entity is the small cell histology of prostate cancer. This may arise spontaneously as a primary small-cell carcinoma of the prostate, or may evolve from a conventional prostate adenocarcinoma with a subsequent transformation. Clinically, this histologic entity should be suspected in patients with the following features:

• Rapidly progressing local or distant metastatic disease, especially in patients with pelvic masses.

• Visceral involvement of the liver or lungs.

• Osteolytic (as opposed to osteoblastic) bone metastases.

• Hypercalcemia related to PTHrP.

• Parenchymal brain metastases.

• Serum PSA in these patients undetectable or low/declining despite evidence of rapid disease progression.

• Elevated serum chromogranin-A levels and/or elevated urine serotonin metabolites.

The diagnosis should always be confirmed with a biopsy, which may show neoplastic cells expressing a number of neuroendocrine markers such as synaptophysin, chromogranin-A, serotonin, or somatostatin. These characteristics may be present in a background of conventional prostatic adenocarcinoma, or may occur alone suggestive of a pure small cell/neuroendocrine prostate carcinoma.

Small cell/neuroendocrine carcinoma is largely unresponsive to androgen-suppressive therapies, and its management often mimics that of small-cell carcinoma of the lung. These tumors are highly sensitive to radiation therapy and platinum-etoposide combination chemotherapies, but invariably recur and are usually fatal within 12 months.

If the disease appears to be limited to the pelvis, then a combined-modality approach consisting of doublet chemotherapy (cisplatin and etoposide) plus concurrent external beam radiation therapy provides the best chance of local disease control. In these instances, prophylactic cranial irradiation is also usually recommended.

If the disease is metastatic at presentation (which is often the case), then therapy usually consists of systemic combination chemotherapy used alone. Despite high initial response rates with chemotherapy and radiation treatment, outcomes for men with small cell prostate carcinoma remain poor (progression-free survival of 4-5 months; overall survival of 10-12 months), and clinical trial participation should be strongly encouraged.

Follow-up surveillance and therapy/management of recurrences.

Surveillance after primary therapy

After a patient has undergone primary therapy for localized or locally advanced prostate cancer (with prostatectomy or radiation), surveillance patterns may vary but a reasonable follow-up schedule would be as follows:

• PSA measurements and rectal examinations every 3 months for the first year after primary therapy.

• PSA measurements and rectal examinations every 6 months for the second year.

• PSA measurements and rectal examinations every 12 months thereafter.

Approximately 30-70% of patients will be expected to be cured with optimal local therapies. This is evidenced by a PSA level reaching and remaining at 0 ng/mL (in the case of primary prostatectomy), or a PSA reaching and remaining at a nadir value of 0-2 ng/mL (in the case of primary radiation therapy).

After prostatectomy, PSA nadir occurs by 8 weeks. However, after radiation therapy, PSA nadir may take up to 12 months to occur.

Patients who are cured should never have a subsequent elevation of PSA.

Recurrence after prostatectomy

Some patients who initially develop an undetectable PSA level after prostatectomy subsequently develop a PSA elevation. This clinical state is known as biochemically-recurrent prostate cancer. In some cases, patients may still be capable of achieving a cure with salvage pelvic radiation therapy, if the recurrence is confined to the pelvis (which is supported by normal CT and nuclear bone scans).

Patients most likely to benefit from salvage radiation include:

• Those in whom the PSA does initially become undetectable after prostatectomy (compared to those who have persistent PSA elevation after prostatectomy).

• Those who have a PSA level under 1.0 ng/mL before they receive the salvage treatment.

• Those who receive the salvage radiation therapy within one year of their first detectable PSA.

Recurrence after radiation therapy

Because the normal prostate is able to produce some PSA, patients who have had radiation as their primary therapy (instead of prostatectomy) usually do not develop an undetectable PSA. In these men, the PSA level usually drops down to 0-2 ng/mL. Therefore, the definition of biochemical recurrence in men treated with primary radiation requires an increase in the PSA level by 2 ng/mL above the nadir PSA value.

In men who do meet criteria for biochemical recurrence after radiation therapy, a repeat prostate biopsy is usually mandated to confirm the presence of residual local disease. If this is confirmed, and the Gleason grade is no higher than the Gleason grade of the pre-treatment biopsy, then a salvage prostatectomy may be considered.

This approach is only practiced by a handful of surgeons, and many investigators believe that the chance of a cure from a salvage prostatectomy is extremely low. An alternative salvage modality in these patients may include prostate cryotherapy.

Biochemically-recurrent prostate cancer

In the current era, because of the universal availability and high sensitivity of PSA testing, most patients with disease relapse after prostatectomy or radiation therapy present with a rising PSA without local or distant recurrence.

In these patients, it is important to perform a baseline CT scan (of the abdomen and pelvis) as well as a whole-body radionuclide bone scan to exclude radiographically visible metastatic disease. We generally perform CT and nuclear bone scans once the PSA reaches 5.0 ng/mL, and then every 1-2 years in men who continue to undergo observation.

In this setting, biochemical recurrence represents a unique disease state in which a rising PSA level is the only evidence of persistent and progressive prostate cancer. The prognosis (in terms of metastasis-free survival and overall survival) for patients with biochemically-recurrent prostate cancer is most heavily influenced by 2 clinical factors:

• The Gleason score at the time of the original diagnosis (4-6 vs 7 vs 8-10).

• The PSA doubling time (PSADT) at the time of biochemical recurrence.

The PSADT is a measure of how long (in months) it takes for the serum PSA level to double; this can be determined by using several on-line calculators. The PSA doubling time can be separated into four risk-groups:

• High risk of metastasis and cancer-related death (PSADT <3 months)

• Intermediate risk (PSADT 3-9 months).

• Low risk (PSADT 9-15 months).

• Very low risk of metastasis and death (PSADT >15 months).

Overall, the median metastasis-free survival in men with biochemically-recurrent prostate cancer is about 10 years, and the overall survival is about 20 years (counting from the time of PSA recurrence).

Management of men with biochemically-recurrent prostate cancer remains controversial. Treatment options include observation alone, continuous ADT initiated upon PSA recurrence, deferred ADT reserved until clinical or metastatic progression, intermittent ADT, or clinical trial participation.

The biggest dilemma in these patients relates to the optimal timing of androgen suppression. Early ADT is often used in these men, but is also associated with long-term cardiovascular and metabolic risks. An alternative approach is to reserve ADT until the time of metastatic progression or symptomatic disease.

To this end, a recent meta-analysis has concluded that compared to deferred ADT, immediate ADT increases metastasis-free survival, decreases prostate cancer-specific mortality, but increases non-prostate cancer-specific mortality, and has no effect on overall survival. Therefore, there is currently no definitive evidence to guide the optimal timing of ADT in men with biochemically-recurrent prostate cancer.

Finally, a recent randomized study has shown that compared to continuous ADT, intermittent ADT is non-inferior in terms of time to castration-resistance and overall survival duration. Therefore, intermittent ADT may be considered a reasonable standard-of-care in this patient population.

In our practice, we approach ADT initiation and continuation as follows:

• PSADT over 9 months: observation; initiate ADT at the time of overt radiographic metastases.

• PSADT 3-9 months: intermittent ADT (6-month cycles of ADT followed by 6-month cycles of testosterone recovery).

• PSADT under 3 months: continuous ADT indefinitely.

Metastatic prostate cancer

The most common sites of distant metastases in patients with advanced prostate cancer include the bones as well as the retroperitoneal lymph nodes. Frequent sites of bone metastases include the pelvic bones, vertebral spine, and ribs. In addition, other lymph node areas may be involved (inguinal, mediastinal, cervical, and axillary). Visceral metastases of the liver or lung are rare, and usually represent an advanced stage of the disease. Dural metastases and parenchymal brain metastases are extremely uncommon.

Most experts would agree that ADT should be initiated immediately in all patients with metastatic prostate cancer even in the absence of symptoms (although a small minority of patients may wish to defer ADT until symptoms develop).

Traditionally, androgen suppression was achieved by means of a bilateral surgical orchiectomy. However, with the advent of pharmacological androgen-suppressive therapies, orchiectomy is now performed only rarely in the Western world. The most effective method of pharmacological castration involves the use of LHRH agonists or antagonists.

LHRH agonists/antagonists

The goal of these agents is to suppress serum testosterone levels by about 90% (they only suppress testicular production of testosterone, but do not affect extra-gonadal testosterone sources such as the adrenal glands).

There is only one available LHRH antagonist: degarelix (Firmagon). The advantage of degarelix over the LHRH agonist agents is that it does not cause an initial testosterone flare before inducing suppression. There do not seem to be any long-term advantages with the use of degarelix. Regimens include:

Leuprolide (LHRH agonist)

• Lupron 22.5 mg IM every 3 months; or Lupron 30 mg IM every 4 months.

• Eligard 45 mg IM every 6 months.

• Viadur 72 mg subcutaneous implant lasting 12 months (needs to be removed and reimplanted every 12 months).

Goserelin (Zoladex) (LHRH agonist)

• Goserelin 10.8 mg SQ every 3 months.

Triptorelin (Trelstar) (LHRH agonist)

• Triptorelin 11.25 mg IM every 3 months; or Trelstar 22.5 mg IM every 6 months.

Degarelix (Firmagon) (LHRH antagonist)

• Degarelix 240 mg SQ initial dose, followed by 80 mg SQ every 28 days for subsequent maintenance doses.

Anti-androgens

Another class of hormonal agents includes the anti-androgens: bicalutamide, nilutamide, and flutamide. These oral drugs to not affect testosterone production, but instead act as androgen receptor antagonists (although they can also act as partial agonists of the androgen receptor).

It is recommended that antiandrogen therapy should precede or be coadministered with LHRH agonist agents and should be continued for at least 7 days in order to diminish the effects of the testosterone flare, especially in patients with overt distant metastases who are at risk of developing a temporary worsening of symptoms associated with the testosterone flare.

Outside of this setting, combined androgen blockade (the use of an LHRH agents together with an anti-androgen) appears to provide no additional benefit over androgen suppression alone in patients with metastatic disease. In clinical practice, anti-androgen agents are often added at the time when castration-resistance develops. Anti-androgen monotherapy (without an androgen-suppressing agent) is less effective than pharmacological castration with LHRH agents and is not recommended.

Bicalutamide (Casodex)

• Bicalutamide 50 mg PO once daily (key side effects: hot flashes, peripheral edema, hepatotoxicity).

Nilutamide (Nilandron)

• Nilutamide 150 mg PO once daily (key side effects: hot flashes, hypertension, dizziness, impaired night-vision).

Flutamide (Eulexin)

• Flutamide 250 mg PO three times daily (key side effects: hot flashes, rash, nausea, diarrhea, hepatotoxicity).

One typical approach to the use of ADT in patients with newly diagnosed metastatic prostate cancer is described below:

• Initiate an LHRH agonist (e.g., Lupron 22.5 mg IM every 3 months) with or without the concurrent use of an antiandrogen (e.g., bicalutamide 50 mg PO daily).

• Serum PSA and testosterone levels should be checked approximately every 3 months.

• If serum PSA begins to rise at some point in the future, then at least one additional PSA measurement (with a concurrent serum testosterone measurement) should be performed.

• If PSA is rising in the setting of a serum testosterone level <50 ng/dL, then this meets criteria for castration-resistance.

• If PSA is rising but serum testosterone is >50 ng/mL, this represents inadequate pharmacological castration and surgical orchiectomy can be considered.

• If castration-resistant prostate cancer has developed, and the patient has not received an anti-androgen agent, then such an agent can be added to the LHRH therapy at that time (bicalutamide is often used first).

• If the patient is already receiving combined androgen blockade (LHRH agent plus antiandrogen), then the next step is to stop the antiandrogen: in 30-40% of patients the PSA may drop after antiandrogen withdrawal.

• If PSA continues to progress, then the use of a second antiandrogen (e.g., nilutamide or flutamide) is appropriate, and may produce a further PSA decline.

• As third-line hormonal therapy, high-dose ketoconazole has been used (400 mg PO three times daily). This agent also suppresses adrenal cortical function, and requires the co-administration of hydrocortisone (20 mg PO in morning, 10 mg PO in evening). Key toxicities of ketoconazole include rash/hypersensitivity, nausea, hepatotoxicity, myopathy and neuropathy. However, ketoconazole has largely been replaced by novel adrenal inhibitors such as abiraterone and the 2^nd-generation anti-androgen, enzalutamide (see below), both of which are well-tolerated and have demonstrated overall survival benefits in the pre-chemotherapy CRPC setting.

• During the course of treatment with multiple hormonal therapies, it is also advisable to repeat imaging with a CT and bone scan at each PSA progression event; rapidly advancing skeletal or visceral disease might encourage the earlier use of chemotherapy in those patients.

ADT toxicities

Short-term side effects:

• hot flashes

• night sweats

• fatigue

• muscle weakness

• decreased libido

• erectile dysfunction

• weight gain.

Long-term complications:

• hypertension

• hyperlipidemia

• insulin resistance/glucose intolerance

• metabolic syndrome

• osteopenia and osteoporosis

• increased risk of clinical fractures

• increased risk of cardiovascular events

• increased risk of cerebrovascular events

• possibly neurocognitive decline

Patients receiving chronic ADT should receive calcium supplementation (1200 mg daily) as well as vitamin D3 supplementation (1000 IU daily). In addition, men at high risk of osteoporotic fracture (10-year risk exceeding 20% using the FRAX algorithm) should also consider treatment with zoledronic acid (54 mg IV once annually) or alendronate (70 mg orally once weekly).

CYP17 Inhibition

Ectopic (adrenal, prostatic, intratumoral, paracrine) androgen production in the setting of gonadal ablative therapies represents an important resistance mechanism in CRPC. Abiraterone acetate (Zytiga) is an oral, potent, selective, and irreversible inhibitor of the steroidogenic enzyme CYP17, blocking both its 17α-hydroxylase and its C17,20-lyase activity. As a result, extra-gonadal androgen production is impaired through the inability to convert pregnenolone to dehydroepiandrostenedione and progesterone to androstenedione.

The primary toxicities of abiraterone (which include hypertension, hypokalemia, and peripheral edema) appear to be related to a syndrome of secondary mineralocorticoid excess due to feedback upregulation of mineralocorticoid synthesis, and are largely reversible with administration of an aldosterone receptor antagonist (e.g., eplerenone) or a corticosteroid (e.g., prednisone).

For this reason, most trials investigating abiraterone have combined this drug with low-dose prednisone. Other adverse events with abiraterone include liver function abnormalities (the drug is contraindicated in patients with moderate-to-severe liver impairment) and cardiac complications (mainly related to heart failure).

Initially studied in castration-resistant metastatic prostate cancer (see discussion below) two key trials presented in June 2017 demonstrated a benefit to the early initiation of abiraterone along with ADT in castration-naïve patients. STAMPEDE and LATITUDE demonstrated similar improvements in both overall and progression-free survival. While LATITUDE was restricted to patients with “high risk” metastatic disease, 48% of patients in STAMPEDE had only nodal or prostate-confined disease. This subgroup also benefited from adding abiraterone early, however to a smaller magnitude than metastatic patients (HR for death 0.61 for metastatic patients, 0.75 for non-metastatic). Abiraterone plus prednisone (5 mg daily) was continued along with ADT until progression or toxicity for metastatic patients in both studies, and for a maximum of 2 years for the non-metastatic patients in STAMPEDE. For both trials, the results were similar to the benefits seen with the use of early docetaxel in castration-naïve patients with a high-volume of disease (discussed below). Currently there is no consensus on the use of abiraterone over docetaxel along with ADT in castration-naïve patients. FDA approval of abiraterone in this setting is anticipated and it is already being utilized in clinical practice.

• Abiraterone (Zytiga) 1000 mg (four 250-mg tablets) PO daily, plus

• Prednisone 5 mg PO daily, plus

• Androgen deprivation therapy to maintain castrate levels of testosterone (<50 ng/dl)

Chemohormonal therapy

The CHAARTED trial (ECOG 3805) evaluated the role of “upfront” docetaxel chemotherapy (maximum of 6 cycles) plus ADT compared to ADT alone in men with metastatic hormone-sensitive prostate cancer. In the first interim analysis, the chemohormonal therapy arm had lived over 13 months longer than the ADT-alone arm (mOS 57.6 months versus 44.0 months). The difference was even more pronounced in the high-volume disease subgroup. While there was an initial trend to improved survival in the low-volume subgroup, a subsequent analysis with longer follow-up demonstrated no difference between the arms. This study is practice-changing for “chemo-fit” men with high-volume metastatic disease. The utility of upfront chemotherapy for men with low-volume disease remains unclear.

Although ADT is a very effective therapy for the vast majority of patients with metastatic prostate cancer, this is not a curative treatment and resistance to androgen suppression eventually develops in all patients within 12-48 months (median 18 months). When this occurs, the disease transforms to a new state known as castration-resistant prostate cancer which often leads to death.

Castration-resistant prostate cancer (CRPC)

CRPC is defined as the presence of progressive disease (by PSA elevations, clinical progression, or radiographic progression) in the setting of castrate serum testosterone levels (i.e. <50 ng/dL), and represents the lethal form of prostate cancer. In general, LHRH antagonists/agonists are continued in this setting, with other agents added to these agents.

There are currently 7 FDA-approved therapies for the management of metastatic CRPC (listed in order of approval):

• Mitoxantrone (an anthracycline chemotherapy agent)

• Docetaxel (a taxane chemotherapy agent)

• Sipuleucel-T (an autologous immunotherapy agent indicated for men with minimal or no symptoms)

• Cabazitaxel (a taxane chemotherapy agent)

• Abiraterone acetate (an androgen-suppressing agent)

• Enzalutamide (a 2^nd generation anti-androgen)

• Radium-223 dichloride (an alpha-emitting radiopharmaceutical)

Chemotherapy for metastatic CRPC

Mitoxantrone

The first chemotherapy drug to be approved for metastatic prostate cancer was the anthracycline agent, mitoxantrone (Novantrone). In 1996, a randomized control trial investigated mitoxantrone and prednisone against prednisone alone. In this trial, the combination of mitoxantrone and prednisone did not demonstrate a survival advantage over prednisone alone, but did provide pain relief in patients with bone pain from osseous metastases, thereby improving quality-of life in these patients and resulting in FDA approval.

Usual mitoxantrone dose:

• Mitoxantrone 12 mg/m²; IV every three weeks.

Mitoxantrone is now mainly reserved for patients who are refractory to other more effective chemotherapy drugs. Mitoxantrone is an anthracycline with the potential to cause cardiotoxicity, cumulative mitoxantrone doses above 120 mg/m²should only be used with extreme caution.

Docetaxel

In 2004, docetaxel (Taxotere) was the first drug to show an overall survival advantage in men with metastatic CRPC, leading to the FDA approval of this chemotherapy agent. Docetaxel was evaluated in the pivotal TAX327 trial, which enrolled over 1000 patients (who had not previously received chemotherapy) to one of three arms: mitoxantrone (given every 3 weeks) plus daily prednisone, docetaxel (given every 3 weeks) plus prednisone, or docetaxel (given weekly) plus prednisone. Prednisone is administered with these regimens because it has some intrinsic antitumor activity and it attenuates some of the acute toxicities of docetaxel including hypersensitivity and peripheral edema.

Overall survival in the 3-weekly docetaxel arm was 18.9 months (with a pain response rate of 35%, and a PSA response of 45%), contrasted with weekly docetaxel at 17.3 months (pain response of 31%; PSA response of 48%). This translated into a 24% reduction in the risk of death using 3-weekly docetaxel.

Patients on the mitoxantrone arm had a median survival of 16.4 months (pain response of 22%, PSA response of 32%). The clinical efficacy of docetaxel was also demonstrated in the SWOG-9916 trial.

Usual docetaxel dosing:

• Docetaxel 75 mg/m²; IV every 3 weeks, plus

• Prednisone 10 mg PO daily.

Common adverse events with docetaxel include hypersensitivity reactions, peripheral edema, hair thinning, myelosuppression, and hyperlacrimation. With continued exposure, the main cumulative toxicity of docetaxel is peripheral neuropathy that manifests as a sensory neuropathy in the fingertips and toes.

Cabazitaxel

The safety and efficacy of cabazitaxel in patients with docetaxel-refractory prostate cancer was definitively evaluated in a pivotal randomized phase III trial (TROPIC) that was conducted in 755 men with who had progressed during/after prior docetaxel-based chemotherapy. Patients were randomized to receive mitoxantrone or cabazitaxel.

Overall survival in men receiving cabazitaxel was 15.1 months compared to 12.7 months in men receiving mitoxantrone (representing a 30% reduction in the risk of death). Compared to mitoxantrone, cabazitaxel also significantly lengthened progression-free survival (2.8 months vs 1.4 months), extended time to PSA progression (6.4 months vs 3.1 months), increased radiographic tumor response rates (14.4% vs 4.4%), and increased PSA response rates (39.2% vs 17.8%).

Usual cabazitaxel dosing:

• Cabazitaxel 25 mg/m²; IV every 3 weeks, plus

• Prednisone 10 mg PO daily.

The most common serious adverse events related to cabazitaxel were hematologic, including neutropenia in 82% of patients (febrile neutropenia in 8%), leukopenia in 68% of patients, and anemia in 11% of patients. This degree of myelosuppression begs the question of whether a lower dose of cabazitaxel (e.g. 20 mg/m²😉 may have been more appropriate, and a randomized trial comparing the safety and efficacy of these two doses (25 mg/m²; vs 20 mg/m²😉 is now being conducted.

In the absence of efficacy information on lower cabazitaxel doses, use of growth factor support (e.g. with filgrastim or PEG-filgrastim) should be strongly considered, as reflected in several national guidelines. Other non-hematologic toxicities of cabazitaxel include diarrhea and fatigue.

Importantly, although peripheral neuropathy was observed in 14% of patients receiving cabazitaxel, only 1% developed clinically significant neuropathy. This relative lack of cumulative neurotoxicity with cabazitaxel is encouraging, especially given the known neurological sequelae of docetaxel.

Sipuleucel-T

Prostate cancer may be an ideal target for immunologic attack because it produces several tissue-specific proteins that may serve as tumor antigens: these include prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP).

This notion has been applied to the development of sipuleucel-T (Provenge), an autologous PAP -loaded dendritic cell immunotherapy. During treatment with sipuleucel-T, a patient’s own antigen-presenting cells are collected by leukapheresis and co-incubated with a fusion protein containing PAP linked to granulocyte macrophage–colony-stimulating factor (GM-CSF).

After culturing this fusion protein with the collected antigen-presenting cells, the primed immunotherapy is then reinfused into the patient, activating T cells via MHC class I and class II molecules and resulting in a PAP-specific antitumor immune attack. This leukapheresis-then-reinfusion process is conducted three times at two week intervals, for a total treatment duration lasting 4 weeks. Adverse events with sipuleucel-T are generally mild and include fever, chills/sweats, myalgias, and headache. These usually occur during or shortly after infusion of the immunotherapy.

In a double-blind placebo-controlled randomized phase III trial (IMPACT), 512 patients were randomized (2:1) to receive sipuleucel-T or placebo. Notably, this study did not enroll men with visceral (lung, liver) metastases or those taking opioids for cancer pain, and most patients (85%) had not received prior chemotherapy. Median overall survival was 25.8 months in the sipuleucel-T group versus 21.7 months in the placebo group (representing a 22% reduction in the risk of death), despite 64% of patients on the placebo arm crossing over to receive salvage sipuleucel-T upon progression.

In the subset of patients with prior chemotherapy exposure, overall survival trended in favor of sipuleucel-T, but this effect was not statistically significant. There was no difference in progression-free survival between the two treatment arms, and sipuleucel-T did not produce any significant PSA responses.

Sipuleucel-T is the first therapeutic cancer vaccine to gain FDA approval for any cancer. It is intended for patients with asymptomatic (or minimally symptomatic) metastatic CRPC, and is probably most effective in men who have not received prior chemotherapy. The main challenges with widespread adoption of this treatment modality include limited manufacturing capacity of the immunotherapy product, the high cost of the intervention ($93,000 for three infusions), and the eukapheresis procedure, which requires a blood bank or apheresis center.

Abiraterone acetate

In a placebo-controlled blinded randomized phase III trial (COU-AA-301), almost 1,200 men with docetaxel-pretreated metastatic CRPC were randomized (2:1) to receive either abiraterone 1000 mg daily plus prednisone 10 mg daily or placebo plus prednisone. Median overall survival was 14.8 months in the abiraterone arm and 10.9 months in the placebo arm (representing a 35% reduction in the risk of death), with concomitant improvements in radiographic and PSA progression-free survival. The follow-up COU-AA-302 trial of chemotherapy-naïve men with CRPC was stopped early for efficacy in progression-free survival as compared to placebo, but demonstrated overall survival of 35.3 months for abiraterone versus 30.1 months in the placebo arm. On the basis of these trials, the FDA approved abiraterone in the pre-chemotherapy CRPC setting as well as following docetaxel.

Usual abiraterone dosing:

• Abiraterone 1000 mg (four 250-mg tablets) PO daily, plus

• Prednisone 5 mg PO twice daily.

In patients with mild liver impairment, abiraterone should be given at lower doses of 250-500 mg daily, and in patients with moderate-to-severe liver dysfunction this agent is contraindicated.

Enzalutamide

Enzalutamide (Xtandi) is a 2^nd generation anti-androgen with increased affinity for the androgen receptor compared with 1^stgeneration drugs including bicalutamide, nilutamide, and flutamide. Additionally, enzalutamide prevents nuclear translocation of the androgen receptor, thereby preventing the receptor from binding to DNA. Unlike abiraterone, concurrent steroid administration is not required. In the AFFIRM trial of enzalutamide versus placebo in men with docetaxel-resistant CRPC, enzalutamide demonstrated a 37% reduction in the risk of death and the study was stopped early for efficacy. In the follow-up PREVAIL study in the pre-chemotherapy setting, enzalutamide demonstrated a 30% reduction in the risk of death versus placebo. On the basis of these trials, the FDA has approved the drug in both the pre-chemotherapy and post-chemotherapy settings.

The drug is generally well-tolerated with fatigue, diarrhea, and hot-flashes more common in the treatment arm. Seizures were somewhat more frequent (1% vs 0%) in the enzalutamide arm; however, there was no increase in seizures noted in the follow-up PREVAIL study in the pre-chemotherapy setting. Patients with pre-dispositions to seizure were excluded from this trial and an alternative therapy should likely be considered for such patients.

For patients who require dose reduction for toxicity, the FDA-approved modifications include a decrease from 160 mg daily to 120 mg daily or 80 mg daily. For patients in whom fatigue is the limiting toxicity, we have also experienced success with every-other-day therapy. For patients concurrently treated with inhibitors of CYP2C8 such as gemfibrozil or trimethoprim, the recommended dose is 80 mg daily.

Radium-223 dichloride

Whereas prior radiopharmaceuticals such as strontium-89 and samarium-153 emit β radiation that penetrates deeply into the bone marrow, radium-223 dichloride (Xofigo) is an α-particle emitter, with much shorter wavelength and higher energy penetrance. Acting as a calcium mimetic, radium-223 binds to the hydroxyapatite in bone lesions, theoretically releasing radiation to the surrounding tumor but sparing the marrow.

In the ALSYMPCA trial, radium-223 was compared to placebo in men with bone but not visceral metastases who either had progressed on docetaxel or were unfit for docetaxel therapy. Radium-223 demonstrated a 30% reduction in the risk of death with median survival of 14 months and 11.2 months in the radium and placebo arms respectively and also improved the time to SRE. Toxicity was low with somewhat increased rates of neutropenia and thrombocytopenia.

One remaining question is that of dosing. In ALSYMPCA, all patients received 6-monthly cycles of 50 kBq/kg, however patients with a body weight over the median appeared to do better in the treatment arm, suggesting – given the favourable toxicity profile – that patients under the median weight may have been underdosed. An ongoing post-marketing study is thus randomizing men to standard dose radium-223, high-dose (80 kBq/kg x 6 doses), or extended-dose (50 kBq/kg x 12 doses).

Treatment algorithm for men with metastatic CRPC:

Asymptomatic mCRPC

• Observation

• Secondary hormonal manipulations (nilutamide, flutamide).

• Antiandrogen withdrawal.

• High-dose ketoconazole (plus hydrocortisone).

• Abiraterone 1000 mg PO daily (plus prednisone 5 mg PO twice daily).

• Enzalutamide 160 mg PO daily.

• Sipuleucel-T.

Minimally Symptomatic mCRPC

• Secondary hormonal manipulations (nilutamide, flutamide).

• High-dose ketoconazole (plus hydrocortisone).

• Abiraterone 1000 mg PO daily (plus prednisone 5 mg PO twice daily).

• Enzalutamide 160 mg PO daily.

• Sipuleucel-T.

Symptomatic mCRPC (e.g. bone pain, weight loss, urinary tract obstruction, tumor-induced myelosuppression)

• Docetaxel 75 mg/m²; IV every 21 days, continue until radiographic progression (imaging every 12 weeks) or unmanageable toxicity.

  Radium-223 dichloride 50 kBq/kg IV every 4 weeks x 6 doses (if bone-only disease and unfit for docetaxel).

• Mitoxantrone 12 mg/m²; IV every 21 days (if unfit for docetaxel).

• Abiraterone 1000 mg PO daily (plus prednisone 5 mg PO twice daily).

  Enzalutamide 160 mg PO daily.

Docetaxel-refractory mCRPC

• Cabazitaxel 25 mg/m²; IV every 21 days (dose-reduction to 20 mg/m²;, or addition of PEG-filgrastim, if patients is age >65 years).

• Abiraterone 1000 mg PO daily (plus prednisone 5 mg PO twice daily).

• Enzalutamide 160 mg PO daily.

• Radium-223 dichloride 50 kBq/kg IV every 4 weeks x 6 doses (if bone-only disease).

• Mitoxantrone 12 mg/m²; IV every 21 days (if unfit for cabazitaxel).

Palliative treatments

• External-beam radiation to single painful bony metastasis.

• Radiopharmaceuticals for multifocal painful bone metastases (e.g. radium-223, strontium-89, samarium-153).

• Zoledronic acid or Denosumab for prophylaxis against skeletal-related events.

Pathophysiology

Development of prostate cancer is thought to occur through a multi-step carcinogenesis process by which normal prostatic epithelium progresses through proliferative inflammatory atrophy (PIA), to prostatic intraepithelial neoplasia (PIN), and finally to prostatic adenocarcinoma. Although the precise sequence of genetic changes in this process is unknown, a key early event is the methylation and inactivation of the glutathione-S-transferase-p (GSTp) gene which is involved in detoxification of oxidants produced by chronic inflammation.

In addition, it is known that prolonged oxidative DNA damage promotes progression from PIA and PIN to prostate adenocarcinoma, and that when GSTp is down regulated non-steroidal anti-inflammatory drugs may halt oxidative stress. There is now mounting evidence that chronic or recurrent inflammation probably plays a role in the development of many cancers, including prostate cancer.

Another important molecular feature of prostate cancers is the somatic alteration of a gene known as PTEN. PTEN is a tumor suppressor gene that is present in normal prostatic epithelial cells as well as in PIN. In prostate cancer, the expression of PTEN is frequently reduced, particularly in high-grade or high-stage cancers. This usually occurs from somatic loss of the PTEN gene.

In a study of prostate cancer metastases recovered at autopsy, somatic PTEN alterations were more common than in primary prostate tumors, and heterogeneity in PTEN defects was observed in different metastases from the same individuals.

The mechanism by which PTEN might act as a tumor suppressor in the prostate may involve the inhibition of the PI3K-Akt signaling pathway which is essential for cell cycle progression and cell survival. To this end, although it is generally difficult for cancer therapeutics to target tumor suppressors such as PTEN, multiple investigational new drugs are now targeting the PI3K-Akt pathway for the treatment of advanced prostate cancer.

In 2005, a recurrent chromosomal rearrangement (TMPRSS2-ETS) was discovered to occur in a large percentage of prostate cancers. This rearrangement produced a gene fusion between the TMPRSS2 gene and several ETS-family genes (which function as transcription factors). Importantly, the promoter of the TMPRSS2 gene contains an androgen-response element (ARE) that can be activated by dihydrotestosterone to mediate the overexpression of the ETS family members in prostate cancer.

In addition, the TMPRSS2-ETS fusion does not appear to be present in PIA or PIN lesions, and therefore is probably a unique event found in prostate adenocarcinoma only. It is now appreciated that about 50-60% of prostate cancers harbor this type of fusion. However, the prognostic and predictive implications of the TMPRSS2-ETS fusion still remain uncertain, and efforts to clarify this issue are ongoing.

What other additional laboratory studies may be ordered?

Circulating tumor cells (CTCs)

There are several technologies available to measure the presence and concentration of prostate cancer cells that are found circulating in the bloodstream in patients with metastatic prostate cancer. The best-validated platform is the CellSearch assay produced by Veridex.

In patients with metastatic castration-resistant prostate cancer (CRPC) who are receiving chemotherapy, the use of CTCs was cleared by the FDA as a prognostic marker of survival in these patients. Using the Veridex platform, these cells can be enumerated in 7.5 mL of whole blood either prior to beginning systemic chemotherapy or during the course of chemotherapy.

The number of CTCs in whole blood has been shown to correlate with overall survival in this setting.

• Patients with a baseline CTC count of less than 5 cells (per 7.5 mL volume) have improved overall survival compared to men with a baseline CTC count of more than 5 cells.

• Patients who convert from a CTC count of more than 5 cells (unfavorable count) before chemotherapy to less than 5 cells (favorable count) during chemotherapy have a survival that matches those who have favorable CTC counts at baseline.

• Patients who convert from less than 5 cells to more than 5 cells during chemotherapy treatment have an overall survival that is as poor as those with baseline unfavorable CTC counts.

Although CTCs are not credentialed at this time as surrogate biomarkers of clinical benefit and thus should not been used to guide therapeutic choices in men with CRPC, the ability to detect and characterize these tumor cells holds promise as a predictive tool to aid in personalized medicine approaches.

Indeed, CTC analysis is now being incorporated in several large prospective trials in order to try to validate this methodology as a surrogate measure of survival in patients with metastatic CRPC. In addition, CTCs from an individual patient can be further characterized in research settings for molecular profiling, indicating their potential to help guide systemic therapy choices in the future.

The use of CTCs in routine clinical care has not been widely adopted yet and may be premature. However, one possibility is to collect baseline CTC counts for patients embarking on chemotherapy treatment, with a subsequent CTC determination 3 months later. Those patients who have converted from unfavorable to favorable CTC counts may continue with the same chemotherapy agent. Those patients who fail to convert from unfavorable to favorable CTC counts could be switched to an alternative chemotherapy agent such as cabazitaxel.

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