Advanced Prostate Cancer

What is 'Advanced Prostate Cancer'?

Advanced prostate cancer is traditionally defined as disease that has spread beyond the confines of the prostate itself. Advanced prostate cancer may be:

  1. Locally advanced: beyond the capsule but not elsewhere

  2. Systemically advanced: to lymph nodes, bone or both

Cure may be possible in locally advanced prostate cancer. This often requires multi-modality treatment to ensure the best result - combinations of hormones, chemotherapy, surgey and radiation.

Prostate cancer has a strong affinity for spreading (metastasizing) to bone and lymph nodes in addition to spreading outside the capsule of the prostate.  When prostate cancer has spread to the lymph nodes and bone cure is rarely possible. However, patients with advanced disease often live for many, many years and the treatments for advanced prostate cancer continue to improve. Participation in clinical trials is an important contribution that men can make to their own care and to those who come after them.

Determining Risk and Prognosis to Optimize Treatment

Each man with advanced prostate cancer is unique. Each has his own story of how he came to have advanced prostate cancer, what his current disease state is, his health issues and where he is in life. All of these factors are important considerations in management. 

  1. Prior treatment: e.g. None ('treatment naive'), radiation, surgery

  2. Pathologic factors: volume of disease, Gleason score, PSA

  3. Stage of disease: presence of local extensive disease, lymph node or bone involvement

  4. Volume of disease

  5. Other health issues

  6. Risk tolerance and side effect tolerance for treatments

The ultimate goals of treatment are always QUALITY and QUANTITY of life. It is important to recognize that the various tests that we use to assess prognosis and to predict response to treatment are meant to provide insight into what might happen in the future. They do not provide a crystal ball into the future and the ultimate outcome is only known as it unfolds over time.

'Disease States' in Advanced Prostate Cancer

There are several different disease states within advanced prostate cancer.  Prognosis and treatment options very with each disease state. Interpretation of lab results also needs to be taken in context of the specific state a man is in. 

  1. Hormone sensitive: responds to standard/first line Androgen Deprivation Therapy (ADT)

    1. Leutenizing Hormone Receptor Agonists (LHRH agonists)

    2. Leutenizing Hormone Receptor Antagonists

    3. Antiandrogen (AA)

    4. Surgical castration

  2. Castrate Resistant Prostate Cancer (CRPC): Unresponsive to standard/first line ADT = rising PSA + 'castrate' level of testosterone (generally less than 0.5 ng/mL). Important characteristics of CRPC include:

    1. Presence of symptoms

    2. Amount of disease (volume) - usually determined with CT/bone scan

    3. Prior treatment details (surgery, radiation, types of medications)

    4. Course of disease leading up to development of CRPC 

Hormone sensitive disease is defined by response to first line treatments as specified above. Castrate Resistant Prostate Cancer is only declared when the PSA rises DESPITE these treatments and IN THE PRESENCE of a 'castrate level of testosterone'. It  is important to note that the PSA may be allowed to rise in men with advanced disease when they are on an Intermittent Androgen Deprivation program - in these cases the testosterone also rises and therefore the patients do NOT have castrate resistant diseasee.

The traditional approach to advanced prostate cancer has been to remove testosterone - an approach for which the Canadian researcher Charles Huggins was awarded the Nobel Prize in 1966. The approach of castration (with medicine or surgery) has provided palliation and been the mainstay of treatment for advanced disease decades. Over the last couple 10 years or so, however, it has been recognized that the relationship between blood levels of testosterone and prostate cancer is more complex than originally thought. In addition, multiple new novel treatment approaches to treating advanced prostate cancer, including chemotherapy and immunotherapy, have arisen. As a result, approaches to castrate resistant disease still include approaches that affect hormone production (abiraterone and enzalutamide are 2 examples). 

The setting in which these treatments is being applied continues to evolve - that is, the best order or sequencing of medications is not well understood. The traditional paradigm has been to exhaust first line treatments (anti-androgens and LHRH agonists) and then proceed with chemotherapy using docetaxel. The timing and sequencing (order in which drugs are given) is an area of intense research and continues to evolve - ultimately, the decision is made with your treating physician.

When is treatment started?

This is highly dependent on the circumstance. It is important to note that in many cases just because the PSA is rising this does NOT mean that any change in treatment or starting a treatment is necessary or even beneficial. Changing or starting a treatment is based on where the clinical trials showed benefit.

Hormone Sensitive Disease (Non-Castrate Resistant)

+ Abiraterone (Abiraterone and Enzalutamide)

Many of the current clinical trials are exploring starting earlier treatment for the newest agents, but until the results are in it is impossible to state if earlier treatment will be more beneficial than harmful.

+ Docetaxel

2 studies were completed in 2015/2016. These looked at patients without castrate resistant disease (that is, hormone sensitive disease) - a group where the standard of care for many years has been androgen deprivation therapy (ADT). Prior studies did not show any benefit when chemotherapy was added to hormone treatment with a low disease burden. When treating men with high disease burden (visceral metastases, disease beyond the axial skeleton or a high number of lesions) a survival benefit was suggested. Using the endpoints of biochemical, symptomatic or radiographic progression, those treated with chemotherapy wre less likely to progress - 20 months vs. 12 months. In addition, patients who received combined therapy had a longer survival - median survival with combination chemo and ADT was 49 months as compared to 32 months with ADT alone. The Docectaxel chemotherapy was started within 3 months of starting the androgen deprivation and given for 6 cycles. Patients obviously did not have any contraindications to treatment. (E3085 Study NEJM 2015)

Castrate Resistant Disease

The major pre-requisite for treating patients is that they be castrate resistant. In some circumstances, the benefit of the medication was only demonstrated after chemotherapy had ceased to be effective or until there was the development of symptoms or a high disease burden. The criteria for treatment in clinical settings is generally derived from how the clinical studies were designed - you can see the general criteria in the table below.

Outcomes for Different Chemotherapies in Advanced Prostate Cancer

IMPORTANT: the differences in overall survival are NOT comparable between these studies. The survival is affected by many factors, including:

  1. Treatment group

  2. Type of comparison group

  3. Prior treatments

  4. Study design

Because of the large differences in the population of patients who were studied and the differences in design of the trials, the 'Overall Survival' data presented here should NOT be used to decide which is the best treatment in your particular circumstance. For example, the best overall survival is for enzalutamide - but his was in patients with mCRPC who were chemotherapy naive and who had met criteria specific to that clinical trial. Treatment is individualized - and the final decision is made in conjunction with your doctor.

Agent Comparison Group
Patient Population
(Study Name, Date)		 Overall Survival (median, months)
Docetaxel + Predinsone Mitoxantrone + Prednisone
mCRPC/Pos-ADT failure/Chemo naive
(TAX 327, 2004)		 18.9 vs 16.4
Docetaxel + Estramustine Mitoxantrone + Prednisone
mCRPC/Post-ADT failure/Chemo naive
(SWOG-9916, 2004) 		17.5 vs 15.6
Docetaxel + ADT Androgen Deprivation Therapy (LHRH)
Hormone sensitive/High disease burdern
(E3085, 2015)		 49 vs 32
Cabazitaxel Mitoxantrone + Prednisone
mCRPC/post-docetaxel
(TROPIC, 2010)		 15.1 vs 12.7
Abiraterone + Prednisone Placebo
mCRPC/post-docetaxel
(COU-AA301, 2013)		 14.8 vs 10.9
Abiraterone + Prednisone Placebo
mCRPC Asymptomatic/minimally Symptomatic/chemo-naive
(COU-AA302, 2012)		 16.5 vs 8.3
Enzalutamide Placebo
mCRPC/post-docetaxel
(AFFIRM, 2012)		 18.4 vs 13.6
Enzalutamide Placebo
mCRPC/chemotherapy naive
(PREVAIL, 2014)		 32.4 vs 30.2
Sipuleucel-T Placebo
mCRPC/Asymptomatic/minimally symptomatic/post-docetaxel
(IMPACT, 2010)		 25.8 vs 21.7
Radium-223 Placebo
mCRPC with bone metastases (no visceral metastases)/post-docetaxel or docetaxel unfit
(ALSYMPCA, 2013)		 14.9 vs 11.3
 

+ Abiraterone (Zytiga)

Dose: Abiraterone 1000 mg orally daily + Prednisone 5 mg twice daily taken on an empty stomach

Category: hormonal agent

Mechanism: inhibits testosterone synthesis (CYP17 inhibition)

Adverse events and management:

  • Those related to low testosterone
  • Low potassium: potassium supplement
  • Hypertension: add or increase dose of antihypertensive
  • Cardiac toxicity: generally contraindicated with NYHA class III or IV heart failure, EF <50%, data-preserve-html-node="true" atrial fibrillation or arrhtyhmia

Monitoring:

  • Pre-treatment ECG and echo may be useful

Comments:

  • Similar efficacy in older and younger patients but slighlty higher incidence of grade 3 and 4 adverse events if older than 75 (57%) vs. less than 65 (40%) years of age

+ Enzalutamide (Xtandi)

Dose: 160 mg orally daily

Mechanism: (1) blocks AR interaction (2) inhibits AR translocation to the nucleus (3) impairs AR binding to DNA (4) inhibitis coactivator recruitment and receptor mediated DNA transcription

Category: hormonal agent

Adverse events:

  • Those related to low testosterone
  • Fatigue
  • Headache
  • Seizure
  • Falls risk (from reduced muscle mass, especially older males)

+ Radium-223 (Xofigo)

Dose: given monthly for 6 cycles

Mechanism: blocks new bone growth near metastases

Category: Radiopharmaceutical

Adverse events:

  • Inhibition of bone marrow
  • GI toxicity
  • Contraindicated in visceral metastases and bulky lymph nodes

+ Docetaxel (Taxotere)

Dose: Docetaxel 75 gm/m2 every 3 weeks; dose reduced 50 mg/m2 every 2 weeks

Category: Chemotherapy

Mechanism: induces cell cycle arrest and inhibits cell proliferation

Adverse events and management:

  • Mainly low grade: fatigue, nausea, vomiting, hair loss and nail changes, diarrhea, sensory neuropathy, anorexia, changes in taste and stomatitis
  • Promotes Thrombosis
  • Neutropenia
  • Mild in 70-80%, moderate 20%, hospital admission in <5% data-preserve-html-node="true"

Monitoring:

Comments:

  • Effective for overall pain and PSA response
  • Relatively contraindicated with history of TIA, CVA and atrial fibrillation because of prothrombotic effects of treatment

+ Cabazitaxel (Jevtana)

Dose: Cabazitaxel 35 mg/m2 every 3 weks + prednisone x 10 courses

Category: Chemotherapy

Mechanism: tubulin binding taxane

Adverse events and management:

  • Neutropenia - often requiring gCSF for support; risk of neutropenia death 5% in trials

Monitoring:

Comments:

  • Not effective in patients who rapidly progress on docetaxel

+ Denosumab (Xgeva/Prolia)

Dose:

  • For prevention of treament induced bone loss: Denosumab 60 mg subcutaneously twice yearly
  • For bony mets: Denosumab 120 mg subcutaneously monthly

Category: Bone agent

Mechanism: RANK ligand inhibitor

Adverse events and management:

  • Osteonecrosis of the jaw
  • Hypocalcemia

Monitoring:

  • Serum calcium

Comments:

  • No survival benefit

On the Web

General Prostate Cancer Web-Resources

Prostate Cancer Canada Resources

Prostate Cancer Basics: Screening and Diagnosis

Prostate Cancer Treatment Options

Prostate Cancer Post-Treatment Recovery and Side Effects

Memorial Sloan-Kettering Cancer Center in New York is an excellent resource for information on prostate cancer. Balanced, unbiased discussions of the disease, including discussion regarding some of the controversies in prostate cancer.

General Information on Cancer

UNDERSTANDING CANCER - Metrovan Urology info on the principles of diagnosis, staging, prognosis and more.

American Cancer Society

BC Cancer Agency: Good general website from the British Columbia Cancer Agency. Has contact information on locations.

National Cancer Institute: Excellent source of understandable and mainly unbiased information. Several very good brochures on every stage of prostate cancer.

National Comprehensive Cancer Network: peer-reviewed expert content/prostate cancer guidance on evidence-based cancer diagnosis and management. Best for Prostate and Kidney Cancer. The most in-depth information is located in the physician section and requires registration.