Prostate Cancer
Prostate cancer is the second leading cause of death in men in the United States. One in six will be diagnosed with prostate cancer at some time during their lives. There will be 288,000 cases diagnosed this year and 35,000 deaths. Sixty percent of prostate cancers will be diagnosed in men over 65, with its occurrence being rare in men younger than 40. New cases of prostate cancer are 70% higher in black men than in white men.
Risk Factors
Disease is confined to the prostate gland or localized in regions around the gland in 90% of cases, with the 5year survival approaching 100%. However, If the cancer has metastasized to more distant regions the 5-year survival is only 30%, reinforcing the recommendation for examination and consideration of PSA testing especially based on an individual’s risk assessment.
General risk factors include:
Age: prostate cancer increases with age especially over the age of 50, but rises significantly in men >65, to sixty percent.
Black men have a higher risk than white men, develop it at an earlier age, and experience a more aggressive disease.
Hispanic men have a lower risk than white non-Hispanic men.
A familial non inherited component occurs in 20% of cases. It is believed to be related to a combination of lifestyle or environmental exposure within their community combined with some unknown genetic susceptibility.
A genetically inherited risk occurs in only 5% of men and is traceable either to multiple generations or having three or more first degree relatives. Having just one first degree relative with prostate cancer doubles the cancer risk, with increasingly greater probability if more first-degree relatives have it.
Men with Hereditary BRCA1 and/or BRCA2 mutations have increased risk of aggressive prostate cancer as well as breast cancer.
Exposure to agent orange in post-Vietnam veterans.
Lower socioeconomic status
Dietary risk factors include:
Processed beef products, red meat and organ meats.
Choline from poultry skin and egg yolks stimulates prostate cancer inflammation and growth. PET/CT scans in prostate cancer use choline instead sugars as choline is rapidly taken up by the prostate unlike other organs.
Diet high in saturated fats
High sugar intake stimulating IGF-1, insulin like growth factor.
Environmental exposure to:
The heavy metal cadmium from exposure to smoking tobacco
Elevated bad cholesterol
Exposure to xenohormones (synthetic substances that acts like estrogen) including pesticides, fertilizers, and many household cleaners. AND
Bis-phenol-A, a xenoestrogen, found in, Epoxy resins, plastic food wrap, polycarbonate plastics like water pipes, cash register receipts and metal cans. It is a hormone sensitizer that can increase prostate cancer growth,
The Prostate Gland
The prostate gland is a structure located behind the rectum, on digital exam, weighing about an ounce. It produces a fluid that combines with fluid from the seminal vesicles, and sperm from the testicles to create semen. The outside of the gland consists of a capsule of smooth muscle and elastic connective tissue which contracts to push this fluid into the urethra during ejaculation. At that time the sphincters on the prostate and bladder close the urethra to prevent ejaculate from going into the bladder, while during urination the sphincter on seminal vesicles closes.
The tissue in the gland is comprised of three distinct areas:
The Peripheral Zone: the main outer part of the prostate and represents approximately 70% of the gland.
The Transition Zone: the urethra extends from the penis to the bladder, through the prostate to carry fluids, semen, and urine. The transition zone is inside the gland and represents 10%. It surrounds the urethra from the upper part of the urethra, in the prostate, to the bladder.It is this portion that grows with aging and while not cancerous presses against the bladder and urethra causing urinary symptoms. This called benign prostatic hyperplasia or BPH.
The Central Zone surrounds the ejaculatory ducts and has a different embryologic orgin than the other zones.
The PSA and Interpretation
In evaluating the prostate, its anatomic position behind the rectum allows it to be examined during a digital rectal exam. However, the surface that can be examined is limited. It is a circular organ, and a digital rectal exam can palpate the top and sides to detect nodules or firm or hard areas that differ from the normal gland but is unable to access the front and inner portions of the gland. Because it cannot evaluate the entire structure, a test is needed that can biochemically indicate abnormalities within the gland. The epithelial cells of the prostate gland secrete a specific antigen which is distinctive only to this gland, called the prostatic specific antigen (PSA). It is a protein digesting enzyme that is made by the epithelial periurethral glands cells of the prostate gland and its function is primarily to liquefy the fluid mass occurring during ejaculation so that sperm can become mobile and find the egg to fertilize it. Testing of this antigen provides a range of values that differentiate normal from abnormal values and can be used to indicate potential prostate cancer.
PSA also activates Insulin Like Growth Factor (IGF-1) which stimulates prostate growth whether in benign hyperplasia (BPH) or prostate cancer.
As a laboratory biologic marker, the prostatic specific antigen, PSA, was introduced in 1986 to initially monitor progression in prostate cancer. In 1994 it became utilized, combined with a digital rectal exam, as a marker for diagnosing prostate cancer as it indicates the total amount of prostate tissue, so its values can be used to correlate a number value with the amount of growth. Testing should begin at 40 with high-risk individuals and otherwise at 50, with a digital rectal exam to detect palpable asymptomatic nodules.
However, several other prostate conditions can elevate the PSA, besides cancer, and can have similar symptoms often making a definitive diagnosis of prostate cancer difficult.
Available Testing with Advanced Biomarkers, Based on PSA Findings
NON-Invasive testing can:
Improve diagnostic accuracy.
Recognize potentially aggressive cancers.
Indicate whether initial or repeat biopsy should be done.
Provide support for actively watching.
Select MDx
This is a noninvasive urine liquid biopsy which can determine a high (Gleason score>7) or low risk of prostate cancer. It measures 2 mRNA cancer biomarkers, HOXC6 and DLX1, that when combined with risk factors such as age, digital rectal exam, prostate size and PSA can help determine the benefit of biopsy and early detection or that avoiding biopsy and continuing follow up is appropriate. It has a predictive value of 95% and high
Exo Dx prostate Test is a urine based liquid biopsy that is indicated for men >50 years old with a PSA of 2-10, who are unsure what to do and are considering a prostate biopsy. It provides a risk score of the potential risk of clinically significant prostate cancer, which is a Gleason score > 7. It is 91% sensitive and 92 % predictive.
Symptoms and Signs common to benign and malignant prostate disease include:
Urinary frequency and urgency
Weakness of the stream or difficulty starting it, especially at night
Blood in the urine or semen
Localized pain associated with the back, hips legs or shoulders can be indicative of cancer-causing pain that has spread beyond the prostate.
Causes of PSA Elevation include:
BPH (benign prostatic hypertrophy
Constipation
Urinary retention
Previous prostate biopsy
Perineal trauma
Recent ejaculation
Prostatitis
Medications that can lower PSA include:
5 alpha reductase medications, finasteride and dutasteride are used to reduce prostate size but also reduce PSA (by 50%)
NSAIDS
Statins
Acetaminophen
Since both benign and malignant prostate disease can present with the same symptoms and signs and an increase in PSA, careful evaluation and repeat monitoring are often required to separate these sometimes-overlapping conditions.
Because of the similarity of benign versus malignant disease, questions have created debate about the usefulness ( sensitivity and specificity) of performing the PSA, as there are questions in prostate cancer diagnosis.
There is evidence from randomly controlled studies that PSA’s can reduce prostate cancer specific mortality.
If the PSA is positive, other doctors believe that a positive test, with an elevated value, can potentially affect a person’s quality of life because it leads to a high proportion of overdiagnosis and therefore overtreatment that is unnecessary.
A European study revealed that while screening PSA testing did uncover a higher incidence of prostate cancer, the benefits from testing were restricted only to men 55-69 years old but that in other groups, mortality (death) from the disease was not reduced.
It is important then, that when deciding to do PSA testing, any decision involve a shared discussion between practitioner and patient.
When You Get a PSA, What Do the Numbers Indicate?
Or what is your risk of prostate cancer based on the number?
The consensus is that there is no absolute number that guarantees all is normal for 100% of men.
The consensus among clinicians is that if your PSA is < 4.0 it is within a zone of being unlikely to indicate prostate cancer. With numbers between 4-10 the risk of cancer is 25%, and above 10 there is both a 50% chance of cancer and a likely extension of disease outside the prostate outer capsule. If the PSA is elevated, a free PSA test is used to gain additional information. Free PSA, measures the % of unbound PSA, in blood, and If it is >25%, indicates a likely benign condition, but if <10% ,a biopsy is indicated when the PSA is high.
The PSA is very important to uncover and/or monitor any cancer recurrence, which occurs in 25% of men. A rise in PSA > 0.2 ng/ml after surgery or > 2ng/ml after radiation indicate probable recurrence.
However, some urologists are now seeing prostate cancer in 15% of men even with a PSA less than 4.0 so they believe biopsy should be performed in the range of 2.5-3.0, for certainty. This again raises questions of subjecting men to many unnecessary biopsies. If your age is >75 most agree that a PSA of <3.0 makes biopsy unnecessary as cancer risk is very low. Also in younger age groups, a value of <2.5 suggests it is safe to do less frequent testing.
Ultimately integrating multiple factors such as, clinical experience, urinary signs and symptoms variables such as race, younger ages, family history and existing health problems all need consideration in the decision to do a biopsy related to the PSA value.
The 4 K Score is a blood test that can be performed after abnormal finding on PSA or digital rectal exam. Based on the PSA findings, the decision to perform a prostate biopsy can use this test to assess the probability of an aggressive cancer, which is considered a Gleason score > 7. It improves the specificity that biopsy would reveal such an aggressive cancer versus men at low risk. It measures PSA, free PSA, intact PSA (an inactive enzyme form of PSA) and human Kallikrein(hK2) combined with age, digital rectal exam, and previous biopsy history to give a personal risk score. Human Kallikrein is an enzyme that breaks down proteins. It is similar to PSA and is produced by the same epithelial cells in the prostate but is associated with highly aggressive prostate cancers.
Proenzyme PSA is used for early detection of prostate cancer in the PSA range of 2-4.
It measures a precursor form of PSA composed of 7 amino acids. 75% of potential prostate cancers can be detected, with 59% of unnecessary biopsies being avoided using the % of proenzyme PSA.
Biopsy
A biopsy of the prostate gland is a sampling of prostate tissue that is currently used as the definitive test to diagnosis prostate cancer and its potential level of aggressiveness.
For decades the standard used in prostate biopsy has been the transrectal ultrasound scan (TRUS) and Biopsy. Using local anesthesia, a biopsy gun inserts a needle into suspected areas and tissue is removed. This entails 12-14 or more individual specimens being taken from mapped anatomical areas of the prostate but done blindly and randomly as the ultrasound cannot differentiate normal from abnormal tissues. It also is unable to reach the midline frontal transition zone which can lead potentially to sampling errors and possibly a missed diagnosis.
In the last several years, innovative techniques as MRI guided biopsy, or MRI and ultrasound biopsy (called a fusion biopsy) have been introduced. These imaging techniques provide real time imaging to reveal the tumor or tumors and their location, size and shape. It is done under local anesthesia, requires fewer needles, in is a more targeted approach.
Additional Available Testing Associated with Biopsy
PCA 3 (Pro cancer antigen 3)
This antigen is measured in the urine of patients having a follow up digital rectal exam, who have had a negative prostate biopsy. It measures a noncoding RNA that is prostate specific and when overexpressed, with a value > 50, indicates probable prostate cancer. It implies existing prostate cancer that was not diagnosed initially and requires additional testing, more biopsies.
When a biopsy is performed, the following complications occur in one third of patients:
Fever
Bleeding
Urinary infection
Pain
Confirm MDx Test
This test is based on using prostate tissue in patients where there is a suspicion of cancer but had a negative transrectal ultrasound biopsy. Since these biopsies are random and cancer can be in more than a single area, if the biopsy is negative but the PSA is rising or elevated it creates a dilemma of what is the next step. This test measures, in the biopsy tissue, three biomarkers for the presence of hypermethylation in the DNA genetic code, which are associated with growth of prostate cancer. Having a positive test places an individual at higher risk of having cancer, and recommends re biopsy.
There are also biopsies that show cells that are not cancer but look different.
Prostate Intraepithelial Neoplasia (PIN)- These cells are seen in 15% of biopsies and are considered precancerous. However, in over 50% of men these cells will transition into prostate cancer.
There is Low Grade Intraepithelial neoplasia in which cells appear close to normal and have a very low related risk of prostate cancer.
High Grade intraepithelial neoplasia indicates cells that look more abnormal and have an increased risk of prostate cancer . In this setting, close follow up is necessary and periodic biopsy or one of the noninvasive predictive tests can be used to attempt early recognition of cancer if it is developing.
The Gleason Score
The Gleason score is a measure of how likely, the risk, that the cancer will grow and spread.
The scores indicate the degree of abnormality of the cancer cells on the biopsy. The higher the number implies that the cells look less and less normal and tend to be more aggressive and higher risk toward progression of the cancer.
There are two numbers listed in the score, which reflect the different grades of disease of the two most common cell types. The first number is the area where the cancer cells are most prominent, and this number is listed first. and the second is the secondary area where they are not quite as prominent. They are added together to comprise the Gleason score.
Scores
2-4 look similar to normal cells.
5-7 look moderately differentiated.
8-10 look different from normal cells.
Gleason Score, survival
Score 2-6: 99% 5-year survival, 98% 10-year survival
Score 3+4: 98% 5-year survival, 92% 10-year survival
Score 4+3: 88% 5-year survival, 76% 10-year survival
Score 8-10: 86% 5-year survival, 69% 10-year survival
Imaging for Prostate Cancer
If the Gleason score is elevated enough to suggest a more aggressive cancer, usually >7, there is a consideration to image the surrounding tissues and lymph nodes to determine if the cancer has spread beyond the prostate outer capsule. As was mentioned above, imaging is also utilized for localizing the biopsy areas for the initial diagnosis, and it can also be used for evaluation if there is suspicion of recurrence after treatment.
Magnetic Resonance Imaging (MRI)
This technique offers clear and detailed pictures of the soft tissue and prostate, using radio waves and large magnets.
It is being used to screen for prostate cancer, in some countries, to reduce unnecessary biopsies.
It is used during prostate biopsy to guide the needles.
It can be used to detect locally invasive disease outside the prostate capsule or invading the seminal vesicles.
It can detect bone metastasis.
Helps determine options for therapy.
Positron Emission Tomography (PET Scan)
This technique is molecular imaging that allows visualization of anatomic areas of cancer growth using radioactive tracer material, injected into the blood, that can be seen by a camera. Virtually all solid cancers can be imaged using sugars as the tracer, but not prostate cancer. Newer tracers use Fluciclvine (F18) and Choline allow for much better detection of the location of the cancer. And even newer PET scans are moving toward using a prostate specific membrane antigen (PMSA) PET scans which uses a newly approved radioactive imaging agent ( 68Ga-PMSA-11)to mark prostate cancer cells, which allows greater sensitivity of recurrence and metastatic disease.
Sometimes it is not unknown precisely where the cancer has spread. In other situations where the PSA begins to rise after treatment and it is unclear whether new disease has emerged, PET scan can be very useful.
Bone Scan
Prostate cancer commonly metastasis to bone. This test uses a low level of radionucleotide material that travels to the bones throughout the body and can be viewed with a camera that detects radioactivity , it creates a skeletal image of the bones. It is not a stand-alone test and confirmation with another type of imaging is needed, whether x-ray, CT or MRI.
Computerized Tomography (CT scan) is all used for viewing the body areas in cross sections. It is not indicated if the cancer is confined to the prostate but is useful for evaluating spread to local lymph nodes or determining in recurrence if it has spread to other organs or tissues.
Treatment Options
For men with newly diagnosed prostate cancer, there are multiple options for treatment, that are risk stratified based on a composite of the information integrated at the initial evaluation, before treatment starts. The variables that are considered in treatment decisions are:
Digital rectal exam, and whether an abnormal exam indicates cancer.
Serum PSA test.
The Gleason score and how the cells look under the microscope, called the histologic grade.
The Gleason scores are now placed in a grading system with the two most prominent patterns. These include from best, grade 1 to worst grade 5.
Group 1-Gleason scores 3+3
Group 2-Gleason scores 3+4
Group 3-Gleason scores 4+3
Group 4- Gleason scores 4+4,3+5, or 5+3
Group 5-Gleason scores 4+5, 5+4, or 5+5
Localization and Risk Combinations
It is most important to understand how these above combinations influence and direct decisions in treatment. The impression would be that if the cancer is confined to the prostate gland the prognosis is better. And overall, this is true---BUT even if cancer is confined to the gland, with higher elevations of PSA numbers, higher Gleason scores, and /or multiple positive biopsies the risk of progression increases and is distinctly different than men with lower valuations. Often in these higher risk situations, further imaging is indicated, to rule out locally invasive or distant disease as well as consideration of more aggressive treatment initially.
Risk Assessment
Very Low
Intermediate Risk
Unfavorable Intermediate Risk
High Risk
Very High Risk
All risk assessments also need to take into account a person’s age, constitutional strength, other medical issues, symptoms, and personal input as to preferences in treatment.
Prolaris: Is a risk assessment test that can be utilized prior to the initiation of treatment. It uses clinical findings with pathologic staging, but with a genetic assessment as to the aggressiveness of the cancer.
Promark relies on the signature of 8 proteins that reveal the likely hood of lower risk and allow considerations for lower-level therapy considerations.
Staging
The staging system is a standard way of describing the anatomic extent of disease or where it is located. It is used for solid tumors, and is described as :
TNM, tumor/nodes/metastasis.
Stage T1: is not detected on digital rectal exam or imaging. It is an incidental finding when prostate surgery is done for some other reason.
Stage T2: the tumor is confined to the prostate.
Stage T3: the tumor extends outside the prostate.
Stage T4: the tumor has spread to tissues near the prostate.
Stage N: the tumor is in the nearby regional nodes.
Stage M: the tumor has spread to distant areas.
Precision Medicine: Using biopsy material, tissue-based profiling of specific prostate cancer biomarkers have developed to improve risk stratification for treatment management decisions. These tests use the highest Gleason pattern to assist whether to consider active surveillance, identify significant disease, or after prostatectomy whether to use additional adjunctive treatment or radiotherapy.
Decipher is a genomic test, from the tissue biopsy. It is based on 22 relevant RNA genes that uses its databases to create a score to indicate the level of risk of an individual’s prostate cancer. It calculates survival, metastasis risk, and also men at low risk that could choose active surveillance.
Studies are still ongoing to assess their accuracy on long term outcomes, quality of life and survival.
The Initial Approach to Low Grade Localized Disease ( Stage 1 and Stage 2)— is based on a cancer diagnosis from a biopsy where there is a low Gleason score, usually 3+3 or 3+4, and the cancer is categorized as localized, low grade and low risk. Even when the cancer is localized when found, higher Gleason scores suggest a higher risk of spread, and in discussion with the patient, most commonly treatment is recommended, as the cancer is no longer considered low grade and low risk.
If the biopsy does reveal a low-grade localized disease, studies can confirm a recommendation more conservative approach to treatment, Active surveillance. It is the postponement of definitive treatment unless there is clinical evidence of progression, with the intention then to have curative treatment. Watchful waiting is very different. It is a decision made at the outset of diagnosis that there will be no definitive treatment, with palliative treatment when progression occurs. These patients often have very short life span or other serious illnesses.
Clinically Localized, Low Risk Prostate Cancer
In what is considered clinically localized low risk cancer, the growth rate is very slow, and it often takes years before symptoms or signs develop.
Based on this pattern, active surveillance has been practiced for 20 years. It has become recognized and widely adopted for Gleason Scores 3+3. All men in active surveillance require close follow up and require periodic PSA’s every 3-6 months, a DRE yearly and another prostate biopsy within 6-12 months, and then a biopsy every 2-5 years. And for selective men with Gleason 4+3 whose percentage of grade 4 cells is low, as well as a negative MRI, provided they too are followed closely, active surveillance can be an acceptable choice.
If testing and biopsy do reveal progression, then the consensus is that treatment should be initiated. Even practicing strict compliance to the surveillance protocol, for many men it is an unacceptable choice due to high levels of anxiety over the possibility of progression.
Active surveillance does confer a slightly higher risk of progression of 0.2-5% over 15 years but there are now biomarker tests that can assist in the decision process and reveal those with greater risk.
It is acknowledged that men in active surveillance have a better quality of life due to avoidance of the complications associated with definitive treatment. Currently this is the chosen option of 42% of men.
If treatment rather AS is chosen in this localized low risk group, the current recommendation for definitive therapy is radical prostatectomy, brachytherapy, or external beam radiation when life expectancy is greater than 10 years.
Studies support the premise that in low-risk disease, the choice of treatment with AS or a choice of definitive care with radical prostatectomy or radiation, offers a low risk of cancer death, regardless of choice of therapy. It should be noted that in a major study, a higher risk of progression in the active surveillance group was seen BUT had also included men with intermediate and high-grade cancers that were localized to the prostate.
For Local Disease if Active Treatment Is the Option
Surgery
Radical Prostatectomy is the surgical removal of the entire prostate along with the seminal vesicles and may also include removal of the pelvic lymph nodes. It is effective control of localized disease and provides tissue samples that make it possible to get much better prognostic information. Also, If the PSA starts increasing the source of recurrence would be known to involve adjacent regional tissues, lymph nodes or distal spread as the glandular source has been removed. Cancer recurrence, after surgery is considered to have occurred if the PSA increases by 0.2ng/mL on two separate occasions.
Complications
Two of the major complications with surgery include:
Erectile dysfunction- impotence is common and expected in all men if the technique of nerve sparing surgery is not performed. Several centers report potency rates of 80% with nerve sparing surgery, in their select group, but this frequency is much lower when patients are asked. In situations of persistent erectile dysfunction treatment modalities include penile injections, vacuum devices, and penile prosthesis.
Urinary incontinence- is most common immediately after surgery, and gradually improves. Often biofeedback and physical therapy are utilized during the early post op months to help control symptoms as the nerves and sphincter function improves.
Radiation Therapy
Robotic Prostatectomy is the surgical removal of the entire prostate with a small incision, like the radical prostatectomy, but the surgery is carried out with the surgeon using a mechanical arm that has a camera for viewing the field.
Both procedures have similar results in cancer control, urinary control, and erectile issues. Younger men in good health (< 65 and >10-year life expectancy) seem to get better cancer control than older men.
Incontinence is generally temporary but can be permanent in a small percentage of men. But again, younger men fair better than older men. The frequency of this problem is similar regardless of the technique used but is more influenced by the amount of prostate tissue that is removed and the skill of the surgeon doing the procedure.
There are the Partin tables, that combine the variables of the Gleason score, the PSA and the clinical stage to provide an accurate predictive probably of the Pathologic stage after the radical prostatectomy.
The goal of radiation therapy for localized prostate cancer is to deliver the calculated therapeutic dose to the tumor that is necessary, while minimizing its effect on normal tissues. Its use in prostate cancer includes:
Using external beam or brachytherapy for localized low risk prostate cancer achieves the same disease control as radical prostatectomy.
As the first treatment for cancer that has extended outside the prostate gland into normal tissue, in combination with hormone therapy.
For situations where there is incomplete tumor removal, or it recurs in an area after prostate surgery.
In palliation, to attempt to keep the cancer controlled and especially to relieve symptoms.
With radiation therapy as well as brachytherapy, the PSA does not drop to an undetectable level, so it is deemed a biochemical failure, or unsuccessful treatment, if the value of the PSA rises 2ng/ml or higher, above that individual’s lowest measured point, after treatment is completed.
External Beam Radiation Therapy is a stand-alone treatment for local low risk prostate cancer and to relieve bone pain in metastatic disease. It is directed from an external source outside the body at the prostate tumor areas and the margin around it. When used as the primary disease treatment its success is similar to that achieved with radical prostatectomy. Treatment is given on a daily basis, using measured increments of radiation until the calculated therapeutic dose is achieved. It is often 4-6 weeks but newer protocols are shorter in duration.
The standard of care now uses a 3-dimensional radiation therapy approach that can deliver higher doses to the tumor, with less toxicity to normal tissues. Some techniques use imaging guided treatments, allowing variations in intensity to irregular or complex tumors or allow for accelerated rapid courses of treatment. Another external beam treatment is proton beam therapy which uses charged proton particles which are more focused on the target and with less spread into normal tissues. It does not appear to offer any benefits over the above-mentioned approaches.
Complications
Urinary symptoms occur in 50% of patients with symptoms of dysuria, urgency, and radiation cystitis. These issues resolve after several weeks as the bladder inflammation heals.
Erectile dysfunction increases over time and can be in the moderate to severe range, affecting two thirds of men.
A Gastrointestinal side effect is acute radiation proctitis that occurs in 20% of men with pain, cramps, urgency and frequent stools and it can persist long term in a small percentage of men. If the nodes are radiated there can also be inflammation of the intestines, called enteritis.
Brachytherapy is indicated for very low, low, and favorable intermediate risk prostate cancer. It involves placing radioactive seeds into the prostate tissue via a trans perineal approach using ultrasound or MRI guidance. The goal is to place a maximum dose of radiation directly into the prostate cancer, killing cells, while being able to minimize radiation exposure to normal areas.
It is generally used in early, low grade slow growing prostate cancer or is combined with external beam radiation for cancer that has extended outside the gland.
There are two types of Brachytherapy:
High-dose implants
In this treatment, the radiation source is left in for 10-20 minutes at a time, then removed. Thin needles are inserted between the scrotum and anus( the trans perineal approach) and into the prostate. The radioactive material is iridium 192 or cesium 137. Typically, 2-4 treatments are given over 2 days.
Brachytherapy offers the advantage of one or a few treatments rather the daily requirement with external beam radiation. This therapy is equal to surgery and external beam radiotherapy in control of prostate gland tumors.
These therapies should be avoided if there co existing chronic urinary issues, a previous prostate surgery for urinary symptoms from BPH or currently a large prostate.
With the diagnosis of prostate cancer in younger men, and the use of less invasive treatments in low grade disease, such as surgery, it is important to know that there is a link between radiation therapy and bladder cancer and colon cancer. Therefore, long term follow up is needed with the completion of treatment.
Low -dose brachytherapy with Permanent implants
Radioactive seed implants are inserted with iodine 125 or palladium-103 using thin needles inserted through the skin between the scrotum and anus. These are permanently placed, and the implants remain in the body for life. The radiation is released slowly mostly in the first 3 months, and by 8 months most of the radiation has dissipated. The seeds work in a small area creating less damage to healthy tissue. It is advised to remain away from pregnant women and children for months after therapy, and if traveling the radiation may set of the TSA detection system.
Complications:
Urinary symptoms include frequency, dysuria and urgency which slowly develops several days after the seeds are implanted. The prostate can also acutely swell obstructing urine flow and requiring catheterization. There are late issues with urethral stricture and urine retention and incontinence.
Erectile dysfunction takes variable time intervals to develop. It does appear the older you are and the higher your BMI the more likely there will be dysfunction.
Gastrointestinal symptoms are less frequent than urinary ones but occur in 10% of men can be symptomatic with diarrhea and urgency, to bowel ulceration, or fistulas; which are abnormal connections between the rectum and prostate.
Radiopharmaceuticals for Targeting Prostate-specific Membrane Antigen (PMSA)
This protein antigen, PMSA, exists in large amounts on prostate cancer cells. The radiopharmaceutical called Lu=PSMA=617 or Pluvicto can attach to this antigen thereby bringing radiation directly to the cancer cells. To see if the cancer has this antigen, a PET scan with PMSA is used to demonstrate these receptors on the cancer cells, indicating that this treatment is appropriate. It is indicated in advanced disease that has failed both hormone therapy and chemotherapy. It is infused via vein weekly for 6 doses.
Possible side effects:
85% low lymphocytes
56% low white blood cells
43% fatigue
36% dry mouth
24% decreased kidney function
Localized Intermediate-Risk Prostate Cancer
These men have prostate cancer localized to the gland, but the extent of disease is much more, involving more than half of one lobe or bilateral disease, in both lobes. There is no extension outside of the prostate or involvement of the seminal vesicles.
These men are further divided into:
Favorable Intermediate risk disease:
Stage T2b, a single nodule in over ½ of one lobe or T2c, tumor in one or both lobes OR
Gleason score 3+4=7, which is Grade 2 OR
PSA 10-20 ng/mL AND
Number of + biopsies < 50%
In favorable disease, treatments can be utilized in a similar manner to low risk, with close surveillance and necessary compliance by the patient.
Unfavorable Intermediate Risk disease:
The T scores are the same.
The Gleason scores are Grade 2 or 4+3, a Grade 3
PSA 10-20 ng/mL
And > 50% + biopsies.
Therapies for Localized Intermediate Risk that is unfavorable.
Radiation Therapy with either external beam or Brachytherapy are utilized in this category of disease. But because there is an increased risk of recurrence and spread with radiation alone, androgen deprivation therapy (ADT) is recommended as combination therapy. There is information on this combination as being more effective than radiation therapy alone. Using tissue based molecular assays can also offer more information and perspective on what the prognosis of risk are using these therapies.
Systemic Treatments
These treatments are used in multiple situations that include:
Higher risk of progression of localized disease
Recurrent disease
Locally advanced disease
Metastatic disease.
Systemic Hormone Therapies in Prostate Cancer treatment
The drug side effects mentioned here are only those that occur in a high percentage of men, but don’t reflect many others that can potentially occur.
Androgen Deprivation Therapy
An essential feature for prostate cancer progression is the stimulation of growth from the binding of male hormones, androgens, on prostate cancer cells. Therapies are designated to act like castration, which would be the removal of male testicles and thereby remove androgen hormones. These drug therapies are therefore called androgen deprivation therapies (ADT) as they target the androgen receptors on the prostate cancer cells, blocking tumor progression and causing their regression.
Androgen deprivation therapies (ADT) can either block the production of androgen hormones, or once made, can prevent them from binding to cancer cells. These are effective first line treatments for hormone sensitive prostate cancers. Since most of the androgens in the body are made in the testes, another uncommon option, used by 5% of men, is the actual removal of the testicles using a surgical procedure called an orchiectomy, or surgical castration. Once surgery is done, it is permanent whereas with medications some level of function can return if the drugs are stopped. In situations where prostate cancers become resistant to hormone therapy or are aggressive and at high risk of spread, combinations of these and other therapies are used.
Often men already receiving radiation therapy for intermediate risk and high-risk prostate cancer will chose to combine it with androgen deprivation therapy to enhance the possibility of a cure.
LHRH or GnRH agonists or also called analogs--- work to control the brains stimulation of androgen production.
The pathway for androgen production originates in the hypothalamus, in the brain, which produces LHRH, luteinizing releasing hormone, (also called GnRH) which then messages the pituitary gland to produce another hormone, Luteinizing hormone, LH. This LH hormone then stimulates the Leydig cells in the testes to produce androgens, or sex hormones like testosterone.
This system is a feedback loop, based on supply and demand. When enough androgen is produced, this hypothalamus/pituitary axis, as it is called, reduces their hormone secretion to slow androgen production but when hormone levels fall, these hormones are again increased and androgen production increases. Hypothalamus regulation is not completely understood; but is probably regulated in part by messaging via the central nervous system and also by the body’s testosterone levels. The system then is activated or slowed based on both hormonal and neurologic cues. But androgen increases or decreases are not an all or nothing effect. Levels are constantly titrated and adjusted, up or down, to maintain a constant balance of homeostasis.
In 1941, Dr’s Huggins and Hodges reported the dramatic effect of suppressing testosterone on advanced prostate cancer. It could be accomplished either via castration, which removed the source of androgens or by the suppression of LHRH, in the hypothalamus, using DES, diethylstilbestrol. Both methods achieved their goal of decreasing bone pain from metastasis, and improved quality of life. And while DES was associated with cardiac toxicity, DES hormonal treatment became widely adopted, at that time, and used for advanced prostate cancer.
In 1971, a purified form of LHRH was developed which downregulated or desensitized the pituitary cell receptors, so they produced less LH and therefore less androgens. This drug, Lupron (Leuprolide) replaced most treatment with castration and all DES. It is called an LHRH agonist, or analog that lowers the amount of testosterone made by the testicles. It is also called medical castration as it lowers testosterone just as removing the testicles would.
LHRH agonists: can all lower androgens, male sex hormones, to levels equivalent to castration by blocking the pituitary gland from secreting Luteinizing hormone, but it does not stop adrenal production. Several are currently available.
Lupron (Leuprolide, long-acting suspension)
98% excessive sweating
24% pain
31% depression
Zolodex (Gosrelin, implant)
64% hot flashes
Trestar (Tritorelin, injection)
73% hot flashes
40% Impotence
Ventas( Histrelin) subcutaneous)
66% hot flashes
Similar side effects are seen in all these drugs and include: Hot flashes 62%, Diarrhea 36%, Erectile dysfunction 18%, Sexual dysfunction 21%
The effects of these drugs are reversible, and some level of androgens can again be produced when these drugs are stopped.
There is a phenomenon called testosterone flare which can occur with the initial use of these drugs. The LHRH agonists can cause a temporary increase in testosterone by causing a temporary LH surge before blocking its release. Its effect can cause increased existing symptoms of bladder obstruction, bone pain or compression of the spinal cord. To reduce this risk another hormone is given that block the increased androgen produced.
LHRH Antagonists (not agonists)
These hormones block LHRH receptors in the pituitary and prevent LHRH from binding there and thereby preventing LH from being secreted, and effectively prevents the testes from producing androgens. These do not cause testosterone flare. Their use is for mainly in advanced disease.
Firmagon (Dargelix), an injection
47% Increased liver functions
44% injection site pain, redness, swelling.
40% low hematocrit
26% hot flushes
20% abnormal EKG
Orgovyx (Relugolix), a pill
44% elevated blood sugar
54% hot flashes
30% musculoskeletal pain
29% elevated liver functions
Anti-Androgen Therapies
Androgen receptor blockers, also called Androgen receptor antagonists
The androgen receptor blockers are used when the hormone therapies that block the production of androgens are no longer effective. This is situation is called drug resistance and implies that androgens are increasing in amount and can bind on the prostate cancer cells and augment growth. The anti-androgens are drugs that can be used to occupy the androgen binding sites making them no longer available for native androgens to attach and allow cancer progression.
However, they are not commonly used alone to treat prostate cancer, as they do not stop the production of androgens. To effectively create a stronger or complete blockade of these male hormones, they are combined with an LHRH drug or orchiectomy as these drugs stop the production of androgens in the testes.
First generation androgen blockers
Casodex (Bicalutamide)
35% generalized pain
25% back pain
21% pelvic pain
53% hot flashes
Nilandron (Nilutamide)
57% impaired adaption to night vision
60% hot flashes
25% pai 24% nausea
20% constipation
Second generation drugs are stronger at blocking the androgen receptors than the early drugs.
Xtandi (Enzalutamide)
59% fatigue
29% back pain
20% hot flashes
22%constipation/diarrhea
14%high blood pressure
Erleada (Apalutamide)
70% anemia
40% low white cells and lymphocytes
35% fatigue
24% high blood pressure
Nubeqa ( Daroluamide)
23% Elevated liver functions
16% fatigue
Androgen Synthetase Inhibitors block production of all androgens in the body, as medical therapies and castration don’t prevent the adrenals and prostate cells from producing small amounts androgens, and any production can support the growth of prostate cancer. These synthetase inhibitors lower testosterone to the greatest extent of any treatment by inhibiting an enzyme that makes testosterone from cholesterol.
Zytiga (Abiraterone)/prednisone or Yona (Abiraterone) is an androgen biosynthesis inhibitor that stops the production of androgens including in the adrenals.
63% increased triglycerides
56% increased blood sugar
38% low lymphocytes( immune cells)
21% high blood pressure
Ketoconazole an anti -fungal
Aminoglutethimide used in the medical disease Cushing’s syndrome when the adrenals make too much hormone.
ADT Intermittent Use
These drugs act on the adrenal cortex and slow or block steroid production. It effects testosterone production that is not controlled by the hypothalamus/pituitary/teste’s pathway of androgen production.
The initial use of androgen deprivation therapies was continuous, for life, or until it was no longer was effective in controlling the cancer. Over the recent years, there have been studies that recommend the use of androgen deprivation therapy (ADT) intermittently. It is often used for six months, stopped temporarily, allowing testosterone to be produced and then reinitiating therapy when the PSA begins to rise. There is no consensus among oncologists what amount of rise dictates restarting therapy, however.
And while it does not appear to as effective as lifelong ADT, it does allow for a reduction in the side effects due to low testosterone and it offers an improved quality of life. It is contraindicated in men with metastasis.
Androgen Deprivation Side effects: All the drugs that block the production, the effects or actions of androgens are considered to cause androgen deprivation.
These drugs, for an unknown reason, increase the risk of metabolic syndrome; a complex of obesity, elevated blood pressure and cholesterol that raise the risk of cardiovascular disease and diabetes. Both medication and surgical castration cause this and even if it is short term medical hormone therapy that is temporary.
The side effects mentioned for all the drugs discussed in this section affect the highest percentage of people but refer to the appendix to see the other potential side effects of these treatment drugs. There are however many milder ill effects that are temporary related to medications, but the effects can persist for several years. Please discuss the benefits as well as the potential risks associated with hormone therapy to understand what treatment entails.
Most have the following therapies with long term use, to some extent cause:
Osteopenia or osteoporosis
Depression
Weight gain
Insulin resistance
Muscle mass loss
Treatment of Bone Loss
The effects are well known of the increased bone loss and increased fracture risk associated with the hormone deprivation in prostate cancer. It is essential to maintain bone mass for a higher quality of life and greater longevity. It is essential to know that with nonmetastatic disease offering prevention, regular screening and necessary therapies are essential to preserve bone.
ADT causes the most significant bone loss in the first year as well as decreases muscle mass, with an increased risk of frailty and fractures from a fall. Fracture rates are 2.9% in the first year and up to 20% at 10 years.
Current measurement of bone loss is with a DXA scan which is accurate for bone mineral density (BMD) but not at predicting fracture risk. This can be provided by a FRAX assessment which is a tool that integrates BMD and other variables for fracture risk. Pharmacologic treatments include:
Prolia or Xgeva (Denosumab) a monoclonal antibody that blocks a protein that causes cells to break down bone and increase loss.
Reclast or Zometa (Zolendronic acid) are bisphosphonates that reduce bone loss reducing the resorption or breakdown of bone and release their minerals.
Integrative treatments Include:
Avoid refined sugars and soft drinks, reduce caffeine and alcohol.
Calcium 600-1200mg/day
Magnesium 300-600mg/day, Trace minerals
Maintain adequate Vitamin D levels > 50.
Ipriflavone is synthetic soy flavonoid from Daizein that has been shown to reduce bone loss.
How Is Hormone Therapy Used
Early-Stage Prostate Cancer with an intermediate or high risk of recurrence
Hormone therapy is often given to men in these categories. While it is early disease there are factors that require consideration, making it more likely to have recurrence.
Tumor grade determined by Gleason score, the higher the score the greater the risk.
Additional testing that might suggest higher risk of progression.
Treatment initially is prostatectomy or radiation, but often hormone therapy can be given before, during or after radiation, or before or after prostate removal. Any extension beyond the prostate or involving lymph nodes is considered advanced disease, making combination therapy important so as to reduce the risk of progression.
Recurrent Prostate Cancer
Following radiation therapy or prostatectomy, many men achieve cure. Twenty to twenty-five percent men however will develop what is termed biochemical recurrence, which is considered a rising PSA after these forms of therapy. It occurs usually between 2-3 years after treatment and Radiology imaging with MRI, CT or bone scan, does not reveal metastatic cancer. The diagnosis is based on the rising PSA.
After prostatectomy, the PSA falls to zero and a rise in the PSA of 0.2ng/mL on two separate occasions is considered to signify recurrent disease. One option for continued treatment is radiation. Factors that influence this treatment decision depend on the Gleason score, how long it has taken for disease to reoccur, the pathologic stage and the speed of change in the PSA over time, called PSA doubling time. Even with radiation treatment for biochemical recurrence, it is also recommended that hormone therapy with androgen receptor blocker or androgen deprivation therapy be given, as biochemical recurrence is considered a systemic not a local recurrence.
After radiation therapy, there is still some normal prostate tissue left, so each individual’s lowest PSA value is considered their baseline. A rise of 2ng/mL above that lowest value or nadir is indicative of recurrent disease. Treatment in this situation is also systemic, using androgen receptor blocker or androgen deprivation therapy.
Biochemical recurrent disease is considered advanced disease but there are less definitive recommendations, especially which androgen deprivation treatment and how long to use it. The clinical experience of your oncologist is the most reliable source of information and treatment skill for your individual situation.
Erleada (Apalutamide)
70% elevated glucose
70% anemia
25% high blood pressure
24% rash
Casodex (Bicalutamide)
35% generalized pain
25% back pain
21% pelvic pain
53% hot flashes
Xtandi (Enzalutamide)
51% fatigue
29% back pain
21 % joint pain
22% diarrhea/constipation
Nubeqa (Daroluamide)
23% Elevated liver functions
16% fatigue
Nilandron (Nilutamide)
57% impaired adaption to night vision
60% hot flashes
25% pain
24% nausea
20% constipation
Castration Resistant Prostate Cancer
If you are taking hormone therapy, it is not possible to predict the length of time it will be effective for your cancer. CRPC is considered advanced disease and is said to have occurred if there is progression of existing disease despite being treated with androgen depletion therapy. Your oncology follow up visit reveals that the PSA continues to increase, or imaging shows there are new metastatic lesions. These both indicate the cancer is growing, and no longer completely responsive to hormone therapy, even while maintaining low testosterone levels (<50 ng/dl). Current treatments will maintain your ADT as stopping it will allow the testosterone to increase and that would contribute to more cancer growth.
The available therapies used in this situation include the following options:
Androgen Receptor Blockers
Taxotere (Docetaxel)
98% low white blood cell count
94% anemia
98% hair loss
60% fluid retention
54% rash
Jevtana ( Cabazitaxel)
Approved as chemotherapy for men already treated with Taxotere.
Side effects include:
96% Anemia
94% low white blood cell count
47% diarrhea
37% fatigue
Chemotherapy
Zytiga (Abiraterone)/Prednisone
Zytiga (Abiraterone)/prednisone is an androgen biosynthesis inhibitor that stops the production of androgens including the adrenals.
Side effects include:
63% increased triglycerides
56% increased blood sugar
38% low lymphocytes( immune cells)
21% high blood pressure
Provenge (Sipuleucel-T)
Immunotherapy uses a cell-based vaccine made from a man’s own immune cells to fight metastatic prostate cancer.
71% infusion reaction
41% fatigue
31% fever
30% back pain/19% joint ache
20% nausea
18% headache
Xofigo (Radium-223 dichloride)
51% fatigue
29% back pain
21 % joint pain
22% diarrhea/constipation
Rubraca (Rucaparib camsylate)
PARP inhibitors are drugs that inhibit an enzyme PARP which helps to repair damaged DNA. These drugs are used to treat castration resistant prostate cancer that have certain mutations.
79% nausea
45% hives
31% anemia
61% low white blood cells
Nilandron (Nilutamide)
57% impaired adaption to night vision
60% hot flashes
25% pain
24% nausea
20% constipation
Olaparib (Lynparza)
PARP inhibitors are drugs that inhibit an enzyme PARP which helps to repair damaged DNA. These drugs are used to treat castration resistant prostate cancer that have certain mutations.
98% anemia
77% decreased lymphocytes
67% fatigue
60% nausea
24% diarrhea
Androgen Synthesis Inhibitors
Metastatic Hormone Sensitive Prostate Cancer
Metastatic disease is incurable but can be controlled for extended periods with newer treatments. Often metastatic disease may be progressing, but it is usually slow growing, and many men will die from other causes than their cancer. Prostate cancer, as with many types of cancer, are today becoming chronic illnesses with people living extended lives while remaining on medications. There are large numbers of people with chronic conditions; heart disease, chronic lung disease, diabetes, and autoimmune diseases who have chronic long-term diseases which are controlled on medication, reducing symptoms, and offering a high quality of life; and the same is occurring with advanced prostate cancer.
Metastatic prostate disease might be diagnosed in newly diagnosed situations with imaging or as a manifestation of disease progression. If there is a high level of testosterone then disease is termed metastatic without castration, implying androgens are being made. In previous decades androgen deprivation therapy (ADT)was the standard of treatment and used until progression developed, which was then termed castration resistant disease, or a person’s cancer was resistant to hormone therapy. Recently, trials have shown that the addition of other therapies, in combination with ADT, have extended survival longer than just using ADT.
Androgen Synthesis Inhibitors
Taxotere (Docetaxel)
Used in castration resistant progressive metastatic prostate cancer when added to ADT. Studies have shown this combination to increase overall survival.
Erleada (Apalutamide) is an androgen receptor antagonist used in metastatic hormone sensitive disease, which confirmed in the Spartan study that it improved metastasis free survival by 2 years.
76% elevated cholesterol
70% elevated glucose
70% anemia
25% high blood pressure
24% rash
Zytiga (Abiraterone)/prednisone is an androgen biosynthesis inhibitor that stops the production of androgens including the adrenals. It is used currently:
In newly diagnosed metastatic cancer that is hormone sensitive
In castration resistant progressive metastatic prostate cancer which when added to ADT is shown to increase overall survival. (Prednisone is added to decrease some of Zytiga’s other side effects).
63% increased triglycerides
56% increased blood sugar
38% low lymphocytes( immune cells)
21% high blood pressure
Xtandi (Enzalutamide) is an androgen receptor antagonist indicated for non-metastatic castration resistant prostate cancer. It was found to delay metastasis.
51% fatigue
29% back pain
21% joint pain
22% diarrhea/constipation
Metastatic Castration Resistant Prostate Cancer
Xtandi (Enzalutamide) is an androgen receptor antagonist indicated for non-metastatic castration resistant prostate cancer since it was found to delay metastasis. This drug might be considered in aggressive rapidly progressive disease.
51% fatigue
29% back pain
21% joint pain
22% diarrhea/constipation
Zytiga (Abiraterone)/prednisone is an androgen biosynthesis inhibitor that stops the production of androgens including the adrenals. It is used currently:
In castration resistant progressive metastatic prostate cancer which when added to ADT is shown to increase overall survival. (Prednisone is added to decrease some of Zytiga’s other side effects).
In newly diagnosed metastatic cancer that is hormone sensitive.
63% increased triglycerides
56% increased blood sugar
38% low lymphocytes( immune cells)
21% high blood pressure
Metastatic Bone Pain
Strontium and Samarium are beta emitting radioactive substances that when injected are absorbed near the bone and radiate the area, attempting reduce the tumor size and thereby reduce pain. It does not improve survival.
Radium 223 is another radioactive substance that is used in castration resistant cancer for bone pain.
Integrative Support
Pectasol C has shown in a recent study from Israel that was used to treat non metastatic biochemical relapse with a supplement, modified citrus pectin. It is recognized by the FDA as safe, and the data after 18 months of treatment showed that 62% experienced decreased or stable PSA, 85% had no signs of disease progression based on scans and biochemical testing. Also, there were no adverse effects or toxicity seen.
A study suggests that higher levels of omega 3 fish oils can decrease prostate cancer mortality. But the recommendation is for more studies to confirm this finding.
Multiple studies have concluded that the sulforaphane from broccoli and brassica family veggies both prevent the development and progression of prostatic tumors.
Studies have shown the Ganoderma(Reishi) mushrooms suppress prostate cancer cell migration, proliferation and growth.
Prostate Prevention
Coffee: a ten-year study of 48,00 men revealed:
6 cups/ day lowered the risk of prostate cancer by 20%
Highest intake( café or non-café) reduced aggressive prostate cancer by 60%
1-3 cups also lowered risk of aggressive prostate cancer by 30%
Cruciferous Vegetables:
Cruciferous veggies reduce the risk of prostate cancer, by decreasing initiation as well as blocking progression. It is believed it acts by affecting the messaging, epigenetics, on prostate cancer cells. The protection comes from the chemical constituents in the vegetables, indole 3 carbinol and sulforaphane.
Erectile Dysfunction
The data seems to be about ED in men that do not have cancer and is usually related to vascular disease. The information is worth considering related to ED associated with prostate cancer.
Men with very low Vitamin D levels seem to benefit by increasing the levels as a level <30 seems to promote endothelial ( the inner lining of blood vessels) dysfunction.
There are also studies that in men with vascular ED, nitric oxide is the physiologic stimulus for erection. Men given L-arginine, the precursor to nitric oxide and L citrulline, which is converted to L- arginine have improved erectile function. Again, it has been studied in men with vascular issues related to ED but it may be worth considering if other medication as techniques fail.