This is the prostate cancer natural history. As you can see in the figure it progresses very slowly and the patient may survive for years after diagnosis. The first peak correlates with localized disease and is treated with local therapy in most of the cases. We will discuss this in detail later.
The second peak correlates with recurrence after local therapy or metastatic disease. It is treated with local or systemic therapy.
The third peak correlates with the castrate-resistant prostate cancer, that is the disease which has progressed on hormonal therapy. It is usually treated with chemotherapy but other agents may also be used.
Androgen Deprivation Therapy or Hormonal Therapy for Prostate Cancer
Hormonal therapy, also known as androgen suppression therapy or androgen deprivation therapy (ADT), is one of the most effective and most widely used therapy option for Prostate cancer. Hormonal therapy consists of various drugs that act by decreasing the concentration of androgens in the blood or by inhibiting the stimulatory action of androgens on the prostate cancer cells.
ADT is the most commonly used primary systemic therapy for the management of localized or advanced prostate cancer. It can be employed as neoadjuvant (prior to surgery or radiation), concomitant (in combination with surgery or radiation), or adjuvant (after surgery or radiation) therapy for the management of locally advanced or metastatic (that has spread to distant body parts like bones, liver, lungs, or brain) prostate cancers.
The pituitary gland releases LH and FSH, which directly acts on the testis to release testosterone. ACTH released from the pituitary gland acts on the adrenal gland to release DHEA, which subsequently gets converted into testosterone.
The testosterone released from testis and adrenal gland enters the prostate cell and gets converted into DHT which causes the growth and survival of prostate cancer cells.
GnRH agonists/antagonists (Leuprolide, Goserelin, Dagarelix)
These act on the pituitary gland and prevent the release of LH/FSH and ACTH as shown in the figure below.
Cytochrome 17P Inhibitors
These prevent the release of testosterone from testes and adrenal gland as shown below. Cytochrome P450 type 17(CYP17), an enzyme required for the secretion of androgen from the adrenal glands.
Cytochrome 17P Inhibitors prevent the release of testosterone from testes and adrenal gland as shown below.
Abiraterone has been approved, in combination with low-dose prednisone, for the treatment of the asymptomatic patients with metastatic CRPC who have not received prior chemotherapy or patients with metastatic CRPC who have initially received the docetaxel-containing chemotherapy.
Androgen Receptor Blockers (Bicalutamide, Nilutamide, Enzalutamide)
These prevent the binding of testosterone on androgen receptors on prostate cancer cells, thereby reducing their growth and survival. Enzalutamide has been approved as the first-line treatment for the asymptomatic patients with metastatic CRPC who have not received prior chemotherapy or subsequent-line treatment for patients who have received prior docetaxel-containing chemotherapy. Another method for androgen deprivation is surgical castration in which both testes are removed. Unlike medical construction, it is a one-time procedure.
Treatment of Hormone Sensitive Prostate Cancer
The prostate cancer treatment depends on patient’s performance status, life expectancy, comorbidities, stage of the disease, along with other factors. For hormone naive disease, the treatment decision is taken based on the risk of the disease.
Very Low to Low-Risk Disease
T1a-2 N0 M0, PSA<10, GG=1
Active surveillance is the preferred treatment approach in such cases.
T2b-2c N0 M0 PSA<20 GG=1 TO T1-2 N0 M0 PSA<20 GG=3-4
Active surveillance is the preferred treatment for elderly, comorbid patients with less than 10 years of life expectancy. Whereas, radical prostatectomy and/or radiotherapy is recommended for younger patients with good performance status and better life expectancy. Androgen deprivation therapy may also be required in some cases. Chemotherapy is also an option for some cases.
T1-2 N0 M0 PSA>/=20 GG=1-4 TO Any T N0 M0 Any PSA GG=5
In high risk disease, radical prostatcetomy or radiotherapy is the standard treatment. Androgen deprivation therapy may be added. Chemotherapy is also an option for some cases. In case of an elderly patient with poor life expectancy, androgen deprivation therapy or active surveillance may be considered.
Low volume metastasis can be treated with androgen deprivation therapy with or without radiotherapy. Chemotherapy may also be considered. For high volume metastatic disease with a vast spread of disease to distant organs, chemotherapy plus androgen deprivation therapy is the standard treatment.
Difference between Observation and Active Surveillance
These are the options mainly in early stages of disease. Observation is preferred when the life expectancy of the patient is less than 10 years. PSA is done every 6 to 12 months for an initial 5 years, and then annually. Active surveillance is done when the life expectancy of the patient is more than 10 years. In this, PSA is done every 6 months and DRE, prostate biopsy and MRI pelvis are done annually.
Treatment of Castrate Resistant Prostate Cancer
After some years of starting androgen deprivation therapy, PSA may start rising, or there may be a disease progression on scans. This state is called as castrate-resistant prostate cancer.
If the patient has localized CRPC, then the treatment options are the observation or androgen deprivation therapy with a different agent that used previously.
And for metastatic CRPC, the treatment options are androgen deprivation therapy, chemotherapy, cancer vaccine or bone-directed therapy.
CRPC is the disease which has progressed on GnRH analogs, so non-GnRH analogs are used for the treatment, such as androgen receptor blockers or 17 hydroxylase inhibitors.
Treatment of Recurrent Prostate Cancer
The second peak correlates with recurrence after local therapy or metastatic disease. We will discuss it one by one. Recurrence after surgery may be in the form of PSA persistence, that is a failure to fall to normal, or PSA recurrence, that is, rising after becoming undetectable.
And recurrence after radiation therapy may be in the form of rise in PSA or positive DRE. For localized recurrence, the treatment options are observation, surgery if initially treated with radiotherapy, radiotherapy if initially treated with surgery and androgen deprivation therapy.
And for metastatic recurrence, androgen deprivation therapy is the mainstay of treatment. The patients who present directly with metastatic disease are treated directly with hormonal therapy and chemotherapy may be added in some patients who present with high volume disease.
When we use androgen deprivation therapy for the first time for localized, metastatic or recurrence after local therapy, it may be in form of medical or surgical castration. GnRH agonists or antagonists are used for medical castration, and for surgical castration, both the testes are removed, called as bilateral orchiectomy.
Immunotherapy for Prostate Cancer
Immunotherapy act by stimulating the immune system to kill and destroy cancer cells. It is a type of cancer treatment that enhances the body’s own immune system to fight effectively against cancer. Following are the immunotherapeutic agents which are approved for the treatment of advanced-stage prostate cancer.
It is the only approved cancer vaccine for the treatment of prostate cancer. Similar to conventional vaccines that stimulate the immune system to fight against specific infections, Sipuleucel-T stimulates the immune system to attack the prostate cancer cells. It is an autologous vaccine, that is, it is made from man’s own immune cells.
The patient’s white blood cells are first removed using a process called leukapheresis. The cells are then exposed to prostatic acid phosphatase (PAP), a glycoprotein enzyme normally produced by the prostate cells, which is usually elevated in patients with metastatic prostate cancer and is generally associated with poor prognosis. The cells are then infused back to the patient.
This process is generally repeated 2 more times, 2 weeks apart, to deliver a total of 3 doses. The modified white blood cells attack and kill the prostate cancer cells. Sipuleucel-T has been approved for the treatment of asymptomatic or minimally symptomatic patients with metastatic CRPC with no liver metastases, life expectancy >6 months, and ECOG performance status 0-1 (overall in good health).
It is an anti-PD1 antibody or commonly known as an immune-checkpoint inhibitor. It acts by preventing the interaction of immune-checkpoint with its ligands and thereby removing the breaks from the immune cells that attack and kill the cancer cells.
It has been approved for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair (MMR)-deficient solid tumors (including prostate cancer) who have progressed on prior treatment and who do not have a satisfactory alternative treatment option available.
Role of Radiopharmaceuticals in the treatment of Prostate cancer
Various radiopharmaceuticals (e.g. Radium-223, Strontium-89, and Samarium-153) are used for the palliation of pain due to bone metastasis that commonly occurs in the case of advanced-stage prostate cancer.
It is an alpha particle-emitting radioactive agent, which is preferentially taken up by rapidly growing bone cells within the metastatic bone lesions due to its chemical similarity with calcium. Within the metastatic bone lesions, Ra-223 kills cancer cells by emitting alpha-rays and inducing double-strand DNA breaks.
Thus, Ra-223 has a specific action against bone metastases resulted from prostate cancer and helps in improving the survival of patients with CRPC and bone metastasis. It has been approved for treatment of metastatic CRPC in patients with symptomatic bone metastases and no known visceral metastases. It can be safely combined with secondary hormonal therapy drugs approved for the treatment of metastatic CRPC, e.g. abiraterone or enzalutamide.
Strontium-89 (89Sr) and Samarium-153 (153Sm)
These are beta-emitting radiopharmaceuticals that specifically target bone metastases in prostate cancer. The beta-emitters do not have a survival advantage as that of Ra-223 but can be used for the palliation of pain associated with wide-spread bone metastases. These agents provide significant pain relief with minimum side effect compared to other palliative treatments in patients with multifocal bone pain and who are not the candidate for chemotherapy.