19.02.2014:  PROSTATE CANCER (MEDICAL TREATMENT, ADVANCED DISEASE, CHEMOTHERAPY, HORMONOTHERAPY, IMMUNOTHERAPY, BONE METASTASIS)

P. Kosmidis
Medical Oncologist

Prostate cancer is the commonest non cutaneous malignancy in men. Prostate cancer is androgen dependent. A portion of patients with early prostate cancer may relapse and progress to other organs following initial treatment with radical prostatectomy or radiotherapy. Another portion of patients present from the very beginning with advanced cancer. The most frequent sites of metastasis in prostate cancer are the bones. PSA elevation is the most common laboratory finding, although the patients may or may not be symptomatic.
The androgens work through the androgen receptors (AR) which are located in the prostate cancer cells. Androgens derive from testicles, the adrenal gland and the tumor itself.
The standard treatment for this group of patients is Androgen – Deprivation Therapy (ADT). Antiandrogen therapy includes Androgen receptors antagonists, such as bicalutamide and flutamide as well as antiandrogenic drugs such as Ketoconolazone. This last drug is used only when the two prior drugs have failed. In addition to androgen receptors antagonists, chemical castration is achieved with injections of Luteinizing hormone releasing hormone (LHRH) agonists or more recently LHRH antagonists. Surgical castration (removal of Testicles) is rarely used. Therefore, an injection every month or every 3 months along with a pill daily compose the initial treatment of advanced prostate cancer.
However, a resistance to these drugs may develop by average in 2 years and the treatment is getting ineffective. The commonest sign of resistance is the elevation of PSA. This is called Castration Resistant Prostate Cancer (CRPC).
Up to 2014 chemotherapy with Mitoxantrone was the only available treatment for metastatic CRPC. During the past decade a number of new treatments have been developed for this stage of cancer. Chemotherapies, hormonal therapies, targeted agents and immunotherapy are some of these treatments, which are reviewed in the following lines.

Chemotherapy
1)Docetaxel
In 2004, following the results of TAX-327 trial, Docetaxel given at a dose 75mg/m² every 3 weeks along with prednisone showed improved survival, improved pain control, better quality of life, decreased PSA, in comparison to Mitoxantrone. Docetaxel is the standard of care in terms of chemotherapy for patients with metastatic CRPC. Side effects are asthenia, nail changes, diarrhea, neuropathy, stomatitis and peripheral edema.

2) Cabazitaxel
Cabazitaxel belongs to the taxanes and was approved following the TROPIC trial. Cabazitaxel is given to those patients who have initially received Docetaxel and have developed resistance. It is a second line treatment and it must be given in patients with adequate hepatic, renal and cardiac functions.

Hormonal treatment
1)Abiraterone
Abiraterone Acetate is a CYP17 inhibitor which lowers testicular, adrenal and intratumural testosterone synthesis. It is given along with Prednisone. Abiraterone has been approved in patients with metastatic CRPC either before or following Docetaxel chemotherapy. This approval was based on two successful trials i.e. the cou-AA-301 and cou-AA-302. This hormonal treatment must be given carefully in patients with cardiac malfunction, chronic renal or liver disease and hypertension. Interaction with other drugs must be controlled. Serum Kalium and blood pressure must be carefully monitored.

2)Enzalutamide
Enzalutamide is an antiandrogen which binds to the androgen receptor with high affinity and inhibits the nuclear translocation of this receptor. Enzalutamide was approved for the treatment of metastatic CRPC following the AFFIRM trial in which it was given following Docetaxel. Enzalutamide improves overall survival, radiological response as well as lowers PSA. The toxicity is mild and the main side effects are fatigue, diarrhea and seizures.  Enzalutamide seems to be beneficial even when it is given prior to Docetaxel.

Immunotherapy
The field of cancer immunotherapy is rapidly evolving. Sipuleucel-T is a novel immunotherapy agent which was approved for the treatment of asymptomatic or minimally symptomatic metastatic CRPC. It is used as first-line treatment and may induce long-lasting durable responses. It may cause infusion-related fever, tremor and myalgia.

Bone and Prostate cancer   
Bones are the most frequent metastatic sites in prostate cancer. The management of the symptoms but also the prevention of skeletal related events are extremely important for this group of patients.

Treatment of bone metastasis
Radium-223 is a radioactive calcium mimetic which is approved for symptomatic patients with metastatic CRPC only to bones without large lymph nodes (>3cm).
Radium-223 is given following Docetaxel chemotherapy and may improve overall survival, decrease bone pain, delays skeletal-related events.
Nausea, vomiting, diarrhea, bone pain and mild anemia are the main side-effects.
It must be remembered that external radiotherapy plays a crucial role for the palliation of bone symptoms.

Prevention of Skeletal-related events
Skeletal-related events (SRE) include fractures and cord compression which affect dramatically the quality of life of patients with metastatic CRPC. There are two drugs available that have proven effective in preventing SRE. Zoledronic acid the first bisphosphonate that was used successfully. More recently, Denosumab was also found effective. Denosumab is a nonoclonal antibody directed against RANKL which plays an important role is osteoclast formation, function and survival.
Denosumab in comparison to Zoledronic acid was found superior in delaying SRE. Denosumab is given subcutaneously every 3-4 weeks while Zoledronic acid is given intravenously every 3-4 weeks following renal function. Side effects of both drugs are almost similar i.e. osteonecrosis of the jaw, hypocalcemia, fever. It is also advisable to give Vitamin D supplements and calcium in addition to the drugs.

Sequence of treatments
For patients with metastatic CRPC, the optimal sequence of drugs has not been determined yet. Docetaxel is the cornerstone of treatment especially in those patients with more aggressive disease i.e. high Gleason score, short response to androgen deprivation therapy, rapid elevation of PSA etc.
In less aggressive cases hormonal therapy can be given before Docetaxel. Certainly, further studies will solve this problem. However, it must be remembered that LHRH agonists always accompany any treatment in metastatic CRPC.