Radiation Oncology Synopsis

Metastatic Prostate Cancer

Background

In the PSA era, prostate cancer has experienced a stage migration. Only 10% - 20% of patients newly diagnosed present with locally advanced or metastatic disease. The incidence of metastatic prostate cancer has decreased with the introduction of PSA testing in the early 1990s has decreased by 52% based on SEER data for diseases diagnosed between 1990 and 1994.

Most cases of metastatic prostate cancer are identified by isolated biochemical recurrences (PSA elevations). A much smaller percentage are detected by signs and/or symptoms of metastatic disease. About 95% of patients with metastases have an abnormal PSA. PSA is the most sensitive and specific disease marker.

After biochemical failure, following local therapy the median time to development of metastases is 8 years and the median time to death is 13 years. The most common adverse prognostic indicators after biochemical recurrence following local therapy are:

(D'Amico J. Urol 2004, Katz, JCO, 2004, Stephenson, JAMA 2004, Zhou JCO 2005)

Prostate cancer most commonly metastasizes to the axial skeleton. The lesions are predominantly osteoblastic.

Workup

Metastatic prostate cancer commonly metastasizes to the bones. Bone scans (99mTc) CT of the abdomen and pelvis with contrast and chest imaging are commonly used. Radiographs or MRI should only be used if other studies are equivocal.

Both bone scans and CT scans are rarely positive until PSA values are ≥ 30 ng/ml in the absence of prior androgen deprivation therapy. Higher PSA velocities make these studies more likely to be positive. (Mike Cher, J Urol, 1998).

MRI does not yet have an established role and has not been completely evaluated. A prospective study of 66 patients with high risk prostate cancer found the sensitivity and specificity of 100%/88% compared with bone scan sens/spec of 63%/64% in detecting metastases.

111In capromab pendetide (ProstaScint), a radiolabeled monoclonal antibody is used to target prostate specific membrane antigen. It is FDA approved for detecting localized disease recurrence after RP but not metastatic disease. The data concerning the role of Prostascint are mixed. Most studies show a poor positive predictive value for detecting extraprostatic disease. It is not commonly used as part of a recurrence work up.

Rebiopsy should be considered in post radiation therapy biochemical evidence of recurrence should be considered if > 2 years have elapsed since completion of radiation therapy, based on the ASTRO consensus guidelines.

Treatment

Androgen deprivation therapy is the mainstay in initial treatment of metastatic prostate cancer. Formerly, orchiectomy was the first line treatment, while more modern treatment consists of a GnRH analog as a first line treatment of metastatic prostate cancer. Androgen deprivation was first reported in a study by Huggins in 1941 when he revealed that androgen deprivation through castration and estrogen administration leads to the death of prostate cancer cells.

Long term studies have confirmed the equivalence of castration and GnRH agonists, both randomized trials and meta-analyses. The biggest advantage to castration (orchiectomy) is the psychological impact and irreversibility of castration. GnRH agonists are generally considered first line therapy, but have the disadvantage of expense. A recently publshed study has shown the equivalence of intermittent GnRH administration to continuous administration in terms of progression free survival, overall survival and has demonstrated better quality of life using intermittent therapy.

The most commonly used GnRH agonists are all available as depot formulations:

Firmagon (degarelix) is a relatively new GnRH antagonist. which can produce a faster reduction of testosterone levels without the boney flare of GnRH agonists.

In addition to GnRH agonists and castration, anti-androgens (Casodex/bicalutamide) estrogens (DES) and ketoconazole which blocks cyt P450 pathway are used in androgen suppression or blockade.

The timing of initiation of ADT is not comletely clear, when to start ADT. There are ongoing trials which will help answer this question. These studies (ELAAT, OCOG) have not been completed yet. Some institutions initiate ADT in patients with high risk features (GS > 7 and rapid PSA-DT). In any case, ADT should be initiated in asymptomatic but radiologically apparent metastases. Studies have shown improved PFS with early initiation of ADT over deferred therapy until clinical signs of progression (MRC-UK 1997 Br.J.Urol).

Klotz/NCIC Intermittent ADT compared with continuous ADT ASTRO 2011 Meeting. Recently published data have demonstrated the non-inferiority of intermittent androgen deprivation therapy. This study by Klotz as part of an NCIC CTG PR.7/SWOG JPR.7 was presented at the ASTRO 2011 meetings. This study used hormone therapy on an intermittent basis with each cycle lasting 8 months and restarting when PSA exceeded 10 ng/ml. The study showned no difference in overall survival.However, what the study also showed was that although the overall survival rates were similar, those on intermittent hormone therapy were more likely to die of prostate cancer, while those on continuous hormone therapy were more likely to die of non-prostate cancer causes. The death rate on continuous therapy from prostate cancer was 14%, while that of those on intermittent hormone therapy was 17.6%

Anti-androgens as sole modality treatment has mixed data. The use of bicalutamide has been demonstrated in adjuvant treatment (salvage radiation of the RTOG 9601 Bicalutamide + RT v. RT alone preliminary report). It has not been demonstrated as superior to medical/surgical castration. A meta-analysis of several trials have shown small but significant OS benefits with complete (both GnRH/castration and androgen blocker therapy) androgen blockade. The available evidence shows that GnRH has a trend toward better OS than anti-androgen agents. This results in a common practice of using both GnRH agonists and anti-androgens.

Several randomized trials and meta-analyses have demonstrated a small but significant survival benefit with complete androgen blockade. In addition, GnRH may cause a boney flare with initial treatment which can be mitigated by a GnRH antagonist or an anti-androgen.

Prostate cancer will be suppressable by ADT, but eventually the prostate cancer becomes resistant to ADT. Generally it takes about 2-3 years for androgen independent prostate cancer to develop. The anticipated OS5 is 25.4% for prostate cancer patients treated with ADT and metastatic disease.

Androgen Refractory Prostate Cancer

Androgen refractory prostate cancer can be treated with a withdrawal of the anti-androgen and may experience a PSA decline, if they were being treated with CAB. If GnRH agent was being used, switching to an anti-androgen may help. Bisphosphonates may help slow the progression of boney metastases. Focal or systemic radiation therapy may also help control boney pain or prevent impending pathologic fractures.

Ketoconazole is a commonly used antifungal agent which inhibits steroidogenesis and is cytotoxic to prostate cancer. It is commonly used against androgen independent prostate cancer in combination with hydrocortisone to prevent adrenal insufficiency . It has a 3-6 month duration of response and is associated with a 20 - 50% reduction in PSA. Caution should be given to the use of ketoconazole if clinical trial entry is anticipated as its use may exclude some trials.

Chemotherapy

Docetaxel/prednisone is now the standard of care in hormone refractory prostate cancer. This is based on the results of two key trials: TAX327 and SWOG 9916.

TAX 327 Taxol compared with mitoxantrone in progressive, metastatic, hormone refractory prostate cancer. (Tannock, 2004, NEJM) This trial randomized 1006 men to one of three arms, two containing a taxol based regimen and a third using mitoxantrone.

SWOG 9916 Trial of combined taxane based chemotherapy with mitoxantrone (perylak 2004 NEJM) Randomized 770 men to extramustine/docetaxel/dexamethasone or mitoxantrone and prednisone. The docetaxel arm significantly improved median survival at 17.5 months v. 15.6 months and PSA response 50% v. 27%. As in the TAX 327 trial, there was more grade 3-4 hematologic toxicities.

Novel Prostate Cancer Therapies

Novel therapies considered for metastatic prostate cancer include Gene transfer immunotherapy to express immune stimulation compounds. Examples include Prostavac. Gene transfer cytoreduction agents are designed to introduce lytic viruses that preferentially target prostate cancer cells.

A SWOG trial (SWOG 0421) is ongoing to examine endothelin receptor antagonists designed to prevent the inhibition of apoptosis. Monoclonal antibodies are being examined in Phase I/II trials. Abiraterone, a 17-α hydroxylase inhibitor is now approved in chemo-naive castrated patients and in those with prior docetaxel based chemotherapy. Selective androgen modulator receptors are laso being investigated.

Toxicity of Treatment

Androgen Deprivation

Short term: hot flashes, decreaed li bido, fatigue

Long term: gynecomastia, anemia, decreased muscle mass, decreased bone mineral density, obesity, mood changes, dyslipidemia, insulin resistance, diabetes, coronary artery disease.

Anti-androgen therapy side effects (primarily bicalutamide), include breast tenderness, gynecomastia (50%), loss of libido, diarrhea and hepatotoxicity. It is generally prescribed for the first 2 -4 weeks of GnRH agonists to prevent boney flare and to reduce testosterone more quickly.