There feedbacks to the piece on prostate cancer (PrCa) screening. I would like to share this particular feedback. I was diagnosed with prostate cancer a few years ago. I opted for hormonal therapy which comprised of three monthly injection with Goserelin injection. Recently I was informed that the prostate cancer was castration resistant and therefore has to be on another regime. I was aghast when I learnt that my prostate cancer was castration resistant. Throughout my therapy with Goserelin injection, I did not realize that I was more or less being castrated. Prostate cancer is primarily fueled testosterone. Treatment is primarily of androgen deprivation either through surgical removal of the testes or chemical/hormonal therapy. In either options the net effect is a low amounts of testosterone and therefore less fuel for the cancer.
In responding to the enquirer. I looked at a publication by Petrylak et al in the American Journal of Managed Care titled “Castration-Resistant Prostate Cancer: Addressing Treatment Challenges, Managed Care Aspects, and Integration of Existing andNew Therapies Into Practice”, December 2013 – Vol. 19, No. 18, Sup.
In males, the probability of developing invasive prostate cancer (PrCa)increases with each decade of life, with a risk that rises from 1 in37 males between 40 and 59 years of age to 1 in 8 males for thosewho are 70 years and older. Improvements in the early detection of PrCa have led to asubstantial reduction in the number of patients who are diagnosedwith advanced stages of the disease.
Increased rates of screeningfor levels of prostate-specific antigen (PSA) have led to a notabledecline in late-stage diagnoses of PrCa. Analyses of data from theSurveillance, Epidemiology and End Results (SEER) databasebetween 1992 and 2008 identified a 75% reduction in late-stagedisease incidence.
Notwithstanding these improvements in early detection, PrCa continues to be a leading cause of mortality among males, invariably due to the emergence of hormone-refractory, androgen-independent disease. Although higher levels of PSA at baseline in a patient is indicative of greater riskfor metastatic disease or subsequent disease progression, it shouldbe noted that PSA remains an imprecise marker of risk. PSA alonemay not predict the onset of metastatic disease. Other factors, such as PSA doubling time, patient life expectancy, and comorbidities, may often prescribe when hormonal therapy is utilized.
In patients with advanced disease, androgen deprivation blockade, which may be achieved pharmacologically or surgically, leads to theregression of metastatic disease in the majority of patients.
With androgen blockade, patients with high-risk, locally advanced, or metastatic disease may experience long-term regressionsin disease activity, but advanced PrCa virtually always progresses to castration-resistant PrCA (CRPC), which is also known as androgen-independent PrCa (AIPC).
CRPC is clinically detected by recurring symptoms, a rise in PSA levels, progression in soft tissue disease, or progression on bonescan. The rise in PSA occurs in the context of the patient havingcastrate levels of serum testosterone (<50 ng/dL) following a withdrawal of antiandrogen therapies for at least 4 weeks, despite secondary hormonal manipulations and/or radiologicevidence for disease progression.
The management of CRPC presents a number of difficultclinical challenges. Systemic therapeutic optionsfor this stage of PrCa have been very limited in the past. In the past, for patients with PrCa who failed hormonal therapy, traditional treatments were only approved for, andused primarily to provide, symptomatic benefits. These therapies included bisphophonate agents to protect the
skeletal integrity in patients with bony metastases, secondary hormonal manipulations, such as ketoconazole combinedwith hydrocortisone. There were also addition of antiandrogenchemotherapy and beta-emitting radioactive isotopes.
The mechanisms of androgen independence inCRPC have been researched extensively, including pathwaysthat are mediated by the androgen receptor (AR), as well asthe pathways that bypass this receptor. In addition, themechanisms that are common to all cancer types underlyingmalignant proliferation, angiogenesis, metastatic spread, andthe avoidance of immune surveillance also play major roles in the progression of PrCa to castration-resistant disease.
Prostate function and cellular differentiation depend uponandrogen receptor signaling (ARS), a component that is alsocritical in the progression of PrCa. The AR is expressed tosome degree in almost all primary PrCas, and there appears tobe a relationship between the AR on a cellular level, primaryprostate tumors and metastatic lesions, and the subsequentprogression of disease to CRPC. While ADT is highly effective, PrCa eventually becomes unresponsive to hormonaltreatments, leading to CRPC.
CRPC cells are capable ofadapting to low circulating levels of androgens, and AR canbecome hypersensitive and activated by these low androgenlevels, as well as through various other cellular mechanisms.
Measurement of PSA is the most commonly used evaluationto detect progression of disease, and rising levels of PSA mayindicate dysfunctional AR activity in CRPC. It needs to be stressed that patients can progress in boneand in soft tissue disease in PrCa without a significant rise in PSA.
AR amplification/overexpression is considered one of themajor causes of disease progression to CRPC. Mutations in the AR gene have been detected with higherfrequency in patients with castration-resistant, distant, metastatic tumors compared with patients who have lower-gradeprimary tumors or those who have been treated solely withcastration.
Most identified mutationsare associated with increased functional activity of theAR, leading to a receptor that is more sensitive to low levelsof androgen or can be activated by other steroids (e.g. adrenal androgens, estrogens, progestins) as well as antiandrogensthat are designed to treat PrCa.
Proliferation of PrCacan also be regulated via indirect pathways through growth factors (insulin-like growth factor-IGF, transforming growth factor-β-TGF-β, fibroblast growthfactor-FGF, and epidermal growth factor-EGF). These growth factors have been demonstrated to stimulatethe expression of androgen-responsive genes, in spite of androgen levels.
AR signaling may also be increased in CRPC by therepletion of endogenous AR agonists within the tumor tissueitself. While dihydrotestosterone (DHT) levels may be similaror depleted in CRPC tumors when compared with those of untreated (pre-castration) tumors, intra-tumoral testosterone levels may be similar to untreated tumors in patients withcastration-resistant disease. CRPC tissue can have levels oftestosterone similar to that of androgen-stimulated benignprostate tissue.
Data have shown that evensmall amounts of prostatic DHT, such as those that may resultfrom adrenal androgens following castration, may stimulateprotein synthesis of tumor epithelial cells. Intra-tumoral conversion of adrenal androgens and the steroid synthesis/conversionof adrenal precursors are other potential pathways thatare implicated in the progression of PrCa to castration-resistant disease, and are currently undergoing investigation.
CRPC is usually diagnosed by a progressive rise in serum PSA levels, anidentified progression of preexisting disease, and the appearance of new metastases. Bone is the most common site formetastatic spread of cancer, which can develop whenevercancer cells relocate to the bony skeleton from the primarytumor site, making bone metastasis of special clinical concern in patients with PrCa. Bone metastases have a marked impacton quality of life (QOL) for patients with advanced PrCaas they can cause severe pain, hypercalcemia, and increasedrisk of fracture. Further, metastases (spread of cancer) to the spine are common, and can lead to spinal cord compression and neurologicalimpairment.
The American Urological Association Guidelines forCRPC. These are,Index Patient 1-Asymptomatic, non-metastatic CRPC; Index Patient 2–Asymptomatic or minimally symptomatic CRPC without prior docetaxel therapy; Index Patient 3–Symptomatic m CRPC with good performance status and no prior docetaxel therapy; Index Patient 4–Symptomatic mCRPC with poor performance status and no priordocetaxel therapy; Index Patient 5–Symptomatic mCRPC with good performance status and prior docetaxel therapy; Index Patient 6–Symptomatic mCRPC with poor performance status and prior docetaxel therapy. These present other aspects of the knotty issues in the management of prostate cancer.
EDWARD O. AMPORFUL