Advanced carcinoma prostate:Management options

Prostate cancer is one of the most common cancer which attributes significantly to the morbidity and mortality among elderly male population. With the introduction of screening programmes for prostate cancer detection, improved modalities of staging, improvements in surgical techniques and monitoring led to early detection and better survival rates compared to that in the past. In countries where screening programmes are not routine, a considerable number of people present with advanced disease (Like in India). Advanced prostate cancer results from any combination of lymphatic, blood, or contiguous local spread. We are coming out with this information as many cancers detected in India are advanced in initial presentation unlike in Western population where majority are locally confined. So routine screening is necessary for early detection of the cancer and also it has been proved to reduce the mortality(as per studies)albeit not dramatically.








Symptoms and signs:
Manifestations of metastatic and advanced prostate cancer may include anemia, bone marrow suppression, weight loss, pathologic fractures, spinal cord compression, pain, hematuria, ureteral and/or bladder outlet obstruction, urinary retention, chronic renal failure, urinary incontinence, and symptoms related to bony or soft-tissue metastases causing bony pain, sometimes disseminated intravascular co-agulation because of bone marrow metastases.
Treatment-related symptoms, such as rectal bleeding, gross hematuria, and urethrorectal fistula, can occur after brachy or systemic radiotherapy.
Physical examination:
• On Per-Rectal Examination grossly hard nodular prostate can be felt reaching pelvic walls.
• Physical examination findings of iliac adenopathy, lower-extremity edema and scrotal oedema, and bony tenderness may indicate metastatic disease. The patient may have paraplegia because of spinal compression, urinary incontinence because of either prostatic obstruction of neurogenic in origin because of spinal cord compression.
• Anemia and systemic symptoms of loss of weight and appetite can be present.
• Chronic renal derangement either because of trigonal infiltration or because of retroperitoneal lymphnodal enlargement.
Work up:
• Hematological workup should include a complete Blood picture and a chemistry profile, including serum creatinine, liver function tests, serum PSA, and acid and alkaline phosphatase.
• Urinalysis should be performed and if necessary complemented with a urine culture, especially if the patient is symptomatic.
• Note that not all patients with a relatively high-grade prostate cancer have elevated PSA levels, nor do elevated PSA levels always signify disease progression. Some anaplastic prostate carcinoma especially with neuronal differentiation.
Imaging Studies
• Bone scan: A bone scan may be performed as a baseline for treatment response in patients with recurrent metastatic disease at high risk of having bony metastatic disease. Regardless of these guidelines, a bone scan is indicated in patients with prostate cancer who have symptoms suggesting bony metastases.
• Chest radiography is usually done to reveal rare pulmonary metastases in select cases.
• MRI/CT SCAN: May be needed for the evaluation of organ where metastases are suspected. For example; MRI spine for the spinal metastases.
Procedures
• Transrectal ultrasound-guided needle biopsy of the prostate is indicated for tissue diagnosis in patients who present with elevated PSA levels or abnormal digital rectal examination findings or findings suggestive of advanced prostate carcinoma with bony metastases.
• Those patients who progress after radical radiotherapy/radical prostatectomy will show PSA level rising.
(Staging
The Whitmore-Jewett classification of stages A-D is no longer widely used. Prostate cancer does not necessarily progress in a sequential manner.
• Currently, the accepted international tumor, node, metastasis (TNM) staging system pertaining to prostate cancer includes the extent of local disease (T), status of regional lymph nodes (N), and distant metastasis (M).
o Stage T1-2c - Organ-confined disease
o Stage T3a - Extracapsular extension of the tumor
o Stage T3b - Invasion of the seminal vesicle(s)
o Stage T4 - Tumor fixed or tumor invading adjacent structures other than seminal vesicles (eg, bladder neck, external sphincter, rectum, levator muscles, and/or pelvic floor)
o Stage NX - Regional lymph nodes cannot be assessed
o Stage N0 - No regional lymph node metastasis
o Stage N1 - Regional lymph node(s) metastasis
o Stage MX - Distant metastasis cannot be assessed.
o Stage M0 - No distant metastasis
o Stage M1 - Distant metastasis
o Stage M1a - Distant metastasis other than regional lymph nodes
o Stage M1b - Metastasis to bone(s)
o Stage M1c - Other site(s)
o Stage pM1c - Metastasis to more than 1 site
• The definition of stage D by Whitmore-Jewett has been further stratified by Crawford and Blumenstein. The additional stratification is thought to improve classification and understanding of a subset of patients who have hormone-insensitive prostate cancer. The staging is as follows:
o Stage D1 - Involvement of pelvic lymph nodes
o Stage D1.5 - Rising PSA level after failure of local therapy (ie, biochemical failure)
o Stage D2 - Metastatic disease to bone and other organs
o Stage D2.5 - Rising PSA after nadir level
o Stage D3 - Hormone-refractory prostate cancer
o Stage D3.5 - Sensitive to hormones
o Stage D4 - Insensitive to hormones)
Management:

o Bilateral orchidectomy as a treatment modality for carcinoma prostate, introduced by Hodges and Huggins in 1941 has revolutionized the treatment of carcinoma prostate and fetched them Nobel prize. The treatment modalities available for advanced carcinoma prostrate are mainly based on androgen deprivation (hormonal manipulation). The initial response rate of androgen deprivation therapy is more than 80%. This response is usually temporary and palliative. The 5 year survival rate is around 10-20%. The median time to progression and survival for metastatic disease is 12-18 months and 24-36 months respectively. Androgen deprivation has many side effects like: osteopenia, anemia, asthenia, hot flashes and sarcopenia.
o A study by Saad et al (2008) found that the risk of osteopenia, osteoporosis, and bone fractures caused by ADT can be mitigated by appropriate bisphosphonate therapy. The decision to institute bisphosphonate therapy should be based on the risk of these complications on a case-by-case basis. Patients determined to be at risk for such complications should be educated about measured to reduce the risk, including lifestyle modifications that may benefit their general and bone health.
o Different forms of androgen deprivation has been in vogue for ex:o Continuous androgen blockage(CAB) recognizes the 10% contribution of adrenal androgens to the total body testosterone. A GnRH antagonist with a nonsteroidal antiandrogen is used concurrently for what was thought to be complete ADT. However, multiple randomized trials have shown conflicting findings regarding significant improvement in survival.
o Labrie and colleagues described the concept of CAB, in which LHRH accomplished medical castration and antiandrogens achieved peripheral blockade. Initially, they reported improved response and survival rates. Additional studies supported these findings.
o A recent meta-analysis by the Prostate Cancer Trialists' Collaborative Group included 22 trials with a total of 5710 patients with advanced prostate cancer. Both medical castration and bilateral orchiectomy were included. The overall mortality rate was 56.3% in those receiving CAB versus 58.4% receiving medical or surgical castration alone. Estimated 5-year survival rates were 26.2% with CAB and 22.8% with castration alone. No statistically significant survival advantage was found with CAB. The current American Society of Clinical Oncology (ASCO) guidelines recommend castration alone with either an orchiectomy or GnRH agonist.
o Intermittent androgen suppression is a well-established treatment offered to patients with advanced prostate cancer; however, it is not considered standard of care. Some indications for androgen withdrawal therapy include newly diagnosed metastatic disease, localized disease with high risk of systemic relapse, PSA level rise during treatment, lack of tolerance for side effects, and biochemical failure after local therapy. Intermittent androgen suppression may delay androgen-independent cancer and increase quality of life (i.e., fewer issues regarding potency and libido). Ongoing research is investigating the utility of intermittent treatment.
• Early versus delayed treatment
o In the years following the introduction of hormone therapy for prostate cancer by Huggins and Hodges, early institution of such treatment was recommended based on comparison with historical controls.
o Later, the Veterans Administration Cooperative Urology Research Group (VACURG) studies reversed the recommendation of early hormone therapy; instead, hormone therapy was deferred until symptomatic progression. Thus allowing patient to have quality of life avoiding ADT. The Medical Research Council study published in 1997 was a randomized study of 938 patients with locally advanced or asymptomatic metastatic prostate cancer. Patients received treatment with orchiectomy or LHRH agonist, either immediately or after symptoms occurred. Development of extraskeletal metastases, pathologic bone fractures, spinal cord compression, and ureteral obstruction was twice as common in the deferred-treatment group. Overall survival was significantly prolonged in those who were treated early.
o However, virtually all patients develop hormone-refractory disease. Although hormone therapy is associated with significant responses, its curative potential is limited because of the inherent heterogeneity of prostate cancer and the inability of hormones to eradicate all prostate cancer clones, both the androgen-dependent and androgen-independent components.
Many theories were proposed to explain this hormone independent stage:
1. Androgen independent cell line reaching critical proportion.
2. Phenotypic changes
i) Morphologic transformation
ii) Growth pattern and differentiation change
iii) Cellular antigenic expression modification
3. Biological change
a) Mutation
b) Oncogenes
c) Enhanced tumour angiogenesis
d) Altered expression of androgen receptors (AR)
Rising PSA level is usually the first manifestation of disease progression after androgen deprivation. This rise in serum PSA precedes approximately 6 months before clinical evidence of the disease. Progression of the disease is suspected if there is a rise in PSA level or worsening symptoms and the progression can be seen in imaging studies most of the times.
The biological mechanism of the failure of hormonal therapies is not completely understood but many factors are likely to contribute. Throughout the progression of prostate cancer AR continues to be the primary effector of tumor growth and progression despite castrate testosterone, even in the presence of anti-androgens. Amplification of the AR gene is present in HRPC and it has been shown to correlate with increased AR protein expression. AR mutations are most common in patients with progressive disease despite treatment with antiandrogen, reflecting the strong selection pressure induced by these agents. A practical implication of this data is that each antiandrogen may interact uniquely with AR. Therefore, it is reasonable that a patient progressing while receiving antiandrogen may still respond to another member of this class of agents.
After hormonal therapy alternative signaling mechanisms through AR maintain cellular proliferation and survival despite castrate testosterone. They consist of mechanisms that occur in a ligand dependent or a ligand independent manner. The former includes AR mutations, which lead to receptor promiscuity and activation by a range of steroid hormones, and amplification of the AR gene. The latter includes AR activation by nonclassic factors, such as certain growth factors (epidermal growth factor, insulin-like growth factor-1 and keratinocyte growth factor), receptor tyrosine kinases, activation of the AKT (protein kinase B) and mitogen-activated protein kinase pathways, recruitment of coactivators such as ARA70 and alternative signaling pathways. The recent finding that an increase in AR expression is associated with resistance to antiandrogen therapy may provide insight into the development of new diagnostic and treatment strategies for advanced prostate cancer. A provocative thought is that AR over expression may allow the continued growth of prostate cancer cells due to minute amounts of testosterone undetectable by conventional assays.
An increasing body of data on second-line endocrine manipulations in patients with evidence of disease progression after initial androgen deprivation suggests that there may be a role for this approach before institution of other therapies. Although response rates between 20% and 80% have been reported in various studies, the median duration of response in the patients treated in the reported experience is short, ranging between 2 and 4 months. Of castrate patients with HRPC treated with high doses (150 to 200 mg) of bicalutamide 20% to 24% have PSA decreases of 50% or greater with most responses seen in those who received prior flutamide therapy.

Ketoconazole (200 or 400 mg 3 times daily) is an antifungal that interferes with cytochrome 3A4 and inhibits steroidogenesis in the testes and adrenal glands. The most common side effects are weakness or lack of strength, gastrointestinal complaints such as nausea or vomiting, hepatotoxicity, skin reactions and a potential risk of adrenal suppression. The principal side effects of ketoconazole are related to gastric irritation, leading to nausea and anorexia in at least 10% of patients. Glucocorticoid repletion is a standard supportive therapy in patients treated with agents that inhibit adrenal function. These agents may also have modest anticancer activity. Diethylstilbestrol is an inexpensive synthetic estrogen that decreases testosterone by decreasing LHRH secretion as well as directly inhibiting LH secretion by the pituitary gland. DES at a dose of 3 mg daily results in castrate testosterone in 1 to 2 weeks by the inhibition of LHRH production from the hypothalamus. Several studies have demonstrated the modest efficacy of estrogens in the context of HRPC with PSA responses of 26% to 66% at 1 to 3 mg DES. DES is associated with significant cardiovascular toxicities, including myocardial infarction, stroke and pulmonary embolism, especially at moderate to high doses. Anticoagulation with Coumadin is recommended to prevent these side effects. Nonstandard secondary hormonal manipulations, such as estrogens, antiestrogens and progestins, are associated with low response rates In patients with castrate serum testosterone levels, hormone-refractory prostate cancer is defined as 2-3 consecutive rises in PSA levels obtained at intervals of greater than 2 weeks and/or documented disease progression based on findings from CT scan and/or bone scan, bone pain, or obstructive voiding symptoms. In a subgroup of patients, the PSA level does not rise at diagnosis or throughout the entire course of the disease.


Nonhormonal approaches are required for the treatment of HRPC. The options available are:
1. Chemotherapy
2. Radiotherapy
3. Gene therapy
4. Newer systemic approaches



The options for the treatment of HRPC are limited; many chemotherapy regimes have been shown to be ineffective and associated with significant toxicity. More recently, alternative chemotherapy regimens, such as those based on mitoxantrone, estramustine and taxanes, have been identified and are increasingly used to control the cancer. Docetaxel belongs to the taxane class of chemotherapy drugs. It works by inhibiting tubulin, a protein essential to cell division, thus preventing cancer cells from dividing and growing in number. Most of the studies with docetaxel are done in combination with other drugs like thalidomide, etramustine and prednisolone. The results are encouraging. Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive androgen-independent prostate cancer. Docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic, hormone-independent prostate cancer was compared in one of the trials where 770 men were randomized to one of two treatments, each given in 21-day cycles: 280 mg of estramustine three times daily on days 1 through 5, 60 mg of docetaxel per square meter of body-surface area on day 2, and 60 mg of dexamethasone in three divided doses before docetaxel, or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily. The primary end point was overall survival; secondary end points were progression-free survival, objective response rates, and post-treatment declines of at least 50 percent in serum prostate-specific antigen (PSA) levels. In the sudy result was out Of 674 eligible patients, 338 were assigned to receive docetaxel and estramustine and 336 to receive mitoxantrone and prednisone. In an intention-to-treat analysis, the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone (17.5 months vs. 15.6 months, P=0.02.The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone (P<0.001). PSA declines of at least 50 percent occurred in 50 percent and 27 percent of patients, respectively (P<0.001), and objective tumor responses were observed in 17 percent and 11 percent of patients with bidimensionally measurable disease, respectively (P=0.30). Grade 3 or 4 neutropenic fevers, nausea and vomiting, and cardiovascular events were more common among patients receiving docetaxel and estramustine than among those receiving mitoxantrone and prednisone. Pain relief was similar in both groups. This study shows improvement in median survival of nearly two months with docetaxel and estramustine, as compared with mitoxantrone and prednisone, provides support for this approach in men with metastatic, androgen-independent prostate cancer.

Radiotherapy:HRPC responds poorly to radiotherapy. Role of radiotherapy in these cases is limited to palliation of bone pain and in treating spinal cord compression due to metastases. Adverse effects of EBRT include cystitis, proctitis, enteritis, impotence, urinary retention, and incontinence.

Gene therapy:
Molecular medicine has resulted in the identification of numerous antigens associated with several cancers, including adenocarcinoma of the prostate. Induction of antitumor immune responses after immunization has been demonstrated in preclinical studies. Specific immune cells responsible for tumor killing in the laboratory have been shown to detect target cells by recognizing major histocompatibility complex proteins in the membrane of these cells, and evidence of antitumor activity has been detected in vivo. Among the most potent antigen-presenting cells are dendritic cells, which have been used as vehicles for tumor-specific antigens such as prostate-specific membrane antibody, and this constitutes the background for immunostimulatory strategies against prostate cancer. Initial phase I and phase II studies with a dendritic cell vaccine have demonstrated safety in patients with advanced hormone refractory disease, and additional trials are in process to evaluate the efficacy of this approach. Cytoreductive approaches include the use of granulocyte-macrophage colony-stimulating growth factor transduced allogeneic prostate cancer cells. Tumor-specific immune responses have been reported, along with evidence of safety in patients with advanced disease; clinical trials are in process to further define the efficacy in prostate cancer. Other approaches include the transduction of suicide genes, such as the thymidine kinase gene, that can be activated by agents such as gancyclovir; use of toxins such as diphtheria and Pseudomonas; and targeting against critical cellular promoters, such as adhesion molecules and various other mechanisms involved in tumor cell–specific cell kill.
Newer systemic therapy:
Newer systemic approaches include antiangiogenic drugs like thalidomide. Angiogenesis is a process of new blood vessel development from pre-existing vasculature. It plays an essential role in embryonic development, normal growth of tissues, wound healing, female reproductive cycle (i.e., ovulation, menstruation and placental development) and also is central to several pathological processes such as tumour growth and metastasis. Particular interest has been focused on cancer, since tumours cannot grow beyond a few millimeters in size without developing a new blood supply. Angiogenesis therefore is necessary for the spread and growth of tumour cell metastasis.
Bevacizumab blocks the activity of a protein called vascular endothelial growth factor (VEGF). Many cancers use VEGF to help form the new blood vessels they need for continued growth. Furthermore, high levels of VEGF in the blood and urine of patients with hormone-refractory prostate cancer have been found to indicate a reduced likelihood of survival.
A previous phase II clinical trial that combined docetaxel and bevacizumab resulted in improved outcomes over historical controls.
Other novel agents: Suramin acts via growth factor inhibition. It remains active in patients with hormone-refractory cancer and may be used in combination with other agents. Adverse effects include edema, leukopenia, infection, hyperglycemia, anemia, anorexia, dyspnea, platelet abnormalities, elevated creatinine levels, malaise, arrhythmias, and coagulopathy.

Radio-Isotope therapy:

More than two-thirds of the patients with osseous metastases experience debilitating bone pain, requiring some form of pain relief. Analgesics are limited in their efficacy. Palliative application of hemi-body external beam radiation therapy in the treatment of multiple osseous metastases also is limited due to toxicity associated with large treatment ports. Intravenous injections of bone seeking radioisotopes (Phosphorus 32 /strontium) are effective in the palliation of pain with fewer side effects.
Surgery:

Surgical intervention of weight-bearing bones involved in pathologic fractures is mandatory.
Consultations

• Consultation with a radiation oncologist should be obtained for palliative radiation therapy for bone metastases, locally extensive tumors, and on an emergent basis for spinal cord compression.
• Consultations with a neurosurgeon for spinal cord compression and an orthopedic surgeon for pathologic fractures are appropriate.
• Consultation with a medical oncologist may also be considered for chemotherapy.
Diet
• Because a high-fat diet is linked with a higher incidence of prostate cancer, a low-fat diet may be beneficial for patients at high risk of developing prostate cancer (namely those with positive family history, African American males) and for patients undergoing treatment for advanced prostate cancer.
• Tomatoes, broccoli, green tea, soy, lycopenes, licorice root, selenium, and antioxidants have all been hypothesized to be beneficial.




• The Physicians' Health Study II, a long-term randomized controlled trial involving male physicians, recently found that neither vitamin E nor C supplementation reduced the risk of cancer—prostate or otherwise.
• Similarly, the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized placebo-controlled trial involving 35,533 relatively healthy study participants from 427 US sites, found that neither selenium nor vitamin E (alone or in combination), at the doses and formulations used, prevented prostate cancer.
Activity

• Patients diagnosed with impending paralysis due to spinal cord compression or patients with pathologic fractures should be immediately immobilized until appropriate consultations are obtained. They should be immediately given methyl prednisolone injection to reduce the oedema so as to further prevent the damage to spinal cord.
• A study conducted by Agarwal et al has shown the bone mineral density of Indian men is low even before androgen supplementation; so careful follow-up with BMD measurement with calcium, alpha –D3, zoledronic acid supplementation and daily atleast 30-45 minutes of activity –like walking would help Indian men with advanced prostate cancer to cope with the effects of loss of Bone Mineral Density .