Early Prostate Cancer
Salient Features about early prostate cancer:
A. The prostate is a gland in the male reproductive system that makes and stores a component of semen
B. The most common risk factor for prostate cancer is age
C. Most of the time prostate cancer does not initially cause symptoms. By the time symptoms do occur, the disease may have spread beyond the prostate
D. Two tests can be used to detect prostate cancer in the absence of symptoms: A digital rectal exam (DRE) and a blood test to detect a substance made by the prostate called prostate-specific antigen (PSA).
E. A diagnosis of prostate cancer can be confirmed only by biopsy .
F. Prostate cancer is described by both grade and stage
G. Three treatment options are generally accepted for men with localized prostate cancer: Radical prostatectomy, radiation therapy, and active surveillance (also called watchful waiting)
What is the prostate?
The prostate is a walnut-sized gland that forms part of the male reproductive system. The gland is made of two lobes, or regions, enclosed by an outer layer of tissue. As the diagrams show, the prostate is located in front of the rectum and just below the bladder, where urine is stored. The prostate also surrounds the urethra, the canal through which urine passes out of the body.
1. What is prostate cancer?
Prostate cancer is a malignancy usually arising from the glandular tissues of the prostate. Initial stages it is confined to the prostate; the patient being asymptomatic. Gradually it causes enlargement and local symptoms due to pressure on the urethra (urinary problems),pressure on bladder base(irritative urinary problems).
In advanced stages it can cause spread to adjacent organs and can even spread to farther organs like bones,liver,lungs etc. 
2. Who is at risk for prostate cancer?
An important risk factor is age; more than 70 percent of men diagnosed with this disease are over the age of 65. African American men have a substantially higher risk of prostate cancer than white men, including Hispanic men (This may be because of the high testosterone levels in Afro-American Males).
Genetic factors also has a role to play, particularly among families in which the diagnosis is made in men under age 60. The risk of prostate cancer rises with the number of close relatives who have the disease. Certain genes have been implicated in causation of the prostate cancer.
Some evidence suggests that dietary factors may increase or decrease the risk of prostate cancer. Certain foods aggravate the risks while certain foods like-lycopene containing foods.
3. What are the symptoms of prostate cancer?
Most of the time, prostate cancer does not initially cause symptoms. By the time symptoms do occur, the disease may have spread beyond the prostate. Symptoms of prostate cancer may include the following:
• Urinary problems:
• Not being able to urinate.
• Frequency,nocturia.
• Weak flow of stream.
• Pain in the urination.
• Erectile dysfunction/ejaculatory dysfunction.
• Blood in the urine or semen (hematospermia).
• Bony pain (lower back, thighs) if bony metastases.
4. Can prostate cancer be found before a man has symptoms?
Yes. Prostate cancer screening is looking for the disease before a person has any symptoms. Two screening tests commonly used to detect prostate cancer in the absence of symptoms are the digital rectal exam (DRE), in which a doctor feels the prostate through the rectum to find hard or lumpy areas, and a blood test that detects a substance made by the prostate called prostate-specific antigen (PSA). Both testes can give greater sensitivity for detection of the prostate cancer.
5. How reliable are the screening tests for prostate cancer?
Neither of the screening tests for prostate cancer is perfect. Most men with an elevated PSA level do not have prostate cancer (false positives), and some men with prostate cancer have a low PSA level (false negatives). The DRE is also associated with false positives and false negatives. Using the DRE and PSA together will miss fewer cancers (greater sensitivity) but also increases the number of false positives and subsequent biopsies in men without cancer (lower specificity).
6. Does prostate cancer screening save lives?
This is a confusing scenario.But everybody would agree that screening reduces the mortality to certain extent.
Currently, researchers are conducting a large randomized clinical trial, called the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, to determine whether screening with PSA tests and DREs reduces the death rate from this disease.
7. How is prostate cancer diagnosed?
A diagnosis of prostate cancer can be confirmed only by biopsy. 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. 
8. How the prostate cancer is Staged
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)
9. How is localized prostate cancer treated?
Three treatment options are generally accepted for men with localized prostate cancer: Radical prostatectomy, radiation therapy (with or without hormonal therapy), and active surveillance (also called watchful waiting).
a. Radical prostatectomy is a surgical procedure to remove the entire prostate gland and nearby tissues. Sometimes lymph nodes in the pelvic area (the lower part of the abdomen, located between the hip bones) are also removed. Radical prostatectomy may be performed using a technique called nerve-sparing surgery that may prevent damage to the nerves needed for an erection. However, nerve-sparing surgery is not always possible.
b. Radiation therapy involves the delivery of radiation to the prostate. Radiation therapy is usually administered in an outpatient setting using an external beam of radiation. Radiation can also be delivered in a technique known as brachytherapy, which involves implanting radioactive seeds directly into, or very close to, the tumor using a needle. Patients with high-risk prostate cancer are candidates for adding hormonal therapy to standard radiation therapy.
c. Active Surveillance (watchful waiting) may be an option recommended for patients with early-stage prostate cancer, particularly those who have low-grade tumors with only a small amount of cancer seen in the biopsy specimen. These patients have regular examinations, PSA tests, and, sometimes, scheduled biopsies. If there is evidence of cancer growth, active treatment may be recommended. Older patients and those with serious medical problems may also be good candidates for active surveillance.
ADVANCED PROSTATE CANCER:
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.
Management:
> 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.
> 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.
> Different forms of androgen deprivation has been in vogue for ex: 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.
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 like Androgen independent cell line reaching critical proportion or Phenotypic changes: Morphologic transformation and Growth pattern and differentiation change 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.
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 regimens 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.
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.
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 .