Extensive investigations have been conducted on the pathophysiology of the prostate (Altman, 1993; Bostwick et al., 1999; Fahmy and Bissada, 2003; Gronberg et al., 1997; Habuchi et al., 2000; Hardy et al., 1996; Irvine et al., 1995; Marks, 1999; Meyer and Nash, 1994; Miller, 1993; Montie and Pienta, 1994; Trent and Issacs 1996).
The prostate, which is partly glandular and partly muscular, is situated immediately below the internal urethral orifice at around the commencement of the urethra. It is located in the pelvic cavity, below the caudal part of the symphysis pubis, above the deep layer of the urogenital diaphragm. It is positioned ventral to the rectum, through which it may be palpated, especially when enlarged. The human prostate is 4 cm transversely at the base, 2 cm in anteroposterior diameter and 3 cm in vertical diameter, and weighs approximately 20 g. It is held in position by puboprostatic ligaments; by the deep layer of the urogenital diaphragm, which invests the prostate and the commencement of the membranous portion of the urethra; and by the anterior portions of the levatores ani, which pass backward from the pubis and hold the sides of the prostate. These portions of levatores ani, called levatores prostatae, support the prostate.
The prostate is enveloped by a thin but firm fibrous capsule, distinct from that derived from the subserous fascia, and separated from it by a plexus of veins. This capsule adheres firmly to the prostate and is structurally continuous with the stroma of the gland, being composed of the same tissues: non-striped muscle and fibrous tissues (Figures 11.1-11.5).
Figure ll.l Left (a) Cell structure: normal body cells have an organized and regular skeleton made up of microscopic tubules that allow for normal growth. Cancer cells have lost this organized pattern, with distortion of the normal microtubules and loss of the normal cell shape and growth patterns. (b) Testosterone is important to the prostate, but not in its original form; it must be transformed to an active form. Testosterone is converted by an enzyme called 5a-reductase to dihydrotestosterone (DHT), the major androgen or male hormone inside the prostate cell. Testosterone circulates in the blood; it enters cells in the prostate by diffusion, like water through a tea bag, and is soon transformed into DHT. DHT hooks up chemically with a specific protein, moves to the cellular seat of power - the nucleus - and quickly becomes a powerful force in transmission of genetic information (DNA) from prostate cells
Muscular tissue constitutes the main prostatic stroma with scanty connective tissue between the muscular fibers forming thin trabeculae in which vessels/nerves of the gland ramify. Muscular tissue is arranged so that immediately beneath the fibrous capsule is a dense layer that forms an investing sheath for the gland. Around the urethra as it lies in the prostate is another dense layer of circular fibers that is continuous above with the internal layer of the muscular coat of the bladder, and blends below with fibers surrounding the membranous portion of the urethra. In the part of the gland situated in front of the urethra the muscular tissue is dense, with no glandular tissue, while in the part that is behind the urethra, the muscular tissue has a wide-meshed structure, which is densest at the base of the gland (near bladder), becoming looser and more sponge-like towards the apex of the organ.
Figure 11.2 The three zones of the prostate (sagittal view)
Figure 11.3 Anterior view of the human prostate/prostatic urethra. The anterior walls of the left ampulla, left seminal vesicle, have been cut away
The glandular tissue of the prostate is composed of several follicular pouches with papillary elevation of lining follicles opening into elongated canals which join to form 12-20 excretory ducts. The ducts are connected by areolar tissue, supported by prolongations from the fibrous capsule and muscular stroma, and enclosed in a delicate capillary plexus. Columnar epithelium lines the canals and terminal vesicles. The prostatic ducts open into the floor of the prostatic portion of the urethra and are lined with two layers of epithelium, the inner layer consisting of columnar and the outer of small cubical cells. Colloid masses, known as amyloid bodies, are often found in gland tubes.
Arteries supplying the prostate are derived from internal pudendal, inferior vesical and middle rectal arteries. Veins form the prostatic plexus, which surrounds the sides and base of the gland. The plexus receives the dorsal vein of the penis and empties into the internal iliac veins and anastomotic connections with the vertebral system of veins, through which metastases of carcinoma may reach the bones or even the brain. Nerves are derived from pelvic plexus.
The prostate is perforated by the urethra and ejaculatory ducts. The urethra lies along the junction of its anterior with its middle third. The ejaculatory ducts pass obliquely through the posterior part of the prostate and open into the prostatic portion of the urethra.
The prostate has a base, an apex, a posterior, an anterior and two lateral surfaces. The base is close to the caudal surface of the bladder. The greater part of this surface is directly continuous with the bladder wall; the urethra penetrates it nearer to its ventral than its dorsal border. The lateral surface of the prostate is prominent, covered by the ventral portions of the levatores ani and separated from the gland by a plexus of veins. Caudally it is in contact with the deep layer of the urogenital diaphragm. The posterior surfaces (dorsal and rectal surfaces) are flattened from side to side and slightly convex craniocau- dally; they are separated from the rectum by its sheath and important recto-vesical fascia. Near its cranial border is a depression through which the two ejaculatory ducts enter the prostate. This depression divides the posterior surface into a lower larger and an upper smaller part. The cranial smaller part constitutes the middle lobe of the prostate and intervenes between the ejaculatory ducts and the urethra; it varies greatly in size. The caudal larger portion can have a shallow median furrow, which imperfectly separates it into a right and a left lateral lobe. These form the main mass of the gland and are directly continuous with each other dorsal to the urethra. Cranial to the urethra the lobes are connected by a band, the isthmus, which consists of the same tissues as the capsule and is devoid of glandular substance.
Figure 11.4 Detailed view of urethra and the orifices of the prostatic/ejaculatory ducts
Figure 11.5 (a) A midline section through the male lower urinary tract, the lumen of the bladder and urethra is dilated and the right half of the trigone is indicated as a surface feature.The detrusor muscle (D) is in direct continuity with the morphologically identical deep trigone (DT).The superficial trigone (ST) extends inferiorly as far as the verumontanum.The smooth muscle of the bladder neck forms the internal urethral sphincter (IS) and is continuous with the prostatic capsule (P).The distal or external urethral sphincter (ES) is shown surrounding the membranous urethra. (b) Viewed from the front, the trigone is represented as a surface feature on the luminal aspect of the trigonal detrusor. PS, per urethral striated muscle
The urethra emerges from the anterior surface of the prostate a little cranial and ventral to the apex of the gland.
Enlargement of the prostate can cause obstruction of urinary flow through the urethra; this condition is more common in older men. Multiple ducts from the gland empty directly into the urethra. The prostate is a nodular gland with two narrow lobes connected by a thin transverse isthmus. The prostate secretes a thin, milky fluid containing calcium, citrate ions, phosphate ions, a clotting enzyme and a profibrinolysin. During emission the prostatic capsule contracts simultaneously with the contraction of the vas deferens; therefore the milky fluid may be quite important for successful fertilization, since the fluid of the vas deferens is relatively acidic owing to the presence of citric acid and metabolic end products of sperm (pH 3.5-4.0). Sperm do not become optimally motile until the pH of the surrounding fluids rises to 6.0-6.5. The slightly alkaline prostatic fluid seems to neutralize the acidity of other seminal fluids during ejaculation to enhance sperm motility and fertilizability. The clotting enzyme from prostatic fluid causes the fibrinogen of the seminal vesicle fluid to form a weak fibrin coagulum that holds the semen in the deeper regions of the vagina at the cervix. The coagulum then dissolves within 15-30 min because of lysis by fibrinolysin from the prostate.
PROSTATE CANCER
Physiopathology
The ductal epithelium of the prostate is surrounded by a sleeve of stromal cells, which consists primarily of smooth muscle cells that are involved in muscle contraction and innervation. The stroma contains fibroblasts, neuroendocrine cells and blood vessels. The structure and function of the prostate are dependent on androgens, particularly 5a-dihydrostestosterone (DHT), which preferentially binds to the androgen receptor. The reduction in prostate size that occurs after castration is primarily owing to the selective loss of the androgen-dependent secretory epithelial cells which undergo apoptosis. Prostate cancer is a disease of the aging male, and response to androgens, or androgen withdrawal, may be significantly influenced by age. Several antioxidant enzymes cause lobe-specific age-related decreases in the prostate: catalase, superoxide dismutase, glutathione peroxides and glutathione reductase. Normal body cells have an organized and regular skeleton composed of microscopic tubules that allow for normal growth. Cancer cells have lost this organized pattern, which causes the distortion of the normal microtubules and loss of the normal cell shape and growth patterns.
Incidence
The incidence of prostate cancer varies dramatically from country to country as well as between racial and ethnic groups. The age-matched rates for prostate cancer among American blacks and whites nearly tripled between 1973 and 1992. In the USA, 244 000 new cases of prostate cancer were estimated to be diagnosed in men over 50 years of age in 1995. This means an increase of 44 000 new cases being diagnosed within 1 year alone, as compared with 200 000 new cases in 1994. The lowest incidence rates have been observed in Asian populations: about 6/100 000 in Japan and less than 2/100 000 in China. The rates in Asians increase after immigration to the USA.
The pattern of prostate cancer parallels that of breast cancer in the female, and colon and pancreatic cancer in both sexes. Worldwide the incidence of mortality is unequally distributed, occurring more frequently in North America and northern Europe, and less frequently in Asia. Although the rate of prostate cancer in Japan is much less than that in the USA, it is continuously increasing; this may be due to a westernized diet, widespread environmental contamination and improved screening by prostatespecific antigen (PSA).
Endocrine parameters
Testosterone is important to the prostate, but not in its original form; it must be transformed into an active form. Testosterone is converted by the enzyme 5a-reductase to DHT; DHT is the major androgen, or male hormone, in the prostate. Testosterone circulates in the blood. It enters cells in the prostate by diffusion, like water through a tea bag, and is soon transformed into DHT. DHT binds with a specific protein, moves to the nucleus, and quickly becomes a powerful force in the transmission of genetic information (DNA) from prostate cells.
The estrogen: androgen ratio increases with aging because of the gradual decline in androgen levels. The relative decrease of androgens compared with estrogens is an initiating factor for benign prostatic hyperplasia (BPH). Strong correlation occurs between prostate cancer risk and high normal testosterone levels. Racial variation in the incidence may be explained by differences in testosterone biosynthesis and metabolism. Other initiating factors include androgen tissue concentrations, rate of testosterone reduction to DHT and sensitivity of androgen receptors. Prostate cancer is commonly multifocal, with an average of five apparently independent foci at the time of diagnosis. BPH is not prostatic carcinoma and is not related to family history.
Of testosterone in plasma 98% is bound to protein as testosterone binding globulin (TBG). Testosterone in the prostate is converted to DHT by the enzyme 5a-reductase. The inhibitor ‘Proscar’ inhibits the growth of BPH. A prospective study is under way by the Southwest Oncology Group on the preventive effect of Proscar in prostate cancer. Androgenic hormone depreciation in prostate cancer is accomplished by various methods.
Screening and testing
Screening should be initiated among men at high risk for prostate cancer before the age of 45 years. Screening in families with hereditary cancer is initiated at least 5 years before the earliest age at diagnosis in the family, and at least 10 years before the age at which metastatic disease appeared. PSA screening is terminated at the age of 70 years for men with consistently normal levels, since the risk of dying of prostate cancer is low. Men with PSA >3 ng/ml should undergo biopsy, and if the results are negative they should undergo repeat biopsy or re-examination at short time intervals. Men from families with hereditary prostate cancer (HPC) are concerned about their increased risk, and it is of psychological importance to these individuals that something be done to reduce their risk of dying of cancer. The risk of false-positive PSA tests should be discussed with the patient before he is offered regular screening.
PSA levels change with age, prostate volume and prostate cancer. Untreated hypogonadal men can have lower serum PSA concentrations than controls; absence of testosterone does not change PSA levels in eugonadal men, and patients with prostate cancer and low serum testosterone concentrations have lower serum PSA levels than those with normal serum testosterone levels. A prostate biopsy should be performed only if abnormalities are detected by digital rectal examination (DRE) or if PSA levels are rapidly increasing during testosterone therapy (an increase of 1.5ng/ml or greater). Castration causes an 85% and 81% decrease in the total epithelial weight and total ventral prostate lobe weight, respectively; hypogonadal men have a reduced total prostate volume compared with eugonadal men. Non-obstructive BPH is not a contraindication to testosterone therapy. However, prostate cancer is an absolute contraindication to testosterone therapy, because testosterone administration may promote the growth of subclinical prostate cancer. DRE and serum PSA measurement should be performed before testosterone treatment, at 3 and 6 months, and yearly thereafter. PSA should be measured 1 month after initiation of therapy to detect any patient with previously undiagnosed prostate cancer that may behave in a very aggressive fashion after testosterone replacement therapy. Testosterone may be administered using a gel or patch to achieve a physiological pattern.
Testing is performed on leukocyte DNA from ordinary blood samples. Presymptomatic genetic testing has important psychological, medicolegal and ethical consequences. Testing should always be preceded by thorough education and counseling, and written informed consent. There should be active follow-up after counseling for genetic testing, regardless of whether testing was actually performed. The large number of genes involved in prostate cancer susceptibility, and the probable importance of environmental and additional genetic factors that modify cancer risk, make genetic analyses complicated.
The incidence of prostate cancer being detected at autopsy in older men is very high and increases steadily with age. However, the vast majority of these cancers remain insignificant. The progression to clinically detectable and/or lethal cancer varies in different geographic locations and ethnic populations. Patients with localized prostate cancer can be cured of their cancer. However, not all require a curative treatment with its attendant morbidity. Patients with limited life expectancy who have prostate cancer with good characteristics (low volume, low grade) do well for many years with expectant management (watchful waiting). Many elderly patients will die of competing causes long before prostate cancer progression. However, patients who have a long life expectancy and localized prostate cancer will eventually have disease progression causing significant morbidity and mortality. Unfortunately, patients with poor disease characteristics (large volume, non-organ confined and high grade) often do poorly despite therapeutic intervention. The majority of patients have intermediate disease characteristics and their prognosis is less predictable.
HEREDITARY PROSTATE CANCER
There is no difference between patients with HPC and those with sporadic prostate cancer regarding tumor grade and pathological stage at diagnosis. The clinical characteristics of cancer depend on which susceptibility gene is involved in a family HPC. Between 5 and 10% of prostate cancer is caused by dominantly inherited genes. HPC is diagnosed at a comparatively early age of onset. Patients from families with HPC are diagnosed 6-7 years earlier than those with sporadic disease. HPC may account for one-third of prostate cancer cases diagnosed before age 60, and more than 40% of those diagnosed before age 55. HPC should not be treated differently from the sporadic disease, other than that watchful waiting might be a less suitable option for men who have had the painful experience of having a close relative die of the disease. Men concerned about a possible hereditary predisposition to prostate cancer should be offered basic genetic counseling: explanation of the genetic mechanisms of autonomic dominant and X-linked traits, and notification of the risk in absolute and relative terms (Figure 11.6 and Table 11.1).
Figure 11.6 Manifestation and grades of prostate carcinoma. (a) Stages of prostate cancer using both the TNM (tumor nodes metastases) and the Whitmore-Jewett system. (b) Extent of prostate cancer according to the TNM staging system. (c) Histological grades of adenocarcinoma showing appearance of cancer cells according to the Gleason grade (Bostwick et al., 1996). (d) The four stages of prostate cancer
Genome-wide search with linkage analysis resulted in mapping the prostate cancer susceptibility gene to chromosome 1q24-25; this gene named HPC is linked to prostate cancer in 33% of patients. Linkage to HPC1 was mainly found in families with male-to-male germline transmission of early-onset disease diagnosed in five or more family members, with 29% of the families fulfilling these three linked criteria. A second gene has been located on the long arm of chromosome 1 (1q42.2-43) based on a linkage analysis susceptibility gene located on the X (Xq27-28). Less common genes include: HPCX on chromosome Xq27-28, CAPB on chromosome 1p36, HPC2 on chromosome 17p12 and HPC20 on chromosome 20q13.
Table ll.l Effect of family history of prostate cancer on lifetime risk of clinical prostate cancer
|
Family history |
Relative risk |
% Absolute risk |
|
Negative |
1 |
8 |
|
Father affected at age 60 or older |
1.5 |
12 |
|
One brother affected at age 60 or older |
2 |
15 |
|
Father affected before age 60 |
2.5 |
20 |
|
One brother affected before age 60 |
3 |
25 |
|
Two affected male relatives* |
4 |
30 |
|
Three or more affected male relatives+ |
5 |
35-45 |
*Father and brother, or two brothers, or a brother and a maternal grandfather or uncle, or a father and a paternal grandfather or uncle. The absolute lifetime risk for mutation carriers is probably 70-90% for high penetrance genes such as HPC1
Unaffected men in families with HPC overestimate their lifetime risk of the disease. Thus, such information will often reduce concerns about cancer risk. For members of families with HPC who experience close relatives dying of cancer, often at an early age, causing anxiety or depression, psychological aspects of cancer predisposition should be addressed at counseling. The onset of HPC, which is associated with higher mortality, increases the potential gain in survival by curative treatments and decreases the proportion of men treated for tumors that would not have progressed to symptomatic systemic disease within their lifetime.
The positive predictive value of PSA varies with the prevalence of prostate cancer in the screened population. The higher is the prevalence, the higher the positive predictive value. Thus, the risk of prostate cancer for men with a slightly to moderately elevated PSA is much higher for those with a positive family history than for those with no affected relatives. The urologist should therefore decide whether to perform prostatic biopsies in men with a PSA of 3-10 ng/ml, considering family history and other established factors, such as the ratio of free-to-total PSA, PSA density and patient age. In some families there is X-linked inheritance as well as recessive inheritance.
Of patients having a relative with prostate cancer 40% had a positive biopsy compared with 29% of patients with a negative family history.
Table 11.3 Effects of testosterone therapy on prostate specific antigen (PSA) levels and prostate volume in hypogonadal men
|
Duration (months) |
Administration route |
Effects |
|
|
PSA |
Prostate volume |
||
|
41.5 ± 36.2 |
Oral,TTS, IM |
NS |
NS |
|
18 |
Anabolic steroid abusers |
NS |
TPV:NS;CPV:20% |
|
Up to 12 |
IM,TTS |
NS |
NS |
|
12-36 |
TTS |
NS |
NS |
|
32 |
Implants, IM |
NS |
TPV: NS; CPV: NS |
IM, intramuscularly; TTS, transdermal therapeutic system; TPV, total prostate volume; NS, not significant; CPV, central prostate volume
Prophylactic radical prostatectomy might be an option when presymptomatic genetic testing becomes feasible and gene carriers with extremely high risk (70-90%) of prostate cancer can be identified. Mutation carriers should be identified and offered prophylactic treatment or intensive surveillance. HPC carriers can be assured that their cancer risk is not higher than that of the general population. Hereditary cancer susceptibility is caused by germline mutations.
Most genes involved in hereditary susceptibility to prostate cancer are relatively site specific. The small difference in age at onset between hereditary and sporadic prostate cancer (6-7 years compared with 20 years in breast, ovarian and colorectal cancers) implies that environmental factors may be of importance in many families with HPC.
Little is known about the genes that modify the expression or penetrance of the prostate cancer, which could partly explain the difficulties in confirming and cloning the mapped genes. Most cases of prostate cancer seem to occur in a genetically predisposed minority of the population. This could form the basis of a future selective screening strategy.
Protooncogenes
Mechanisms involved in oncogenesis include protooncogene activation, mutation or loss of tumorsuppressor genes, activation of antiapoptotic genes or loss of proapoptotic genes. The effect of genes that enhance a process is shown as +, whereas the effect of genes that suppress a process is shown as -. Cell division and proliferation are stimulated (+) by the products of protooncogenes. Some tumor-suppressor genes directly regulate protooncogene function (gate keepers); others act more indirectly by maintaining genome integrity and correcting mutations during DNA replication and cell division (caretakers). Activation of antiapoptotic genes has the same effect. Activation of oncogenes or antiapoptotic genes is dominant and requires only a single mutant allele. The action of tumor-suppressor genes is recessive; when both alleles are mutated or lost, cell growth is unregulated or genomic integrity is compromised. Loss of proapoptotic genes may occur through loss of both alleles or through a dominant negative mutation in one allele.
THERAPEUTIC APPROACHES
Management of hormone refractory prostate cancer (Table 11.2)
Prostate cancer that is progressive despite the maintenance of castration levels of testosterone is generally referred to as hormone refractory or androgenindependent prostate cancer. These terms, however, are misnomers, as most progressive cancers remain sensitive to androgens and some may respond to alternative hormonal manipulations. Development of hormone refractory prostate cancer is a significant clinical finding which usually has a median survival of 9-12 months.
Hormone refractory prostate cancer is a heterogenous disease and prognosis may vary among different subgroups of patients. Patients may present only with a rising PSA without significant disease-related symptoms, or they may present with multiple osseous metastases, a declining performance status and severe pain. Mechanisms implicated in the development of androgen independence may include androgen receptor mutations and expression of antiapopotic protein, bcl-2. Assessing disease response to treatment has been a barrier in development of new treatments, as about 60% of patients will have disease confined to bone, which is not amenable to classic response criteria (Figures 11.7 and 11.8).
Chemotherapy has been extensively evaluated in the management of patients with hormone refractory prostate cancer. In a randomized trail, combination of mitoxantrone and prednisone was shown to be superior to prednisone alone, primarily with regard to palliation of symptoms (Pilepich et al., 1995; Soloway et al., 1995).
Figure 11.7 Role of the mitochondrion and Bcl-2 family proteins in programming cell death. From Lee and Tenniswood, 2003, with permission. Fash, Fas ligand; FADD, Fas-associated death domain;TNF, tumor necrosis factor; R, receptor;TRAF, tumor necrosis factor receptor-associated factor;TRADD,TNF receptor-associated death domain; NIF, neutrophil inhibitory factor; PTEN, phosphatase and tensin homolog; IKK, IkB kinase; NF, nuclear factor;AIF, apoptosis-inducing factor; APAF, apoptotic protease-activating factor; NUMA, nuclear mitotic apparatus; snRNP, small nuclear riboproteins; ICAD, inhibitor of caspase-activated DNase
Synthetic non-steroids
A new family of synthetic non-steroidal molecules displays selective preferential activities for androgen receptors in certain tissues such as muscle, bone and the central nervous system. Specific androgen receptor modulators are not substrates of the 5a-reductase enzyme and are therefore not converted to DHT. Consequently, they do not have proliferating activity in the prostate (Negro-Vilar, 1999).
Non-steroidal antiandrogens
These include flutamide, bicalutamide (Casodex) and nilutamide. They have been used for long- or short-term combined androgen blockade (in conjunction with luteinizing hormone releasing hormone (LHRH) agonists) and as single agents. Currently, antiandrogen monotherapy is not considered to be as effective as surgical or medical castration in the initial management of advanced prostate cancer. However, they may have a role in combined androgen blockade. Furthermore, they are used during the transitional phase of hormone refractory prostate cancer at which time patients may still respond to secondary hormonal management, e.g. by use of high- dose bicalutamide, estrogen therapy or other steroid antiandrogens such as ketoconazole. The timing of androgen withdrawal is not strictly defined. All symptomatic patients and those with evidence of skeletal metastases clearly benefit from androgen deprivation. Furthermore, patients with pelvic lymph node metastases also benefit from early androgen deprivation.
Radioactive seed implants
Interstitial radioactive seed implantation for prostate cancer offers another viable treatment option for patients with prostate cancer. The advantages over surgery are the avoidance of a major surgical procedure, less incidence of significant complications, such as incontinence, and the rapidity with which normal functions can begin. Erectile dysfunction continues to be a concern. Most feel that the true rate of erectile dysfunction after Brach therapy is approximately 50%. The major advantages over external beam radiotherapy involve the time commitment by the patient. Modern external beam radiotherapy is a 7-8-week treatment course, whereas Brach therapy is now largely an outpatient procedure. Longer follow-up is needed adequately to evaluate how successful Brach therapy will be for the treatment of localized prostate cancer (Pollack and Zagars, 1997; Roach et al., 1996).
External beam management with high-dose conformal radiotherapy
External beam radiotherapy has been used for the curative treatment of prostate cancer for many years. The problems with traditional means of treating prostate cancer with radiotherapy have been a less than optimal cure rate and an unacceptable frequency of unpleasant adverse effects, most notably intestinal problems.
Angiogenesis and survival period of cancer patients
‘Angiogenesis’ cutting off a tumor’s blood supply improves cancer survival, but does not cure the disease. Treatment with angiogenesis is based on the drug AvastinTM, which acts against vascular endothelial growth factor, one of the more than 20 chemicals that help the blood vessels of the tumor to grow and survive.
In a recent study at Duke University, 923 colon cancer patients all received a standard chemotherapy cocktail of irinotecan, 5-fluorouracil and leucovorin. They were also randomly given either Avastin or placebo. Those on Avastin survived an average of 20 months, compared with almost 16 months in those receiving only standard treatment (personal communication). The results are a surprise, since an earlier study found no benefit of Avastin against breast cancer.
Nutrition
Nutritional recommendations for patients with prostate cancer emphasize the role of a healthy diet, low in fat and high in fruit, vegetables and grains. Fat intake should be <40 g (and preferably <33 g). Consumption of adequate amounts of vegetables and fruit is recommended including cooked tomatoes and berries. The role of nutritional supplements, vitamin E, selenium, lycopenes, ellagic acid and some soy components is being studied.
Molecular parameters
Extensive investigation has been conducted on the molecular mechanisms of cell death in human prostate cancer (Lee and Tenniswood, 2003). Emphasis was placed on the role of mitochondria and Bcl-2 family proteins in programmed cell death and the stages of apoptosis in individual glandular epithelial cells (Figures 11.7 and 11.8).
Recommended research
Recommended future research includes investigation of the:
(1) Long-term effects of androgen replacement therapy on the prostate;
(2) Role of androgens in pathogenesis of benign prostatic hyperplasia (BPH) and prostate cancer;
(3) Effects of testosterone therapy on BPH or prostate cancer;
(4) Effects of testosterone therapy on an existing cancer;
(5) How PSA levels are affected by androgen deficiency and androgen replacement.
Large-scale, long-term clinical studies are needed to resolve the issues related to andropause and assess the long-term risk versus benefit profile of androgen replacement therapy.