Cancer chemoprevention and treatment by diet therapy

Lung tumours are induced by weekly gavage doses of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) plus benzo[a]pyrene (BaP). Intervention can begin during the carcinogen treatment period (shown here at week four) or afterwards. 1; or with BaP plus NNK and a mixture of PEITC-NAC (N-acetylcysteine conjugate of phenethyl isothiocyanate) and myo-inositol in the diet, starting 24 hours after the fourth administration of BaP plus NNK. Single-therapy androgen suppression in men with advanced prostate cancer: A systematic review and meta-analysis. The efficacy and safety of degarelix: A 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. Bicalutamide monotherapy versus flutamide plus goserelin in prostate cancer patients: Results of Italian Prostate Cancer Project study.
Development of a second generation anti-androgen for treatment of advanced prostate cancer.
Randomised protective study of intermittent versus continuous androgen suppression in advanced prostate cancer. In men, testosterone derived from testicular secretion is the primary circulating androgen, and 3 to 10 mg of it is secreted daily from the testes.
Another 500 μg of it is collectively generated by both direct secretion and the peripheral conversion of androstenedione secreted by the adrenal. The effect of castration, of estrogen and of androgen injection on serum phosphatase in metastatic carcinoma of the prostate.
Two isoforms of this enzyme are known- type I and type II.[2] The latter isoform is the most prevalent type within the normal prostate and is also elevated in benign prostatic hyperplasia (BPH). Castration can be surgical orchiectomy or with hormonal therapy with estrogen agonists, gonadotropin hormone-releasing (GnRH) agonists and GnRH antagonists.
All of these treatment modalities have specific adverse effects and affect the quality of life (QOL) of the patient, and their proper use and timing remain controversial.As many as 94% of cancer prostate patients do respond to androgen deprivation. The cellular mechanisms behind this suggest that the tumors that were previously thought to be androgen-independent are actually androgen-hypersensitive and are thus called castration-resistant prostate cancers (CRPC). This has led to a paradigm shift in thinking and provided the rationale for secondary endocrine therapies that further reduce androgen concentrations or interact with the AR.
Currently, novel drugs are being developed such as the new anti-androgen MDV3100 and inhibitor of androgen synthesis abiraterone. The life expectancy of those who have recurrence after local therapy is still 10-15 years in contrast to those with metastatic disease where it is only 3 years. Substantial ambiguity prevails in whether treatment should be initiated early in those with long life expectancy and whether treatment should be continuous.
This is crucial keeping in mind the side-effects of ADT and the detriments it imposes on the QOL of the individual patient.
Finasteride, which is a specific inhibitor of type-2 5α-reductase, was tested in Prostate Cancer Prevention Trial (PCPT). There was, however, an increase in the detection of high-grade prostate cancer (HGPC) in the finasteride-treated population compared with the placebo group.
The PCPT trial data thus suggested that finasteride does not reduce the chances of HGPC as effectively as in low-grade disease.
Dutasteride is the drug that inhibits both isoforms of 5α-reductase and thus could be a better chemo-preventive agent against cancer prostate.

It was tested in Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, which observed that it significantly reduced the rate of biopsy-detectable prostate cancers compared with placebo. For chemoprevention, ARIs reduce but do not eliminate the risk of being diagnosed with cancer prostate. However, current clinical guidelines are reluctant to give recommendations for prostate cancer chemoprevention, reflecting the insufficiency of available data.The pathologist assigns a grade to the most common tumor pattern and a second grade to the next most common tumor pattern [Table 1].
This decreases LH secretion and hence testosterone production falls down to castrate levels. Rather, the initial response is an increase in testosterone production for a period of 1-2 weeks. The raised levels of testosterone not only stimulate tumor growth but also increase the size of bony metastases and can lead to malignant spinal cord compression.
To avert this, anti-androgens are co-administered along with GnRH agonists for a period of 3-4 weeks, and the said adverse effect is rarely seen now-a-days.The choice between orchiectomy and GnRH agonists represents a major question.
Surgical orchiectomy assures the clinician of several benefits- it produces a rapid and assured decrease in serum androgen levels, does not require patient compliance long term, and is effective in inducing tumor regression in nearly 90% of patients. They bind directly to GnRH receptors in the pituitary and bring about a reduction in serum testosterone level as early as brought by orchiectomy.
The widespread use of GnRH antagonists awaits the test of time.Side-effects of ADTADT produces a multitude of adverse effects apart from just loss of libido and erectile dysfunction [Table 4].
These drugs cross the blood-brain barrier, raise LH secretion and, therefore, testosterone secretion from the testes. Thus, they are the agents that can help avoid castration for the treatment of cancer prostate. These side-effects are not seen with bicalutamide, which is the best tolerated drug in this group.
However, the same mechanism also leads to gynecomastia and breast pain in most men receiving it. Apart from this, all non-steroidal AR antagonists may have AR agonist activity, especially in association with CRPC. It has 4-8-fold higher affinity for AR than bicalutamide and has reduced agonistic activity. A meta-analysis of studies involving more than 2700 patients suggested that recurrence was greater with anti-androgen monotherapy than with medical or surgical castration.
Serum PSA determinations provide an easy method for early detection of tumor growth during the period when treatment is withheld. The possible advantages include QOL improvement during off-treatment periods and postponement of hormonal resistance. Data is available that documents the effectiveness of IAD as much as continuous therapy in patients with locally advanced disease and relapse after curative treatment, but not in those with metastases. Therefore, GnRH agonists have been used with anti-androgens in what is known as complete or combined or maximal androgen blockade (MAB). Contrary to the belief, however, randomized trials have not conclusively proven superiority of MAB over castration in patients with metastatic cancer, and a meta-analysis has showed only a minimal improvement in 5-year survival.
For relapses after initial ADT, addition of an anti-androgen produces response in a third of patients though for short periods.
However, if the initial therapy was MAB, clinical responses lasting 3-6 months are produced just by withholding the anti-androgen in as many as 30% of the patients.

Other secondary hormonal agents include ketoconazole and hydrocortisone, which reduce adrenal androgens. Though these drugs bring about a reduction in PSA levels, none has shown survival advantage in patients with CRPC. The current guidelines favor the SAB strategy and use of anti-androgens only after relapse from medical or surgical orchiectomy. ADT in combination with surgery: Neo-adjuvant and adjuvant approachesIn clinically localized disease, many studies have shown that 3 months of neo-adjuvant therapy before radical prostatectomy reduces prostate size and the incidence of positive margins. They also do not put forward any evidence of beneficial role of neo-adjuvant ADT before surgery.
Thus, no advantage of neo-adjuvant ADT, both in recurrence rate and in reduction of complications of radical prostatectomy, has been demonstrated so far. Thus, adjuvant ADT is recommended only for the patients who have evidence of metastatic disease in the form of early time to PSA recurrence, rapid PSA doubling time, and adverse pathologic features (Gleason score 8-10, positive lymph nodes, and seminal vesicle invasion).ADT in combination with radiotherapy (RT)The rationale behind this combination is multi-factorial. Secondly, it inhibits repopulation during irradiation, thus reducing the chances of relapse.
The points favoring delayed ADT include the substantial side-effects and the fact that it is not curative. Contrary to this, early therapy prolongs overall and disease-free survival as shown in various studies in different populations. Thus, survival benefit offered by early therapy must be weighed against the QOL detriments that attend it. To summarize, the present data favors the use of early ADT in both-metastatic (M1) as well as locally advanced, high volume, high grade, or lymph node-positive disease. Moreover, their use augments the ability of raised PSA level to correctly identify patients having cancer prostate.
But, current clinical guidelines are reluctant to give recommendations for prostate cancer chemoprevention, reflecting the insufficiency of available data. ADT in the form of surgical or medical castration (with estrogens, GnRH agonists, and antagonists) is an effective therapy for locally advanced and metastatic disease, but it brings along adverse effects and QOL issues. To circumvent this, anti-androgens especially bicalutamide have been tested as monotherapy but proven less effective.
IAD is as effective as continuous therapy in patients with locally advanced disease and relapse after curative treatment. For MAB, studies and meta-analyzes have not conclusively proven superiority over single agent ADT in patients with metastatic cancer. Adjuvant hormonal therapy with surgery delays disease progression, but provides no survival benefit.
For the timing of such therapy, the present data favors the use of early ADT in both-metastatic as well as locally advanced disease.
Novel drugs such as the new anti-androgen MDV3100 and inhibitor of androgen synthesis abiraterone are already under development for this.

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