How the Addition of Hormones Improves Outcome: Hormone Therapy and Chemotherapy

1. Introduction 

The field of hormone therapy combined with chemotherapy is difficult to review as there is a few of randomized, controlled trials on this subject [1].

It has been known for some time that the growth of the prostate cancer is dependent on dihydrotestosterone which acts via androgen receptors. It is also known that androgen receptor activity can be correlated with disease aggressiveness. Since 1941, it has been known that both normal prostatic tissue and prostate cancer tissue are androgen-dependent.

In the hormonal management of prostate cancer, surgical or medical castration with estrogen causes tumour reduction and remission in 80% of patients with advanced disease. The 5-year survival rate in castrated patients is reported to be 20% compared with 0% in untreated patients [2].

In advanced disease it is known that patients with definite metastatic disease cannot be cured with androgen ablation alone since it cannot eliminate the portion of cells that are androgen-independent [3]. Prostatic basal cells are not androgen-dependent.

2. Hormone-refractory prostate cancer (HRPC) 

Prostate cancer is said to be hormone refractory when there is a rise in PSA following androgen deprivation and secondary hormonal manipulations with serum testosterone levels at castration level (<50ng/dl). Three consecutive PSA rises measured 2 weeks apart at least two times above PSA nadir or a PSA increase 4–6 weeks following antiandrogen withdrawal also indicate a hormone refractory state. There may also be progression of bi-dimensional measurable metastases (Table 1) [4].

Table 1. Definitions of hormone-refractory prostate cancer [4]

	⋅	PSA rise following androgen deprivation and secondary hormonal manipulations.
	⋅	Serum testosterone levels at castration level (<50ng/dl).
	⋅	Three consecutive PSA rises measured 2 weeks apart at least two times above PSA nadir.
	⋅	PSA increase 4–6 weeks following anti-androgen withdrawal.
	⋅	Progression of bi-dimensional measurable metastases.

The most common treatment for HRPC is chemotherapy including estramustine-based chemotherapy, anthracyclines, suramin or oral chemotherapy. The limitations of chemotherapy are primarily a lack of effective drugs and the fact that a complete response is rarely achieved with a single agent. In addition, in older patients there may often be impaired organ function, e.g. renal function so they will not tolerate the treatment.

A review of 26 clinical studies published from 1987 to 1991 showed an overall response rate of only 8.7% (95% confidence interval, 6.4–9.0%), with chemotherapy alone in HRPC and no survival benefits [5]. These results confirm previous findings and indicate that HRPC still fails to respond to most cytotoxic agents. Only six agents had an objective response rate greater than 10%, including vinblastine by continuous infusion, trimetrexate, mitoguazone, and estramustine. Although multidrug resistance may explain the marginal efficacy of cytotoxic drugs, methods to overcome such resistance and, more importantly, new classes of agents need to be developed.

As a result, it is recommended that chemotherapy is combined with other treatments such as hormonal deprivation or radiation.

3. Are androgen receptors in HRPC sensitive to androgen? 

It is known that androgen receptors in HRPC are sensitive to androgen. Studies have shown that both primary and metastatic prostate cancer cells show elevated androgen receptors by ligand-binding assays when compared to non-malignant prostate tissue.

The mechanism of hormonal resistance is complex. Some mechanisms those mentioned are (1) selection of hormonal independent clones (2) mutation of androgen receptors (3) amplification of androgen receptors. But Immunohistochemistry studies show that there are elevated androgen receptors in prostate cancer cells, mostly in hormone-relapsed and metastatic hormone-refractory prostate cancer.

HRPC patients treated with chemotherapy alone have significantly lower survival rates than those who are also given continuous hormonal therapy [6]. Another two studies have shown only marginal survival benefits in patients given an LHRH analogue in combination with chemotherapy [7], [8]. There are no prospective, randomised trials that give a definite answer to this issue, in particular the costs effectiveness of this treatment. Most studies suggest that androgen deprivation should be continued when chemotherapy is started.

4. Continuation of androgen therapy 

Crawford et al. suggested that antiandrogen drug should be stopped 4–6 weeks prior to the use of chemotherapy allowing an anti-androgen withdrawal effect [9]. As hormone refractory prostate cancer can still be androgen-sensitive and further progression can occur upon exposure to androgens, it is important that medical androgen deprivation should not be discontinued but rather be continued indefinitely in addition to other treatments.

5. Growth effects of hormone therapy 

Studies have been undertaken to investigate the effect of leuprorelin, alone or combined with other agents, on cell growth and PSA gene expression in human prostatic cancer cells [10].

Leuprorelin was ineffective in regulating cell growth, when used alone in both hormone-sensitive and -insensitive cell lines. Nevertheless, it counteracted the stimulatory action of androgens on proliferation of LNCaP cells, which respond to low concentrations of dihydrotestosterone. Leuprorelin had an inhibitory effect on the mitogenic action of epidermal growth factor (EGF) in androgen-unresponsive PC-3 cells. It reduced PSA gene expression in both hormone-sensitive and -insensitive cells. The authors concluded that LHRHa might behave like a negative growth factor, which directly regulates cell growth and PSA gene expression. This could be a beneficial property when hormonal therapy is combined with others agents, such as chemotherapy.

6. Early or delayed hormonal therapy/chemotherapy 

Early hormonal therapy is thought to be more effective than delayed treatment. It is also known that the greater the tumour burden, the poorer the response. Thus, it may be beneficial to start chemotherapy earlier in the disease, while the patient is still responding to hormonal therapy but their PSA is already rising.

7. Conclusions 

Chemotherapy alone is only poorly effective in the treatment of HRPC and does not produce survival benefits. It is recommended that chemotherapy should be considered a part of a multimodality therapy and combined with other treatments, such as hormonal deprivation or radiation.