Hormone-resistant prostate cancer

By Alexandre R. Zlotta, Department of Urology, Erasme University of Brussels, Belgium

Prostate cancer, the most common neoplasm in men, often progresses from an androgen-dependant state (and is commonly treated by androgen ablation therapies) to a hormone-refractory stage, therefore making hormone therapy ineffective. The response duration to androgen ablation therapy is finite and ultimately most prostate cancer will become hormone-insensitive.

Therapy of hormone-refractory prostate cancer has been very disappointing for both patients and physicians. If hormone-refractory prostate cancer is dominated by osseous metastases, leading to bone pain and pathological fractures, nowadays many patients present with rising serum PSA values alone despite hormone therapy. Thus tumour burdens may vary substantially between patients, although all are termed as having hormone-refractory (or resistant) prostate cancer.
Until now, hormone-refractory prostate cancer was considered non-curable and most forms of treatment aimed only at improving the quality of life of patients who commonly had painful bone metastases at this stage. Indeed no effective standard treatments are currently available for patients with hormone-refractory prostate cancer. Median survival is around one year from onset at that stage.

Recently rapid advances in the management of hormone-refractory prostate cancer have been achieved and new therapeutic modalities are investigated.
We present here the significant and most important aspects of these improvements in hormone-refractory prostate cancer.

a) Prostate cancer is not chemo-insensitive as previously thought
Recently large, randomised studies have confirmed a role for systemic chemotherapy for hormone-refractory prostate cancer.
Previously, hormone-independent prostate cancer had not generally been treated with chemotherapy, except for palliation of symptoms, since no chemotherapeutic agent had been shown to lengthen survival significantly.
However, new chemotherapeutic agents such as the taxanes or the combination of mitoxantrone and corticosteroids have changed these old concepts dramatically. There is clearly an emerging, renewed enthusiasm for the role of non-hormonal therapy in hormone refractory prostate cancer..
Mitoxantrone and prednisone might potentially delay time to treatment failure, especially in asymptomatic patients when the tumour burden, is logically smaller than in extensive disease. However most studies failed to observe significant differences in median survival.
Combination chemotherapy with paclitaxel, estramustin and carboplatin is one the many investigated. Other regimens have included doxorubicin with estramustin.
The current trend in prostate cancer is the earlier use of chemotherapy, possibly even at the stage when prostate cancer is not hormone-refractory yet.

b) Bone-targeted therapies in androgen-independent prostate cancer
Biphosphonates, which block bone destruction and remodelling, have been used in many rheumatic diseases to alleviate pain but they also play a key role in oncology. Zoledronic acid, a new powerful biphosphonate, has been studied in a randomised, placebo-controlled trial in patients with hormone-refractory prostate cancer to prevent skeletal complications. At a dose of 4mg, zoledronic acid reduced skeletal-related events by 11% compared with a placebo (Saad et al, 2002).
Another biphosphonate, pamidronate had already been shown to prevent bone loss during androgen-deprivation therapy for prostate cancer.
New avenues include the possible use of biphosphonates to prevent bone metastases in patients with rising PSA despite hormonal therapy.
Two years ago, a randomised study using doxorubicin and strontium, in a selected group of patients with advanced androgen-independent prostate cancer, was among the first to demonstrate a significant benefit in terms of survival (28 months versus 14). Strontium-89, a radioactive analogue of calcium selectively irradiates metastatic sites in the bone, while generally sparing normal bone tissue.

c) New targets in hormone-refractory prostate cancer
Many factors have been linked to the progression of cancer and especially of skeletal metastases. The potent endothelin-1, originally purified from entothelial cells, stimulates mitogenesis in osteoblasts and decreases osteoclastic bone resorption and osteoclast motility.
Endothelin-1 is produced by prostate epithelial cells and prostate cancer cells. A selective inhibitor of endothelin A receptor (atrasentan) has been investigated in hormone-refractory prostate cancer in double-blind randomised placebo controlled trials.

Atrasentan has been demonstrated to suppress markers of biochemical and clinical prostate cancer progression in bone and shown to have a potential clinical activity for hormone-refractory prostate cancer.

Other targets include growth factor inhibitors, differentiation agents, cyclin dependent kinases, activators of apoptosis, anti-angiogenesis and immunotherapy.

Possible cascade of therapy in hormone-resistant prostate cancer
Confirm testicular androgen suppression - Discontinue anti-androgen therapy: anti-androgen withdrawal responses have been reported after cessation of the use of the anti-androgen. These may activate specific mutant androgen receptors cloned from prostate cancers.

Second anti-androgens - Oral chemotherapy + anti-androgen: estramustine phosphate is well-known cojugate of a nitrogen mustard and estradiol, whose mechanism of action is likely antimitotic, specifically by binding to microtubule associated proteins. Estramustine phosphate is often used in combination with other agents, then using intravenous chemotherapy (see further)
Adrenal androgen inhibitors - Aminogluthetimide, ketoconazole and corticosteroids act through this pathway (although corticosteroids may have direct actions as well). Ketoconazole is used in combination with corticosteroids. Corticosteroids are also used in combination with chemotherapeutic agents such as mitoxantrone.

Consider chemotherapy - Mitoxantrone + corticosteroids, Estramustine combinations (+ vinblastine, oral etoposide, cyclophosphamide, taxanes).

Consider using biphosphonates during hormonal therapy and in hormone-resistant prostate cancer, to prevent skeletal events.

Radio-isotopes - Strontium for decreasing painful metastases or in combination with chemotherapy.

New targets and investigational drugs - Anti-endothelins, CDK inhibitors, anti-angiogenesis, use of immune therapies such as dendritic cells, gene therapy protocols.

Palliative care - The current trend is the transformation of hormone-refractory prostate cancer in a chronic stage, namely in a stage not curable but which is controllable by new therapeutic agents. The next step will be the emergence of truly effective therapies with a direct impact on survival, which unfortunately has not been achieved so far with any of the drugs or agents.
E-mail: azlotta@ulb.ac.be