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Table 3.8 Second-line treatment options for hormone-escaped disease.
Anti-androgen Withdrawal
Paradoxically, in some patients who have been receiving combined androgen blockade (CAB), withdrawal of the anti-androgen component may be useful, resulting in reductions in PSA levels and possibly radiographic responses. Responses ranging from 15-33% have been reported, although these tend to be short-lived, lasting about 3 months. Withdrawal responses may take sometime to appear and this may be related to the pharmacokinetics of the anti-androgen. The longer the half-life, the longer the time for potential responses to be seen. For flutamide with a half-life of 6 hours, response may be seen in 4 weeks, whereas with bicalutamide, which has a half-life of approx 6 days, it may take up-to 8 weeks.
Agents with hormonal activity e.g. Ketoconazole. Corticosteroids
Ketoconazole or aminoglutethimide, which are adrenal suppressants, may benefit selected patients. Ketoconazole, which is orally active, blocks both adrenal and testicular androgen biosynthesis. Dependent on the dose used, it can reduce levels of circulating androgens to castrate levels, within 48 hours. If painful spinal cord compression occurs there is evidence that ketoconazole can produce a rapid response. Ketoconazole plus hydrocortisone has also demonstrated PSA responses and reduction in symptoms, although some studies have not supported these findings. Toxicity can be an issue, particularly with high dose regimens, with gastrointestinal disturbances, fatigue and liver function abnormalities being particular problems, with up-to 20% of patients discontinuing therapy due to intolerable side effects. It should be noted that, dependent on the country, these agents might not be approved for use in prostate cancer.
Glucocorticosteroids e.g. prednisone, dexamethasone are also known to be active in prostate cancer. Decreases in PSA and improvement in symptoms have been identified in up-to 33% of patients with low dose (10-20mg per day) prednisone, although higher rates of PSA response have been reported with dexamethasone, which is a more potent glucocorticosteroid. It must be remembered that these agents have well defined side effects including glucose intolerance, easy bruising and steroid myopathies.
Cytotoxic chemotherapy
Initial randomised studies of cytotoxic regimens e.g. mitoxantrone plus glucocorticosteroid, demonstrated improvement in quality of life and particularly palliation of pain, but no survival advantage. Similarly, oral estramustine has been shown to provide no survival advantage. Other cytotoxics e.g. paclitaxel, vinblastine and etoposide usually in combination with estramustine have produced palliative responses and some disease regression.
Recently two large randomised studies (TAX 327 and SWOG 99-16) have provided evidence of not only palliative benefit, but also improvements in survival with the use of docetaxel. In the TAX 327 study involving over a thousand patients, docetaxel/prednisone was compared to mitoxantrone/prednisone. It was demonstrated that a three weekly regimen of docetaxel resulted in a statistically significant (p=0.0094) improvement in overall survival (2.4 months) compared to mitoxantrone. In addition there was a significant improvement in pain response and PSA responses. A second study (SWOG 99-16) in 770 patients demonstrated a significant improvement (p=0.02) in overall survival (2 months) when docetaxel/estramustine was compared to mitoxantrone/prednisone. The most commonly occurring adverse events included anemia, neutropenia, infection, nausea, sensory neuropathy, fluid retention, alopecia, nail changes, diarrhea, and fatigue. Docetaxel plus prednisone has now been approved by a number of regulatory authorities for the treatment of metastatic hormone-refractory prostate cancer
Bisphosphonates
Bisphosphonates e.g. zoledronic acid are pyrophosphate analogues that block the osteoclastic activity in bone, thereby favouring bone stabilisation and recovery. In patients with HRPC and radiological evidence of bone metastases, zoledronic acid given every 4 weeks has been shown in a randomised, prospective study to reduce the incidence of adverse skeletal-related events (e.g. fracture, need for EBRT) compared to placebo. In addition the time to these events was substantially delayed, as was the progressive increase in average pain intensity.
Other measures, which can help to optimise bone health, include calcium and vitamin D supplementation, healthy diet and regular weight bearing exercise.
EBRT
EBRT is very useful for the treatment of focal, symptomatic bone metastases where a short course provides quick pain relief with response rates of >80%. The optimal dose schedule is controversial and varies greatly between a single fraction and 10 treatments over 2 weeks. EBRT is also used in the treatment and prevention of spinal cord and nerve root compression
Radiopharmaceuticals
Bone seeking radiopharmaceuticals e.g. strontium-89 and samarium-153 are useful for the treatment of diffuse symptomatic metastatic disease. They have the potential to palliate pain at multiple sites and may also delay the development of new symptomatic sites. Studies have shown that a single dose of strontium-89 (150MBq - 4 mCi) can produce response rates of 35% - 89% with duration of response, which ranges from 3 to 12 months.
Palliative Care
Patients with HRPC can develop local disease progression, which can manifest itself as ureteral or bowel obstruction, urinary retention, persistent haematuria or troublesome proctitis. Medical management such as anti-cholinergic therapy for voiding symptoms or steroid enemas for proctitis are preferred, but surgical intervention may be necessary in some cases.
Metastatic bone pain is the most intractable problem associated with HRPC. Conventional analgesics, such as paracetamol, aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) or narcotics should be used to provide pain relief. Antidepressant or anticonvulsant drugs are sometimes useful for treating neuropathic or nerve pain and corticosteroids can provide temporary, but significant relief of pain due to spinal cord compression.
Other non-pharmacological approaches e.g. psychological, psychosocial and spiritual strategies, may also be useful, as may physical techniques such as acupuncture, massage and transcutaneous electrical nerve stimulation.
Good palliative care frequently involves a multi-disciplinary team approach.
Investigational Agents
There are numerous investigational agents currently undergoing evaluation as possible future treatment for HRPC. These include such diverse approaches as:
- Endothelin Antagonists e.g. Atresentan, AZD4054. Alterations in the regulation of the potent vasoconstrictor endothelin axis, that is endothelin-1 (ET-1), ET-2, and ET-3, has an effect on cell proliferation, apoptosis, matrix proliferation, and pain. ET-1 is the most common form, which exerts its effect through either the endothelin A (ETA) or endothelin B (ETB) receptors. Blockade of the ETA receptor blocks or reverses the effects of ET-1, which may impact on disease progression and morbidity.
- ZD4054 is an orally active specific ETA receptor blocker [1]. The results of the phase II study will be reported at ECCO 14 in Paris September 2007. Phase III trials are planned.
- Atresentan, which is an orally active selective antagonist of the ETA receptor, is currently being investigated in the treatment of prostate cancer in metastatic hormone-refractory disease in combination with docetaxel [2].
- Immunotherapy. This approach uses the body’s own defences to fight the cancer. Research on agents such as interferons, interleukins, tumour necrosis factor and monoclonal antibodies is being conducted to investigate whether agents of this nature can restore and perhaps enhance the natural immune response. In addition the potential value of vaccines is also being investigated, using either the ‘whole cell’, ‘antigen specific’ e.g. PSA or ‘dendritic cell’ approach. Current evidence suggests that whilst all vaccines are safe, the ‘dendritic cell’ approach is more successful with not only an immune response being seen, but also an impact on PSA levels. It has been suggested that since there is unlikely to be a single ‘cancer antigen’, a multivalent approach using a number of new technologies is necessary. One example of the development of vaccine technology is a vaccine which consists of autologous dendritic cells, loaded ex vivo with a recombinant fusion protein consisting of prostatic acid phosphatase linked to granulocyte-macrophage colony stimulating factor.
- Gene Therapy. One approach to gene therapy is to supply cells with healthy copies of mutated genes. Several other approaches have been tested in clinical trials including incorporating cancer-fighting genes into immune cells to help them attack cancer cells more forcefully; removing cancer cells from the body, changing their genetic make-up, then returning them to the body where they trigger a strong immuno-response and injecting genes to make the cancer cells vulnerable to treatment with a specific drug, such as an antibiotic. Subsequent treatment with that drug kills the tumor cells that contain the new gene but should not harm any other cells that do not contain the gene.
- Other Targets. Angiogenesis is a major target for novel agents, since it plays an essential role in the development of blood vessels in metastases. Vascular endothelial growth factor (VEGF) is involved in this process and the anti-VEGF antibody bevacizumab has been shown to cause partial radiographic responses and to reduce PSA in patients with advanced prostate cancer. Thalidomide is thought to be active against platelet-derived growth factor (PDGF) rather than VEGF and in a Phase II study, when used in combination with docetaxel, a trend towards improved progression free survival and overall survival was seen in HRPC. Oblimersen an oligonucleotide, is an anti-sense treatment which is designed to reduce the expression of Bcl-2, a protein that is expressed in many cancers including prostate cancer. In prostate cancer models, Bcl-2 has been shown to have an effect on the transition from and androgen dependent to and androgen independent state and is also thought to be involved in the development of resistance to cytotoxic agents. Phase I studies combining oblimersen with docetaxel have shown a PSA response and Bcl-2 inhibition in HRPC cells.
The outcome of controlled, randomised, comparative studies will determine the potential role of such therapies in the treatment of prostate cancer.
