Department of Medical Oncology and Hematology, Princess Margaret Hospital and University of Toronto, 610, University Avenue, Toronto, ON M5G 2M9, Canada
* Email: ian.tannock{at}uhn.on.ca
Recognition that chemotherapy can provide useful palliation for patients with hormone-refractory prostate cancer (HRPC) is relatively recent. Most early clinical trials either evaluated response to chemotherapy in (the relatively rare) patients with measurable disease or used criteria developed by the National Prostate Cancer Project (NPCP), where response included stable disease on bone scans [1]. These criteria could not separate patients who were experiencing meaningful effects of chemotherapy from those with slow progression of disease that was not influenced by treatment. Patients with HRPC are often elderly, and have co-morbid conditions, so that chemotherapy is relatively toxic. In the mid-1980s, two reviews of this prior experience suggested that there was no routine role for chemotherapy in the management of HRPC and that it should only be used in the context of a well-designed clinical trial [2
, 3
]. More recently, the role of chemotherapy has been revisited with the use of less toxic regimens and the development of more relevant outcomes. A decline of at least 50% of the serum level of prostate-specific antigen (PSA) has been adopted as a surrogate marker for tumour response in the absence of clinical or radiographic evidence of disease progression. This end point is useful in phase II trials that seek to demonstrate the activity of new agents or combinations [4
]. Palliative end points that are more relevant to pragmatic phase III trials have been developed based on control of symptoms, using validated self-report scales for pain and quality-of-life questionnaires [5
].
Patients with symptomatic HRPC were often treated with glucocorticoids, and a randomised trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC) indicated better quality of life and higher palliative response in patients receiving prednisone compared with second-line antiandrogen treatment with flutamide [6]. Low-dose prednisone was used in the control arm in early phase III clinical trials that evaluated chemotherapy. Treatment with mitoxantrone and prednisone showed a significantly better palliative benefit (defined by a reduction of self-reported pain and analgesic consumption) compared with prednisone alone in symptomatic patients with metastatic HRPC [5
]. Based on this study, and a related study undertaken by the Cancer and Leukemia Group B [7
], mitoxantrone with a corticosteroid was approved by the US Food and Drug Administration (FDA) and became the reference treatment for comparison with other regimens. Mitoxantrone is associated with a low rate of side-effects, so that it can be given to elderly patients. Nausea and alopecia are uncommon, and myelotoxicity is predictable and rarely severe. Cardiotoxicity is observed after high cumulative doses, but is rare if the total dose is limited to 120 mg/m2. Several studies have confirmed the activity of mitoxantrone used with a corticosteroid, with PSA response rates in the range of 30% to 35% [5
, 7
, 8
] and about 48% for asymptomatic patients [9
], but with no evidence for improvement in overall survival.
Taxanes have shown quite high activity for patients with HRPC in phase II trials, as measured by PSA response, and two large randomised clinical trials have compared docetaxel-based regimens with mitoxantrone and prednisone. The TAX-327 study [10] randomised 1006 patients with HRPC to receive docetaxel plus prednisone (weekly or every 3 weeks) or mitoxantrone and prednisone. The trial included both symptomatic and asymptomatic patients, and the primary end point was overall survival, with secondary end points of PSA response (in those with serum PSA
20 ng/ml at baseline), and pain response (in those with predefined levels of pain at baseline). The 3-weekly docetaxel plus prednisone schedule led to better median overall survival, PSA response rate and pain control compared with mitoxantrone and prednisone (18.9 versus 16.5 months, 45% versus 32% and 35% versus 22%, respectively). As expected, docetaxel was associated with greater toxicity, although this was low-grade and annoying rather than life threatening. There was no benefit (in either response or toxicity) to giving weekly docetaxel in comparison to the 3-weekly schedule [10
]. The SWOG 9916 trial [11
] randomised 770 patients to receive docetaxel plus estramustine or mitoxantrone and prednisone, and the primary end point was again overall survival. A significant improvement of survival was observed in patients treated with docetaxel and estramustine compared with mitoxantrone and prednisone (median overall survival: 18 versus 16 months). Although cross-comparison of trials can be misleading, there was no evidence that estramustine added therapeutic benefit to docetaxel compared with prednisone, and gastrointestinal and cardiovascular toxicities were more often observed with the inclusion of estramustine. Docetaxel 75 mg/m2 every 3 weeks plus prednisone 5 mg twice daily, is now approved by the US FDA for treatment of patients with HRPC.
The results of these two important trials will probably change the standard of care in patients who present with symptomatic HRPC. However, the modest gain in median survival (23 months) obtained with docetaxel needs to be balanced against the side-effects and costs of the treatment. Residual questions from these trials are: (i) could some of the benefits in the docetaxel arms be due to the higher doses of steroids (i.e. dexamethasone) used in the preparative regimens; and (ii) given that few patients in the TAX-327 trial received docetaxel after failing to respond to mitoxantrone [10], could equivalent results be obtained by initiating the cheaper and less toxic mitoxantrone, and crossing over to docetaxel in patients who do not respond after two to three courses?
In this issue of Annals of Oncology, Abratt et al. [12] report the results of a randomised clinical trial that compared vinorelbine and hydrocortisone with hydrocortisone alone (± aminoglutethimide) in 414 patients with HRPC who had progression after primary hormonal therapy. The primary end point was progression-free survival (PFS), and secondary end points included overall survival, PSA response rate, toxicity and clinical benefit. The vinorelbine regimen was well tolerated (with less than 7% grade 4 neutropenia and 1% cardiotoxicity). There was a statistically significant difference of 1 month in median PFS favouring vinorelbine but no difference in overall survival (median 15 months). Clinical benefit defined by improvement in pain intensity, analgesic consumption and Karnofsky performance status was more frequently observed in patients treated with vinorelbine and hydrocortisone compared with steroids alone (30% versus 19%, P=0.01). As pointed out by the authors, these results suggest palliation comparable to that which can be achieved with mitoxantrone and prednisone, although the impact of treatment on quality of life and symptom control was not as well documented as it has been for mitoxantrone and prednisone [5
, 8
]. Vinorelbine and a glucocorticoid can be regarded as an alternative to mitoxantrone and prednisone in patients who are averse to the greater toxicity of docetaxel, particularly if they have a history of cardiac disease.
The role of bisphosphonates for patients with HRPC has been addressed in double-blind randomised controlled trials. Use of clodronate did not improve the palliative benefit of mitoxantrone plus prednisone [8]. Another large trial [13
, 14
] demonstrated that the more potent bisphosphonate zoledronate reduced bone-related events and the FDA has approved this drug for patients with HRPC and bone metastases. However, there were several side-effects associated with this expensive treatment (given every 3 weeks in this study) and overall quality of life was not improved [15
]. Less frequent administration of zoledronate (3-monthly) might be more appropriate to prevent bone loss due to antiandrogen therapy in both hormone-sensitive and hormone-refractory phases of the disease [16
].
What then, are reasonable policies for treatment of patients with HRPC? Recently, Shulman and Benaim [17] described the natural history of androgen-independent prostate cancer in a chemotherapy-naïve group of patients. Nadir PSA during androgen deprivation, time to PSA recurrence and PSA doubling time (PSADT) were strongly correlated with survival. A PSADT of less than 6 months was also a predictor for cancer-specific complications. Thus, for the patient who is asymptomatic and has a slowly rising PSA, continued observation remains appropriate, or treatment with further hormonal manoeuvres such as glucocorticoids, alone or with ketoconazole [18
] or low-dose oestrogen. Symptomatic patients and those with more rapidly rising PSA should be considered for chemotherapy. The results of the randomised trials described above should be presented to patients, so that they understand the significant but small survival benefit from docetaxel and prednisone, and the toxicities encountered with this regimen. This will allow an informed choice between starting with a less toxic regimen (mitoxantrone and prednisone for most, with vinorelbine and a glucorticoid as an option for those with cardiac history), versus immediate treatment with docetaxel and prednisone.
The next generation of trials for patients with HRPC will seek to build on current results, and docetaxel and prednisone will be the reference regimen. Combinations of docetaxel with other anticancer drugs (including mitoxantrone or vinorelbine) might be studied, but haematological and/or neurotoxicity is likely to limit any added benefit. Calcitriol might augment the therapeutic effects of docetaxel through modulation of apoptosis, cell cycle arrest and/or cellular differentiation, mediated by the vitamin D receptor; this combination gave promising results in a phase II trial and a large phase III trial has completed accrual [19]. Many biological targeted agents are undergoing clinical trial in prostate cancer but inhibitors of growth factor receptors including gefitinib, trastuzumab and atresentan have given rather disappointing results and seem unlikely to increase survival further [20
]. Increased understanding of gene expression and of signalling pathways in prostate cancer cells is ultimately likely to lead to the development of more specific therapeutic approaches.
References
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