Docetaxel and Thalidomide as a Treatment Option for Androgen-Independent, Nonmetastatic Prostate Cancer

OPTIMIZING TREATMENT FOR ADVANCED PROSTATE CANCER Docetaxel and Thalidomide as a Treatment Option for AndrogenIndependent, Nonmetastatic Prostate Cancer Gregory D. Leonard, MD, William L. Dahut, MD, James L. Gulley, MD, PhD, Philip M. Arlen, MD, William D. Figg, PharmD National Cancer Institute, Bethesda, MD Prostate cancer usually presents with early-stage disease, yet a significant proportion of patients present or will progress to androgen-independent, nonmetastatic prostate cancer (AIPC). Chemotherapy has demonstrated statistically significant improvements in palliation of AIPC. Docetaxel in particular has demonstrated high response rates as a single agent. Thalidomide is effective in treating many malignancies, including prostate cancer. Thalidomide may act synergistically with docetaxel through their antiangiogenic effects. We performed a phase II trial of docetaxel with or without thalidomide in patients with AIPC and demonstrated encouraging response rates with combination therapy. We advocate further investigation of this promising combination regimen. [Rev Urol. 2003;5(suppl 3):S65-S70] © 2003 MedReviews, LLC Key words: Androgen-independent prostate cancer • Docetaxel • Thalidomide • Palliative therapy rostate cancer is the most common non–skin cancer in the United States. In 2003, it is expected to account for 33% of new cancers among men; lung cancer is the second most common cancer among men, accounting for only 14%.1 However, lung cancer is the most common cause of cancer death in men and is estimated to contribute to 31% of cancer deaths in 2003, with prostate cancer the second most common at 10%. It is anticipated that there will P VOL. 5 SUPPL. 3 2003 REVIEWS IN UROLOGY S65 Docetaxel and Thalidomide Combination Therapy continued be 220,900 new cases of prostate cancer and 28,900 deaths in 2003.1 The discrepancy between the incidence and mortality rates is due to the large proportion of prostate cancer that is diagnosed at an early stage and cured and to the relatively indolent natural history of the disease, which occurs largely in older men who often die of other conditions. Early diagnosis is likely due to screening, which contributed to the large increase in prostate cancer incidence in the late 1980s. Approximately 11% of black and 4% of white male patients present with metastatic disease and 10%–50% but one study analyzing 26 trials of cytotoxic chemotherapy given between 1987 and 1991 found an overall response rate of 8.7%.3 These figures have improved with combination regimens, although responses are often defined by reductions in prostate specific antigen (PSA) levels and more accurate measures may be quality-of-life assessments and overall survival. Two chemotherapy trials have shown a significant benefit in symptom control in AIPC. The Canadian study randomized 161 patients with hormone refractory disease and pain to mitoxantrone (Novantrone®, The development of hormone refractory or androgen-independent prostate cancer confers a poor prognosis, with a median survival of 9 to 12 months. of early-stage cancers progress to metastatic disease.1,2 Standard therapy is androgen ablation and often results in median survival of 2–3 years.2 The development of hormone refractory or androgen-independent prostate cancer (AIPC) confers a poor prognosis with a median survival of 9 to 12 months. Bone-only disease is found in 60% of patients but can contribute to spinal cord compression or pathologic fractures in 30% of these patients. Systemic therapy options for AIPC are limited and palliative therapy is the primary goal. Chemotherapy has been studied extensively in AIPC, and while no prospective randomized phase III trial has demonstrated a survival benefit, results of two such trials are forthcoming. Comparison of chemotherapy regimens is often limited by variable definitions of response and difficulty in demonstrating response by radiologic techniques. Studies of single-agent chemotherapy have revealed response rates up to 30%, S66 VOL. 5 SUPPL. 3 2003 Serono, Inc., Geneva, Switzerland) and prednisone or prednisone alone.4 Palliative response was found in 29% of patients on chemotherapy and 12% in the control arm (P = .01). The Cancer and Leukemia Group B 9182 study randomized 242 patients to mitoxantrone and hydrocortisone or hydrocortisone alone.5 Pain symptoms were reduced in the combination arm. Other parameters in favor of chemotherapy were a PSA decline of > 75% (14% vs 7%) and improved time to progression (218 days vs 122 days; P = .005). Neither trial was able to demonstrate a statistically significant survival benefit to chemotherapy. Mitoxantrone and steroids have now become the reference regimen with which other therapies are compared in the treatment of AIPC. A phase II trial treated 103 AIPC patients with induction chemotherapy, composed of ketoconazole (Nizoral®, Janssen Pharmaceutica Products, LP, Titusville, NJ) and doxorubicin (Adriamycin®, Pharmacia and Upjohn, REVIEWS IN UROLOGY Kalamazoo, MI) alternating with estramustine (Emcyt®, Pharmacia and Upjohn, Kalamazoo, MI) and vinblastine (Velbe®, Eli Lilly Australia, West Ryde, New South Wales).6 Clinically stable or responding patients were then randomized to receive doxorubicin with or without strontium-89 (Metastron®, Amersham Health Inc., Princeton, NJ). The median survival in patients treated with doxorubicin alone was 16.8 months but was 27.7 months for doxorubicin and strontium-89 (P = .0014). These trials offer promise for systemic therapy in AIPC and suggest an added benefit in outcomes by combining chemotherapy with other agents or therapies. One such combination is docetaxel and thalidomide. We will examine the rationale for the use of these agents in AIPC and present our experience with this combination. Docetaxel Docetaxel (Taxotere®, Aventis Pharmaceuticals, Bridgewater, NJ) is a semisynthetic taxane. Its cytotoxic effects are mediated through two mechanisms. It binds to tubulin and induces stabilization of microtubules preventing microtubular depolymerization. This process inhibits mitosis resulting in the arrest of cells in the G2M phase of the cell cycle and results in apoptosis. Docetaxel may also cause phosphorylation and inactivation of bcl-2, which is found overexpressed in over 60% of AIPC biopsy specimens and leads to activation of the proapoptotic protein bax. Both of these mechanisms of action have been found to be more potent in docetaxel compared with paclitaxel. Docetaxel has shown activity in many solid tumors and has antiangiogenic effects in vitro.7 It is the optimal regimen for platinum refractory non–small cell lung cancer and is one of the few therapies to exhibit a survival advantage in metastatic breast Docetaxel and Thalidomide Combination Therapy cancer. Side effects include fluid retention, hypersensitivity reactions, gastrointestinal disturbance, skin and nail changes, and paresthesias. Docetaxel in Prostate Cancer Clinical trials of single-agent docetaxel in AIPC have demonstrated response rates of 20%–60% (both PSA and measurable disease responses), which are superior to response rates with other single-agent chemotherapies in this disease.8 These studies include docetaxel administration regimens of every 21 days and weekly. The weekly regimen has been shown to have a more favorable toxicity profile and is better tolerated in the elderly, which makes up most of the target population.9 A number of trials have assessed the use of docetaxel in combination with estramustine. Estramustine was chosen because it also affects microtubular function and had shown synergy with other agents that effect tubulin, such as vinblastine. In the initial phase I trial, Petrylak and colleagues10 treated Figure 1. Mechanism of action of thalidomide. TNF-, tumor necrosis factor ; IL, interleukin. Inhibits angiogenesis Inhibits TNF- IL-6 IL-10 IL-12 Thalidomide Increases IL-2 IL-4 IL-5 CD4+/CD8 Tumor Cell Alters adhesion molecules 99-16 trial.12 This is a multicenter, randomized phase III study of docetaxel and estramustine versus mitoxantrone and prednisone in patients with hormone-refractory prostate cancer. Results from this trial are expected in 2004. Docetaxel has also shown encouraging results in combination with novel therapies such as Docetaxel has shown encouraging results in combination with novel therapies such as calcitriol, exisulind, and trastuzumab. 34 minimally pretreated or extensively pretreated patients with estramustine and escalating doses of docetaxel every 3 weeks. PSA responses of > 50% were seen in 63% of evaluable patients, and 28% of evaluable patients with bi-dimensionally measurable disease obtained a partial response. The overall survival at 1 year was 68%. Results from a phase II trial in 37 patients by the same investigator noted > 50% PSA responses and measurable disease partial responses in 68% and 55% of patients, respectively.11 Similar results in other studies prompted the design of the Southwest Oncology Group Direct Toxicity calcitriol, exisulind (Aptosyn®, Cell Pathways, Inc., Horsham PA), and trastuzumab (Herceptin®, Genentech, Inc., South San Francisco, CA). Thalidomide Thalidomide (-N{phthalimido} glutarimide [C13H10N2O4]) is a synthetic glutamic acid derivative that was initially used as an over-the-counter sedative-hypnotic. It was used for pregnancy-associated morning sickness but caused teratogenicity and neuropathies and was taken off the market.13 However, thalidomide was noted to have anti-inflammatory and immunomodulatory effects and was reintroduced to clinical practice by the Food and Drug Administration in 1998 for the treatment of erythema nodosum leprosum. To prevent further episodes of teratogenicity, the manufacturing company set up a program known as the System for Thalidomide Education and Prescribing Safety (STEPS). Thalidomide is now used in many diseases including Behçet’s, Crohn’s, discoid lupus, complex pain syndrome, and rheumatoid arthritis. The main side effects of thalidomide are constipation, sedation, and neuropathy; however, it has been well-tolerated at lower doses. The mechanism of action of thalidomide is poorly understood because it has the potential to work through many pathways (Figure 1). One such mechanism is antiangiogenesis as seen in animal corneal models. These antiangiogenic properties are mediated through metabolites of the parent compound and are likely due to inhibition of basic fibroblast growth factor and vascular endothelial growth factor. Thalidomide also inhibits tumor necrosis factoralpha (TNF-) along with other cytokines and can alter adhesion molecules. The multiplicity of the VOL. 5 SUPPL. 3 2003 REVIEWS IN UROLOGY S67 Docetaxel and Thalidomide Combination Therapy continued effects and efficacy of thalidomide in nonmalignant conditions stimulated interest in the antitumor activity of this compound. Thalidomide in Cancer Singhal and associates14 gave escalating doses of oral thalidomide to 84 patients with refractory multiple myeloma who had received previous treatment. Serum or urine paraprotein levels were reduced by > 25% in 27 patients; of those 27 patients, 8 patients had a > 90% reduction in serum or urine paraprotein levels. Kaplan-Meir estimates of the mean overall survival after 12 months of follow-up was 58%. The efficacy of thalidomide was attributed to a direct effect on myeloma cells, antiangiogenesis, and the other properties previously described. However, microvascular density in bone marrow did not change in patients with a paraprotein response. Other studies have confirmed the beneficial effects of thalidomide in myeloma. Thalidomide has also shown activity in solid tumors. Most of the responses seen have been in Kaposi sarcoma although responses have also been documented in melanoma, brain, colorectal, hepatocellular, and renal cancers. FDG Study: 68-year-old man with AIPC Pre-treatment SUVmax = 5.4 Metabolic Volume = 18.1 cm3 CT Volume = 16.4 cm3 PSA = 41 ng/mL Post-treatment SUVmax = 3.4 Metabolic Volume = 6.0 cm3 CT Volume = 13.5 cm3 PSA = 28 ng/mL Figure 2. Correlation of prostate specific antigen (PSA) decline with resolution of bone metastasis on positron emission tomography (PET) in a 68-year-old man after treatment with thalidomide for androgen-independent prostate carcinoma (AIPC). SUVmax , maximum standard uptake value; CT, computed tomography. Figure 3. Correlation of prostate specific antigen (PSA) decline with resolution of bone metastasis on positron emission tomography (PET) in a 73-year-old- man after treatment with thalidomide for androgen-independent prostate carcinoma (AIPC). SUVmax , maximum standard uptake value; CT, computed tomography. Thalidomide and Prostate Cancer Microvessel density (MVD) has been reported to be higher in prostate cancer tissue than in adjacent hyperplastic or benign tissue.15 Preclinical evidence also suggests that angiogenesis may play a key role in the development of aggressive prostate cancer lesions.16 Clinical studies have observed a correlation between increased angiogenesis in primary tumor specimens and the future development of metastatic disease. The apparent importance of angiogenesis in the evolution of prostate cancer provides a rationale for the investigation of antiangiogenesis S68 VOL. 5 SUPPL. 3 2003 REVIEWS IN UROLOGY FDG Study: 73-year-old man with AIPC SUVmax = 7.1 Metabolic Volume = 45 cm3 CT Volume = 81 cm3 PSA = 79 ng/mL SUVmax = 3.4 Metabolic Volume = 71 cm3 CT Volume = 154 cm3 PSA = 34 ng/mL Docetaxel and Thalidomide Combination Therapy agents in AIPC. Figg and colleagues17 previously reported our data on the use of thalidomide in 63 patients with AIPC. Thalidomide was administered in doses ranging between 200 mg and 1200 mg. This therapy resulted in a > 40% fall in PSA levels in 27% of patients and improvement in clinical symptoms in all responding patients. PSA declines often resulted in striking reductions in measurable disease on positron emission tomographic scan (Figures 2 and 3). No responses were seen in patients receiving high doses of thalidomide, and there was no correlation between MVD in the primary tumor and response to therapy. These encouraging results confirm the benefit of thalidomide in solid tumors and particularly AIPC. Docetaxel and Thalidomide in Prostate Cancer Single-agent docetaxel appears to be a promising chemotherapeutic agent in AIPC and may have improved efficacy in combination with other therapies. Thalidomide has also demonstrated efficacy in AIPC. A combination of docetaxel and thalidomide may be a reasonable therapeutic approach. To answer this question, we performed a randomized phase II trial on 75 patients with AIPC. Patients were treated with intravenous docetaxel (30 mg/m2 for 3 of 4 weeks) with or without evening doses of oral the combination was well tolerated. The incidence of depression increased in the thalidomide containing arm of the study (10% vs 4%). Patients with a history of depression must be monitored closely. In our study, one patient committed suicide although he had no previous psychiatric history and A > 50% fall in PSA was found in 50% of patients in the combination arm and in 37% treated with docetaxel alone. thalidomide (200 mg/d) and both arms of the study had similar patient and tumor characteristics. A > 50% fall in PSA was found in 50% of patients in the combination arm and in 37% treated with docetaxel alone. Although this study was not powered to detect a statistically significant difference in survival, the median overall survival was doubled from 14.7 months in the docetaxel-alone arm to 28.9 months in the combination arm (P = .11). As anticipated, the addition of thalidomide to docetaxel contributed to an increase in some gastrointestinal and neurologic symptoms but overall died within 30 days of stopping thalidomide for progressive disease. Also of concern was the development of venous thromboembolism in 9 patients and transient ischemic attack or stroke in 3 of the first 43 patients treated with thalidomide and docetaxel, with no thromboembolic events in patients on docetaxel alone. In light of these findings, we treated subsequent patients enrolled to the combination arm with lowmolecular-weight heparin and no further episodes of thromboembolism were reported. Prostate cancer, like all cancers, is prothrombotic but overall is associated with a low inci- Main Points • Clinical trials of single-agent docetaxel in androgen-independent prostate cancer (AIPC) have demonstrated response rates of 20%–60%, which are superior to response rates with other single-agent chemotherapies used in this disease. • Docetaxel plus estramustine has been assessed in a number of trials. Estramustine was chosen because it, like docetaxel, affects microtubular function and has shown synergy with other agents that effect tubulin, such as vinblastine. • After being removed from the market, thalidomide was reintroduced by the Food and Drug Administration in 1998. Thalidomide has anti-inflammatory and immunomodulatory effects and is used for the treatment of such diseases as Behçet’s, Crohn’s, discoid lupus, complex pain syndrome, and rheumatoid arthritis. • A correlation between increased angiogenesis in primary tumor specimens and the future development of metastatic disease has been observed in clinical trials. The apparent importance of angiogenesis in the evolution of prostate cancer provides a rationale for the investigation of antiangiogenesis agents in AIPC. • Docetaxel is a promising treatment for AIPC, and it has improved efficacy when combined with other therapies. Thalidomide has also demonstrated efficacy in AIPC, and so a combination of docetaxel and thalidomide may be a reasonable therapeutic approach. • When given alone, thalidomide and docetaxel are associated with a low risk for thrombosis; in combination, however, venous thromboembolism (VTE) becomes a concern. Low-molecular-weight heparin was given to reduce the risk of VTE in patients receiving combination therapy with docetaxel and thalidomide. VOL. 5 SUPPL. 3 2003 REVIEWS IN UROLOGY S69 Docetaxel and Thalidomide Combination Therapy continued dence of deep venous thrombosis or pulmonary embolism. Similarly, thalidomide and docetaxel as single agents are associated with a low risk for thrombosis. However, a number of studies using thalidomide have reported an increased incidence of thromboembolism in myeloma and one study reported it in renal cell carcinoma. Chemotherapy agents that have a predilection for endothelial damage, such as anthracyclines or taxanes, may exaggerate the prothrombotic effects of thalidomide. Summary Our trial of combined docetaxel and thalidomide compared with docetaxel alone in pretreated AIPC patients revealed significant benefits for the combination arm. This combination regimen compares favorably with other data on systemic therapy for AIPC. PSA and tumor responses were similar to previous trials and the survival advantage for combination therapy was encouraging. The regimen was relatively well tolerated although prophylactic anticoagulation is recommended to prevent thrombotic complications. Cardiotoxicity can be a significant complication with mitoxantrone and steroids but was rarely seen with docetaxel and thalidomide. A trial dedicated to analyzing endpoints such as overall survival and quality of life is warranted to determine the true significance of our findings. Conclusion Prostate cancer is the most common male cancer and the second most common cause of cancer death among men. Most men who die of prostate cancer have AIPC yet there are no prospective, randomized, phase III data of any therapy reporting a survival advantage with this stage of disease. Chemotherapy, however, has demonstrated improve- S70 VOL. 5 SUPPL. 3 2003 ments in symptom control, and at present, a combination of mitoxantrone and steroids is considered the standard of care for patients who are healthy enough for chemotherapy. Docetaxel has proved successful as a single agent in the treatment of AIPC. It has improved response rates in combination with estramustine and is currently under investigation combined with many novel agents. Thalidomide is frequently used for nonmalignant conditions and was shown to be of benefit in prostate cancer. Both docetaxel and thalidomide have antiangiogenesis properties and may be synergistic although their exact antitumor activity is likely multifactorial. Our experience with the combination of docetaxel and thalidomide in the treatment of patients with AIPC is promising. We have demonstrated response rates with this combination that compare favorably to historical results with either thalidomide or docetaxel alone. A doubling of the overall survival with the addition of thalidomide to docetaxel, although not statistically significant, is also encouraging. Caution must also be exercised in the use of this combination regimen as venous thromboembolism and depression may be increased. We advocate anticoagulation therapy and close supervision of all patients treated with the docetaxel and thalidomide combination. Our data warrants further investigation to determine whether this efficacious and relatively well-tolerated regimen can offer improvements in outcome to patients with AIPC. Larger trials with adequate power may detect a significant improvement in survival and will provide more data on toxicity and quality-of-life indexes. Alternative options to the present therapy of AIPC are welcome and would provide palliation and perhaps improved survival to a large popula- REVIEWS IN UROLOGY tion of the cancer community. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 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