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Journal of Clinical Oncology, Vol 22, No 13 (July 1), 2004: pp. 2532-2539 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.05.074 Randomized Phase II Trial of Docetaxel Plus Thalidomide in Androgen-Independent Prostate CancerFrom the Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD Address reprint requests to William D. Figg, Pharm D, National Cancer Institute, 10 Center Dr, Building 10, Room 5A-01, Bethesda, MD 20892; e-mail: wdfigg{at}helix.nih.gov
PURPOSE: Both docetaxel and thalidomide have demonstrated activity in androgen-independent prostate cancer (AIPC). We compared the efficacy of docetaxel to docetaxel plus thalidomide in patients with AIPC. METHODS: Seventy-five patients with chemotherapy-naïve metastatic AIPC were randomly assigned to receive either docetaxel 30 mg/m2 intravenously every week for 3 consecutive weeks, followed by a 1-week rest period (n = 25); or docetaxel at the same dose and schedule, plus thalidomide 200 mg orally each day (n = 50). Prostate-specific antigen (PSA) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decline, and time to progression. RESULTS: After a median potential follow-up time of 26.4 months, the proportion of patients with a greater than 50% decline in PSA was higher in the docetaxel/thalidomide group (53% in the combined group, 37% in docetaxel-alone arm). The median progression-free survival in the docetaxel group was 3.7 months and 5.9 months in the combined group (P = .32). At 18 months, overall survival in the docetaxel group was 42.9% and 68.2% in the combined group. Toxicities in both groups were manageable after administration of prophylactic low-molecular-weight heparin in the combination group. CONCLUSION: In this randomized phase II trial, the addition of thalidomide to docetaxel resulted in an encouraging PSA decline rate and overall median survival rate in patients with metastatic AIPC. After the prophylactic low-molecular-weight heparin was instituted to prevent venous thromboses, the combination regimen was well tolerated. Larger randomized trials are warranted to assess the impact of this combination.
Prostate cancer is the most common nondermatologic malignancy and the second leading cause of cancer-related death in men in the United States. During 2003, an estimated 220,900 men will have prostate cancer diagnosed, and 28,900 men will die of this disease in the United States.1 Hormonal ablation, with either surgical or medical castration, is the cornerstone of initial management of metastatic prostate cancer.2,3 However, there are limited treatment options for patients in whom androgen ablation fails. The use of second-line hormonal agents is generally associated with low response rates and no documented survival benefit. Historically, chemotherapy was not considered to have significant activity in metastatic androgen-independent prostate cancer (AIPC). However, this view changed within the last 10 years owing in part to the availability of prostate-specific antigen (PSA) measurements to monitor tumor burden. Chemotherapy, either as a single agent or in combination, may lead to clinical responses, pain control, and/or improved quality of life.4,5 To date, no benefit in overall survival (OS) has been shown. Several preclinical studies have demonstrated the significant activity of docetaxel in prostate cancer cell lines.6,7 Docetaxel has a 100-fold greater capacity than paclitaxel for inactivating bcl-2,8,9 overexpression of which has been identified in approximately 65% of AIPC biopsy specimens.10,11 Clinical studies of docetaxel in patients with AIPC, either as monotherapy or as a component of combination therapy, have shown notable PSA decline and objective responses in patients with measurable disease.10–12
Thalidomide ( This report describes the results of a randomized phase II trial of docetaxel alone or with thalidomide in patients with metastatic AIPC. The rationale for combining docetaxel and thalidomide is based on the individual activity of each agent and in vitro evidence20 suggesting that the combined effects of a taxane plus an antiangiogenic agent may be more than additive.
The primary objective of this study was to determine whether the combination of thalidomide and docetaxel can produce a sufficiently high clinical response rate to warrant further investigation in patients with AIPC.
Patient Eligibility
Study Design
Treatment Plan The dose of thalidomide was reduced by 50% for patients who experienced greater than National Cancer Institutes Common Toxicity Criteria grade 2 sedation and constipation, with slow escalation back to upper limit of tolerability. Patients who developed a greater than grade 2 peripheral neuropathy had their drug held until the toxicity resolved to grade 1, at which time the thalidomide was restarted at a 50% dose reduction. Patients who developed recurrence of a greater than grade 2 peripheral neuropathy on the lower dose were withdrawn from further study participation. Thalidomide was discontinued if a patient experienced a skin rash, and was resumed only after appropriate clinical evaluation. Docetaxel was held for patients experienced grade 4 hematologic or a greater than grade 3 nonhematologic toxicity. Patients were required to have an absolute neutrophil count greater than 1,500 cells/mm3, a platelet count greater than 75,000 cells/mm3, and resolution of any nonhematologic toxicity to less than grade 1 or baseline in order to reinitiate docetaxel treatment, at which time docetaxel was restarted at a 25% dose reduction. Patients could continue to receive thalidomide without dosing changes if docetaxel was discontinued or held.
Toxicity Evaluation and Response Evaluation Standard objective criteria were used to assess soft tissue lesion changes.23 PSA criteria for response and progression were based on the PSA Working Group consensus criteria.24 PSA declines of at least 50% (confirmed by a second value at least 4 weeks after the first) with no other evidence of disease progression were recorded for each cohort. Progressive disease was defined by any of the following criteria: (1) 25% increase in the size of all soft tissue masses and/or the appearance of new lesions; (2) the need for radiation therapy; and (3) two consecutively increasing PSA measurements by greater than 50% of the nadir PSA for patients with PSA response, or by greater than 25% of the nadir or baseline (whichever is lower) PSA for patients without PSA response. Patients were not declared to have disease progression based on PSA alone until the PSA had increased by an absolute value of 5 ng/mL or more.
Docetaxel Pharmacokinetic Analysis
Assessment of Changes in Circulating Angiogenic Growth Factors
Statistical Analysis
Patient Data A total of 75 patients were accrued (25 patients to the docetaxel-alone group and 50 to the combination group) from December 1999 to October 2001. One patient was never treated because of a protocol violation after randomization and is excluded from all analyses. A total of 431 cycles were given with 2,240 doses of docetaxel. Patients in the docetaxel-alone arm received a median of five cycles (range, 2 to 31 cycles), with a median of six cycles (range, 2 to 36) given on the combination arm. Patients' baseline demographic data are summarized in Table 1. All treated patients were included in the assessment of efficacy and toxicity, and the analysis of survival. At study entry, patient characteristics were similar in both treatment groups. A total of 17 patients (five in docetaxel group and 12 in the combination group) had received prior palliative radiation therapy. Most patients had assessable disease by bone scan. There was no significant difference between the two treatment groups in age, Gleason score at diagnosis, baseline PSA, prior radiation therapy, Eastern Cooperative Oncology Group performance statues, or baseline levels of lactate dehydrogenase, alkaline phosphatase, glucose, hemoglobin, albumin, and platelets (all P > .05). The number of patients with measurable soft tissue lesions was comparable in both treatment groups. In the control group, 12 patients had bone-only disease, nine patients had bone and soft-tissue disease, and four had soft tissue–only disease. In the treatment group, 23 patients had bone-only disease, 22 had bone and soft-tissue disease, and four had soft tissue–only disease.
Response to Therapy We used the PSA working group consensus criteria combined with radiographic studies to determine the proportion of patients with a PSA decline, and time to progression. Both at the midpoint evaluation and after conclusion of the trial, the proportion of patients with a greater than 50% decline in PSA was higher in the combination arm (nine [37%] of 24 patients in the docetaxel-alone arm [one patient was not assessable for PSA per consensus guidelines since PSA level was < 5.0], and 25 [53%] of 47 patients in the combined group [one patient never received therapy and two patients were not assessable for PSA per consensus guidelines since PSA level was < 5.0]; P = .32 by Fisher's exact test). These response rates satisfied criteria for further evaluation (combination arm) and for consistency with prior results (single-agent arm). Likewise, three (27%) of 11 patients in the docetaxel-alone arm with measurable soft tissue disease by computed tomography scan developed a partial response, and seven (35%) of 20 patients in the combined-treatment group had a partial response in soft tissue disease. None of the patients with bony lesions had a normalization of their bone scan. In the control arm, 12 patients progressed on PSA concentrations alone, three patients had bone and PSA progression, one patient had bone/soft tissue and PSA progression, and one patient had bone/soft tissue progression. In the combination arm, 29 patients progressed based on PSA concentrations: four patients had progression on bone scan; one patient had soft tissue–only progression; three had bone and PSA progression; three had bone, soft tissue, and PSA progression; and four had soft tissue and PSA progression. The median PFS in the docetaxel group was 3.7 months, and 5.9 months in the combined group (P = .32 for the overall difference in the curves), as shown in Figure 1. After a median potential follow-up of 26.4 months, 40 patients are currently alive. The 18-month survival in the docetaxel alone group was 42.9%, while the 18-month survival was 68.2% for the combined group (P = .11 for the overall difference; Fig 2).
Toxicity All patients who received any treatment were evaluated for toxic effects. The observed toxicities after a total of 2,240 weekly docetaxel infusion are summarized in Table 2. Six patients (three in each arm) discontinued treatment secondarily to toxicity. The hematologic toxicities were mild in both treatment arms. Only four patients developed grade 3 neutropenia (all in the combined group and none with infection); three patients had grade 3 anemia (one patient in the docetaxel-alone arm and two patients in the combination arm); and one patient in the docetaxel-alone group experienced grade 3 thrombocytopenia. Two patients had non-neutropenic grade 3 infections.
Of the nonhematologic toxicities (Table 2), the most common adverse events in both treatment arms were grade 1 to 2 fatigue, lower extremity edema, myalgia/arthralgias, dry skin/skin rash, nail changes, dry eyes/tearing, taste disturbances, diarrhea, constipation, dyspnea, dizziness, and hyperglycemia. However, the majority did not require treatment for these symptoms. Overall, 63 patients (85%) had grade 1 to 2 fatigue, and two patients had grade 3 symptoms in the combination arm. These symptoms improved after dose reduction. Pleural effusions were noted in 17 patients (six patients in the docetaxel alone arm and 11 patients in the combination arm). The median time to pleural effusion development was 24 weeks after the initiation of docetaxel (range, 8 to 46 weeks). Four patients (5%) had pericardial effusion, including one patient who required a pericardial window. Twenty-two patients (30%) had transient hyperglycemia at least once during steroid administration; however, the majority of them did not require treatment. Six patients (8%) had reversible transaminase elevations. Since thalidomide is a sedative, as expected, more patients in the combined group experienced symptoms of depressed consciousness. The incidence of depression was also slightly higher in the combined arm (10%) compared with the docetaxel-alone group (4%). Likewise, the incidence of peripheral neuropathy and cardiac arrhythmias was slightly higher in the combined group. There was one grade 5 event in the combination arm. This patient with progressive disease committed suicide within 30 days of stopping therapy. It is not possible to eliminate thalidomide as a contributor to this outcome. One finding of concern was the thromboembolic incidence in the combined group. While there were no thromboembolic events in the docetaxel-alone group, 12 of the first 43 patients treated with the docetaxel/thalidomide combination developed either venous thrombosis (nine patients) or transient ischemic attack or stroke (three patients). Because of the relative high incidence of thromboembolic events, prophylactic anticoagulation with low-molecular-weight heparin was offered to subsequent patients in the combination group, and no further thromboembolic events occurred. Patients with venous thromosis continued on study, with no changes to therapy other than low-molecular-weight heparin. The patients with transient ischemic attack or stroke continued on therapy with docetaxel, but thalidomide was stopped.
Pharmacokinetics
Changes of the Levels of Circulating Angiogenic Growth Factor
Combination therapy with a chemotherapeutic agent and an angiogenesis inhibitor represents a promising new area of investigation for metastatic AIPC. These treatment modalities have complementary mechanisms of action when used in the treatment of prostate cancer and other types of malignancy. Preclinical evidence suggests that prostate tumors require acquisition of the angiogenic phenotype to progress to a state of aggression.28,29 Without angiogenesis, primary prostate tumors typically are confined to a diameter of 1 to 2 mm and remain indolent. Tumor specimens from men with clinical prostate cancer have been characterized by a remarkably high degree of vascularization compared with autopsy-identified prostate tumors from men without clinical disease.30 Furthermore, Siegal et al reported that microvessel density (MVD) was significantly higher in prostate cancer tissue than in adjacent hyperplastic or benign tissue.31 Most studies of the prognostic and diagnostic role of MVD have demonstrated its utility in predicting pathologic disease stage and patient outcome, including the potential for development of metastatic disease. For example, Weidner et al correlated increased angiogenesis in primary tumor specimens from radical prostatectomies with subsequent development of metastatic disease.32 These observations suggest that angiogenesis inhibitors in combination with either radiation therapy, hormonal therapy, and/or chemotherapy, may represent a novel way of treating prostate cancer. Thalidomide has some clinical activity in refractory multiple myeloma, glioblastoma multiforme, Kaposi's sarcoma, and prostate cancer.16–19 In a previous phase II trial, we reported that thalidomide resulted in a greater than 40% decline of PSA in 27% of 63 patients with heavily pretreated AIPC, and the decrease of PSA was associated with an improvement of clinical symptoms in the majority of cases.18 The mechanism of prostate cancer control with thalidomide remains unclear. Thalidomide inhibits angiogenesis in vitro and in animal models, induces apoptosis in culture systems, and reduces the high levels of certain angiogenesis factors, such as VEGF and bFGF, that are present in patients with prostate cancer.33 However, in our study, we did not observe significant changes in circulating angiogenic markers, VEGF, or bFGF levels during treatment. It may suggest that circulating markers are not sensitive enough to predict response, and measurement of change in tumor cells may demonstrate greater sensitivity and biologic relevance than changes in the blood. Single-agent docetaxel induces PSA decline and measurable disease responses in patients with AIPC. The initial administration schedule was every 3 weeks, at a dose of 75 mg/m2, which resulted in a greater than 50% decline of PSA in 38% to 46% of patients with AIPC.12,34 The use of weekly docetaxel in this patient population, compared with a conventional schedule, has demonstrated similar activity and less myelosuppression.35 Favorable response rates also have been reported when docetaxel is used in combination with estramustine.36–38 There have been three phase II trials of the use of a docetaxel/estramustine combinations in patients with metastatic AIPC. Petrylak et al36,37 reported that docetaxel/estramustine treatment resulted in a greater than 50% decline of PSA in 25 (68%) of 37 chemotherapy-naïve AIPC patients, and a 55% partial response in measurable disease. In another phase II trial, Sinibaldi et al demonstrated that 45% of 42 pretreated AIPC patients achieved PSA decreases of greater than 50%, with a median OS of 13.5 months.37 The largest trial, the Cancer and Leukemia Group B (CALGB-9780) trial, examined the effects of a docetaxel/estramustine/hydrocortisone combination in 47 chemotherapy-naïve AIPC patients.37 Sixty-eight percent of patients achieved a greater than 50% reduction in PSA, and the median OS for all patients was 20 months. A randomized phase III trial of the combination of docetaxel/estramustine versus mitoxantrone/prednisone in patients with AIPC is currently underway in the cooperative groups.38 Although the differences observed in the current study did not reach traditional levels of statistical significance, the men randomized to the docetaxel/thalidomide group had improvements suggested in all of the standard outcome measures: PSA response, time to progression, and overall survival. The median OS of the combination group was 28.9 months compared with the docetaxel-alone arm (14.7 months). The 18-month survival was increased from 43% to 68% by adding thalidomide to docetaxel. The OS in the docetaxel-alone arm in our study is comparable with those of other published studies in a similarly defined patient population (range, 12 to 20 months), further confirming the validity of these observations.37–39 Pharmacokinetic studies demonstrated that there was no significant difference in the area under the curve or clearance for docetaxel between the two treatment groups. One possible reason for the OS discrepancy is that the small number of patients on the study makes the estimates too imprecise, though the trend was fairly clear. The combination therapy was well tolerated in the vast majority of patients. The near absence of hematologic toxicity in both treatment groups is particularly encouraging. Whereas grade 1 and grade 2 toxicities were frequent, they were easily managed with conservative treatment. Thromboembolic events in the combination arm are of concern. Twelve of first 43 patients in the combined group developed thromboembolic events. However, there was no thrombosis in the subsequent patients after the initiation of prophylactic anticoagulation with low-molecular-weight heparin. An increased incidence of deep venous thrombosis has also been observed with thalidomide combined with doxorubicin or dexamethasone for the treatment of multiple myeloma.40 The mechanism for this high incidence of thrombotic events is unclear. However, levels of circulating antithrombin III, protein C, and protein S were unchanged.42 It may be related to vascular endothelial toxicity since thalidomide is an angiogenesis inhibitor. Recently, Weber et al41 suggested that it may be related to hyperhomocysteinemia and/or methylenetetrahydrofolate reductase gene mutations. Further characterization of coagulation factors at baseline and during treatment should be addressed, and prophylactic anticoagulation may be warranted in future clinical trials. It is unlikely that the grade 5 neurological toxicity (suicide) was due to thalidomide because it occurred after the discontinuation of the drug. The patient did not have a history of depression, and neither did he have symptoms during treatment. However, since a similar case in our phase II thalidomide trial was reported previously,18 it is important to follow-up mood changes during thalidomide treatment. In summary, combination therapy with docetaxel and thalidomide represents a promising new area of treatment for metastatic AIPC. The addition of thalidomide to docetaxel seems to be a promising therapeutic approach to metastatic prostate cancer, but requires subsequent confirmation due to the size and intent of the present trial. After prophylactic low-molecular-weight heparin was instituted, the regimen was well tolerated. To our knowledge, this is the first randomized trial demonstrating that an antiangiogenisis agent may potentially be associated with improved survival benefit in patients with AIPC. However, these results should be interpreted cautiously given the facts that small numbers of patients were included, the study was not designed to have sufficient patients to evaluate survival as a main end point, further follow-up could alter the results, and statistical significance has not been reached. Larger randomized trials are needed to better evaluate the efficacy of this regimen in men with AIPC. Nevertheless, the data presented here suggest that additional studies of a cytotoxic agent plus an angiogenesis inhibitor are warranted in this patient population. Since the docetaxel/estramustine regimen is one of the most promising chemotherapy combinations, a pilot study of the combination of docetaxel/estramustine and thalidomide has been planned to examine the safety and efficacy in patients with AIPC.
The authors indicated no potential conflicts of interest.
We thank Drs Eddie Reed and Michael Hamilton for clinical assistance with the conduct of this trial. We thank Delmar Henry for data management assistance. We thank Drs Xiaowei Yang and Allyson Parr for vascular endothelial growth factor/basic fibroblast growth factor analyses. We thank Drs Alex Sparreboom and Sharyn Baker for pharmacokinetic analysis. We thank Dr Michael Cox for assistance with manuscript preparation. Jane Carter, Marianne Noone, and Mary Lewis are research nurses who contributed to this trial. In addition, the residents/clinical fellows in both the Urology and the Medical Oncology branches of the National Cancer Institute have contributed substantially to the patient care within this study.
Supported by the Intramural Program of the National Cancer Institute, Bethesda, MD. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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35. Beer TM, Pierce WC, Lowe BA, et al: Phase II study of weekly docetaxel in symptomatic androgen-independent prostate cancer. Ann Oncol 12:1273–1279, 2001 36. Petrylak DP, Macarthur R, O'Connor J, et al: Phase I/II studies of docetaxel (Taxotere) combined with estramustine in men with hormone-refractory prostate cancer. Semin Oncol 5:28–33, 1999 (suppl 17) 37. Sinibaldi VJ, Carducci MA, Moore-Cooper S, et al: Phase II evaluation of docetaxel plus one-day oral estramustine phosphate in the treatment of patients with androgen independent prostate carcinoma. Cancer 94:1457–1465, 2002[CrossRef][Medline]
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
-N-[phthalimido]glutarimide) is a potent teratogen that causes dysmelia (stunted limb growth) in humans.
5.0 ng/mL); (4) patients had to have documented metastatic disease (distant metastasis and positive bone scan); and (5) Eastern Cooperative Oncology Group performance status 0 or 1. All patients gave written informed consent before enrollment. Patients who had received prior chemotherapy or thalidomide were ineligible. However, no restrictions applied to prior hormonal therapies, radiotherapy, or radioisotope administration. Patients with abnormal hematological or biochemical parameters, and/or brain metastases were excluded. Other forms of antitumor therapy were prohibited (including radiation therapy) during the study except continuation of luteinizing hormone–releasing hormone agonists. 
