Thalidomide therapy for renal cell carcinoma

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1 Critical Reviews in Oncology/Hematology 46 (2003) S59/S65 Thalidomide therapy for renal cell carcinoma Robert J. Amato * Scott Department of Urology, Baylor College of Medicine, 6560 Fannin, Suite 2100, Houston, TX 77030, USA Accepted 13 January 2003 Contents 1. Introduction... S59 2. Materials and methods... S60 3. Results and discussion... S Single-agent thalidomide... S Thalidomide and IFN-a... S Thalidomide and IL S Thalidomide with combination chemotherapy... S Future directions... S64 4. Conclusion... S64 Reviewers... S64 References... S64 Biography... S65 Abstract Purpose: To review the use of thalidomide as a therapeutic option for patients with metastatic renal cell carcinoma (RCC). Materials and methods: Studies of thalidomide alone or in combination with immunotherapy or chemotherapy were identified. The clinical benefit of thalidomide was assessed on the basis of objective response (complete and partial) and stable disease rates. Results: Single-agent thalidomide was evaluated in nine phase II studies, producing partial responses in a median of 7% of patients (range: 0/17%) and stable disease in a median of 31% of patients. On average, 40/45% of patients derived benefit from thalidomide. Common toxicities included constipation, lethargy, and with prolonged therapy, neuropathy. Four studies reported deep vein thrombosis and/or pulmonary embolism at rates ranging from 3 to 23%. On the basis of these findings, phase I/II studies of thalidomide in combination with interleukin-2 (IL-2), interferon (IFN), or chemotherapy have been conducted. Although some of these early combination regimens were limited by toxicity, promising findings have been seen with thalidomide/il-2 and thalidomide/ifn/capecitabine. A phase III trial of IFN versus IFN/thalidomide is nearing completion. Conclusion: Thalidomide is active in metastatic RCC, but additional experience with thalidomide-based combinations is needed to better define how this agent should be used in the management of this malignancy. # 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Thalidomide; Renal cell carcinoma 1. Introduction * Tel.: / ; fax: / address: ramato@bcm.tmc.edu (R.J. Amato). Renal cancer strikes more than people annually in the United States and causes nearly annual deaths [1]. Approximately 80% of these malignancies are characterized as renal cell carcinoma (RCC) [2]. Early-stage RCC is managed by radical nephrect /03/$ - see front matter # 2003 Elsevier Ireland Ltd. All rights reserved. doi: /s (03)

2 S60 R.J. Amato / Critical Reviews in Oncology/Hematology 46 (2003) S59/S65 omy, with nephron-sparing surgery used when renal function must be preserved [3]. However, about 20% to 30% of patients develop metastatic disease following nephrectomy and one third to one half of patients present with metastatic disease. Although the overall 5- year survival rate is about 50%, median survival for metastatic disease is 7/11 months. RCC is generally resistant to cytotoxic chemotherapy or radiation therapy, with no regimen consistently producing response rates above 10% [2]. The biological response modifiers interleukin (IL-2) and interferon (IFN)-a produce response rates of 10% to 15% and appear to prolong survival relative to chemotherapy [2,4 /6]. IL-2 plus IFN-a produces generally comparable results, with response rates 10% to 20% [3,7,8]. IL-2 and/ or INF-a plus chemotherapy produces response rates of 15% to 30% [5,9 /13]. However, demonstrating a survival benefit with these combination regimens has been difficult. More effective treatment of RCC and methods of overcoming multidrug resistance are needed. Thalidomide is an immunomodulatory agent that blocks angiogenesis, inhibits cytokines, including tumor necrosis factor-a (TNF-a), modifies cell adhesion molecule expression, and promotes T-helper cell response switch from Th1 to Th2 [14 /17]. Thalidomide also eradicates experimental tumors in animals [18]. Based on this activity, thalidomide is under investigation in various malignancies including renal cell carcinoma (RCC). This review describes the results of studies of thalidomide in RCC to date and discusses how thalidomide and related compounds may be used for future management of RCC. 2. Materials and methods Studies of thalidomide alone or in combination with immunotherapy or chemotherapy were identified. In addition, one study that is currently in press was identified through author s participation as a study investigator. 3. Results and discussion 3.1. Single-agent thalidomide Investigators at Royal Marsden Hospital and University College in London evaluate thalidomide in renal cancer (in consecutive low- and high-dose studies) [19,20]. Patients had Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0/2, adequate renal and hepatic function and bone marrow reserve, and had not received immunotherapy or chemotherapy for at least 4 weeks before starting thalidomide. Thalidomide was continued until disease progression or development of unacceptable toxicity. In the lowdose study, 18 patients with advanced RCC received thalidomide 100 mg orally every night [19]. After a median follow-up of 36 months, three (17%) patients achieved partial responses and another three (17%) patients had stable disease for at least 3 months, including two patients with stable disease for more than 6 months [20]. Low-dose thalidomide was well tolerated, with grades 1 and 2 lethargy being the principal toxicity. In the high-dose study, 25 patients with metastatic RCC were titrated in 100-mg increments over 5 weeks to a planned thalidomide dose of 600 mg daily, given in divided doses in the morning and evening [20]. Due to toxicity including lethargy, constipation, and neuropathy, 60% of patients did not reach the target dose. However, thalidomide 400 mg daily was generally well tolerated. Three patients were not evaluable for response, because they were withdrawn early due to toxicity. After a median follow-up of 20 months, two (9%) of 22 evaluable patients had partial responses and 12 (55%) patients had stable disease, including seven patients with stable disease for more than 6 months. Median survival of the evaluable patients in these two studies was 9 months (range: 1 to /22 months). Low and high thalidomide doses were also evaluated in a randomized phase II study of 14 patients with metastatic RCC conducted at the Stanford Medical Center [21]. Patients in the low-dose arm received 200 mg daily and patients in the high-dose arm received 800 mg with dose escalation to a maximum of 1200 mg daily. All patients had good PS (0 or 1); 10 patients had failed prior immunotherapy and four patients had failed chemotherapy. Two patients had not been treated previously. Patients received thalidomide for a median of two 8-week courses (range: 1/6 courses). Low-dose thalidomide was generally well tolerated, but all patients in the high-dose group required dose reduction for toxicity. Grade 1/2 anemia was the most common hematologic toxicity, affecting 31% of patients; grade 3/4 hematologic toxicity was not observed. Nonhematologic toxicities included constipation (77%, primarily grade 2), grade 1/2 fatigue (69%), grade 1/2 somnolence (38%), grade 2 rash (23%), and grade 1/2 neuropathy (15%). No patient experienced complete response or partial response, but 46% of patients had stable disease, which lasted for a median of 6 months. Two-thirds of those with stable disease were from the low-dose arm. The median survival had not been reached at the time of the publication. At the M.D. Anderson Cancer Center, 20 patients with metastatic RCC who progressed after immunotherapy were enrolled into a pilot study of thalidomide [22]. Patients had bidimensionally measurable metastatic disease, Zubrod PS 0/3, and had not been treated for at least 4 weeks. Patients with brain metastases were eligible if they were neurologically stable and did not

3 R.J. Amato / Critical Reviews in Oncology/Hematology 46 (2003) S59/S65 S61 require intravenous steroids. Thalidomide was started at a dose of 200 mg in the evening and was increased in 100- to 200-mg increments to a target maximum daily dose of 1200 mg. A bowel regimen including sodium docusate was used to minimize constipation. At the higher doses, patients were allowed to take thalidomide in divided doses (usually 20% in the morning and at noon, and 60% at bedtime). Eighteen (90%) of the 20 patients achieved the 1200 mg target dose. The most common toxicities were grade 1/2 constipation, somnolence, and fatigue. Peripheral neuropathy developed after prolonged therapy in 15 patients and required dose reduction. Grade 3/4 deep vein thrombosis or pulmonary embolism occurred in three patients. Most patients had relatively indolent disease, with the median time from diagnosis of metastatic disease to enrollment in the study being 24.7 months. Nevertheless, all patients had a significant disease burden, with nearly half of the patients having metastatic disease in at least three organs. Two (11%) of 19 evaluable patients achieved partial responses after 7 and 11 months of therapy, with responses lasting for 16 and 31 months. Nine (47%) additional patients had stable disease lasting for a median of 14 months (range: 3/17 months). All patients ultimately progressed: the median progressionfree survival was 4.6 months (range: 0.7 /31.3 months). At the time of the report, 15 patients had died: the median survival was 18.1 months (lower limit of 10.7 months). In another study conducted at M.D. Anderson Cancer Center, 34 patients with metastatic RCC who progressed after interleukin-2 (IL-2)-based therapy received single-agent thalidomide [23]. Thalidomide was started at 200 mg daily and escalated in weekly increments of 100/200 mg to a maximum daily dose of 1200 mg unless grade 2 or worse neuropathy was encountered. Seventeen (50%) patients tolerated the maximum thalidomide dose for a median of 3.3 months. Patients in this study had good PS (0 or 1) and a median of 3 metastatic sites. Eighteen patients had progressed while on IL-2 therapy; the other 16 patients progressed after IL-2. Two (7%) of 29 evaluable patients achieved partial responses after 6 and 9 months of thalidomide and nine (31%) patients had stable disease. After a median follow-up of 40 weeks, 11 (32%) of the 34 patients overall were progression-free. Grade 4 toxicities included one case each of sedation and thrombosis. Twenty-six patients with metastatic RCC received thalidomide at the Memorial Sloan-Kettering Cancer Center [24]. Thalidomide was started at 200 mg daily and escalated in 200-mg increments every 2 weeks to a maximum dose of 800 mg. Eleven (42%) patients had not received prior systemic therapy. Only 19% of the patients achieved the maximum 800 mg dose; 69% of patients were treated with dose of 400 or 600 mg daily. Grade 3 dyspnea and neurologic toxicity occurred in three and two patients, respectively. None of the 25 evaluable patients had partial responses to thalidomide, but 16 (64%) patients (95% confidence interval (CI): 43/ 82%) had stable disease. Of these, three patients achieved prolonged stable disease for at least 16 months, including two patients who were refractory to prior cytokine therapy. Progression-free survival at 6 months was 32% (95% CI: 14/50%); at 1 year, 57% of patients (95% CI: 37/76%) were alive. The results of these phase II studies, as well as several others that have been presented only in abstracts, suggest that single-agent thalidomide is active in patients with advanced metastatic RCC (Table 1). Clinical benefit, in terms of either a partial response or stable disease, was seen in about 40% of patients. To attempt to improve on this activity, several studies have been initiated to evaluate thalidomide in combination with either immunotherapy or chemotherapy Thalidomide and IFN-a A phase I trial examined thalidomide plus interferona (IFN-a) in patients with advanced RCC. Thalidomide was initiated at 100 mg per night for 2 weeks and was escalated in 200-mg increments every 2 weeks to a maximum dose of 1000 mg per night or until grade 3/4 toxicities were encountered. IFN-a 5 miu was given subcutaneously three times per week. At the latest report, 12 patients had completed 12 weeks of therapy and were evaluable for response. No complete or partial response was noted, but seven patients demonstrated stable disease. Toxicities leading to study withdrawal were grade 4 fatigue, somnolence, and rash [33]. Thalidomide plus IFN-a was also evaluated in a phase II study of 13 patients with metastatic RCC at several hospitals in London [28]. Patients received IFNa 9 miu given subcutaneously three times per week. Two weeks later, thalidomide was started at 100 mg in the evening and increased in 100-mg increments monthly to a maximum of 400 mg daily. Most (77%) of the patients had PS of 0/1 and only one (8%) patient had received previous immunotherapy. Objective treatment responses were not observed. Four (31%) patients had visual disturbances, one of whom had complex partial seizures and another who had transient numbness in his right arm and loss of speech. Computed tomography scans excluded cerebrovascular events or malignancy in these four patients. One (8%) other patient had a Stevens-Johnson reaction, which resolved on withdrawal of thalidomide/ifn-a and use of steroids. The investigators concluded that thalidomide/ifn-a, at the doses used, is associated with more neurological toxicity than would be expected from either drug alone [34]. ECOG is conducting a randomized phase III trial of IFN-a alone versus IFN-a plus thalidomide in patients with previously untreated metastatic or unresectable

4 S62 R.J. Amato / Critical Reviews in Oncology/Hematology 46 (2003) S59/S65 Table 1 Single-agent thalidomide in metastatic renal cell carcinoma Study Thalidomide dose (mg per day) Patients, n Best response (% patients) Survival (PFS), median Grade 3/4 toxicity (% patients) PR SD Eisen et al. [19] NR None Srinivas and Guardino [21] 200 or 8000/ NR Somnolence (23%), fatigue (15%), constipation (8%), neuropathy (8%) Stebbing et al. [20] 1000/ NR Lethargy (8%), constipation (4%), neuropathy (4%) Novik et al. [25] 1000/ NR DVT (7%) Motzer et al. [24] 2000/ % a Dyspnea (12%), neurotoxicity (8%) Daliani et al. [22] 2000/ m DVT/PE (15%), fatigue (15%), somnolence (10%), neuropathy (5%), sensory neuropathy (5%) Li et al. [23] 2000/ m Constipation (9%), impotence (9%), anemia (6%), DVT (3%), sedation (3%), fatigue (3%), dry skin (3%) Minor and Elias [26] 4000/ NR NR Escudier et al. [27] 4000/ NR DVT/PE (23%), neuropathy in patients treated for 6 months (30%) PR, partial response; SD, stable disease; PFS, progression-free survival; DVT, deep vein thrombosis; PE, pulmonary embolism; NR, not reported. a PFS at 6 months. RCC (ECOG 2898) [35]. The study is designed to evaluate the efficacy of the combination regimen versus IFN-a alone in terms of progression-free survival as well as its safety and impact on quality of life. Patients are stratified according to prior nephrectomy, disease-free interval (1 year versus /1 year), and PS (0 versus 1/2), and then randomly assigned to receive IFN-a 1 miu twice daily by subcutaneous injection with or without thalidomide starting at 200 mg orally at bedtime. The thalidomide dose is increased to 400 mg after 2 weeks and then in 100-mg increments weekly until the maximum tolerated dose or a maximum of 1000 mg has been reached. The trial is nearing its accrual goal of 340 patients Thalidomide and IL-2 Thalidomide has also been administered in combination with IL-2 in phase I studies at the Cleveland Clinic Foundation and at Baylor College of Medicine. At the Cleveland Clinic, the doses of both thalidomide and IL- 2 were to be varied [29]. The first four groups evaluated escalating IL-2 doses plus a fixed daily 100 mg dose of thalidomide. IL-2 was given at daily doses of 4.5, 9, 13.5, or 18 miu/m 2 during the first week and at doses of 4.5 (first group only) or 9 miu/m 2 during the subsequent 5 weeks. According to the study design, the final two groups were to evaluate the highest IL-2 dose in combination with 200 or 400 mg of thalidomide. At the latest report, 20 patients were enrolled and 19 were evaluable for toxicity. Patients had good PS and all but one had undergone prior nephrectomy. Twelve patients had received prior systemic therapy. Dose-limiting toxicity, consisting of grade 3 neutropenia lasting for 7/10 days, occurred in three patients on the third dose level. Other toxicities included grade 2 desquamation and pruritus in five patients and dyspnea in one patient. One patient, previously treated with an IL-2-based regimen, achieved a partial response. Additional patient accrual at the maximum tolerated dose is planned and evaluation of an intermediate dose of IL-2 plus thalidomide 200 mg is being considered. The Baylor study enrolled 15 patients with metastatic RCC, all of whom had good PS and had undergone prior nephrectomy [30]. Eight patients had received prior treatment. Patients had a median of 2 metastatic sites (range: 1/4). Patients received oral thalidomide for 1 week before starting combination therapy. IL-2 was administered at 7 miu/m 2 on days 1/5 for 4 consecutive weeks of a 6-week cycle and thalidomide was given daily for the full cycle. Three thalidomide dose levels were evaluated: three patients received 200 mg daily and six patients each received a dose of 400 or 600 mg. Fifteen patients completed 12 weeks of therapy; of these, one (7%) achieved a complete response, five (33%) achieved partial responses, and two (13%) had stable disease. Objective responses were seen at each thalidomide dose level. Progressive disease was noted in seven (47%) patients. Toxicities included sedation, constipation, rash, flu-like symptoms, fluid retention, hypotension, and deep vein thrombosis. Based on these findings, a

5 R.J. Amato / Critical Reviews in Oncology/Hematology 46 (2003) S59/S65 S63 phase II study was initiated using thalidomide 400 mg and IL-2 in front-line therapy of metastatic disease. Plans are underway for a multicenter randomized phase III study of thalidomide/il-2 versus IL-2 alone versus thalidomide alone in patients with previously untreated metastatic RCC. Thalidomide will be initiated at 200 mg per day and will be escalated to 400 mg per day as tolerated [36] Thalidomide with combination chemotherapy Oral thalidomide has been evaluated in combination with intravenous gemcitabine and prolonged continuous 5-fluorouracil (5-FU) infusion at the University of Chicago [31]. Patients with metastatic RCC who had not been treated previously with the study drugs and who had PS 0/2 were eligible if they had normal hematologic, renal, and hepatic function. Gemcitabine 600 mg/m 2 was administered on days 1, 8, and 15; 5-FU 150 mg/m 2 per day was given by continuous infusion on days 1/21 of a 28-day treatment cycle. Thalidomide was started at 200 mg daily and escalated in 100-mg increments each week to a maximum of 400 mg. Twenty-one patients were enrolled: all had good PS and nine had received prior immunotherapy. The median number of metastatic sites was 2. Nine (43%) patients experienced venous thromboembolism. Among 18 evaluable patients there were two partial responders. Thalidomide plus gemcitabine and 5-FU appear to have increased toxicity, especially for venous thrombosis, relative to that previously reported for combination gemcitabine/5-fu or single-agent thalidomide. The three-drug regimen was not recommended for further development (Table 2). A phase I trial of thalidomide plus IFN-a and capecitabine was conducted at Baylor College of Medicine [32]. Preliminary results of this regimen showed partial responses in three (11%) of 27 patients, minor responses in two (7%) others, and stable disease in an additional four (15%) patients, all of whom had been treated for more than 9 months. Toxicity was evaluable in 27 patients: the majority of patients had hand-foot syndrome necessitating a capecitabine dose reduction and four patients had deep vein thrombosis requiring anticoagulation. For the phase II trial, all patients will be treated with a prophylactic dose of warfarin. Eligible patients will have metastatic RCC, Zubrod PS 0/2, and failed no more than one prior immunotherapy regimen. Thalidomide will be administered at a daily dose of 200 mg for the first week and at 400 mg thereafter. IFN-a will be administered at 1 miu/m 2 daily by subcutaneous injection without interruption. Capecitabine will be given orally twice daily for 2 weeks of a 3-week cycle at 1200 mg/m 2. A phase I study adding gemcitabine to this combination regimen is also being evaluated [37]. Patients with metastatic RCC and Zubrod PS 0/3 who failed any prior immunotherapeutic or chemotherapeutic regimen are eligible. Thalidomide, IFN-a, and capecitabine will be administered daily at the same schedules and doses as in the phase II study, except that Table 2 Thalidomide-based combination therapy in metastatic renal cell carcinoma Study Regimen Number of patients Activity Toxicity Nathan et al. [28] Olencki et al. [29] IFN-a (9 miu three times per week), thalidomide (1000/400 mg per day) a 13 PR: 0% Visual disturbances (31%), Stevens-Johnson reaction (8%) IL-2 (4.5 or 9.0 miu/m 2 per day for 6 weeks 20 PR: 5% DLT: grade 3 neutropenia of 8-week cycle) b, thalidomide (100 mg per day for 8 weeks) 15 c CR: 7%, PR: Sedation, constipation, skin-rash, 33%, SD: 13% flu-like symptoms, fluid retention, Amato et al. [30] IL-2 (7 miu/m 2 per day on days 1/5 for 4 weeks of 4-week cycle), thalidomide 200, 400, or 600 mg per day Desai et al. [31] Gemcitabine (600 mg/m 2 on days 1, 8, and 15 of 4-week cycle), infusional 5-FU (150 mg/m 2 per day for 21 days), thalidomide (2000/400 mg per day) Amato [32] IFN-a (1 miu/m 2 per day), capecitabine (1200 mg/m 2 per day for 2 weeks of 3-week cycle), thalidomide (2000/400 mg per day) hypotension, DVT 21 PR: 10% Grade 3/4 toxicity (46%) including DVT (15%) 27 d PR: 11%, SD: 22% Hand-foot syndrome, DVT (15%) PR, partial response; SD, stable disease; DLT, dose-limiting toxicity; DVT, deep vein thrombosis. a Thalidomide was started 2 weeks after initiation of IFN-a therapy; first IFN-a dose was 4.5 miu. b Groups of 3/6 patients received IL-2 at doses of 4.5, 9, 13.5, or 18 miu/m 2 daily during the first week, then either 4.5 or 9 miu/m 2 in the subsequent 5 weeks of the 8-week cycle. c Fifteen patients completing 12 weeks of therapy were evaluable for response. d Nineteen patients were evaluable for response.

6 S64 R.J. Amato / Critical Reviews in Oncology/Hematology 46 (2003) S59/S65 capecitabine will be started at 1000 mg/m 2. Gemcitabine will be given intravenously on days 1 and 14 starting at 200 mg/m 2. Response to treatment will be evaluated after four cycles. Responding patients will be eligible to continue treatment until disease progression or development of unacceptable toxicity. Reviewers Dr. Tim Eisen, FRCP, Section of Medicine, Institute of Cancer Research, Royal Marsden Hospital, Downs Road, Sutton SM2 5PT, UK Ronald M. Bukowski, M.D., Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA 3.5. Future directions Thalidomide has been used as a template to design analogs with enhanced immunological activity and potentially less toxicity and teratogenicity. Known as immunomodulatory drugs (IMiDs), these analogs act, like thalidomide, by an unknown mechanism that inhibits TNF-a production and augments IL-10 production. IMiDs also stimulate anti-cd3-induced T-cell proliferation, augment IL-2 and IFN-g production, and inhibit IL-1 and IL-6 production. Some IMiDs are 100 /1000 times more potent than thalidomide in regulating cytokine production and providing a costimulatory signal for T-cell activation [38]. Moreover, some analogs, such as CC-1069, inhibit endothelial cell proliferation more efficiently than thalidomide and may be more effective in blocking angiogenesis [39]. CC-5013 (formerly CDC-501) has been administered safely to volunteers in single doses of 50/400 mg and in multiple 100 mg doses for 7 days [38]. Currently, CC-5013 is being evaluated in phase I/II studies of multiple myeloma. Additionally, trials are being planned for the IMiDs CDC-4047 in RCC and CDC-394 in genitourinary cancer. 4. Conclusion The results of phase II studies suggest that thalidomide is active in patients with metastatic RCC, producing response rates and progression-free survival comparable to those achieved with IL-2 and IFN-a. These results prompted studies of thalidomide in combination with IL-2, IFN-a, and chemotherapy. Although several regimens were limited by toxicity, promising results were seen in single studies of thalidomide/il-2 and thalidomide/ifn-a/capecitabine. Despite these findings, it is important to recognize that positive results in phase II trials do not always translate into clinical benefit in randomized controlled trials. Periods of disease stabilization often occur as part of the natural history of metastatic RCC. Accordingly, the results of large phase III studies are needed to determine what role thalidomide will play, either as a single agent or in combination with immunotherapy or chemotherapy, in the treatment of RCC. 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Unexpected toxicity of combination thalidomide and interferon a-2a treatment in metastatic renal cell carcinoma. J Clin Oncol 2002;20:1429. [35] Gordon MS. Phase III randomized trial of interferon alfa-2b alone versus interferon alfa-2b plus thalidomide in patients with previously untreated metastatic or unresectable renal cell carcinoma. Protocol E Available at: Accessed April 11, [36] Amato RJ. Multicenter, randomized, controlled, parallel-group, double-blind study comparing the efficacy and safety of combination thalidomide plus low-dose interleukin-2 versus low-dose interleukin-2 alone versus thalidomide alone therapy in subjects with previously untreated metastatic renal cell cancer. Protocol T- RCC-001. [37] Amato RJ. Pilot trial of low-dose interferon alpha, thalidomide with gemcitabine and capecitabine in patients with progressive metastatic renal cell carcinoma. Study Protocol. [38] Stirling D. Thalidomide: a novel template for anticancer drugs. Semin Oncol 2001;28:602. [39] Moreira AL, Friedlander DR, Shif B, Kaplan G, Zagzag D. Thalidomide and a thalidomide analogue inhibit endothelial cell proliferation in vitro. J Neurooncol 1999;43:109. Biography Robert J. Amato, D.O., Associate Professor at Baylor College of Medicine, Scott Department of Urology, Genitourinary Oncology Section. He received his D.O. at the University of North Texas Osteopathic Medicine. He completed an internship at the Fort Worth Osteopathic Medical Center, followed by Residency in Internal Medicine at the University of North Texas Osteopathic Medicine and a Fellowship in Medical Oncology at the University of Texas, M.D. Anderson Cancer Center.