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Journal of Clinical Oncology, Vol 24, No 3 (January 20), 2006: pp. 401-406 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.6046 Phase II Study of Temozolomide and Thalidomide in Patients With Metastatic Neuroendocrine TumorsFrom the Department of Medical Oncology, Dana-Farber Cancer Institute; Division of Hematology/Oncology, Beth Israel-Deaconess Medical Center; Division of Hematology/Oncology, and Department of Biostatistics, Massachusetts General Hospital; and Channing Laboratory, Brigham and Women’s Hospital, Boston, MA Address reprint requests to Matthew H. Kulke, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: matthew_kulke{at}dfci.harvard.edu
Purpose: Standard, intravenous chemotherapy regimens for neuroendocrine tumors have been associated with limited response rates and significant toxicity. We evaluated the efficacy of an oral regimen of temozolomide and thalidomide in patients with metastatic carcinoid, pheochromocytoma, or pancreatic neuroendocrine tumors. Patients and Methods: Twenty-nine patients were treated with a combination of temozolomide, administered at a dose of 150 mg/m2 for 7 days, every other week, and thalidomide at doses of 50 to 400 mg daily. Patients were followed for evidence of toxicity, biochemical response, radiologic response, and survival. Results: Treatment with temozolomide and thalidomide was associated with an objective biochemical (chromogranin A) response rate of 40%, and a radiologic response rate of 25% (45% among pancreatic endocrine tumors, 33% among pheochromocytomas, and 7% among carcinoid tumors). The median duration of response was 13.5 months, 1-year survival was 79%, and 2-year survival was 61%. The median administered dose of temozolomide was 150 mg/m2, and the median administered dose of thalidomide was 100 mg daily. Grade 3-4 toxicities were uncommon, with the exception of grade 3-4 lymphopenia, which developed in 69% of the patient population. Opportunistic infections occurred in three patients (10%) during the time of lymphopenia, and included single cases of Pneumocystis carinii pneumonia, disseminated varicella zoster virus, and herpes simplex virus. Conclusion: Orally administered temozolomide and thalidomide seems to be an active regimen for the treatment of neuroendocrine tumors. In this 29-patient study, this regimen appeared more active in pancreatic endocrine tumors than in carcinoid tumors.
Neuroendocrine tumors represent a typically indolent family of malignancies, often characterized by symptoms of hormonal excess. Systemic therapies for neuroendocrine tumors have, to date, been largely ineffective. Although treatment with somatostatin analogs can usually abate hormonal symptoms, such treatment rarely results in tumor shrinkage.1 Streptozocin-based chemotherapy regimens are associated with only modest activity in patients with advanced neuroendocrine tumors, and may also be associated with significant toxicity.2-7 Dacarbazine (DTIC) has been evaluated as a potential alternative to streptozocin-based therapy in both carcinoid and pancreatic endocrine tumors. In patients with carcinoid tumors, DTIC has been associated with response rates of 8% to 16%.7,8 The Eastern Oncology Group (ECOG) performed a phase II study of DTIC in patients with advanced pancreatic islet cell carcinoma and reported an objective response rate of 33%.9 A combination of DTIC, vincristine, and cyclophosphamide in patients with pheochromocytoma was reported to result in biochemical responses, but was also associated with significant hematologic, neurologic, and gastrointestinal adverse effects.10 As with streptozocin-based therapy, concerns related to the potential toxicity of DTIC have precluded its common use as a treatment for neuroendocrine tumors. Temozolomide is a cytotoxic alkylating agent that was specifically developed as an oral and less toxic alternative to DTIC.11 Temozolomide and DTIC have similar mechanisms of action: Both agents are metabolized to the active agent 5-(3-methyl-triazeno) imidazole-4-carboxamide (MTIC), an inhibitor of nucleoside incorporation. Temozolomide and DTIC have similar efficacy in the treatment of patients with metastatic melanoma.12 In addition, temozolomide has demonstrated activity in patients with glioblastoma, and, when administered in combination with radiotherapy in this setting, improves survival.13 Neuroendocrine tumors are characterized by abundant vasculature and high levels of vascular endothelial growth factor (VEGF) expression, and are therefore potentially susceptible to therapeutic strategies targeting pathways involved in angiogenesis.14 Bevacizumab, a monoclonal antibody targeting VEGF, and SU11248, a small molecule tyrosine kinase inhibitor targeting the VEGF receptor, have both recently been shown to have single agent activity in neuroendocrine tumors.15,16 Thalidomide is postulated to have antiangiogenic activity through its ability to interfere with the VEGF and basic fibroblast growth factor (bFGF) pathways, and was associated with apparent disease stabilization in a small phase II study of patients with metastatic neuroendocrine tumors.17,18 We therefore conducted a multi-institutional phase II trial to assess the efficacy of a combination regimen of temozolomide and thalidomide in a cohort of patients with advanced neuroendocrine tumors. Patients were treated with temozolomide, administered at a dose of 150 mg/m2 for 7 days, followed by a 7-day rest, and thalidomide administered at doses of 50 to 400 mg daily without interruption. All patients were followed for evidence of toxicity, biochemical and radiologic response, and survival.
Study Population The study population consisted of patients with histologically confirmed, locally unresectable or metastatic neuroendocrine tumors, excluding small-cell carcinoma. Prior treatment with chemotherapy, other than DTIC, temozolomide, or thalidomide, was permitted, as was prior treatment with chemoembolization or cryotherapy. Lesions treated with prior radiation, cryotherapy, or chemoembolization were not considered measurable disease for the purpose of this protocol, and concurrent treatment with these treatment modalities was not permitted. Further inclusion criteria included: ECOG performance status of 0, 1, or 2; life expectancy  12 weeks; adequate renal function (serum creatinine  1.5x the upper limit of normal [ULN]), adequate hepatic function (total and direct bilirubin 2x the ULN), ALT and AST 5x the ULN, and alkaline phosphatase 2x the ULN or 5x the ULN in the setting of liver metastases; and adequate bone marrow function (absolute neutrophil count 1,500/mm3, platelets 100,000/mm3, hemoglobin 9 g/dL). Exclusion criteria included: patients with either clinically apparent CNS metastases or carcinomatous meningitis, history of myocardial infarction 6 months before protocol treatment, history of major surgery within 2 weeks before treatment initiation, HIV infection or AIDS-related illness, other serious medical or psychiatric illness, insufficient recovery from toxicities of prior therapies, and patients who were pregnant or lactating. Patients from the Dana-Farber Cancer Institute, Massachusetts General Hospital, and the Beth-Israel Deaconess Hospital were eligible for enrollment. Participation in the STEPS program (System for Thalidomide Education and Safety; Celgene Corp, Warren, NJ) was required for both investigators and patients. All patients provided informed consent as required by the institutional review boards of the respective institutions.
Treatment Program Dose modifications for thalidomide were made based on thalidomide-related toxicity. If no thalidomide-related toxicity was noted, the patient’s dose of thalidomide was increased weekly by 100 mg until a maximum dose of 400 mg/d or until toxicity developed. If toxicity developed before dose escalation, thalidomide was reduced by 100 mg/d. If no improvement was seen within 7 days, the dose was further reduced by 50 mg. Patients who did not tolerate thalidomide administered at a dose of 50 mg/d were removed from study therapy. If dose-limiting thalidomide toxicities occurred after dose escalation, thalidomide doses were decreased by 100 mg. If symptoms were not resolved to grade 1 within 7 days of dose modification, doses of thalidomide were further reduced by 100 mg; patients who experienced toxicity at a dose of 100 mg underwent dose reduction to 50 mg daily. Radiologic tumor assessments with computed tomography scan were performed every 8 weeks after initiation of treatment. Patients with evidence of response (complete [CR] or partial response [PR]) to treatment or stable disease remained on treatment until there was evidence of disease progression, unacceptable toxicity, or withdrawal of patient consent. Radiologic response was classified according to Response Evaluation Criteria in Solid Tumors criteria. CR required disappearance of all target lesions lasting for at least 4 weeks. PR required a decrease of more than 30% in the sum of the largest perpendicular diameters of all measurable lesions, persisting for at least 4 weeks, without progression of any nonmeasurable sites and without the appearance of new lesions. Progressive disease included an increase of 20% or more in the sum of longest diameters of target lesions, taking as references the smallest longest diameter recorded since the treatment started or the appearance of one or more new lesions. Stable disease was defined as having neither sufficient shrinkage to qualify as a PR, nor sufficient increase to qualify as progressive disease. Biochemical response, a secondary end point in the protocol, was defined as a decrease in chromogranin A by 50% or more from baseline (in patients with an elevated chromogranin A at baseline).
Statistical Considerations
Patient Characteristics A total of 30 patients were entered on the study at three centers (Dana-Farber Cancer Institute, Massachusetts General Hospital, and Beth Israel Deaconess Medical Center). One patient withdrew from the study before receiving therapy and was excluded from the analysis. The baseline patient characteristics of the 29 treated patients are presented in Table 1. Patients had a median age of 56 years; 62% were male, and 37% were female. The majority (69%) had an ECOG performance status of 0. Fifteen patients (52%) had metastatic carcinoid tumors, 11 (38%) had metastatic pancreatic neuroendocrine tumors, and three (10%) had metastatic pheochromocytoma or paraganglioma. Twenty-eight patients had well-differentiated, typical neuroendocrine tumors; a single patient had poorly differentiated neuroendocrine carcinoma. Thirteen (45%) patients had received prior chemotherapy; the prior chemotherapy regimens generally included platinum-based therapy or neuroendocrine tumor regimens containing streptozocin, doxorubicin, or fluorouracil. Eleven patients received prior therapy with octreotide and remained on octreotide at the same dose during study therapy. No patient initiated octreotide while receiving study therapy. The median chromogranin A level at baseline was 204 ng/mL, with a range of 1 to 6,800 ng/mL; 20 patients had elevated chromogranin A levels (> 39 ng/mL) at baseline and were subsequently assessable for biochemical response. Seven carcinoid patients had elevated 24-hour urinary 5-HIAA levels at baseline (> 6 mg/24 hours), and the median 5-HIAA level of these seven patients was 119 mg (range, 7 to 2,050 mg/24 hours).
Duration of Treatment Twenty-nine patients received treatment for a median of 7.3 months (range, 1 to 23 months). A single patient required dose reduction of temozolomide during the course of treatment for thrombocytopenia. Sixteen patients required dose reductions for thalidomide-related toxicities. Of these 16 patients, 14 required dose reduction to 100 mg, and two ultimately required dose reductions to 50 mg daily. Nine patients continued thalidomide at their starting dose of 200 mg, and four patients were able to undergo dose escalation to 400 mg. The median thalidomide dose for patients at the conclusion of treatment was 100 mg/d.
Toxicity
A total of eleven patients developed infections while receiving study treatment. The infections included three opportunistic infections: one case of Pneumocystis carinii pneumonia, one case of disseminated varicella zoster virus, and one case of cutaneous herpes zoster limited to one dermatome. These three patients had all received more than 6 months of therapy and all developed grade 3 or grade 4 lymphopenia. Grade 3 to 4 lymphopenia, developed in 69% of the patient population. Lymphopenia generally developed in the absence of significant leukopenia or neutropenia: grade 3 or 4 leukopenia developed in only four patients, and grade 3 or 4 neutropenia, in only two patients during study treatment. Other toxicities were relatively mild. Eleven patients developed drug rashes attributed to thalidomide. Mild (grade 1-2) constipation occurred in 11 patients (38%), and grade 3 constipation, in two patients (7%). Mild mood changes and dizziness, also attributed to thalidomide, developed in 10 (31%) and 11 (37%) patients, respectively. Sinus bradycardia occurred in two patients (7%), and one patient (3%) developed thrombosis.
Efficacy
Twenty patients had elevated chromogranin A levels at baseline and were subsequently assessable for chromogranin A response. Of these patients, eight (40%) experienced decreases of chromogranin A of more than 50%, seven had stable chromogranin A levels (< 50% decrease or < 25% increase), and five (35%) had progressive chromogranin A levels as their best response to treatment. Of the seven patients with radiologic response to therapy, four also had chromogranin A responses, and two were not assessable for chromogranin A response. One patient experienced a radiologic response without a chromogranin A response. The median follow-up time for the patient cohort was 26 months (range, 3 to 31 months). Only four patients developed progressive disease while receiving study therapy, and median progression-free survival was not reached (Fig 1). Similarly, median overall survival was not reached. The 1-year survival rate was 79%, and the 2-year survival rate was 61% (Fig 2).
This phase II study demonstrates that an oral regimen of temozolomide and thalidomide is associated with antitumor activity in patients with metastatic neuroendocrine tumors. Treatment with temozolomide and thalidomide was associated with an overall objective radiologic response rate of 25%, a biochemical response rate of 40%, and a 2-year survival rate of 70%. Although the toxicities associated with this regimen were relatively mild, particularly when compared with other cytotoxic chemotherapy regimens commonly used for neuroendocrine tumors, cumulative toxicities associated with the regimen did result in the majority of patients discontinuing therapy before any disease progression. Unique toxicities associated with this regimen included neuropathy and selective lymphopenia. Previous studies of intravenous chemotherapy regimens have suggested that pancreatic endocrine tumors may be more responsive to chemotherapy than are carcinoid tumors. Objective response rates associated with streptozocin-based regimens in patients with carcinoid tumors have ranged from 16% to 33%.3,4,7 In an initial study of patients with pancreatic endocrine tumors, the combination of streptozocin and doxorubicin was associated with a combined biochemical and radiologic response rate of 69%.5 Although small retrospective analyses have reported objective radiologic response rates of less than 10% in pancreatic endocrine tumor patients receiving streptozocin and doxorubicin, a retrospective analysis of 84 patients with either locally advanced or metastatic pancreatic endocrine tumors receiving streptozocin, fluorouracil, and doxorubicin showed that this three-drug regimen was associated with an overall response rate of 39%.6,20,21 In our study, pancreatic endocrine tumors also seemed to be more responsive to treatment with temozolomide and thalidomide than carcinoid tumors, though the relatively small size of our study limits the interpretation of these results. Among the 11 patients with pancreatic endocrine tumors, five (45%) had PRs or CRs, as compared with only one (7%) of 15 patients with carcinoid tumors. One of three patients with pheochromocytoma also responded, suggesting that temozolomide and thalidomide may also have activity in this patient subgroup. Responses with temozolomide and thalidomide were often prolonged—the median response duration was 13.5 months, and one response lasted 31 months. The relative contributions of temozolomide and thalidomide to the antitumor activity observed in our study are difficult to determine. While the observed radiologic response rate of 45% in pancreatic endocrine tumors is somewhat higher than the response rate of 33% observed a previous phase II study of single-agent DTIC in this patient population, conclusions drawn from this observation are limited by potential differences between patient populations in the studies, and potential differences in the antitumor activity of temozolomide and DTIC.9 Our observed response rate of 7% in carcinoid patients parallels response rates of 8% to 16% observed in phase II studies of single-agent DTIC.7,8 Given the neurosecretory activity of many neuroendocrine tumors, biochemical responses have also been considered a meaningful treatment end point in clinical trials for such patients. Chromogranin A is a secreted 49-kD protein that is contained in the neurosecretory vesicles of neuroendocrine tumor cells, and measurement of serum chromogranin A is commonly used clinically to monitor response to therapy.22 In our study, treatment with temozolomide and thalidomide was associated with a significant improvement in biochemical parameters, with 40% of patients experiencing decreases in serum chromogranin A levels of more than 50%. While most toxicities associated with temozolomide and thalidomide seemed mild in comparison with other regimens, a high proportion of patients (55%) were removed from study therapy for toxicity. This observation is likely in part related to the fact that patients remained on therapy for prolonged time periods: the median time to treatment discontinuation for treatment-related toxicity was 8.4 months, and only four patients experienced progressive disease while receiving study therapy. The toxicities associated with temozolomide and thalidomide differed from the traditional toxicities anticipated with standard cytotoxic chemotherapy. Mild decreases in bowel motility, somnolence, and neuropathy attributed to thalidomide, were observed in approximately one third of the patients in the study, and raise the question of whether dose escalation of thalidomide should be performed in future studies. Myelosuppression was rare; however, we observed a high incidence of grade 3-4 lymphopenia. We further observed three instances of opportunistic infections, representing one case each of P carinii pneumonia, cutaneous herpes simplex virus, and disseminated varicella zoster virus. Lymphopenia and opportunistic infections have previously been reported in patients who have received dose-intense temozolomide regimens for prolonged periods.23 Although patients in the current study did not receive routine prophylaxis, our confirmation of opportunistic infections developing in the setting of temozolomide-induced lymphopenia suggests that prophylaxis against P carinii pneumonia and herpes simplex virus should be utilized in future patients treated with this regimen. In conclusion, we report that the combination of temozolomide and thalidomide seems to be an active oral regimen for the treatment of metastatic neuroendocrine tumors and represents a reasonable treatment alternative to older, intravenous regimens for this patient population. Our study suggests that this regimen may be more active in pancreatic endocrine tumors than in carcinoid tumors. Further studies to more precisely assess the relative efficacy of this regimen in pancreatic endocrine and carcinoid tumors are warranted, as are studies to assess the relative contributions of temozolomide and thalidomide to the antitumor activity observed with this combination.
The authors indicated no potential conflicts of interest.
We thank Taylor S. Spear for assisting in the preparation of this article.
Supported by Schering-Plough and Celgene, in part by NIH Grants No. K23 CA 093401, K30 HL04095 (M.H.K.), and gifts from Dr Raymond and Beverly Sackler, the Caring for Carcinoid Foundation, and the Stephen and Caroline Kaufer Fund for Neuroendocrine Tumor Research. Presented in part at the 2003 Chemotherapy Foundation Symposium, New York, NY, November 12-15, 2003. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Faiss S, Pape U, Bohmig M, et al: Prospective, randomized multicenter trial on the antiproliferative effect of lanreotide, interferon alpha, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors-the international lanreotide and interferon alpha study group. J Clin Oncol 21:2689-2696, 2003 2. Bukowski R, Johnson K, Peterson R, et al: A phase II trial of combination chemotherapy in patients with metastatic carcinoid tumors. Cancer 60:2891-2895, 1987[CrossRef][Medline] 3. Engstrom PF, Lavin PT, Moertel CG, et al: Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor. J Clin Oncol 2:1255-1259, 1984[Abstract] 4. Moertel CG, Hanley JA: Combination chemotherapy trials in metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer Clin Trials 2:327-334, 1979[Medline] 5. Moertel CG, Lefkopoulo M, Lipsitz S, et al: Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 326:519-523, 1992[Abstract] 6. Kouvaraki M, Ajani J, Hoff P, et al: Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol 22:4762-4771, 2004 7. Sun W, Lipsitz S, Catalano P, et al: Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol 23:4897-4904, 2005 8. Ramanthan R, Cnaan A, Hahn R, et al: Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma: Study of the Eastern Cooperative Oncology Group E-6282. Ann Oncol 12:1139-1143, 2001 9. Bukowski R, Tangen C, Peterson R, et al: Phase II trial of dimethyltriazenoimidazole carboxamide in patients with metastatic carcinoid: A Southwest Oncology Group study. Cancer 73:1505-1508, 1994[CrossRef][Medline] 10. Averbuch S, Steakley C, Young R, et al: Malignant pheochromocytoma: Effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med 109:267-273, 1988[Medline] 11. Stevens M, Hickman J, Langdon S, et al: Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazole[5,1-d]-1,2,3,5-tatrazin-4(3H)-one (CCRG81045; M&B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res 47:5846-5852, 1987 12. Middleton M, Grob J, Aaronson N, et al: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic melanoma. J Clin Oncol 18:158-166, 2000 13. Stupp R, Mason W, vandenBent M, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005 14. Terris B, Scoazec JY, Rubbia L, et al: Expression of vascular endothelial growth factor in digestive neuroendocrine tumours. Histopathology 32:133-138, 1998[CrossRef][Medline] 15. Kulke M, Lenz H, Meropol N, et al: A phase 2 study to evaluate the efficacy and safety of SU11248 in patients (pts) with unresectable neuroendocrine tumors (NETS). J Clin Oncol 23, 2005 (abstr 4008) 16. Yao J, Ng C, Hoff P, et al: Improved progression free survival (PFS) and rapid, sustained decrease in tumor perfusion among patients with advanced carcinoid treated with bevacizumab. J Clin Oncol 23, 2005 (abstr 4007) 17. D’Amato RJ, Loughnan MS, Flynn E, et al: Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 91:4082-4085, 1994 18. Xu Y, Ellison C, Martin E, et al: A phase II study of thalidomide in metastatic neuroendocrine tumors. Proc Am Soc Clin Oncol 20, 2002 (abstr 1931) 19. Kaplan E, Meier P: Nonparametric estimation for incomplete observation. J Am Stat Assoc 53:457-481, 1958[CrossRef] 20. Cheng PN, Saltz LB: Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma. Cancer 86:944-948, 1999[CrossRef][Medline] 21. McCollum A, Kulke M, Ryan D, et al: Lack of efficacy of streptozocin and doxorubicin in patients with advanced pancreatic endocrine tumors. Am J Clin Oncol 27:485-488, 2004[CrossRef][Medline] 22. Nehar D, Lombard-Bohas C, Olivieri S, et al: Interest of chromogranin A for diagnosis and follow-up of endocrine tumors. Clin Endocrinol (Oxf) 60:644-652, 2004[CrossRef][Medline] 23. Su Y, Sohn S, Krown S, et al: Selective CD4+ lymphopenia in melanoma patients treated with temozolomide: A toxicity with therapeutic implications. J Clin Oncol 22:610-616, 2004 Submitted July 25, 2005; accepted October 21, 2005. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
