Abstract 5754: Temozolomide therapy for progressive metastatic paraganglioma/pheochromocytoma: SDHB mutation as a prognosis biomarker for efficacy

Abstract Malignant pheochromocytoma and paraganglioma (PPGLs) are rare diseases with a heterogeneous behaviour. Nowadays systemic therapies, including 131I-MIBG therapy and the cyclophosphamide-dacarbazine-vincristine chemotherapy regimen (CVD), constitute the most popular options in case of aggressive tumors. We have investigated the antitumor effect of temozolomide (TMZ), in patients with metastatic PPGLs. All patients were assessed for TMZ efficacy, with CT scan and PET scan performed every 3 months. Safety and identification for prognosis factors of response were secondary endpoints. Fifteen consecutive patients with progressive (n=14) or symptomatic (n=1) metastatic PPGLs began TMZ therapy at our institution between November 2007 and January 2011. There were 12 men (80%); median age was 43 years, with a functioning tumor in 73% of the cases. Germline mutations were screened: 10 patients harbored SDH B mutation and 5 patients had no mutation among SDH A, SDH C, SDH D, NF1, RET or VHL genes. Primary was located in the adrenal gland for 53% of the patients, thorax for 40 % and neck for 7%. TMZ was given at a dose of 150 mg/m2/d for five days of a 28-days cycle for the first cycle and then at 200 mg/m2 for five days each subsequent cycle. Seven patients received TMZ as first line therapy, 2 patients as second line and 6 patients as third line. Median number of cycle administered was 7, mean dose intensity was 171 mg/m2 (95% CI 160.7-181) for each treatment cycle. TMZ was well tolerated: the most frequent all grade toxicities included asthenia, nausea and anemia. Grade 3 toxicities were lymphopenia (n=2) and hypertension (n=1). According to RECIST 1.1 criteria, 11 patients were evaluable: 4 patients experienced a partial response, 6 a stable disease, 1 patient a progressive disease. With a median follow up of 29 months (range 6.4-37.9), median overall survival was not reached and median progression free survival (PFS) was 9.6 months. Partial response was observed in 4 out of 10 SDHB mutated patients but no sporadic case. Patients with SDH B mutations or with no mutation had a median PFS of 16.7 months or 2.6 months, respectively (log-rank, p=0.013); Patients with SDH B mutations or with no mutation had a 12-month PFS of 60% or 0%, respectively. Expression of Methyl Guanine Methyl Transferase (MGMT) by immunohistochemistry (IHC) was analyzed in 4 patients, including 3 responders and, was found negative. MGMT IHC is ongoing in the remaining patients This study demonstrates for the first time the antitumor efficacy of TMZ in a large series of metastatic PPGLs as well as the potential role for SDH B mutation as a prognosis biomarker of response of response. Loss of MGMT expression in SDH B mutated patients could explain these results. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5754. doi:1538-7445.AM2012-5754