Continued Tumor Reduction of Metastatic Pheochromocytoma/Paraganglioma Harboring Succinate Dehydrogenase Subunit B Mutations with Cyclical Chemotherapy

Abstract

Patients harboring germline mutations in the succinate dehydrogenase complex subunit B (SDHB) gene present with pheochromocytomas and paragangliomas (PPGL) that are more likely malignant and clinically aggressive. The combination chemotherapy cyclophosphamide, vincristine, and dacarbazine (CVD) was retrospectively evaluated in patients with SDHB-associated metastatic PPGL.Query Twelve metastatic PPGL patients harboring SDHB mutations/polymorphisms with undetectable SDHB immunostaining were treated with CVD. CVD therapy consisted of 750 mg/m² cyclophosphamide with 1.4 mg/m² vincristine on day 1 and 600 mg/m² dacarbazine on days 1 and 2, every 21-28 days. Treatment outcome was determined by RECIST criteria as well as determination of response duration and progression-free and overall survivals. A median of 20.5 cycles (range 4-41) was administered. All patients had tumor reduction (12-100% by RECIST). Complete response was seen in two patients, while partial response was observed in 8. The median number of cycles to response was 5.5. Median duration of response was 478 days, with progression-free and overall survivals of 930 and 1190 days, respectively. Serial [¹⁸F]-fluorodeoxyglucose positron emission tomography and computed tomography imaging demonstrated continued incremental reduction in maximal standardized uptake values (SUV_max) values in 26/30 lesions. During treatment administration, the median SUV decreased from > 25 to < 6, indicating the efficacy of chemotherapy over a prolonged period of time. Prolonged therapy results in continued incremental tumor reduction, and is consistent with persistent drug sensitivity. CVD chemotherapy is recommended to be considered part of the initial management in patients with metastatic SDHB-related PPGL.

Keywords: Cyclophosphamide; Dacarbazine; Pheochromocytoma/paraganglioma; Succinate dehydrogenase; Vincristine.

Fig. 1

SDHB immunostaining of pheochromocytoma and paraganglioma tumors. a Positive control; b negative control; c–g tumors staining less (granular) than normal control (clumps). h SNP negative for SDHB

Fig. 2

Waterfall plot. Waterfall plot depicting response to chemotherapy as assessed by RECIST

Fig. 3

[¹⁸F]-FDG PET images and gradual reduction in SUV_max with chemotherapy in three patients treated with chemotherapy for 600–1300 days. Each line depicts the results in an individual lesion. The images on the left (Panel A) depict a patient who had widespread disease that responded to therapy, but an abdominal mass that measured nearly 15 cm did not demonstrate much of a change in SUV_max despite a 12% reduction in size by RECIST (This is shown as the least response on the Waterfall Plot). (Panel a = Patient #3; Panel b = Patient #8; Panel c = Patient #7)