Metronomic temozolomide as second line treatment for metastatic poorly differentiated pancreatic neuroendocrine carcinoma

Abstract

Neuroendocrine Neoplasms (NEN) are a group of heterogeneous malignancies derived from neuroendocrine cell compartment, with different roles in both endocrine and nervous system. Most NETs have gastroentero-pancreatic (GEP) origin, arising in the foregut, midgut, or hindgut. The 2010 WHO classification divides GEP-NETs into two main subgroups, neuroendocrine tumors (NET) and neuroendocrine carcinomas (NEC), according with Ki-67 levels. NET are tumors with low (<20 %) Ki-67 value, and NECs, including small cell lung carcinomas and Merkel Cell carcinomas, are all NETs with high Ki-67 levels (>20 %-G3). Poorly differentiated neuroendocrine carcinomas (NEC) are usually treated with cisplatin-based chemotherapy regimens. Here we present a case of a patient with pancreatic NEC progressing after cisplatin and etoposide, treated with temozolomide as palliative, second line treatment. According with the poor Performance Status (PS = 2) and to reduce the toxicity of the treatment was chosen an intermittent dosing regimen of metronomic temozolomide (75 mg/m(2)/day-one-week-on/on-week-off). MGMT resulted methylated. On July 2014 the patient started the treatment. On August 2014 the patient obtained a significant clinical benefit (PS = 0) and the total body CT scan performed on October 2014 showed a RECIST partial response on all the sites of disease. No drug-related side effects were reported by the patient. After 18 months of therapy the treatment continues without significant toxicity, and with further remission of the metastases. Treatment with metronomic "one-week-on/on-week-off" Temozolomide can be considered a good treatment option in patients with poor performance status, affected by pNEC with MGMT methylation.

Keywords: Immunotherapy; Metronomic treatment; Neuroendocrine tumors; Pancreatic neuroendocrine carcinoma; Second line therapy; Temozolomide.

Figures

Fig. 1

Histological examination with immunohistochemistry and hematoxylin-eosin staining (e/e). a CD 56 20 × magnification; b e/e 20 × magnification; c chromogranin 20 × magnification; d Synaptophysin 20 × magnification; e Ki-67 40 × magnification

Fig. 2

Peritumoral lymphocytes and leucocytes infiltrating tumor microenviroment. Tumor-infiltrating CD8 + T cells (circles) have been detected in the pNEC tumor biopsy of the patient. These cells infiltrating tumor micro environment are frequently associated with favorable clinical outcome in a remarkably large spectrum of cancers as MCC and pNEC

Fig. 3

Detection of MGMT methylation by MSP and MethyLight qMSP. Isolated DNA from tumor specimen is treated with sodium bisulfite, which changes unmethylated cytosine (C) into uracil (U), but not methylated cytosine (mC), which remains unchanged. The modified DNA is used as a template for MSP or MethyLight qMSP. (MSP/agarose gel electrophoresis) When MGMT in neuroendocrine tumor is methylated (DNA M), the band is high, while the unmethylated band (DNA U) is low. The gel shows the presence of methylation band in BT1, brain tumor a with strong methylated, DNA M, used as positive control, and unmethylation band in BT2, brain tumor a with strong unmethylated, DNA U, used as negative control

Fig. 4

Hepatomegaly reduction. CT portal-phase contrast-enhanced images: Coronal plane reconstruction and Axial Maximum Intensity Projection (MIP) reconstruction at time 0 (a) and at 4 (b), 7 (c), 10 month (d) follow up examinations. Progressive reduction of longitudinal diameter of the liver measured in the mid-clavicular line was observed at follow up study. Progressive reduction of lower margin extension below costal arch was also detected. Caudal displacement of right kidney at time 0 (white arrow) gradually disappears at successive studies. Axial MIP images show progressive reduction of the displacement effect on the portal bifurcation due to decrease of metastatic parenchymal lesions: space between left and right portal trunk (angle) gradually decrease over time. Note the increased caliber of portal trunks and progressive reduction of the swelling of liver profile (arrowhead) related with hepatomegaly, with increased thickness of perivisceral fat

Fig. 5

CT portal-phase contrast-enhanced images of two different planes at time 0 (a) and at 4 (b), 7 (c), 10 month (d) follow up examinations. Conspicuous volume reduction of paraesophageal and paracardial lymph nodes was observed over time. Increased caliber of portal trunks was detected, due to parenchymal architecture changes, reduced mass effect and mild portal hypertension. Note progressive dislocation of left portal trunk asterisk from left to right side due to reduction of hepatomegaly. Also note volume decrease of liver and spleen lesions with gradually remission of parenchymal architecture

Fig. 6

Changes of lesions over time in pancreatic head region, lung, liver and spleen at time 0 (a) and at 4 (b), 7 (c), 10 month (d) follow up examinations. Pancreas: enlargement of pancreatic head region was observed at time 0, with strongly inhomogeneous density, indistinct pancreatic margins and surrounding retroperitoneal fat stranding; some peripancreatic lymph nodes enlarged were detected. Following CT examinations show gradually decrease of pancreatic swelling with better definition of parenchymal lesions, going towards progressive regression e colliquation. Note progressive appearance of right kidney’s upper pole asterisk, according to reduction of displacement effect by liver. Furthermore, note the displacement of superior mesenteric artery (black arrow) to right side due to reduction of pancreatic swelling. Lung: progressive volume reduction of metastatic lesions (white arrow) in anterior basal segment of right lower pulmonary lobe. Liver: one of the major lesions of the liver at the IV segment (arrowhead) underwent progressive volume reducing ad enhancement pattern. Spleen: volume reduction of multiple metastatic lesions