Well-differentiated pancreatic islet cell carcinoma: Is there reversibility in mTOR inhibitor resistance?

Abstract

In 2000, a 48-year-old man presented with epigastralgia. Computed tomography scan revealed a hypervascular pancreatic tumor with multiple liver and mediastinal lymph node metastases. The diagnosis of metastatic well-differentiated pancreatic islet cell carcinoma (pNET) was made by biopsy of the liver lesions. The mitotic index was 3/10 HPF (x40); Ki67 index was 5%. Serum levels of digestive hormones were within normal limits and chromogranin A levels was 220 μg/l. Octreotide scintigraphy showed high-grade activity in liver and mediastinal metastases. The patient was successively treated with chemotherapy (six cycles of streptozotocin-doxorubicin); surgery (cephalic duo-denopancreatectomy in March 2002, due to the local risk of compression and presence segmental portal hypertension); without any treatment and stable disease until February 2004; alpha-interferon for 15 months; chemotherapy (ten cycles of Folfi ri); and everolimus in December 2006 (RADIANT 1 trial). The treatment resulted in a decrease in tumor size (34% using RECIST criteria) at four months; the dis-ease was controlled for 24 months. Because of occur-rence of two new liver metastases, the patient was then included in a phase 3 trial and received sunitinib throughout 12 months; sunitinib was stopped because of occurrence of portal vein thrombosis under enox-aparin; the disease was stable. The patient was then treated with lanreotide in order to maintain disease stabilization; however, new progression ( after a break in treatment or maybe induced by 10% among RECIST criteria and elevation of Chromogranin A from 1982 to 2932 μg/l) occurred three months later. In June 2010, as the patient refused cytotoxic chemo-therapy and because of the particular initial good response to the everolimus, it was decided to add everolimus in association with lanreotide. Three months after starting the treatment, the weight of the patient had increased by 3 kg, fatigue had disappeared and imaging studies showed a response of 23% on RECIST criteria. His disease remains stable six months after this combination started. To our knowledge, this is the fi rst case showing a second effi cacy of mTOR inhibitor for treatment of solid advanced cancer. It enables us to discuss the reversibility of resistance mechanisms of evero-limus, and potential interest of a combined therapy with somatostatin analogs. It has recently been shown that, in patients with pNET, sunitinib or everolimus signifi cantly increase progression-free survival [1,2]. However, even if a control of the disease is frequently achieved, objective responses, such as the one observed in our case, are rare. How can we explain the second effi cacy of everolimus in combination with somatostatin analogs 18 months after the end of the fi rst treatment, as reported here? Some hypotheses may be discussed: a) syner-getic antitumor effect between everolimus and somatostatin analogs; b) emergence of a predomi-nant tumor cell clone, responding to everolimus,