Neoadjuvant strategies for advanced pancreatic neuroendocrine tumors: should combined chemotherapy and peptide receptor radionuclide therapy be the preferred regimen for maximizing outcome?

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With the evolution of peptide receptor radionuclide therapy (PRRT) in the mainstream management of metastatic/advanced neuroendocrine tumors (NETs), one area of particular interest is to define its place in the neoadjuvant setting of pancreatic NET and develop an effective and optimal clinical protocol for treatment, monitoring, and evaluation for surgical feasibility. Hence, it is worthwhile for the nuclear medicine fraternity to be aware of the nuances and the determinants so as to be able to deliver the most effective treatment to maximize the possibility of surgical resection.
The resectability of the locally advanced pancreatic cancers is primarily determined by the following factors: (a) superior mesenteric artery encasement greater/lesser than 180°; (b) any celiac artery abutment (in contrast-enhanced computed tomography manifested by loss of fat plane); and (c) reconstructable/(un)-reconstructable superior mesenteric vein portal vein occlusion. Although for the pancreatic head and body tumors all three factors are important, the first two factors are most important determinants for pancreatic tail tumors. These are defined by the consensus statement of the American Hepato-Pancreato-Biliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract and also included in the National Comprehensive Cancer Network guidelines 1,2. In either of the cases, distant metastases or metastases to lymph nodes beyond the field of resection forms a contraindication. Based upon the aforementioned factors, the locally advanced pancreatic carcinoma can be classified into two subgroups: borderline resectable and locally advanced unresectable pancreatic tumors 3. The consensus statement 1 defines borderline resectable pancreatic tumors having the following features: (i) superior mesenteric artery abutment less than 180°; (ii) gastroduodenal artery encasement up to hepatic artery, either abutment or short segment encasement of hepatic artery, but not involving celiac axis; (iii) superior mesenteric vein or portal vein distortion, narrowing or occlusion with suitable vessel (proximal and distal) to allow safe resection and reconstruction.
Lutetium-177-DOTATATE PRRT is a well-tolerated and convenient treatment modality for metastatic/advanced NETs with minimal adverse effects; the treatment results can be viewed dichotomously: although it produces gratifying results in terms of symptom palliation, disease stabilization, and bettering health-related quality of life, its effectiveness in reducing the tumor size is only modest (25–30%). The determinants of the effectivity are (i) size of the tumor (large volume tumors show less response), (ii) MIB1 labeling index (LI), and (iii) fluorine-18-fluorodeoxyglucose (18F-FDG) avidity of the tumor (high MIB1 LI and 18F-FDG-avid lesions are relatively less responsive) 4. The first factor assumes particular importance in the neoadjuvant treatment setting where we are dealing with relatively large sized lesions. Although there have been reports of occasional successes either in case report or short series 5–8, in our practical experience, the effectivity of PRRT alone allowing complete surgical resection (R0 excision), is only minimal or none. Hence, we believe, addition of chemotherapy is a rational further clinical step for bettering outcome with regard to the surgical resectability.
Role of capecitabine–temozolamide combination especially in G2-chemotherapy naive patients along with octreotide has been evaluated to show improvised overall response rates. This can be utilized as neoadjuvant therapy in these tumors, whereas only octreotide may not achieve major tumor downstaging 9–12. Based upon the tumor MIB1 LI, the etoposide plus cisplatin could also be considered in appropriate cases to downstage the tumor as an extrapolation of results from advanced setting 13. A phase I–II study showed almost 68% overall response rates in low-grade NETs (overall response rate 86% in pancreatic NET vs. 26% in nonpancreatic NETs) when CAPTEM regimen is combined with PRRT without adding major toxicities 14. There is no published data for combination of PRRT with cisplatin–etoposide regimen.

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