Metastatic Pancreatic Poorly Differentiated Neuroendocrine Carcinoma: Current Treatment Considerations

Steven Sorscher, MD

Clinical Advances in Hematology & Oncology

December 2013, Volume 11, Issue 12

Metastatic Pancreatic Poorly Differentiated Neuroendocrine Carcinoma: Current Treatment Considerations 

Steven Sorscher, MD, Department of Internal Medicine, Oncology Division, Washington University, St Louis, Missouri 


Pancreatic poorly differentiated neuroendocrine tumors (PDNETs) are a subtype of neuroendocrine tumors (NETs) that are clinically distinguished by their very rapid growth. They are immunohistochemically diagnosed by having a higher Ki-67 cancer cell staining percentage when compared with well or intermediately differentiated NETs. These tumors are typically treated in the same manner as small cell lung cancer. Recent advances in the treatment of well or intermediately differentiated NETs have raised the question of whether such therapies may also have efficacy in PDNETs.

Case Report 

A 53-year-old patient presented in October 2013 with abdominal pain. A computed tomography (CT) scan of the chest, abdomen, and pelvis revealed a pancreatic head mass (4.9 cm × 3.1 cm) and numerous liver metastases, the largest of which was 13.6 cm × 4.9 cm. There were no chest abnormalities and the patient had no history of cigarette smoking. A liver biopsy revealed a PDNET, with a Ki-67 immunohistochemical staining of 39% and a high mitotic rate (>20/10 high-power field [HPF]). Per the World Health Organization (WHO) criteria, the tumor was classified as grade 3 neuroendocrine carcinoma. The patient received chemotherapy with carboplatin on day 1 (area under the curve [AUC], 5) and etoposide (120 mg/ m2) on days 1 to 3, every 3 weeks for a total of 6 cycles. During that time, a repeat CT scan showed improvement in the tumor burden. The largest liver mass decreased in size to 12.3 cm • 9.1 cm; other masses decreased in size as well. However, shortly after completion of the last 2 cycles, a CT scan on February 27, 2013 showed that the pancreatic mass and liver masses were stable.

On March 12, 2013, a somatostatin-receptor scintigraphy study (octreotide scan) showed abnormal indium 111-pentetreotide activity in the liver lesions and pancreatic mass, consistent with a neuroendocrine carcinoma. The patient received 1 dose of octreotide acetate 20 mg and developed severe nausea and vomiting within a few days, which led to hospitalization. After recovering, the patient underwent chemoembolization of the liver with 100 mg doxorubicin-lipiodol on April 5, 2013 and again on May 7, 2013. A repeat CT on June 5, 2013 showed a “mild” interval decrease in the size of the liver masses, whereas the pancreatic mass had increased in size. Various options were discussed with the patient, including further chemoembolizations, systemic chemotherapy (eg, topotecan), resuming octreotide therapy, everolimus (Afinitor, Novartis), sunitinib (Sutent, Pfizer), or observation.


Pancreatic PDNETs are characterized clinically by rapid growth, initial responsiveness to platinum-based therapy, and a very poor prognosis. The National Cancer Comprehensive Network (NCCN) guidelines for well and intermediately differentiated NETS suggest treating these patients the same way in which small cell lung cancer patients are treated, as was done with our patient.1 The guidelines suggest that octreotide acetate be considered as well, although no references are found in the literature to support a benefit of octreotide acetate in treating PDNETs. In searching the literature, 1 study reported a lack of inhibition of small cell lung cancer cell lines using octreotide.2

Well and intermediately differentiated NETs are treated differently than PDNETs. These tumors are typically far more indolent. Octreotide acetate is a standard therapy, based largely on a significant prolongation in progression-free survival (PFS) of roughly 8 months when compared with a placebo.3 With progression of well or intermediately differentiated NETs, everolimus and sunitinib have shown a significant PFS benefit compared with placebo. These agents have been approved by the US Food and Drug Administration for use with progression of pancreatic NETs of any grade, although the pivotal trials included only patients with metastatic, well or intermediately differentiated NETs.4,5

Per the WHO criteria, intermediate NETs are defined immunohistochemically as having Ki-67 cancer cell staining of 2% to 20%, whereas PDNETs have Ki-67 staining of more than 20%.6 Greco and Hainsworth reported a series of patients with PDNETs of unknown primary site and concluded that the management of these patients should parallel treatments used for small cell lung cancer.7 A recent report suggests that, like other NETs, PDNETs similarly overexpress mTOR, underscoring the possibility that patients with PDNETs should be included in trials involving targeted agent therapies for other NETs.8 Perhaps these therapies will play a role in treating PDNETs and other pancreatic NETs in the future.


1. Kulke MH, Benson AB III, Bergsland E, et al; National Comprehensive Cancer Networks. Neuroendocrine tumors. J Natl Compr Canc Netw. 2012;10(6):724-764.

2. Macaulay VM, Smith IE, Everard MJ, Teale JD, Reubi JC, Millar JL. Experimental and clinical studies with somatostatin analogue octreotide in small cell lung cancer. Br J Cancer. 1991;64(3):451-456.

3. Rinke A, Müller HH, Schade-Brittinger C, et al; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27(28):4656-4663.

4. Pavel ME, Hainsworth JD, Baudin E, et al; RADIANT-2 Study Group. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011;378(9808):2005-2012.

5. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):501-513.

6. Klöppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci. 2004;1014(1):13-27.

7. Greco FA, Hainsworth JD. Poorly differentiated large cell neuroendocrine carcinoma. Cancer. 2008;8(56):2372.

8. Catena L, Bajetta E, Milione M, et al. Mammalian target of rapamycin expression in poorly differentiated endocrine carcinoma: clinical and therapeutic future challenges. Target Oncol. 2011;6(2):65-68.