High-Dose Lanreotide in the Treatment of Poorly Differentiated Pancreatic Neuroendocrine Carcinoma: A Case Report
In February 2009, a 55-year-old woman presented with complaints of loss of appetite and a painful sensation in the gastric region after meals. In the past 30 days, she had also experienced episodes of diarrhea (mean <1/day) and flushing (1–2/day). Because of her age and irregular menstrual cycles, these episodes of flushing were interpreted as a menopausal sign. The patient suffered from arterial hypertension, controlled with bisoprolol 10 mg per day. Clinical examination did not reveal any significant findings, except for a dull pain in the epigastric region. An abdominal computed tomography (CT) scan revealed a mass of about 8 × 5 cm in the hilar region of the liver, involving the head of the pancreas and encasing regional blood vessels (fig. ). Dilated bile ducts were also observed, but there was no evidence of metastases. Dosing of serum chromogranin A (CgA) and neuron-specific enolase was performed. Potential diagnoses included pancreatic adenocarcinoma, cholangiocarcinoma, functional NET or NEC, colon cancer, lymphoma, metastases from melanoma or pheochromocytoma, and chronic pancreatitis.\nPositron-emission tomography-CT (PET-CT) scan using 18F-fluorodeoxyglucose (18F-FDG) confirmed a metabolically active mass in the hilar region of the liver extending to the head of the pancreas. Even though a colonoscopy could have excluded colon cancer from the list of differential diagnoses, it was not performed because the oncologist estimated that another pathology was more likely. CT-guided biopsy was performed; histopathology results revealed a neuroendocrine carcinoma with mitotic count based on 10 high-power fields of >20, and a Ki-67 proliferative index of 22%. Immunohistochemistry showed presence of chromogranin A (+++) and synaptophysin (+). According to the World Health Organization (WHO) 2010 classification, the tumor was graded as a poorly differentiated NEC (G3), small cell type [], and staged as T4NxM0 []. An elevated CgA level of 385 µg/l (reference range: 40–170 µg/l) was noted; neuron-specific enolase level was normal. Somatostatin receptor scintigraphy confirmed that the tumor expressed somatostatin receptors, indicating that treatment with SSAs could be beneficial, despite the poorly differentiated nature of the tumor.\nSurgical resection of the tumor was not an option due to the involvement of the celiac axis. Chemotherapy with carboplatin (target area under the curve = 5 mg/ml/min, administered intravenously on day 1) and etoposide (100 mg/m2, administered intravenously on days 1, 2 and 3) was initiated and repeated every 3 weeks. In addition, treatment with lanreotide Autogel (120 mg/4 weeks), injected deep subcutaneously, was initiated to control symptoms elicited by the secretion of hormones. After 6 cycles of chemotherapy, a partial response was observed: the size of the mass decreased to 2.3 cm, and was then interpreted as locally advanced, involving the epigastric and aortic area; no further lesions or PET activity were noticeable (fig. ). However, the patient experienced important side effects (nausea and vomiting) during the chemotherapy administration.\nAs the tumor size had decreased, surgery became feasible. After consultation with the tumor board and based on minilaparotomy results showing no peritoneal lesions, resection of the PET-positive lesion was performed with maximal debulking. An additional lesion in segment 3 of the liver was also removed. Pathological examination revealed an R1 resection in the distal margin of the resected mass, but no viable tissue in the liver lesion. Intensity-modulated radiotherapy was proposed because of the R1 resection and aggressive histological appearance of the tumor, but the patient refused it due to fear of gastrointestinal toxicity. Biotherapy using lanreotide Autogel (120 mg/4 weeks) was continued by the general practitioner (GP).\nAlthough monitoring of the disease progression using PET-CT and CgA dosing every 3 months was proposed, the patient was lost to follow-up for 10 months. During this time, lanreotide Autogel therapy was administered monthly by the GP. In August 2010, the GP referred the patient to the hospital with loss of appetite, 3–4 episodes of diarrhea per day since 1.5 months and up to 10 episodes of flushes per day since 3.5 months. Clinical examination revealed dull pain in the right hypochondrial and epigastric area and hepatomegaly. Laboratory results revealed CgA levels of 3,568 µg/l; bilirubin was elevated and hepatobiliary enzyme levels (ALT, AST, LDH, GGT) were 3–4 times over the upper limit of normal. A PET-CT scan showed that despite no local recurrence, the right liver lobe was extensively affected by a complex pattern of metastases (fig. ), making surgical resection impossible.\nAt that time, adequate symptom control could no longer be maintained by once per month administration of lanreotide Autogel; thus, biotherapy was continued at a double dose (120 mg/14 days). Fearing gastrointestinal toxicity, the patient refused to undergo chemotherapy with carboplatin and etoposide. An echocardiography was performed because the patient had signs of exercise-induced dyspnea and peripheral edema. The echocardiography revealed dilated right heart cavities, tricuspid valve insufficiency 4/4 (retracted valves, retrograde flow into dilated inferior vena cava and liver veins) and a normal left heart system. Based on these results, carcinoid heart disease was diagnosed, limiting further chemotherapeutic options (e.g. anthracyclines, fluid administration associated with cisplatinum). Treatment with diuretics, angiotensin-converting enzyme inhibitors and low molecular weight heparin was initiated. Right portal vein embolization (RPVE) was performed to ensure fast reduction of the hormone levels causing carcinoid heart disease and the severe burden from flushing and diarrhea. No resection was performed after RPVE, as it had no curative purpose; in addition, the patient refused another abdominal surgery (table ).\nValve replacement surgery was proposed, but was also refused. In September 2010, the patient asked for a pause in active therapy and only supportive treatments were continued. Adequate symptom control was achieved solely by administration of the double dose of lanreotide Autogel. Imaging showed a stable disease after 1.5 months. Three months after RVPE (December 2010), the liver metastases had progressed and bone metastases were also present. Molecular treatment with everolimus was administered at a dose of 10 mg per day. Biotherapy with double-dose lanreotide Autogel was continued and treatment with zoledronic acid at a dose of 4 mg for 4 weeks was initiated. After 6 months, the disease was documented as stable on imaging, but 1 month later the patient showed signs of hepatic failure and clinical disease progression became evident. The patient was switched to best supportive care and died in June 2011.