Prolonged Clinical Benefit of Everolimus Therapy in the Management of High-Grade Pancreatic Neuroendocrine Carcinoma
In June 2008, a 34-year-old woman presented with a 2-month history of epigastric and periumbilical pain, fatigue, anorexia, nausea, and emesis. Physical assessment showed mild abdominal distention with painful hepatomegaly extending to the left hypochondrium, no adenopathy, and normal findings on echocardiogram (left ventricular ejection fraction, 72%). Computed tomography (CT) revealed hepatomegaly with multiple lesions (the largest lesion measured approximately 11.5 cm in diameter), a 5 × 7-cm mass in the tail of the pancreas, and a collection of subcapsular hepatic, perihepatic, and perivascular fluid. An analysis of tumoral tissue obtained by liver biopsy showed electron-dense granules containing synaptophysin and chromogranin A (CgA), high mitotic count (30/10 high-power fields), and high expression of Ki-67 (found in 30–40% of tumor cells) (fig. ). Octreotide scintigraphy confirmed somatostatin receptor expression in the pancreatic tumor and in liver and peritoneal metastases. At the time of diagnosis, the patient's Karnofsky performance status (KPS) was 70%.\nChemotherapy was initiated with streptozocin and 5-fluorouracil in July 2008; the patient received 3 cycles of this first-line chemotherapy. In September 2008, clinical and biomarker evaluation demonstrated progressive disease, and treatment was switched to second-line cisplatin and etoposide for 4 cycles. After disease progression, the patient began treatment with streptozocin and doxorubicin. After the completion of 3 cycles, however, the disease continued to progress rapidly, as assessed by radiologic imaging and changes in biomarker levels (CgA value, 4,381 ng/ml) (table ).\nAfter 9 months of chemotherapy and 3 lines of therapy, the patient had a KPS of 60%, peritoneal metastases, and palpable hepatomegaly. She required high-dose opioids to achieve analgesia. Fourth-line treatment with temozolomide (150 mg/m2 on days 9–14) and capecitabine (1,000 mg/m2 for 14 days every 3 weeks) was subsequently initiated and led to the achievement of partial radiologic response at 12 weeks (4 cycles); however, the patient experienced disease progression after 6 cycles of therapy.\nIn September 2009, after receiving 1 dose of fifth-line weekly paclitaxel, the patient was hospitalized because of toxicity and general deterioration in health. She had uncontrolled pain, esophagitis, and small bowel partial obstruction caused by peritoneal disease progression that prevented her from eating without severe nausea. CgA concentration increased to 4,600 ng/ml, KPS decreased to 50%, and CT demonstrated massive hepatic and peritoneal tumor infiltration (fig. ). Therefore, the patient was given intravenous fluids, morphine, scopolamine butyl bromide, dexamethasone, and subcutaneous octreotide as palliative and conservative therapy. After 1 week, she was able to tolerate oral fluids and drugs and experienced some improvement in general state. Taking into account initial data findings from the recent RADIANT-2 study [], the patient's age, and her request to receive further lines of treatment, everolimus 10 mg/day plus octreotide LAR 30 mg every 4 weeks were initiated upon patient informed consent and compassionate use guidelines. Octreotide LAR had not previously been administered because of the patient's high baseline Ki-67 index (30–40%).\nFifteen days after the initiation of sixth-line therapy with everolimus plus octreotide LAR, the CgA concentration decreased to 1,388 ng/ml. The patient achieved partial radiologic response (>50% decrease in tumor size) after 2 months of treatment (fig. ). By January 2010, her general health status had markedly improved, corresponding to a KPS of 90%, with pain and oral restrictions alleviated. Clinically important partial response (decrease in tumor size >80%) was confirmed by CT (as per RECIST v1.0; fig. ) and by reduced CgA levels after 8 months of therapy with everolimus (fig. ). The lowest CgA value, 137 ng/ml, was achieved in August 2010 after approximately 1 year of treatment.\nThroughout the course of everolimus plus octreotide LAR treatment, the patient experienced grade 1 hyperglycemia and grade 2 anemia, which were treated with an antidiabetic diet and erythropoietin plus intravenous iron therapy, respectively. Grade 1 stomatitis was also documented but did not require pharmacologic intervention. After 1 year of treatment, the patient reported sporadic grade 1 emesis, grade 1 diarrhea, and grade 1 hand-foot syndrome.\nIn December 2010, after 15 months of everolimus and octreotide LAR as sixth-line therapy, the patient continued to be asymptomatic and had a KPS of 90%. Assessment by CT demonstrated an increase in the size of a peritoneal node (from 17 mm in early scans to 25 mm). To prevent disease progression, everolimus was administered at a higher dose (15 mg/day), and 1 month later the node had decreased in size (to 21 mm).\nAfter more than 1 year of treatment benefit with everolimus, during CT evaluation in March 2011, the patient's liver metastases were shown to have progressed. A diagnostic biopsy was repeated. However, it was possible only to confirm the high Ki-67 index and electron-dense granules containing synaptophysin and CgA. Most of the cells were necrotic, and it was not possible to check for tissue expression of potential everolimus response predictors such as mTOR and 4EB1. One week later clinical progression was reported, and 2 weeks later the patient was hospitalized with liver failure, fever, jaundice, painful hepatomegaly, extrinsic compression of the stomach, anorexia, and asthenia. After progressive deterioration in her general health, the patient died on April 4, 2011, 33 months after the initial diagnosis and 19 months after the initiation of treatment with everolimus plus octreotide LAR.