Influence of pretreatment with everolimus or sunitinib on the subacute hematotoxicity of 177Lu-DOTATATE PRRT.

Background: Peptide receptor radionuclide therapy (PRRT) is a validated treatment for somatostatin receptor overexpressing neuroendocrine tumors (NETs). The NETTER-1 trial demonstrated a pronounced positive effect on progression-free-survival compared to high dose somatostatin analogs (SSAs), with a strong tendency toward overall survival benefit. Our aim was to investigate the influence of pretreatment with everolimus and/or sunitinib on subacute hematotoxicity of PRRT. To assess the influence of prior treatment with everolimus/sunitinib might be of clinical relevance due to the link between short-term hematotoxicity and increased incidence of late hematotoxicity.Material and methods: Our single-center retrospective study enrolled all patients treated with 177Lu-DOTATATE PRRT (1-4 cycles of 7.4 GBq), between November 2013 and July 2018. Patients were assigned to two groups according to their pretreatment: no targeted agents (N = 41), or targeted agents (everolimus, sunitinib or both; N = 41). The end point was subacute hematotoxicity, defined as the nadir value between the first administration until 3 months after the last administration, using the CTCAE 4.03 classification. The impact of splenectomy was also explored.Results: Eighty percent of patients had a primary gastroenteropancreatic NET. No statistically significant differences in severe subacute hematotoxicity were seen in the pretreated group vs. the naive group for hemoglobin (grade 3/4: 12% vs. 22%), neither for leucocytes (grade 3/4: 10% vs. 7%), neutrophils (grade 3/4: 5% vs. 7%), lymphocytes (grade 3/4: 49% vs. 37%) and platelets (grade 3/4: 15% vs. 15%). Furthermore, we observed significantly lower toxicity for total white blood cells, lymphocytes and platelets in the subgroup that had splenectomy (N = 12). Limitations of this study include the potential bias in lack of use of targeted agents in patients more susceptible to toxicity, and the limited number of patients and events.Conclusions: In a patient cohort with NET pretreated with everolimus and/or sunitinib, we could not demonstrate a significant effect of prior/pretreatment with everolimus and/or sunitinib on the subacute hematotoxicity of 177Lu-DOTATATE PRRT.

Spectrum of malignant somatostatin-producing neuroendocrine tumors.

OBJECTIVE: To evaluate the clinical manifestations and outcome of patients with somatostatinomas--rare neuroendocrine tumors of pancreaticoduodenal origin. METHODS: We searched the medical archives and tumor registry of our institution for somatostatinomas or somatostatin-staining tumors for the 12-year period from January 1990 to February 2002. In addition, we reviewed laboratory databases for patients who had an elevated serum somatostatin level. Patients with a neuroendocrine tumor and an elevated serum somatostatin level or somatostatin-positive tumor immunostaining were included in this study. RESULTS: Eleven patients qualified (9 men and 2 women; median age at diagnosis, 45 years; age range, 22 to 73). The diagnosis of a somatostatinoma was made by immunostaining of the tumor in 9 patients and by finding elevated serum somatostatin levels in 2. Five primary tumors were of duodenal and 6 of pancreatic origin. Psammoma body formation and association with neurofibromatosis were seen only in the duodenal tumors. The known primary tumor sizes varied from 2 to 6 cm. Liver metastatic lesions were present in 6 patients, abdominal lymph node involvement was found in 10 patients, and lung, spleen, and ovarian metastatic involvement was noted in 1 patient each. Diabetes was present in 4 patients (36%) and cholelithiasis in 7 (64%). The presence of a mass led to the diagnosis in most patients with primary duodenal tumors, whereas patients with pancreatic tumors were more likely to have endocrine manifestations. A Whipple procedure was performed in 6 patients, distal pancreatectomy in 3, hepatic artery embolization or ligation in 3, and partial hepatectomy in 1. Cancer-related death occurred in 4 patients, 1 to 8 years after diagnosis (median, 4.5 years). At last follow-up, 2 patients were alive without evidence of disease (8 and 10 years after diagnosis), and 3 were alive with liver metastatic lesions. The status of 2 patients was unclear. CONCLUSION: Somatostatinomas occurred with approximately equal frequency in the duodenum and the pancreas. The duodenal tumors were more likely to be pure somatostatinomas and have psammoma bodies. Pancreatic tumors were more likely to be multihormonal. Cholelithiasis and diabetes were seen in 64% and 36%, respectively, of the patients. Mass effect of the tumor was the usual manifestation leading to diagnosis. These tumors are slow growing, and long-term survival is possible.

Alkaline phosphatase predicts survival in patients with metastatic neuroendocrine tumors.

The clinical course of patients with metastatic neuroendocrine tumors is highly variable. While some patients experience an indolent clinical course over many years, other patients may rapidly succumb to their disease. Little is known about prognostic factors in these patients, making decisions regarding their management more difficult. We performed a retrospective analysis of 137 patients with metastatic neuroendocrine tumors referred to our institution for treatment. Potential prognostic factors were evaluated using multivariate survival analysis. The median overall survival of patients in our cohort was 6.0 years, although the range of survival times was broad (48 days to 23.4 years). Alkaline phosphatase levels above normal were predictive of shorter survival in both univariate and multivariate analysis. Elevated chromogranin A levels were also associated with shorter survival in univariate analysis; in a multivariate analysis, however, this correlation was no longer significant. There was no association between survival and gender, primary tumor site, or presence or absence of carcinoid syndrome. Elevated alkaline phosphatase is a robust adverse prognostic factor for survival in patients with metastatic neuroendocrine tumors and may be superior to chromogranin A in this setting. Close monitoring of alkaline phosphatase levels may be useful when considering initiation or changes of therapy in patients with metastatic neuroendocrine tumors.

Strategy for pancreatic endocrine tumors.

BACKGROUND/AIMS: The endocrine tumors of the pancreas are rare diseases and there is no established standard therapy for the liver metastasis of pancreatic endocrine tumors. In this study, the therapy for the pancreatic endocrine tumors was evaluated. METHODOLOGY: The endocrine pancreas tumors of 13 patients had been surgically treated. All primary tumors were completely resected. The liver metastasis was recognized in 4 patients. Partial resection of the liver was performed in 2 patients. Lipiodol-transcatheter arterial embolization was performed for synchronous unresectable liver metastases in the other 2 patients. RESULTS: The patients with no liver metastases survived without recurrence (max: 18.8 yr; mean follow-up: 9.2 yr). The patient with resected synchronous solitary liver metastasis died of recurrent multiple liver metastases 5 months after surgery. The other patient with the metachronous liver metastasis completely resected survived 13.9 years. In the 2 patients with unresectable numerous liver metastases, after lipiodol-transcatheter arterial embolization, tumor necrosis rate was more than 90% in both cases and serum gastrin level was normalized. CONCLUSIONS: Complete resection of liver metastasis is favorable, whereas lipiodol-transcatheter arterial embolization is effective for unresectable liver metastases from pancreatic endocrine tumors as palliation. Complete resection of the primary site is recommended even in the cases with unresectable numerous liver metastases.

Somatostatinoma/inhibitory syndrome: a statistical evaluation of 173 reported cases as compared to other pancreatic endocrinomas.

Somatostatin is known to inhibit the secretory release of other peptide hormones. Somatostatinomas associated either with or without somatostatinoma (inhibitory) syndrome are rare neoplasms among gut-pancreatic endocrinomas. Collected from international literature, this study aimed to perform a statistical analysis on 173 patients with somatostatinoma/inhibitory syndrome. The evaluation further attempted to provide investigators in this particular field of research with extensive and precise information on the present situation of somatostatinoma. The 173 patients consisted of 81 with pancreatic somatostatinomas and 92 with extrapancreatic somatostatinomas. Most of the latter were found to have originated in the duodenum and may be termed as carcinoid somatostatinoma. Where data were considered to be adequate, a comparative study was carried out between two groups, pancreatic and duodenal, each consisting of 81 patients. A statistically significant difference between these two groups was found in the incidence of inhibitory syndrome (18.5% versus 2.5%) and von Recklinghausen's disease (1.2% versus 43.2%), large size of tumor (>20 mm) (85.5% versus 41.4%), multisecretory activities (33.3% versus 16.3%), and presence of psammoma bodies (2.5% versus 49.4%). There was no statistically significant difference in the rate of metastases and malignancy between the two groups. The average postoperative 5-year survival rate was 75.2% in 90 patients overall, 59.9% in 44 with metastases and 100.0% in 46 without metastases. Compared with the other pancreatic endocrinomas, including PPomas, glucagonomas, vipomas, gastrinomas, and insulinomas, somatostatinomas were characterized by the low rate of the relevant syndrome and multiple endocrine neoplasia syndrome type 1. There was a low rate of multiplicity, and a high incidence of psammoma bodies in the duodenal group particularly with von Recklinghausen's disease. A high rate of malignancy was recorded, resulting in a low postoperative survival rate of patients with metastases. In conclusion, somatostatinomas exhibited characteristic features quite different from those of the other pancreatic endocrinomas regarding multiple points.

Prognostic factors in patients with endocrine tumours of the duodenopancreatic area.

BACKGROUND: The development of endocrine tumours of the duodenopancreatic area (ETDP) is thought to be slow, but their natural history is not well known. The aim of this study was to determine the factors that influence survival of patients with ETDP. PATIENTS/METHODS: Eighty two patients with ETDP (44 non-functioning tumours, 23 gastrinomas, seven calcitonin-secreting tumours, four glucagonomas, three insulinomas, one somatostatinoma) followed from October 1991 to June 1997 were included in the study. The following factors were investigated: primary tumour size, hormonal clinical syndrome, liver metastases, lymph node metastases, extranodular/extrahepatic metastases, progression of liver metastases, local invasion, complete resection of the primary tumour, and degree of tumoral differentiation. The prognostic significance of these factors was investigated by uni- and multi-variate analysis. RESULTS: Twenty eight patients (34%) died within a median of 17 months (range 1-110) from diagnosis. Liver metastases (p = 0.001), lymph node metastases (p = 0.001), progression of liver metastases (p < 0.00001), lack of complete resection of the primary tumour (p = 0.001), extranodular/extrahepatic metastases (p = 0.001), local invasion (p = 0.001), primary tumour size > or = 3 cm (p = 0.001), non-functioning tumours (p = 0.02), and poor tumoral differentiation (p = 0.006) were associated with an unfavourable outcome by univariate analysis. Multivariate analysis identified only liver metastases (risk ratio (RR) = 8.3; p < 0.0001), poor tumoral cell differentiation (RR = 8.1; p = 0.0001), and lack of complete resection of the primary tumour (RR = 4.8; p = 0.0007) as independent risk factors. Five year survival rates were 40 and 100% in patients with and without liver metastases, 85 and 42% in patients with and without complete resection of primary tumour, and 17 and 71% in patients with poor and good tumour cell differentiation respectively. CONCLUSION: Liver metastases are a major prognostic factor in patients with ETDP. Progression of liver metastases is also an important factor which must be taken into account when deciding on the therapeutic approach. The only other independent prognostic factors are tumoral cell differentiation and complete resection of the primary tumour.

Clinical characteristics, treatment and survival in patients with pancreatic tumors causing hormonal syndromes.

Eighty-five patients with endocrine pancreatic tumors associated with clinical syndromes of hormone excess were retrospectively analyzed regarding symptomatology, means of diagnosis, and results of surgical and medical treatment during follow-up of 3-18 years (median 8 years). The combination of angiography and computed tomography was most successful in pre-operative localization of both primary tumors and metastases. Surgery provided long term cure in 39 of 44 patients with benign islet cell lesions, the majority having insulinomas. Forty-one patients had malignant tumors, which at the time of diagnosis or operation were associated with liver and/or regional lymph gland metastases in 56% and 24%, respectively. Sixteen patients with metastatic disease and/or very large tumors were considered inoperable, 5 patients underwent palliative resection of their malignant tumors, while grossly radical tumor removal was accomplished in 20 patients. Long-term cure was achieved in 5 patients by excision of primary tumors and localized liver or lymph gland metastases. Half of the patients, particularly those with insulinoma, gastrinoma, or vipoma, showed response to streptozotocin, in combination with other cytostatics, for a median of 24 months or a response to interferon for a median of 10 months. The overall 5-year and 10-year survival among the patients with malignant islet cells tumors was 54% and 28%, respectively. Absence of liver metastases at time of operation/diagnosis, smaller size of the primary tumor, grossly radical tumor resection as well as response to medical therapy predicted the more favorable survival.