Association of Upfront Peptide Receptor Radionuclide Therapy With Progression-Free Survival Among Patients With Enteropancreatic Neuroendocrine Tumors.

Importance: Data about the optimal timing for the initiation of peptide receptor radionuclide therapy (PRRT) for advanced, well-differentiated enteropancreatic neuroendocrine tumors are lacking. Objective: To evaluate the association of upfront PRRT vs upfront chemotherapy or targeted therapy with progression-free survival (PFS) among patients with advanced enteropancreatic neuroendocrine tumors who experienced disease progression after treatment with somatostatin analogues (SSAs). Design, Setting, and Participants: This retrospective, multicenter cohort study analyzed the clinical records from 25 Italian oncology centers for patients aged 18 years or older who had unresectable, locally advanced or metastatic, well-differentiated, grades 1 to 3 enteropancreatic neuroendocrine tumors and received either PRRT or chemotherapy or targeted therapy after experiencing disease progression after treatment with SSAs between January 24, 2000, and July 1, 2020. Propensity score matching was done to minimize the selection bias. Exposures: Upfront PRRT or upfront chemotherapy or targeted therapy. Main Outcomes and Measures: The main outcome was the difference in PFS among patients who received upfront PRRT vs among those who received upfront chemotherapy or targeted therapy. A secondary outcome was the difference in overall survival between these groups. Hazard ratios (HRs) were fitted in a multivariable Cox proportional hazards regression model to adjust for relevant factors associated with PFS and were corrected for interaction with these factors. Results: Of 508 evaluated patients (mean ([SD] age, 55.7 [0.5] years; 278 [54.7%] were male), 329 (64.8%) received upfront PRRT and 179 (35.2%) received upfront chemotherapy or targeted therapy. The matched group included 222 patients (124 [55.9%] male; mean [SD] age, 56.1 [0.8] years), with 111 in each treatment group. Median PFS was longer in the PRRT group than in the chemotherapy or targeted therapy group in the unmatched (2.5 years [95% CI, 2.3-3.0 years] vs 0.7 years [95% CI, 0.5-1.0 years]; HR, 0.35 [95% CI, 0.28-0.44; P < .001]) and matched (2.2 years [95% CI, 1.8-2.8 years] vs 0.6 years [95% CI, 0.4-1.0 years]; HR, 0.37 [95% CI, 0.27-0.51; P < .001]) populations. No significant differences were shown in median overall survival between the PRRT and chemotherapy or targeted therapy groups in the unmatched (12.0 years [95% CI, 10.7-14.1 years] vs 11.6 years [95% CI, 9.1-13.4 years]; HR, 0.81 [95% CI, 0.62-1.06; P = .11]) and matched (12.2 years [95% CI, 9.1-14.2 years] vs 11.5 years [95% CI, 9.2-17.9 years]; HR, 0.83 [95% CI, 0.56-1.24; P = .36]) populations. The use of upfront PRRT was independently associated with improved PFS (HR, 0.37; 95% CI, 0.26-0.51; P < .001) in multivariable analysis. After adjustment of values for interaction, upfront PRRT was associated with longer PFS regardless of tumor functional status (functioning: adjusted HR [aHR], 0.39 [95% CI, 0.27-0.57]; nonfunctioning: aHR, 0.29 [95% CI, 0.16-0.56]), grade of 1 to 2 (grade 1: aHR, 0.21 [95% CI, 0.12-0.34]; grade 2: aHR, 0.52 [95% CI, 0.29-0.73]), and site of tumor origin (pancreatic: aHR, 0.41 [95% CI, 0.24-0.61]; intestinal: aHR, 0.19 [95% CI, 0.11-0.43]) (P < .001 for all). Conversely, the advantage was not retained in grade 3 tumors (aHR, 0.31; 95% CI, 0.12-1.37; P = .13) or in tumors with a Ki-67 proliferation index greater than 10% (aHR, 0.73; 95% CI, 0.29-1.43; P = .31). Conclusions and Relevance: In this cohort study, treatment with upfront PRRT in patients with enteropancreatic neuroendocrine tumors who had experienced disease progression with SSA treatment was associated with significantly improved survival outcomes compared with upfront chemotherapy or targeted therapy. Further research is needed to investigate the correct strategy, timing, and optimal specific sequence of these therapeutic options.

Metastatic paraganglioma and treatment with sunitinib: a case report.

Sunitinib malate is a small kinase inhibitor with activity against a number of tyrosine kinase receptors. We treated a young man suffering from a metastatic paraganglioma with sunitinib. In this report we discuss a number of related questions including the correct dosage, schedules and timing of administration of the molecule, the main side effects and their treatment, and evaluation of the treatment response by CT scan. Treatment with sunitinib started at a dose of 50 mg daily for 4 weeks followed by 2 weeks off (4/2). Because of the side effects, the dose was reduced to 25 mg daily (4/2) and then to 25 mg daily (2/1). This resulted in a significant decrease in the plasma chromogranin A value and the radiological size of the metastases, as well as important clinical improvement. After 6 cycles the treatment was stopped because of a rise in plasma NSE values and disease progression. Sunitinib malate can induce marked toxicity, in which case the daily dose should be reduced and a different schedule of administration adopted. Response evaluation by CT scan should take into account tumor necrosis caused by sunitinib. Sunitinib malate is an interesting molecule for targeted therapy also for advanced neuroendocrine tumors. There has been evidence of significant clinical improvement, as in the case reported here.

Role of somatostatin analogs in the management of neuroendocrine tumors.

Neuroendocrine tumors are rare neoplasms. During the last two decades, somatostatin analogs, exerting their activity through both receptor binding and enzymatic inhibition mechanisms, have been a key option in the management of neuroendocrine tumors. The treatment of neuroendocrine tumors with high doses of somatostatin analogs determined high rates of tumor stabilization, but the dose-response of somatostatin analogs on symptomatic relief and stabilization of tumor growth remains unpredictable. Several studies have indicated a higher efficacy of somatostatin analogs in well-differentiated, low-grade malignancy tumors that express a high density of somatostatin receptors. Synthesis of new, more effective molecules, with different pharmacokinetic profiles, receptor affinity and binding stability, will ease the clinician's tasks and improve patient expectancies in terms of survival and quality of life. Further studies are needed to clarify mechanisms underlying the better antiproliferative effect of higher doses of somatostatin analogs and to determine the optimum dose to saturate specific receptor subtypes.

[Endometriosis of the caecum and ileo-caecal valve. A case report and review of the literature]. / Endometriosi del cieco e della valvola ileo-ciecale: osservazione di un caso e revisione della letteratura.

Endometriosis is a non-cancerous disorder characterised by development of endometrial epithelium outside the uterus, in which involvement of the gastrointestinal tract is most common. The most frequent site is the rectosigmoid colon (72%), whereas the caecum is involved in 4% of cases. Endometriosis may present with abdominal pain, constipation, and sometimes intestinal bleeding. The treatment of the disease is surgical when medical therapy fails and in cases of surgical urgency. We report the case of a patient with bowel obstruction due endometriosis of the caecum and ileo-caecal valve in association with metrorrhagia. A segmentectomy of the right colon was performed. Since endometriosis is more frequent on the left side of the pelvis probably due to regurgitated endometrial cells, the case observed is not very frequent and is worth reporting.

Microsatellite Instability in Medullary Carcinoma of the Colon.

Medullary carcinoma (MC) of the large intestine is a relatively new histological type of adenocarcinoma characterized by poor glandular differentiation and an intraepithelial lymphocytic infiltrate. MC can be associated to a defective mechanism for DNA mismatch repair, caused by the so-called microsatellite instability (MSI). We present the case of a 44 years old Caucasian woman, who referred to the Emergency Room with symptoms mimicking an acute appendicitis. Computed tomography and colonoscopy demonstrated an ulcerated and stenotic lesion of the caecum without signs of metastasis and peritoneal carcinosis. Patient underwent a laparoscopic right colectomy. The final pathologic findings provided the diagnosis of medullary carcinoma with MSI. Patient then underwent adjuvant chemotherapy according to the FOLFOX-4 protocol (association of 5-Fluorouracil, Leucovorin, and Oxaliplatin) for twelve cycles. At two-years follow-up, patient is disease free. MC in association with MSI is a non-frequent tumor of the colon characterized by a better prognosis compared to other types of poorly differentiated adenocarcinoma. In the observed case, 24 months after the surgical operation, the patient is in good health and there is no evidence of metastasis or relapse.

Spontaneous Regression of Primitive Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is a rare, aggressive skin tumor that mainly occurs in the elderly with a generally poor prognosis. Like all skin cancers, its incidence is rising. Despite the poor prognosis, a few reports of spontaneous regression have been published. We describe the case of a 89-year-old male patient who presented two MCC lesions of the scalp. Following biopsy the lesions underwent complete regression with no clinical evidence of residual tumor up to 24 months. The current knowledge of MCC and the other cases of spontaneous regression described in the literature are reviewed.

Clinical experience on eight cases of Merkel cell carcinoma.

Merkel cell carcinoma is a rare neuroendocrine neoplasm of the skin. The tumor most frequently affects elderly patients, with a preference for the head and neck. Eight patients affected by Merkel cell carcinoma have been observed at the General Surgery Unit II of the "Istituti Ospitalieri" hospital in Cremona, each in different stages of the disease; 75% of the cases involved the extremities, and in nearly all of the cases the tumor was nodular in appearance, with an average diameter of 2.2 cm. In 2 cases, the tumor was associated with rheumatoid arthritis, suggesting a dependency on the part of the neoplasm on the immune disorder and on steroid treatment. The available data confirm that in stage I of the disease, surgical treatment should be associated with radiotherapy in order to control the development of local relapses or metastases over time. In this stage, we observed a survival of 34 months (range, 24-48). In stages II and III, survival time falls, with very short duration of responses and poor quality of life as a result of the administration of cytotoxic molecules. Bearing in mind that any local relapse tends to appear within 12 months of the removal of the primitive tumor, that lymph node metastases appear in almost half of the patients, and that metastases over time are manifested in over a third of patients, it is essential to adopt a treatment capable of balancing the demand for longer remissions with a better quality of life. In this situation, we observed that treatment with somatostatin analogues achieves interesting responses without side effects, which suggests a close biological relationship between the tumor and somatostatin and that making a careful assessment of the prognostic factors of the disease can guarantee a correct therapeutic choice.

Diffuse neuroendocrine tumor of the small bowel: an exceptional case with long survival and literature review.

Malignant tumors of the small intestine are uncommon. Carcinoid tumors represent 20% of all malignancies occurring in this segment. We report the case of a 53-year-old female who was treated surgically for intestinal obstruction secondary to carcinoid tumors diffuse to the small intestine. This is the first case described in the literature. Carcinoids are considered less aggressive than the more common intestinal adenocarcinomas, but because of the extensive localization of the neoplasm this case can be considered a high-grade malignancy with an aggressive pattern of growth. Surgical resection, although noncurative in this case, can provide the patient with a long survival rate and a good quality of life.

Merkel cell carcinoma: need for information and awareness. A case series of 47 patients from an Italian website.

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. The clinical experience with this tumor is generally limited. A sample of 47 cases of our series was collected from the website www.neuroendocrini.it. The data on these patients offer some insight into the difficulty of managing MCC as a result of inappropriate therapeutic approaches and neglect of exisiting recommendations, which may lead to poor survival associated with a very low quality of life. We have observed that networks can be useful for information sharing so that the needs of the patient can be met.

Merkel cell carcinoma: a retrospective study on 48 cases and review of literature.

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Fourty-eight patients with MCC were observed at the Rare Hormonal Tumors Group of Cremona Hospital, 15 of these with unknown primary site. Due to rarity of Merkel cell carcinoma, clinical experience is generally limited. Data from our series confirm the current recommendations. Wide surgical excision must be associated with radiotherapy also in early stages in order to avoid local relapse and the rapid progression of disease. In advanced stages chemotherapy is the standard despite the short duration of responses and poor quality of life. The data of our series, characterized by a high demand for second opinion, offer some insight about the real rarity of the tumor, the difficulty of managing of disease in our country secondary to a wrong cultural approach to the problem, the indiscriminate use of molecules unnecessary and often expensive, the lack of protocols, and the presence of guidelines often ignored. This results in very poor survival associated with a very low quality of life, requiring to find the right direction towards a correct management of disease.