Therapy for Locoregional Disease: Bronchi

Overview Central endobronchial carcinoid represents often the subtype characterised by the least aggressive behaviour in the entire spectrum of differentiation of neuroendocrine tumours of the lung. Being central, they became generally early symptomatic and therefore is not unfrequent, an early diagnosis when their diffusion is still locoregional. As is well known, WHO Classification [1] subdivides carcinoid on the basis of the mitotic count and the presence or lack of necrosis in typical (TC) and atypical (AC). It should be remarked that these tumours, although may have an indolent biological behaviour, are not benign and even the lower-grade TC may be associated with a haematogenous and lymphatic spread. Therefore the therapeutic approach, either surgical, interventional endoscopic or medical, requires always a careful multidisciplinary planning at the light of the distinctive peculiarities of these subcategories. Finally, an accurate and extensive follow-up plays a crucial role even in the cases apparently radically cured. This chapter will review, starting from the clinics of two evidence-based practice cases, the therapeutic options available for locoregional bronchial carcinoids in a multidisciplinary settin

Surgical treatment of neuroendocrine tumors of the lung

Objective: This report reviews the pattern of neuroendocrine (NE) differentiation, lymph-node involvement, extension of surgery, and survival in 125 NE lung tumor patients. Methods: Standard diagnostic workup included CT scan, bronchoscopy, bronchial biopsy or Fine Needle Aspiration Biopsy, 111In-pentetreotide scan (OctreoScan) and mediastinoscopy in selected patients. NE differentiation was assessed based on the morphology and immunohistochemical reactivity for pan-neuroendocrine markers NSE, CGA, and Synaptophysin. For small cell carcinoma (SCC), only clinical stage I and II patients underwent surgery. Several different surgical procedures were utilized, from limited resections to lobectomy, pneumonectomy, and bronchoplastic procedures. Survival was assessed using Kaplan-Meyer method at 5 years. Results: There were 79 typical carcinoid (TC), eight atypical carcinoid (AC), 18 large cell carcinoma (LCC) and 20 SCC patients. Mean age at diagnosis was 54.6\ub115.2 (ranges from 16 to 77 years) for TC, 68.5\ub19.1 (range 53-81) for AC, 68.7\ub14.6 (range 58-77) for LCC, 64.6\ub17.9 (range 48-82) for SCC. Male/female ratio was 1/1 for TC and AC, 2.6/1 for LCC and 9/1 for SCC. Lymph-node involvement was present in 14% of TC, 0% of AC, 31.5% of LCC, and 45% of SCC. Cancer specific survival was 96% for TC, 87.5% for AC, 37.5% for LCC, and 30% for SCC at 5 years from surgery. Presenting symptoms were invariably of respiratory-related. None had the carcinoid syndrome. History of tobacco abuse ranged from 46% for TC to 100% in SCC. Survival ranged from a minimum of 1 month for SCC to a maximum of 168 months with no evidence of disease for TC. Synchronous multicentric forms were found in 14% of TC. Twenty-one percent (4/19) of the patients with SCC treated by induction therapy and surgery, and in few cases by surgery and adjuvant chemotherapy are alive without the evidence of the disease for 5 years. Conclusions: Due to the high percentage of lymph-node involvement and multicentric forms found in our series lobectomy with radical lymph-node dissection appears, in our opinion, the most appropriate surgical treatment in well-differentiated forms, while more limited resection appears sub-optimal. Also, due to the finding of recurrences many years after surgery, the follow-up must be accurate and protracted in this subgroup. Only Small Cell Lung Carcinoma patients in clinical stage I and II underwent surgery with good long-term results. \ua9 2004 Elsevier B.V. All rights reserved

Multidisciplinary management of advanced lung neuroendocrine tumors

The optimal clinical management of aggressive/advanced lung neuroendocrine tumors (NETs) is still debated, due to their rarity and the lack of prospective randomized studies. Results derive from retrospective mono-Institutional series, and few dedicated prospective trials, recently designed, are still ongoing. In low-grade tumors [bronchial carcinoids (BCs)] surgery, whenever feasible, remains the mainstay of treatment, and chemo/radiotherapy (RT) should be reserved to progressive diseases (PD). In case of resected N1-N2 BCs, a “watch and see” policy associated with a close clinical/radiological follow-up is recommended. Somatostatin analogs (SSA) seem to be effective in controlling BCs associated endocrine syndromes, while SSA antiproliferative effect has also been reported in the past. Targeted therapy with new drugs (Everolimus) seems to be very promising, but further trials are needed. Surgery alone is not sufficient to treat high-grade NETs: adjuvant CT is required also in early stages. Platinum-Etoposide regimen demonstrated to be the most effective; irinotecan and other biological drugs are considered very promising. In conclusion, the management of advanced lung NETs should be individualized by multidisciplinary teams which include Medical and Radiation Oncologists, Surgeons, Pathologists, Pulmonologists, Endocrinologists, Interventional Radiologists, and the prognosis is mainly dependent on tumor grade and its anatomical extent

Cinacalcet therapy in patients affected by primary hyperparathyroidism associated to Multiple Endocrine Neoplasia Syndrome type 1 (MEN1)

Primary hyperparathyroidism is the main endocrinopathy associated with Multiple Endocrine Neoplasia type 1 syndrome. Cinacalcet is a calcimimetic agent licensed for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease, and for the reduction of marked hypercalcemia in patients with parathyroid carcinoma and sporadic hyperparathyroidism requiring surgery but for whom parathyroidectomy is contraindicated. It may provide a medical alternative for the management of primary hyperparathyroidism in subjects affected by Multiple Endocrine Neoplasia type 1. In this longitudinal, intervention study, 33 MEN1 patients had been enrolled, 10 males and 23 females with a mean age of 40 ± 11.9 years, range 20-63. Primary hyperparathyroidism was the first clinical manifestation in 12 patients. All subjects commenced with Cinacalcet 30 mg/day, 22 patients starting therapy with calcimimetics as an alternative to surgery, and 11 patients opting for the medication after the onset of persistent post-surgical primary hyperparathyroidism. Duration of follow-up was 12 months. The results of this study show significant reductions in serum calcium. The changes in hormonal secretions of pituitary and gastroenteropancreatic glands were not significant, demonstrating the overall safety of this drug in this disease. Cinacalcet has been well tolerated by 28 patients, whereas five individuals complained of heartburn and grade 1 nausea, which did not prevent the completion of the study. In conclusion, Cinacalcet has resulted to be well tolerated and safe in patients with MEN1 syndrome and the calcium homeostasis was stabilized

The antiproliferative effect of pasireotide LAR alone and in combination with everolimus in patients with medullary thyroid cancer: a single-center, open-label, phase II, proof-of-concept study

Purpose: Medullary thyroid cancer (MTC) is a neuroendocrine tumour of the thyroid C cells. Pasireotide, a multi-receptor targeted somatostatin analogue, and everolimus, an inhibitor of mTOR, showed antitumour properties in neuroendocrine tumours. Aim of this study was to evaluate pasireotide alone and in combination with everolimus in patients with MTC. Methods: Patients with progressive metastatic or persistent postoperative MTC received pasireotide LAR 60 mg/m for at least 6 months. Patients exhibiting progressive disease received everolimus 10 mg/d as combination therapy. Primary endpoint was progression free survival (PFS). Secondary endpoints included, overall survival, objective response rates, change in circulating markers, safety. Study registration no. NCT01625520. Results: Nineteen consecutive patients were enrolled. Median follow-up was 31 months. Median PFS with pasireotide was 36 months (95% CI: 19.5\u201352.5). Nine patients (47%) had tumour progression: seven of them started everolimus in combination with pasireotide, achieving a median PFS of 9.0 months (95% CI: 0\u201321.83). Five of them (71%) had further tumour progression, one objective response (14.3%), one stopped treatment because of pulmonary embolism. Pasireotide alone and with everolimus was safe and required withdrawal only in one case. Diarrhoea and hyperglycaemia were the most frequent adverse events with pasireotide (grade 3 in 5.3% each). Hyperglycaemia was the most frequent grade 3 toxicity with the combination therapy (28.6%). Conclusions: Pasireotide therapy shows antiproliferative effects in persistent postoperative MTC suggesting further investigation on larger series of patients. In progressive MTC lesions, the combination pasireotide plus everolimus may be of benefit. Both schemes were safe and well tolerated

Risk factors of type 1 gastric neuroendocrine neoplasia in patients with chronic atrophic gastritis. A retrospective, multicentre study

The aim of this retrospective study was to evaluate the presence of risk factors for a type 1 gastric neuroendocrine neoplasia in a large cohort of patients with chronic atrophic gastritis. The study design consisted of an Italian multicentre, retrospective analysis. The study included all consecutive patients with chronic atrophic gastritis with or without type 1 gastric neuroendocrine neoplasias followed at the participating centres. Two hundred and twenty-nine patients with chronic atrophic gastritis were enroled at the participating centres. A total of 207 patients (154 female, 53 males, median age: 56.0 years) were included in the final analysis. One hundred and twenty-six patients had chronic atrophic gastritis without a gastric neuroendocrine neoplasia and 81 had a chronic atrophic gastritis with type 1 gastric neuroendocrine neoplasia. The median Chromogranin A level, evaluated in 141 patients, was 52.0 U/L. At upper gastrointestinal endoscopy, atrophy of the gastric mucosa was mild/moderate in 137 patients and severe in 68. Intestinal metaplasia of the corpus was present in 168 patients. At histological examination, 81 patients had a gastric neuroendocrine neoplasia (42 patients had a NET G1 and 33 a NET G2). The median Ki67 index was 2.0 %. At univariate and multivariate analysis, the risk factors for a gastric neuroendocrine neoplasia were: male gender, chromogranin A greater than 61 U/L, presence of intestinal metaplasia and age equal to or greater than 59 years. Chromogranin A greater than 61 U/L, the presence of intestinal metaplasia and male gender were independent risk factors for a type 1 gastric neuroendocrine neoplasia in patients with chronic atrophic gastritis

Clinical management of patients with gastric neuroendocrine neoplasms associated with chronic atrophic gastritis: a retrospective, multicentre study

To provide data regarding clinical presentation, pathological features, management, and response to different treatments of patients with type I gastric neuroendocrine tumors in stages 0-2A. The study design consist of an Italian multicentre, retrospective analysis of patients with type I gastric neuroendocrine tumors managed with different therapeutic approaches: surgery, endoscopic surveillance, endoscopic resection, or somatostatin analog therapy. Among the 97 patients included, 3 underwent surgery, 45 (46.4%) radical endoscopic resection of the neoplastic lesions, 13 (13.4%) follow-up with upper endoscopy, and 36 (37.1%) somatostatin analog therapy. At the end of the follow-up, all patients were alive and there was no evidence of metastatic disease. Somatostatin analog therapy resulted in a complete response in 76.0% of the patients and stable disease in 24.0%. A prolonged period of therapy, the use of a full dose of somatostatin analogs and higher gastrin levels at diagnosis were related to a complete response to the therapy. The recurrence rate was 26.3% in patients treated with somatostatin analog therapy and 26.2% in patients treated with endoscopic resection, without a statistically significant difference in terms of disease-free survival. Regarding recurrence of the disease, no statistical difference was found according to type of therapy, number of neoplastic lesions, and 2010 WHO classification. The only risk factor for tumor recurrence was a short period of medical treatment. In conclusion, our study suggested that endoscopic surveillance, endoscopic resection and somatostatin analog therapy represent valid options in the management of patients with type I gastric neuroendocrine tumors in stages 0-2A

Proceedings of the IASLC International Workshop on Advances in Pulmonary Neuroendocrine Tumors 2007.

International audienceThe International Association for the Study of Lung Cancer, (IASLC) International Congress on Advances in Pulmonary Neuroendocrine Tumors was a two-day meeting held at the Royal Brompton Hospital in London, United Kingdom on the thirteenth and forteenth of December 2007. The meeting was led by 14 member international faculty-in the disciplines of pathology, surgery, medicine, oncology, endocrinology, nuclear medicine, diagnostic imaging, and biostatistics. The aims were twofold, as an educational meeting, and to develop the IASLC International Pulmonary Neuroendocrine Tumors Registry. The meeting highlighted the difference in presentation of the tumors, management options for early and advanced stage disease including the use of novel agents and approaches. The need, process, and approach to an International Registry of Pulmonary Neuroendocrine Tumors were emphasized. International collaboration to develop a retrospective registry, prospective data collection, virtual tissue bank, and collaborative clinical trials were universally agreed as the best way to advance our understanding and treatment of these rare tumors