Long-term results of PRRT in advanced bronchopulmonary carcinoid.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) for the treatment of neuroendocrine tumours (NET) has been explored for almost two decades, but there are still few trials that have exclusively investigated well-differentiated and moderately differentiated NET arising from the respiratory tree. Thus, the aim of this study was to explore the outcome in patients affected by bronchopulmonary carcinoid (BPC) following PRRT. METHODS: We retrospectively analysed 114 patients with advanced stage BPC consecutively treated with PRRT at the European Institute of Oncology, Milan, from 1997 to 2012 and followed until October 2014. The objective responses, overall survival (OS) and progression-free survival (PFS) were rated, and three different PRRT protocols ((90)Y-DOTATOC vs. (177)Lu-DOTATATE vs. (90)Y-DOTATOC + (177)Lu-DOTATATE) were compared with regard to their efficacy and tolerability. RESULTS: The median OS (evaluated in 94 of the 114 patients) was 58.8 months. The median PFS was 28.0 months. The (177)Lu-DOTATATE protocol resulted in the highest 5-year OS (61.4%). Morphological responses (partial responses + minor responses) were obtained in 26.5% of the cohort and were associated with longer OS and PFS. The (90)Y-DOTATOC + (177)Lu-DOTATATE protocol provided the highest response rate (38.1%). Adverse events were mild in the majority of patients. However, haematological toxicity negatively affected survival. No severe (grade 3/4) serum creatinine increase was observed. Patients treated with (90)Y-DOTATOC alone more frequently showed a mild/moderate decrease in renal function. In patients treated with chemotherapy before PRRT had a shorter OS and PFS, and a higher risk of developing nephrotoxicity. CONCLUSION: In a large cohort of patients with advanced BPC treated in a "real-world" scenario and followed up for a median of 45.1 months (range 2-191 months), PRRT proved to be promising in prolonging survival and delaying disease progression. Despite the potential selection biases, considering the risk-benefit ratio, (177)Lu-DOTATATE monotherapy seems the best option for PRRT. Our results indicate that the use of PRRT in earlier stages of the disease could provide a more favorable outcome.

[Laryngeal Atypical Carcinoid Combined with Squamous Cell Carcinoma: A Case Report].

The primary laryngeal atypical carcinoid is relatively rare, and the tumor combined with other histologic types including squamous cell carcinoma is extremely rare. We experienced a case which was complicated with atypical carcinoid and squamous cell carcinoma. A 79 years old man complaining of sputum was admitted to Hiroshima City Hospital. A tumor was seen in over the right glottis and the right vocal fold was fixed. Squamous cell carcinoma was diagnosed based on a biopsy harvested under laryngoscopy. Imaging studies (CT, MRI) were done. The primary tumor was in the right aryepiglottic fold, and one swollen lymph node was found in level 2 (right side). Based on the findings, the stage was T3N1M0. We performed a total laryngectomy and right neck dissection. Atypical carcinoid and squamous cell carcinoma were detected in the same tumor. There were two lymph node metastases, both of which were atypical carcinoid metastases. Postoperative irradiation was provided. It is now 4 years since the operation, but the patient lives without relapse and metastasis of this disease.

[Neuroendocrine tumors: analysis of 252 cases].

OBJECTIVE: To investigate the epidemiology, diagnosis, and treatment status of neuroendocrine tumors (NETs) in our hospital. METHODS: Medical records of 252 patients with neuroendocrine tumors diagnosed and treated in our hospital from January 1, 2004 to December 31, 2009 were collected and retrospectively reviewed in this study. The clinicopathological data including age of onset, initial symptoms, primary site, pathological conditions (Sny, CgA, Ki-67), disease stage at diagnosis, treatment, and follow up were analyzed. RESULTS: The gender ratio M/F of the 252 cases was 1.9:1, with mean age of 55.2 years, and the high incidence was in age of 60-69 years. The tumors were located in the gastrointestinal tract (117 cases, 46.4%), broncho-pulmonary system (74 cases, 29.4%), other sites (61 cases, 24.2%) and unknown primary site (2 cases, 0.8%). Their first clinical symptoms vary, depending on the primary site. The common symptoms of primary rectal NETs were changes in bowel habits (29.3%) and diarrhea or constipation (17.5%), and most gastric NETs presented epigastric discomfort (86.4%). Most patients (71.4%) were diagnosed with stage I, II, III disease. Among the 252 cases, there were 110 carcinoids (43.7%), 108 neuroendocrine carcinomas (42.9%), 23 atypical carcinoids (9.1%), five neuroendocrine tumors (2.0%), four Merkel cell tumors (1.6%), and two composite carcinoids (0.8%). 206 patients (81.7%) received surgery, 39 (15.5%) received chemotherapy, and 31 cases (12.3%) were treated by palliative radiotherapy. CONCLUSIONS: This single-center retrospective analysis of data demonstrated that males have a higher incidence rate than females. The most common primary sites of NETs are the digestive tract and lungs. The initial symptoms of NETs are different depending on their primary sites. Good prognosis can be achieved in the majority of patients after surgery, chemotherapy and palliative radiotherapy.

¹¹¹In-DTPA°-octreotide (Octreoscan), ¹³¹I-MIBG and other agents for radionuclide therapy of NETs.

This paper is a critical review of the literature on NET radionuclide therapy with (111)In-DTPA(0)-octreotide (Octreoscan) and (131)I-MIBG, focusing on efficacy and toxicity. Some potential future applications and new candidate therapeutic agents are also mentioned. Octreoscan has been a pioneering agent for somatostatin receptor radionuclide therapy. It has achieved symptomatic responses and disease stabilization, but it is now outperformed by the corresponding ß-emitter agents (177)Lu-DOTATATE and (90)Y-DOTATOC. (131)I-MIBG is the radionuclide therapy of choice for inoperable or metastatic phaeochromocytomas/paragangliomas, which avidly concentrate this tracer via the noradrenaline transporter. Symptomatic, biochemical and tumour morphological response rates of 50-89%, 45-74% and 27-47%, respectively, have been reported. (131)I-MIBG is a second-line radiopharmaceutical for treatment of enterochromaffin carcinoids, mainly offering the benefit of amelioration of hormone-induced symptoms. High specific activity, non-carrier-added (131)I-MIBG and meta-astato((211)At)-benzylguanidine (MABG) are tracers with potential for enhanced therapeutic efficacy, yet their integration into clinical practice awaits further exploration. Amongst other promising agents, radiolabelled exendin analogues show potential for imaging and possibly therapy of insulinomas, while preclinical studies are currently evaluating DOTA peptides targeting the CCK-2/gastrin receptors that are overexpressed by medullary thyroid carcinoma cells.

68Ga-DOTA-NOC PET and peptide receptor radionuclide therapy in management of bilateral ovarian metastases from gastrointestinal carcinoid.

The management of neuroendocrine tumours is challenging when curative surgery is ruled out because of distant metastases. We report a case of gastrointestinal carcinoid with bilateral ovarian metastases in a 50-year-old female who received octreotide therapy followed by peptide receptor radionuclide therapy and surgery thereafter. Somatostatin receptor expression on neuroendocrine tumours has implications in diagnosis and therapy. (68)Ga-DOTA-NOC PET is a recent advancement in the field of somatostatin receptor imaging. The lesions which demonstrate tracer uptake on positron emission tomographic studies can be further planned for treatment with octreotide and (177)Lu-DOTA-TATE. The case in discussion responded well to non-invasive treatment options before proceeding to definitive surgical management.

Carcinoid tumor metastatic to the tarsal conjunctivae.

A 64-year-old woman who had been diagnosed with carcinoid tumor of the large intestine over a decade earlier presented with an acute right periorbital inflammatory reaction. On examination, 2 disc-shaped, gelatinous masses were noted on the right upper and lower tarsal conjunctivae. Excisional biopsies of these masses revealed metastatic carcinoid tumor. Her total burden of metastatic carcinoid tumor continued to increase during 2 years of follow-up, with new metastatic foci in the right choroid, in the left upper and lower eyelids, and subcutaneously in the neck and chest. Despite a comprehensive treatment approach including radionuclide therapy with the somatostatin peptide analog, Y-DOTATOC, the patient succumbed to the disease and died. The authors report an unusual case of a gastrointestinal carcinoid tumor metastatic to the tarsal conjunctivae, eyelids, choroid, and orbit.

[A case of pancreatic well-differentiated neuroendocrine carcinoma surviving 8 years and 5 months with treatments for multiple liver tumors diagnosed as carcinoid tumor].

The case was a 58-year-old woman who visited our hospital for a thorough examination after multiple liver tumors were found in her at a nearby hospital. By liver tumor biopsy, we diagnosed them as carcinoid. Bone scintigraphy showed an abnormal accumulation in the external left scapula and in both of her hip joints, but the primary lesion was unclear. She died 8 years and 5 months after disease onset from deterioration of liver lesions, inspite of our treatments, such as gemcitabine administration of systemic chemotherapy, transcatheter arterial chemoembolization for liver lesions, and radiation therapy for bone lesions. Pathological anatomy suggested a pancreatic, well-differentiated neuroendocrine carcinoma.

[Atypical carcinoid of the larynx. Case report and review of literature]. / Atypisches Karzinoid des Larynx. Fallbericht und Literaturübersicht.

BACKGROUND: With an incidence of over 90%, squamous carcinomas are the most frequent laryngeal malignancies. Laryngeal neuroendocrine tumors appear only in approximately 1%. These are aggressive tumours with a high rate of metastases. To date, no diagnosis or treatment guidelines have been established for this entity. CASE REPORT: We describe the case of a 63-year-old man complaining of dysphagia and intermittent hoarseness. Initial laryngoscopy showed a tumour at the laryngeal epiglottic surface. Staging demonstrated an atypical carcinoid tumour with local lymph-node metastasis. At 24 months following revision surgery with safety distance, elective bilateral neck dissection and adjuvant radiotherapy the patient is free of complaints and recurrence. CONCLUSION: In atypical carcinoid tumours total resection as well as bilateral neck dissection should be performed, even in cN0 cases. In the presence of cervical lymph node metastases adjuvant radiotherapy is indicated.

Abscopal effect in pulmonary carcinoid tumor following ablative stereotactic body radiation therapy: a case report.

BACKGROUND: The abscopal effect was described as early as the 1950s, when untreated tumors demonstrated a response after radiation therapy was delivered to an untreated, distant site. The mechanisms underlying this global response to otherwise localized therapy remain unknown, though there is increasing evidence that increased antigen expression following ablative radiotherapy may play a role. CASE PRESENTATION: We report a case of a 69-year-old African American woman with a history of metastatic typical pulmonary carcinoid with multiple lung nodules who had a significant decrease in size of an untreated left upper lobe nodule after stereotactic body radiation therapy to an oligoprogressive left lower lobe lesion. CONCLUSIONS: To our knowledge, this report describes the first case of an abscopal effect in a typical pulmonary carcinoid. Further research is needed regarding the mechanisms responsible for this finding and the role of combining radiation therapy and cancer immunotherapy in patients with pulmonary carcinoid tumors.

Octreotide for resuscitation of cardiac arrest due to carcinoid crisis precipitated by novel peptide receptor radionuclide therapy (PRRT): A case report.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for metastatic carcinoid tumours but can precipitate a carcinoid crisis through release of stored bioamines. Cardiac arrest is an uncommon manifestation of carcinoid crisis and has never been reported as a complication of PRRT. We report a case of a 58-year old female who suffered from cardiac arrest following PRRT for metastatic carcinoid tumour. She was successfully resuscitated using intravenous octreotide following 22 min of failure to resuscitate with a standard advanced cardiac life support protocol. Following resuscitation, severe carcinoid heart disease was diagnosed, and the patient subsequently underwent successful surgical valve replacement. Although there is no trial evidence, considering pharmacological rationale and successful outcome in this case, we suggest early administration of intravenous octreotide during resuscitation of patients suffering cardiac arrest post PRRT for carcinoid disease and recommend preventive strategies.

Peptide Receptor Radionuclide Therapy for Patients With Advanced Lung Carcinoids.

Neuroendocrine neoplasms (NEN) are a family of malignancies of diverse origin, including the lung, gastrointestinal tract, and pancreas. Lung NEN include well differentiated neuroendocrine tumors (NET) classified as typical carcinoids or atypical carcinoids, and poorly differentiated neuroendocrine carcinomas classified as small-cell lung carcinoma or large-cell neuroendocrine carcinoma. According to a recent analysis of a large, population-based registry, approximately one-third of all patients with lung typical/atypical carcinoids have distant metastases at diagnosis, and median survival for these patients is 24 months. At present, only 1 therapy is approved by the US Food and Drug Administration (FDA) for patients with advanced lung typical/atypical carcinoids, everolimus, indicating a clear need for more treatment options in this patient population. Although not yet supported by results from randomized prospective trials, somatostatin analogues are considered an acceptable treatment option for patients with lung typical/atypical carcinoids expressing somatostatin receptors. Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE was recently approved by the FDA for the treatment of gastroenteropancreatic NET; however, the role of PRRT in patients with lung typical/atypical carcinoids remains unclear, because they were not included in the pivotal NETTER-1 (Neuroendocrine Tumors Therapy) trial. Herein we provide a comprehensive review of the available clinical evidence for efficacy and safety of PRRT in patients with lung typical/atypical carcinoids. On the basis of the preliminary evidence of efficacy and the consistent safety profile in this patient group, we propose that experienced multidisciplinary NET teams may consider PRRT alongside everolimus as an option for patients with advanced somatostatin receptor-positive lung typical/atypical carcinoids whose disease is progressing during first-line treatment with somatostatin analogues.

Treatment of early stage thymic tumors: surgery and radiation therapy.

Tumors of the thymus are an uncommon entity, constituting 30% and 15% of anterior mediastinal masses in adults and children, respectively. The majority of these tumors are thymomas, with thymic carcinomas less common, and thymic carcinoids exceedingly rare. Recognition of the distinct clinicopathologic behavior of various thymic neoplasms is crucial to providing optimal treatment. Evidence guiding the treatment of early stage thymic tumors is limited secondary to the low incidence and resulting lack of randomized data. Proper management requires a careful analysis of the available literature with particular attention paid to limitations of the existing studies. This article provides a discussion of the presentation, evaluation, diagnosis, surgical techniques, and treatment outcomes relevant to early stage thymomas, thymic carcinomas, and thymic carcinoid tumors. The role of radiation therapy in the management of early stage thymic tumors remains controversial and is discussed in detail.

Comparison of [177Lu-DOTA0,Tyr3]-octreotate and [177Lu-DOTA0,Tyr3]-octreotide for receptor-mediated radiation therapy of the xenografted human midgut carcinoid tumor GOT1.

The aim of this study was to compare the tumor uptake versus time and the tumor response in nude mice transplanted with a human midgut carcinoid (GOT1), when treated with either [(177)Lu-DOTA(0),Tyr(3)]-octreotide or [(177)Lu-DOTA(0),Tyr(3)]-octreotate and to evaluate if plasma chromogranin A (P-CgA) was a reliable marker of tumor response. The tumor uptake and retention of activity of a single intravenous (i.v.) dose (15 MBq) of [(177)Lu-DOTA(0),Tyr(3)]-octreotate or [(177)Lu-DOTA(0),Tyr(3)]-octreotide were compared in nude mice xenografted with GOT1. The activity concentration 24 hours after injection was significantly higher in animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotate versus [(177)Lu-DOTA(0),Tyr(3)]-octreotide (16%+/-1.4% of injected activity per gram [%IA/g] vs. 8.1%+/-2.1% IA/g, mean +/- standard error of the mean) (p=0.00061). The mean absorbed dose was higher in animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotate (46+/-4.3 vs. 17 +/- 3.4 Gy). The reduction of tumor volume was accordingly more prominent in animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotate than in animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotide (p=0.003). The mean tumor volume for animals given [(177)Lu-DOTA(0),Tyr(3)]-octreotate was reduced to 3% of its initial value. P-CgA values were strongly correlated with tumor volume. Octreotate seems to be a more suitable somatostatin analog than octreotide for receptor-mediated radiation therapy. P-CgA is a simple, accurate method for the estimation of tumor response in this animal model.

Primary well differentiated neuroendocrine tumor of the filum terminale. Case report and literature review. / Tumor neuroendocrino bien diferenciado intradural-extramedular primario del filum terminale. Presentación de un caso y revisión de la literatura.

OBJECTIVE: To present a case of a well-differentiated primary intradural-extramedullary neuroendocrine tumor of the filum terminale and to conduct a literature review. CASE: A 68-years old patient was assessed after presenting lower back pain and sciatica with ineffective pain relief. The patient presented an intradural-extramedullary lumbar lesion arising from the filum terminale, which was partially resected. The pathology diagnosis was a well-differentiated primary neuroendocrine tumor (carcinoid tumor). After a multidisciplinary evaluation, fractionated stereotactic radiotherapy was administered. No progression or metastatic spread was observed in successive assessments. DISCUSSION: Neuroendocrine tumors are heterogeneous neoplasms derived predominantly from enterochromaffin cells, in which chemotherapy plays a very limited role. In contrast, radiotherapy has been described in partially resected lesions. CONCLUSION: Well-differentiated primary neuroendocrine tumors with intradural-extramedullary lumbosacral location are an exceptional rarity. Isolated surgical resection, or associated with an adjuvant radiotherapy treatment in subtotal resections, could be considered an effective therapeutic strategy.

Carcinoid syndrome and carcinoid crisis secondary to a metastatic carcinoid tumour of the lung: a therapeutic challenge.

We describe a 53-year-old male patient, with a known history of metastatic carcinoid tumour of the lung, who developed a variety of symptoms of the carcinoid syndrome and subsequently a carcinoid crisis. Although bronchial carcinoid tumours are very rarely associated with symptoms of the carcinoid syndrome, a subset may develop a severe hypersecretory syndrome and exhibit an aggressive behaviour. In cases with excessive tumour load and difficult-to-control hypersecretory syndrome, management by a specialized multidisciplinary team using evidence-based regimens is mandatory to deal with the life-threatening carcinoid crisis, to improve patients' outcome and quality of life.

Severe toxicity after permanent radioactive seed implantation for mediastinal carcinoid tumors.

PURPOSE: Permanent implantation of 125I seeds may be used when uninvolved surgical margins are unobtainable or close. Two cases of mediastinal carcinoid tumors with prior chemoradiation had tumors adherent to esophageal muscularis. Both underwent intraoperative permanent seed implantation and developed esophageal fistulas requiring surgical correction. METHODS AND MATERIALS: Custom permanent 125I seed mesh implants were fashioned intraoperatively in a geometrically coherent pattern. The implants were directly sutured to the partially resected esophageal wall. The postimplant CT scans were fused with the postfistula scans to provide dosimetric information at the fistula site. Doses were calculated from time of insertion to time of fistula formation. Neither patient showed evidence of disease recurrence at the time of fistula repair. RESULTS: Patient 1 developed an esophageal-pleural fistula 83 days after seed implantation. Patient 2 developed a broncho-pleural fistula 300 days after seed implantation. CONCLUSIONS: These cases demonstrated that implantation in the setting of extensive subcarinal space dissection and partial esophageal wall resection could cause fistula formation and the need for additional surgery. The high mucosal dose, despite the relatively low activity implant, was due to lack of geometric sparing of the mucosa. We recommend that extensive subcarinal space dissection be considered a contraindication to permanent seed implantation.

Effects of treatment with (177)Lu-DOTA-Tyr(3)-octreotate on uptake of subsequent injection in carcinoid-bearing nude mice.

PURPOSE: The aim of this study was to analyze the effect therapeutic injections of (177)Lu-DOTA(0)-Tyr(3)]-octreotate (DOTATATE) had on the tumor uptake of a subsequent injection with (111)In-DOTATATE in GOT1-bearing nude mice. METHODS AND MATERIALS: Nude mice, xenografted with the human midgut carcinoid, GOT1, were first intravenously injected with a curative (30 MBq) or a suboptimal (7.5 MBq) amount of (177)Lu-DOTATATE. At various intervals thereafter (4-13 days), a second injection with (111)In-DOTATATE (0.5 MBq) was given. One (1) day after the second injection, the animals were sacrificed, tumor tissues collected, the tumor (111)In and (177)Lu activity concentration determined, and tumor regression/cell density was recorded. RESULTS: In animals given curative amounts, the uptake of (111)In was lower than in untreated animals. On the other hand, a second late injection (3-13 days) after suboptimal amounts resulted in a twofold higher tumor activity concentration versus untreated animals. When the uptake of the curative injection was corrected for tumor cell density, which decreased from 66% to 4% over 2 weeks, an enhanced uptake per tumor cell was observed. The curative and suboptimal amounts resulted in a different uptake and retention of (177)Lu in tumors. The suboptimal amount resulted in a constant activity concentration, while the curative amount resulted in an increased activity concentration over time. CONCLUSIONS: Our results, as presented in this paper, describe how the second injection in a fractionation protocol will be affected by the first therapeutic amount. This new information might be useful in the optimization of radionuclide therapy.

Orbital carcinoid metastases.

OBJECTIVE: To describe a series of patients with metastatic orbital carcinoid tumors. DESIGN: Retrospective case series and literature review. PARTICIPANTS AND METHODS: Patients were identified from the orbital database and pathology records at Moorfields Eye Hospital. Records were evaluated for age at presentation, race, gender, laterality, visual function and clinical features, site of orbital metastasis, treatment, and outcome. The site of the primary tumor, presence of systemic symptoms, diagnosis and treatment of the primary tumor, and current survival status were also noted. MAIN OUTCOME MEASURES: Time from tumor to death. RESULTS: Thirteen patients (9 male) had an average age at biopsy-proven diagnosis of 65.3 years. The primary tumor was ileal in 7, colonic in 4, and from bronchus and breast (1 each); in 9 patients, the primary tumor was already known. Eleven of the 13 patients had noted a mass, 8 had diplopia, 3 had reduced vision, and only 2 had orbital pain. One patient presented with visual hallucinations. Imaging showed single muscle enlargement in 7 patients, a discrete mass in 5, and diffuse fat infiltration in 1 patient. Six patients underwent a meta-iodobenzyl guanidine/octreotide scan and metastatic disease was found in 4. Four patients underwent exenteration, 5 had radiotherapy after tumor debulking, 2 had radiotherapy alone, and 2 patients had local radiotherapy with receptor-targeted chemotherapy. Seven patients died from metastatic tumor. Kaplan-Meier analysis showed a 5-year survival rate of 72% and a 10-year survival rate of 38%. Comparison of the current series with other published series shows a significant difference (improvement) in survival at 5 years (P = 0.027) but not at 10 years (P = 0.08). CONCLUSIONS: The largest published series of orbital carcinoid tumors is presented, there being a recent trend towards less aggressive surgical management and probably a greater survival rate.