Metastatic Carcinoid Tumor Research Articles

Low plasma tryptophan in carcinoid patients is associated with increased urinary cortisol excretion

Previously we observed in patients suffering from a metastatic carcinoid tumor that irritability, aggression and lack of impulse control are associated with low levels of plasma tryptophan and presumably with low brain serotonin function. In rats we showed that a diet of low tryptophan resulted in higher stress responses and higher corticosterone production. Here we tested in carcinoid patients whether tryptophan depletion due to tumor 5-HT overproduction is associated with high cortisol production. Urinary excretion of cortisol, serotonin, 5-hydroxyindole acetic acid (the main metabolite of serotonin a marker of tumor activity), plasma levels of tryptophan and platelet content of serotonin (index of peripheral serotonin synthesis) were determined in metastatic midgut carcinoid patients. Patients (N = 25) were divided into two groups based on their plasma tryptophan levels (< or = 25 micromol/l, n = 12 and > or = 49 micromol/l, n = 13). Carcinoid patients with low plasma tryptophan levels had significantly higher urinary excretion of free cortisol (p < 0.01), independent of tumor activity. The inter-individual differences in the low tryptophan group, however, were substantial. In a subgroup of the patients suffering from metastatic carcinoid disease the cerebral access of plasma tryptophan is impaired, thus rendering cerebral serotonin neurotransmission suboptimal and leading to hypercortisolism. The present study provides further support to the idea that low serotonergic function is a risk for developing stress-associated psychopathology.

Metastatic carcinoid tumour (MCT): 20 years experience at the Queen Elizabeth Hospital. Does management by a medical oncology unit (MOU) improve outcome?

15581 Background: MCTs have unique treatment approaches and often have an indolent course. Until recently, data on survival and treatment outcome was limited by the infrequent nature of these tumors. We aim to retrospectively assess the impact of care by a MOU (as a measure of active multidisciplinary intervention) on patient outcome. Methods: Patients diagnosed with carcinoid tumors at the QEH/LMH after 1/1/1985 were identified from the SA cancer registry. For patients with MCT the following data was collected; histology, primary site, treatment and survival. Patients with MCT were classified into two groups; those managed by a MOU, and those managed by an alternative specialist (other). The characteristics and outcomes of these groups were compared. Results: 90 patients with carcinoid were identified; mean age = 63, M/F=50/40. The primary site of disease (MCT v local) was: small bowel 54% v 20%, lung 2% v 30%, large bowel 17% v 2%, appendix 0% v 18%. Of the patients with MCT (n=46), 25 were referred to a MOU. The median age for MOU v other was 62 v 75 yrs. Treatment received by the two groups (MOU v other) was; octreotide LAR (76% v 10%), resection of primary tumor (76% v 86%), liver resection (4% v 5%), chemotherapy (8% v 0%), and MIBG (12% v 5%). The median time from diagnosis to commencement of octreotide LAR was 19.6 mths for functional MCT, with >50% reduction in 5HIAA to initial treatment in 79% of patients and no deaths in responders. Median overall survival (MOU v other) was 112 mths v 32 mths (HR 3.07 (1.43 - 7.65), p=0.005), and 10yr survival was 40% v 17%. Survival increased with octreotide LAR use (112 mths v 53 mths, p=0.017) and resection of primary (93 mths v 21 mths, p=0.02). Using Cox proportional hazards regression analysis, age at diagnosis and site of primary disease did not significantly affect survival. The impact of year of diagnosis on outcome will be presented. Conclusions: This single centre experience suggests active multidisciplinary intervention improves survival. Patients not seen in a MOU received minimal observation and few received octreotide LAR. Outcome may reflect referral bias, as referral to a MOU increased in the past 10 years, when more interventions have become available. No significant financial relationships to disclose.

Phase I first-in-human study of s-trans, trans-farnesylthiosalicylic acid (salirasib) in patients with solid tumors

3536 Introduction: S-trans, trans-farnesylthiosalicylic acid (FTS, salirasib) is an oral synthetic small molecule with potent inhibitory properties against oncogenic Ras, which is involved in cell growth, differentiation, and survival in many human tumors. We conducted a phase 1 trial of salirasib in solid tumors. Methods: Salirasib was administered orally for 21D q. 28D. Doses were escalated from 100 to 200, 400, 600, and 800 mg BID. Pharmacokinetic (PK) studies were performed during the first cycle. Results: Twenty-four patients (pts.) were treated. The median age was 56 yrs. (range, 26–76); and 54% were women. Diagnoses were metastatic colon cancer (n=5); appendiceal carcinoma (n=3); pancreatic cancer (n=2); type 2 neurofibromatosis (NF2)-associated tumors (n=2); carcinoid tumors (n=2); osteosarcoma (n=1); ocular melanoma (n=1); and other cancers (n=8). ECOG performance status was 1 in 92% and 0 in 8% of pts. The median number of prior therapies was 3. Eighty-eight cycles were administered (median, 2; range, 1–13+). The most common toxicity was dose-related diarrhea (G1, 54% of pts.; G2, 25%), which was controlled with antidiarrheal agents. Other toxicities included abdominal pain (21% of pts.), nausea, vomiting, and fatigue (17%, respectively). No G3–4 toxicity was noted; and 19 (79%) pts. had no drug-related toxicity >G1. Classic dose-limiting toxicity was not reached, but all 3 pts. treated with 800 mg BID experienced prolonged G1–2 diarrhea, and it was felt that further dose escalation would not be tolerable. Seven (29%) pts. had stable disease (SD) on salirasib therapy for ≥4 months (range, 4–13+) (metastatic carcinoid tumor, n=2; NF2-associated tumors, n=2; myoepithelial cancer of lacrimal gland, n=1; thyroid medullary carcinoma, n=1; and breast cancer, n=1). The median half-life of salirasib was 3.6±2.2 and 2.1±0.9 hours (mean ± SD) on D1 and D15, respectively. PK results were linear with respect to Cmax and AUC across the dose levels studied. There was no difference in PK parameters between single- and multiple-dose salirasib. Conclusion: Salirasib therapy was well tolerated at doses up to 800 mg BID with the major adverse event being dose-related diarrhea. Seven (29%) pts. had SD for ≥4 months. The recommended dose for phase II studies is 800 mg BID. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Averion International Corp Averion International Corp. Concordia Pharmaceuticals, Inc Concordia Pharmaceuticals, Inc

Correlation of chromogranin A levels and somatostatin receptor scintigraphy findings in the evaluation of metastases in carcinoid tumors

Chromogranin A (CgA) has been gaining acceptance as a helpful tumor marker in patients with neuroendocrine tumors, with respect to both diagnosis and prognosis. The objective of this study was to correlate serum CgA levels and somatostatin receptor scintigraphy (SRS) findings in the evaluation of metastases in carcinoid tumors. A total of 125 patients(61 men and 64 women, aged from 23 to 84 years) with histologically diagnosed carcinoid tumor underwent serum CgA assay and SRS for detecting metastasis or disease recurrence. The quantitative determination of CgA was performed in serum using an enzyme immunoassay with a cut-off value fixed at 39 U/l. Scintigraphies were performed with 200-220 MBq of In-111-DTPA-Phel-octreotide including whole-body images as well as single-photon emission computed tomography and computed tomography scans of the chest and abdomen. The primary tumors originated from the gastrointestinal tract in 115 of 125 patients (92.0%), the lung in 7 of 125 patients (5.6%), the kidney in 2 of 125 patients (1.6%), and the breast in 1 of 125 patients (0.8%). The primary tumors originated from the foregut, midgut, and hindgut in 13.6%, 71.2%, and 12.8%, respectively. Correlation of SRS with other imaging modalities and clinical follow-up findings revealed a sensitivity, a specificity, and an accuracy of 82.9%, 97.7%, and 88.0%, respectively, and for CgA 62.2%, 83.7%, and 69.6%, respectively. There was 1 false-positive and 14 false-negative SRS results and 7 false-positive and 31 false-negative CgA analyses. SRS demonstrated higher sensitivity, specificity, and accuracy than CgA for the evaluation of metastatic carcinoid tumors. The concordance between SRS and CgA results was 67.2%. Discrepancies, such as positive SRS with normal CgA levels, were noted in 26 (20.8%) cases, whereas negative SRS with high CgA levels was seen in 15 (12.0%) cases. Combining the results of CgA and SRS increased the sensitivity (92.7%) but decreased the specificity (81.4%) of tumor detection. In our study, SRS proved to be more sensitive, more specific, and more accurate than CgA for metastatic evaluation of carcinoid tumors. Positive SRS correlated with elevation of serum CgA levels. Serum CgA might have some diagnostic utility in patients with negative SRS studies. Nevertheless, both SRS and CgA should be considered useful tools in the evaluation of metastases in carcinoid patients.

Cytology of metastatic thymic well‐differentiated neuroendocrine carcinoma (thymic carcinoid) in pleural fluid: Report of a case

Thymic carcinoid tumors (well-differentiated neuroendocrine carcinomas) are uncommon anterior mediastinal neoplasms. These tumors are frequently accompanied by other endocrinopathies as part of a multiple endocrine neoplasia type I syndrome (MEN type I) and by paraneoplastic Cushing's syndrome and have a poor prognosis. We present the case of a 24-year-old man who presented for follow-up of thymic carcinoid with extensive bony metastases. He had recently completed radiotherapy to lesions involving his skull and mandible. An ultrasound-guided left-sided diagnostic and therapeutic thoracentesis was performed yielding 1 l of cloudy yellow fluid. The cytologic fluid preparations consisted of large "cannonballs" and atypical cell groups with salt and pepper nuclear chromatin. A panel of immunohistochemical stains were performed on the cell block material, and the atypical cells were positive for cytokeratin, synaptophysin, and chromogranin, but not for TTF1. These findings were consistent with metastatic well-differentiated neuroendocrine carcinoma (carcinoid tumor). This is the first reported case of a carcinoid tumor manifesting as large, spherical, smoothly contoured cell aggregates ("cannonballs") in a pleural fluid. Despite its rarity, a metastatic carcinoid tumor should be considered when "cannonballs" are found in effusions.

Urinary 5-HIAA measurement using automated on-line solid-phase extraction–high-performance liquid chromatography–tandem mass spectrometry

Quantification of 5-hydroxyindole-3-acetic acid (5-HIAA) in urine is useful for diagnosis and follow-up of patients with carcinoid tumors and for monitoring serotonin (5-hydroxytryptamine) metabolism in various disorders. We describe an automated method (XLC–MS/MS) that incorporates on-line solid-phase extraction (SPE), high-performance liquid chromatography (HPLC) and tandem mass spectrometric (MS/MS) detection to measure urinary 5-HIAA. Automated pre-purification of urine was carried out with HySphere-Resin GP ® SPE cartridges containing strong hydrophobic polystyrene resin. The analyte (5-HIAA) and internal standard (isotope-labelled 5-HIAA- d 2) were, after elution from the cartridge, separated by reversed-phase HPLC and detected with tandem MS. Total cycle time was 5 min. 5-HIAA and its deuterated internal standard (5-HIAA- d 2) were retained on and eluted from the SPE cartridges in high yields (81.5–98.0%). Absolute recovery was 96.5–99.6%. Intra-assay ( n = 20) and inter-assay ( n = 20) CVs for the measurement of 5-HIAA in urine in three concentration levels ranged from 0.8 to 1.4% and 1.7 to 4.2%, respectively. For urine samples from patients ( n = 78) with known or suspected metastatic carcinoid tumors, results obtained by XLC–MS/MS were highly correlated ( R 2 = 0.99) with the routinely used fluorometric method. This XLC–MS/MS method demonstrated lower imprecision and time per analysis (high-throughput) than manual solvent extraction methods and higher sensitivity and specificity than non-mass spectrometric detection techniques.

High‐resolution analysis of genetic alterations in small bowel carcinoid tumors reveals areas of recurrent amplification and loss

Carcinoid tumors of the small intestine are characterized by an indolent clinical course, secretion of neuropeptides, and resistance to standard cytotoxic chemotherapy. To evaluate the molecular events underlying carcinoid tumorigenesis, we used high-resolution arrays of single nucleotide polymorphisms to study chromosomal gains and losses in 24 primary and metastatic small bowel carcinoid tumors derived from 18 patients. Regions of gain or loss comprising whole chromosomes or large chromosomal regions constituted the most common class of anomalies. Loss of all or most of chromosome 18 was the commonest finding, evident in 11 of the 18 cases. Heterozygosity was also lost on chromosome arms 9p and 16q. The amplitude of observed gains was modest in comparison to those reported in some other tumor types. One focal region of recurrent gain on 14q mapped to the locus of the gene encoding the antiapoptotic protein DAD1, and immunohistochemical staining confirmed DAD1 protein expression in tumor samples. This detailed study of an uncommon neoplasm provides a basis to investigate putative oncogenes and tumor suppressor genes in intestinal carcinoid tumors.

Targeting Vascular Endothelial Growth Factor in Advanced Carcinoid Tumor: A Random Assignment Phase II Study of Depot Octreotide With Bevacizumab and Pegylated Interferon Alfa-2b

Effective systemic therapy for advanced carcinoid is lacking. The combination of bevacizumab (BEV) and pegylated (PEG) interferon alpha-2b was evaluated among patients with metastatic or unresectable carcinoid tumors. Forty-four patients on stable doses of octreotide were randomly assigned to 18 weeks of treatment with bevacizumab or PEG interferon alpha-2b. At disease progression (PD) or at the end of 18 weeks (whichever occurred earlier), patients received bevacizumab plus PEG interferon until progression. Functional computer tomography (CT) scans were performed to measure effect on tumor blood flow. In the bevacizumab arm, four patients (18%) achieved confirmed partial response (PR), 17 patients (77%) had stable disease (SD), and one patient (5%) had PD. In the PEG interferon arm, 15 patients (68%) had SD and six patients (27%) had PD. Progression-free survival (PFS) rates after 18 weeks of monotherapy were 95% in bevacizumab versus 68% on the PEG interferon arm. The overall median PFS for all 44 patients is 63 weeks. Compared with paired baseline measurements on functional CT scans, we observed a 49% (P < .01) and 28% (P < .01) decrease in tumor blood flow at day 2 and week 18 among patients treated with bevacizumab. No significant changes in tumor blood flow were observed following PEG interferon. PEG interferon alpha-2b treatment was associated with decrease in plasma basic fibroblast growth factor (bFGF; P = .04) and increase in plasma interleukin-18 (IL-18; P < .01). No significant changes in bFGF or IL-18 following treatment with bevacizumab were observed. Bevacizumab therapy resulted in objective responses, reduction of tumor blood flow, and longer PFS in patients with carcinoid than PEG interferon treatment.

Gluteal Nodules in Patients with Metastatic Midgut Carcinoid Disease Treated with Depot Somatostatin Analogs

We were referred a patient with metastatic well-differentiated endocrine tumor of the small intestine (midgut carcinoid) in whom asymptomatic sc gluteal nodules had been identified on routine abdominal computed tomography and labeled as metastases. This prompted us to assess the prevalence and cause of these nodules. This was a retrospective, cross-sectional study at a university teaching hospital. Routine abdominal computed tomography scans of 56 patients with metastatic midgut carcinoid were analyzed by two independent radiologists, blinded to treatment status (depot somatostatin analogs). Number of patients with nodules, number of injections, and duration and total cumulative dose per patient were assessed. No nodules were detected in 13 patients not on depot somatostatin therapy. Nodules were found in 29 of 43 patients (67%) on somatostatin analog therapy: 16 of 22 patients on lanreotide Autogel, five of 12 patients on octreotide LAR only, and eight of nine patients who had been treated with both somatostatin analogs. There was no difference in the clinical state of those with or without nodules. Per patient, the average number was seven, and average size was 1 cm. Presence of nodules was significantly associated with total number of injections (P = 0.024), duration on treatment (P = 0.022), and cumulative dose of lanreotide Autogel (P < 0.001). Nodules underwent involution on follow-up imaging. Patients with metastatic midgut carcinoid tumors have large numbers of asymptomatic sc nodules in the gluteal area when on either depot somatostatin analog, but these resolve over time. This clear observation gives reassurance to patients and those managing them that such nodules are unlikely to represent metastases.

Management of hepatic metastasis of gastrointestinal carcinoid tumors

Hepatic resection, radiofrequency ablation, intra-arterial radiation therapy, and chemoembolization are all potential therapies in the treatment of metastatic carcinoid tumors of the liver. The aim of this study was to determine the prognostic factors in the management of hepatic metastases of gastrointestinal carcinoid tumors. We reviewed our prospective database of 1084 hepato-pancreatico-biliary patients for patients with the diagnosis of metastatic carcinoid to the liver from 6/1998 to 9/2006. We identified 54 patients, 21 men, 33 women, median age 59 years (range 37-86), median number of tumors 3 (range 1-27), and median size of hepatic metastasis of 4 cm (range 1-13). Hepatic resection was performed in 23 (43%) with 16 (70%) receiving additional hepatic directed therapy. Hepatic resection was found to have a statistically significant improved overall survival (P < 0.05) when compared to nonhepatic resection patients with an actuarial 5 years survival for surgical (75%) compared to nonsurgical (62%). Multivariate analysis demonstrated that the use of tobacco was a significant factor in poor overall outcome (P = 0.005). Multimodality therapy in the management of hepatic carcinoid metastasis can be done safely and effectively. We recommend the use of hepatic resection when feasible as this treatment most likely offers the best long-term outcome.

Hepatic Artery Chemoembolization in 122 Patients with Metastatic Carcinoid Tumor: Lessons Learned

Hepatic Artery Chemoembolization in 122 Patients with Metastatic Carcinoid Tumor: Lessons Learned

Metastatic cutaneous carcinoid tumor mimicking an adnexal poroid neoplasm

Metastatic cutaneous neoplasms may be difficult to differentiate from primary cutaneous neoplasms. Herein, we report an unusual case of metastatic cutaneous carcinoid tumor mimicking an adnexal poroid neoplasm. A 53-year-old male man presented with a neoplasm on the vertex of the scalp, clinically resembling a pigmented basal cell carcinoma. A shave biopsy was suggestive of an apocrine poroma, however, a metastatic carcinoma could not be excluded. After acquiring additional clinical information and the complete excision of the neoplasm, further immunohistochemical stains supported the diagnosis a metastatic carcinoid tumor. To our knowledge, this is the first case of metastatic carcinoid tumor reported that has mimicked a poroid neoplasm.

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.

Metastasis of carcinoid to the arch of the axis in a multiple endocrine neoplasia patient: a case report

Background context Carcinoid tumors eventually metastasize to the spine, and epidural spinal cord compression is a relatively frequent neurologic complication of carcinoid. However, a case of multiple endocrine neoplasia type 1 (MEN1) presenting with spinal cord compression as a result of a metastatic carcinoid tumor has not been reported previously. Purpose To report an extremely rare case of MEN1 presenting with spinal cord compression by metastatic carcinoid tumor. Study design Case report. Methods A 51-year-old man, with a past history of thymoma, insulinoma, and gastric carcinoid presented with neck pain. Neuroradiological examination revealed that a tumor around the arch of the axis compressed the spinal cord with osteoblastic changes. Results After hemilaminectomy of the axis and removal of the tumor followed by irradiation, the patient returned to his previous job. Histological examination confirmed metastatic carcinoid tumor. Conclusions Spinal metastasis of carcinoid tumor occurred in a multiple endocrine neoplasia patient, and it is significant to note that carcinoid metastasis is one of differential diagnoses for osteoblastic lesions.

Repeat Transarterial Chemoembolization (TACE) for Progressive Hepatic Carcinoid Metastases Provides Results Similar to First TACE

BackgroundTransarterial chemoemobolization (TACE) is commonly used to treat metastatic carcinoid tumors; however, the management of progressive disease is less clear. We sought to determine if patients with disease progression after TACE would benefit from repeat TACE. MethodsThe records of 27 patients undergoing repeat TACE for radiologic or symptomatic progression after TACE for metastatic carcinoid were reviewed and compared to 122 undergoing first TACE. Overall and progression-free survivals were estimated by the Kaplan–Meier method. ResultsMean disease-free interval after first TACE was 11.8 months. Radiologic response was observed in 61% compared to 82% after first TACE (p = 0.058); hormone response in 64% compared to 80% (p = 0.159); and symptomatic response in 77% compared to 92% (p = 0.053). The complication rate after repeat TACE was lower than after first TACE (p = 0.03). Median overall survival was similar after repeat (28.1 months) and first TACE (33.3 months) (p = 0.53). Progression-free survival was shorter after repeat TACE but not significantly so. No factor examined could predict survival after repeat TACE. ConclusionRepeat TACE for patients with hepatic carcinoid metastases failing first TACE or having evidence of disease progression is safe and offers a viable treatment option.

Pasireotide (SOM230): Development, mechanism of action and potential applications

Pasireotide (SOM230) is a multi-receptor ligand somatostatin analogue with high binding affinity for somatostatin receptor subtypes sst(1,2,3) and sst(5). Pasireotide potently suppresses GH, IGF-I and ACTH secretion, indicating potential efficacy in acromegaly and Cushing's disease. The prolonged inhibition of hormone secretion by pasireotide in animal models and expression of multiple sst receptors in carcinoid tumors suggests that pasireotide may have clinical advantages over octreotide in patients with carcinoid tumors. Direct and indirect antitumor activity has been observed in vitro with pasireotide, including sst receptor-mediated apoptosis and antiangiogenesis, suggesting a possible role for pasireotide in antineoplastic therapy. In summary, preclinical evidence, as well as preliminary results from clinical studies suggests that pasireotide is a promising new treatment for patients with symptoms of metastatic carcinoid tumors refractory or resistant to octreotide, de novo or persistent acromegaly, and that pasireotide has the potential to be the first directed medical therapy for Cushing's disease.

Primary metastatic renal metastatic carcinoid tumor in a young male patient: a contribution to the differential diagnosis of neuroendocrine tumors

Primary metastatic renal metastatic carcinoid tumor in a young male patient: a contribution to the differential diagnosis of neuroendocrine tumors

Phase II study of thalidomide in patients with metastatic carcinoid and islet cell tumors

Carcinoid and islet cell tumors are known to be highly vascular. There is no effective systemic therapy currently available for metastatic disease. We conducted a phase II trial to evaluate the efficacy of the anti-antiangiogenic agent thalidomide in metastatic neuroendocrine tumors. Eighteen patients with measurable, histologically proven metastatic carcinoid neuroendocrine carcinomas (well-differentiated, n = 13; moderately-differentiated, n = 5) were enrolled on this study. The majority of the patients had gastrointestinal primaries (small bowel, 8; pancreas, 5; colon, 1). All but one patient had hepatic metastases, and 12 patients (67%) had carcinoid syndrome. All patients had Eastern Cooperative Oncology Group performance status of zero or one. Eight patients (44%) had received previous hepatic artery chemoembolization and 11 (61%) had undergone surgical resection. Patients were started on oral thalidomide at a daily dose of 200 mg that was escalated to the target dose of 400 mg daily after 2 weeks. Tumor response was assessed at 12-week intervals using RECIST criteria. Planned treatment duration was 24 weeks unless unacceptable toxicity or disease progression was observed. No patient achieved a partial remission or a complete remission. Best response was stable disease (SD) in 11 of 16 response-evaluable patients (69%). Serum pancreastatin results did not correlate with clinical response. Grade 3 toxicities included dizziness with orthostatic hypotension (n = 5), sensory neuropathy (n = 2), fatigue (n = 2), hemorrhagic cystitis (n = 1), and deep venous thrombosis (n = 1). Frequent Grade 1-2 toxicities were: fatigue (n = 13), constipation (n = 13), dry mouth (n = 12), somnolence (n = 12), dizziness/syncope (n = 10), weight gain (n = 5), and peripheral neuropathy (n = 5). Thalidomide was fairly well tolerated in patients with metastatic carcinoid/islet cell tumors, but failed to reveal any objective responses. The single stage design of the trial makes it difficult to determine whether observed SD in a subset of patients was attributable to the indolent nature of these tumors, or to beneficial effect of thalidomide.

Polymorphisms of the serotonin transporter and Monoamine Oxidase A gene in patients with metastatic midgut carcinoid tumors

4557 Background: In patients with metastatic midgut carcinoid tumors increased serotonin secretion is related to the carcinoid syndrome and mortality. Free serotonin is taken up via the serotonin transporter (5-HTT) in the liver and the lung and metabolized to 5- hydroxyindolacetic acid (5-HIAA) by Monoamine Oxidase A (MAO-A). The 5-HTT gene has a functional polymorphism in the promoter region (5-HTTPLR), with a short (S, less active) and long (L) allele and a polymorphic region in the second intron with variable number tandem repeats (VNTR-2). The MAO-A gene contains a length polymorphism in its promoter region (MAOA-LPR). To determine the clinical effects of the serotonin metabolizing capacity of individual patients, the association between different genotypes and symptoms (flushes and diarrhea) and survival was studied. Methods: 107 patients with metastatic midgut carcinoid tumors were genotyped for 5-HTTPLR, VNTR-2 and MAO-A-LPR. Differences were tested using Chi-square test and survival according to genotypes was analyzed using Kaplan Meier survival curves and tested with a log rank test. The independent effect of genotypes on survival was studied with multivariate Cox regression analysis with adjustments for the urinary 5-HIAA level, age at presentation and the presence of liver metastases. Results: The various genotypic variants were not related to flushes or diarrhea. Patients with the SS variant of 5-HTTLPR had a shorter median survival (45 months, 95% Confidence Interval (CI) 0.50–90) compared to patients with the LS (113 months, 95% CI 53–172) and the LL variant (90 months, 95% CI 64–115) (P=0.02). After adjustment, survival in patients with the SS variant remained worse with an odds ratio of 0.43 (95% CI 0.23–0.83; P=0.009) and 0.63 (95% CI 0.33–1.11; P=0.1) compared to patients with the LS and the LL variant respectively. Survival was not influenced by the VNTR-2 or MAOA-LPR. Conclusions: The SS genotype of the 5-HTTLPR is independently associated with a worse survival in patients with metastatic midgut carcinoid tumors. No significant financial relationships to disclose.

The effects of pasireotide (SOM230) on health-related quality of life in patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR

4558 Background: Pasireotide is a novel multi-ligand somatostatin analogue with high affinity binding for four of the five somatostatin receptor subtypes (sst1,2,3 and sst5). This Phase II clinical trial showed that pasireotide is effective in controlling the symptoms of diarrhea and flushing in 27% of patients with metastatic carcinoid tumors refractory or resistant to octreotide LAR. The impact of pasireotide therapy on health-related quality of life (HRQL) was also evaluated. Methods: Patients in this open-label, multicenter study initially received pasireotide 300 μg sc bid which was escalated to a maximum dose of 1,200 μg sc bid until clinical response was achieved. Data are reported for the Functional Assessment of Chronic Illness Therapy-Diarrhea (FACIT-D) instrument. FACIT-D comprises the Functional Assessment of Cancer Therapy-General (FACT-G) score, which measures physical, social, emotional and functional well-being, plus a symptom-specific sub-scale which measures HRQL specific to diarrhea. FACIT-D baseline assessment was obtained on day 1 immediately before dosing, and then monthly thereafter. FACIT-D sub-scale and total scores at baseline and after 1, 2, and 3 months of pasireotide treatment are described by categories of clinical response. Results: 45 patients (mean age 61 years; range 40–83) received treatment, and 44 were eligible for the efficacy and HRQL analyses. Functional well-being scores, symptom-specific scores and total FACIT-D scores of non-responders tended to be lower at baseline and during treatment than those of responders. The three sub-scale and summary FACIT-D scores exhibited relatively stable mean HRQL scores and similar patterns of variability in clinical responders and non- responders through the third month of pasireotide treatment. Conclusions: HRQL was stable during treatment with pasireotide in patients with advanced metastatic disease refractory or resistant to octreotide LAR. Additional work in HRQL study design and evaluation of HRQL endpoints in patients with carcinoid disease is indicated, and will further improve our understanding of quality of life in patients with this disease. [Table: see text]