Jorge Garcia-Hernandez

Circulating Tumor Cells As Prognostic Markers in Neuroendocrine Tumors

PURPOSE To determine the prognostic significance of circulating tumor cells (CTCs) in patients with neuroendocrine cancer. PATIENTS AND METHODS In this single-center prospective study, 176 patients with measurable metastatic neuroendocrine tumors (NETs) were recruited. CTCs were measured using a semiautomated technique based on immunomagnetic separation of epithelial cell adhesion molecule-expressing cells. RESULTS Overall, 49% patients had ≥ one CTC, 42% had ≥ two CTCs, and 30% had ≥ five CTCs in 7.5 mL blood. Presence of CTCs was associated with increased burden, increased tumor grade, and elevated serum chromogranin A (CgA). Using a 90-patient training set and 85-patient validation set, we defined a cutoff of < one or ≥ one as the optimal prognostic threshold with respect to progression-free survival (PFS). Applying this threshold, the presence of ≥ one CTC was associated with worse PFS and overall survival (OS; hazard ratios [HRs], 6.6 and 8.0, respectively; both P < .001). In multivariate analysis, CTCs remained significant when other prognostic markers, grade, tumor burden, and CgA were included. Within grades, presence of CTCs was able to define a poor prognostic subgroup. For grade 1, HRs were 5.0 for PFS (P = .017) and 7.2 for OS (P = .023); for grade 2, HRs were 3.5 for PFS (P = .018) and 5.2 for OS (P = .036). CONCLUSION CTCs are a promising prognostic marker for patients with NETs and should be assessed in the context of clinical trials with defined tumor subtypes and therapy.

Goblet cell appendiceal tumors – Management dilemmas and long-term outcomes

BACKGROUND Appendiceal Goblet cell tumors (GCTs) are clinically more aggressive, and have a worse outcome than midgut neuroendocrine tumors (mNETs). Guidelines for management of GCTs are limited. METHODS A retrospective case-study analysis was performed in patients with a diagnosis of GCT, confirmed on histological review. Patients were evaluated clinically, biochemically, and radiologically. RESULTS 48 patients were identified (TNM stage I-II: 27, stage III: 15, stage IV: 6). Median follow-up was 44 months and was complete in all patients. 68.8% presented with acute appendicitis. 44/48 patients had initial appendectomy, followed by prophylactic right hemicolectomy in 41. 10/48 patients had recurrent disease [median time to recurrence 28 months (range 4-159)]. Of those, 9 received systemic chemotherapy (FOLFOX/FOLFIRI), which was also given in 5/48 patients with disseminated disease at diagnosis. Partial response, stable disease and disease progression was noted in 22%, 22% and 56%, respectively. Adjuvant chemotherapy was also administered in 9/48 patients with stage III disease after right hemicolectomy, however in 3/9 the disease recurred. Median progression/disease-free-survival was 44 months (range 3-159) and overall 5-year survival rate was 41.6%. CONCLUSIONS The clinical behaviour of GCTs is more similar to colorectal adenocarcinomas than to NETs. A prophylactic right hemicolectomy is recommended to reduce the risk of recurrence. Systemic chemotherapy, using colorectal adenocarcinoma regimens, is indicated for advanced or recurrent disease and has encouraging results. Prospective studies are needed to define the role of adjuvant chemotherapy and the optimal chemotherapy regimen.

Chromogranin A as a predictor of radiological disease progression in neuroendocrine tumours

BACKGROUND Chromogranin A (CgA) is the best established neuroendocrine biomarker. This study was aimed at investigating the prognostic value of CgA as a predictor of radiological disease progression in neuroendocrine tumour (NET) patients. METHODS Patients with metastatic NETs and evidence of radiological progression (RP) according to RECIST 1.1 were identified from a NET database. Plasma CgA levels were measured 6 and 12 months before RP and at the event of RP. CgA was measured with the Supra-regional-Assay-Service radioimmunoassay (Hammersmith Hospital). RESULTS A total of 152 patients were evaluated including 91 midgut NETs and 61 pancreatic NETs (PNETs). Of these, 56 were G1 NETs, 65 G2, 10 G3, 21 of unknown histology. For all NETs, there was a positive trend in terms of increase of CgA values 6 months prior to RP compared to 12 months before RP. Subgroup analysis at first episode of RP showed that for PNETs there was evidence of a difference in the median CgA levels. CgA 6 months before RP was 100 pmol/L [interquartile 1 (Q1) =53 and Q3 =286.25 pmol/L) and 12 months before was 52 pmol/L (Q1 =36.25 and Q3 =128 pmol/L), W=52, P=0.48. This observation was not confirmed in midgut NETs, where median CgA 6 months before RP was 389.5 pmol/L (Q1 =131.5 and Q3 =791.5 pmol/L) and 12 months before was 319 pmol/L (Q1 =158 and Q3 =753 pmol/L), W=191, P=0.39]. Low grade tumours (G1) had a median CgA value at 6 months significantly higher than at 12 months [181 (Q1 =56.25, Q3 =624) vs. 149.5 (Q1 =44, Q3 =247.25) pmol/L, W=70, P=0.48]. CONCLUSIONS CgA seems to have predictive value 6 months prior to RP for PNETs and G1 tumours. Further prospective analyses are needed to enable more definitive conclusions.

PMO-023 Assessment of quality of life, coping strategies and personal beliefs in neuroendocrine tumour patients

Introduction Medical research is focused on the developing of treatments and improving survival outcomes. In recent years, quality of life (QoL) measurements have been included in clinical trials as a relevant outcome variable; however, other psychological variables might have an impact on QoL. This study aims to determine: H1. Whether NET symptoms have a greater impact on QoL than disease severity. H2. Whether coping strategies influence QoL. H3 Whether internal control beliefs in the potential of control cancer growth are associated with QoL. Methods 74 patients completed a web survey involving: QoL (EORTC C.30 and GI.NET21), a coping styles (Brief cope) and an illness perception measurements. All questionnaires were counterbalanced. Results Endocrine and gastrointestinal symptoms, were negatively associated with self-reported measures of QoL, r=−46, N=73, p.05. Problem focus strategies such as acceptance, active coping and planning were not associated with QoL. Interestingly, emotion focus strategies such as behavioural disengagement, venting and self-blame were negatively associated with QoL, r=−0.48, N=73. Neuroendocrine patients considered that, keeping a positive attitude, not smoking and limiting alcohol intake would prevent cancer from spreading and progressing; however none of them were correlated with QoL. Conclusion Disease severity is not associated with to QoL, whereas specific neuroendocrine symptoms, flushing and diarrhoea are. Active coping, acceptance, seeking emotional or instrumental support, were not correlated to QoL. In contrast, behavioural disengagement, denial and self-blame were negatively associated to self reported measures of QoL. Most of our patients endeavour on active or problem focus strategies where there is agreement of being more adaptive long term than avoidant or emotional strategies. This study has shown the relationship between neuroendocrine symptoms and coping strategies with QoL. Prospective and randomised trials will clarify the causal relationship among these constructs. Future research should include the relationship of psychosocial variables and neuroendocrine biomarkers. Competing interests None declared. References 1. Carver CS. You want to measure coping but your protocol is too long: Consider the Brief COPE. Int J Behav Med 1997;4:92–100. 2. Larsson G, Sjoden PO, Oberg K, et al. Importance-satisfaction discrepancies are associated with health-related quality of life in five year survivors of endocrine gastrointestinal tumours. Ann Oncol 1999;10:1321–7. 3. Miles A, Simon A, Wardle J. Answering patient questions about the role lifestyle factors play in cancer onset and recurrence. J Health Psychol. 2010;15:291–8.

PTU-159 Variable Utility Of Chromogranin A Assays In The Diagnosis Of Gastric Carcinoid Type 1

Introduction Chromogranin A (CgA) is used in the diagnosis and follow-up of patients with neuroendocrine tumours, whilst there is debate over the accuracy of CgA assays in gastric carcinoid type 1 (GC1). Clinical interpretation of CgA results may be affected by the heterogeneity between available assays. The commercial CgA assay, DAKO (DAKO, Denmark A/S, Glostrup, Denmark) is an ELISA which recognises a 23 kD C terminal fragment of CgA; the Imperial Supra-regional Assay Service radioimmunoassay (SAS Hammersmith Hospital, Imperial College, London) is a competitive radioimmunoassay raised against the whole pancreastatin molecule. Present study is aimed at comparing CgA-DAKO and CgA-SAS to determine their accuracy in the diagnosis of GC1. Methods Patients with a confirmed diagnosis of GC1 and available plasma CgA measurements according to two different assays (SAS, DAKO) were included and retrospectively reviewed. CgA values were ranked in 4 groups: 1. normal values, 2. increase <2 upper limit of normal (ULN), 3.increase between 2–5 ULN, 4. increase >5 ULN. Results 26 patients, 17 female and 9 male, mean age 55 years ± 11.75, were identified. At diagnosis, median CgA-DAKO were significantly higher than median CgA-SAS (81, normal range <27 IU/l versus 34.5 pmol/l, normal range <60 pmol/l, T=35.5, p < 0.001). When ranking the data, the results confirmed median CgA-DAKO significantly higher than median CgA-SAS: 3 vs. 1, T=0, p < 0.001. Sensitivity was 77% and 7.7% for CgA-DAKO and CgA-SAS, respectively. Conclusion CgA-DAKO shows a better sensitivity than CgA-SAS for the diagnosis of GC1. Accurate diagnostic biomarkers may identify those patients who may benefit from a closer endoscopic follow-up in cases of raised neuroendocrine markers. Further prospective studies are needed highlighting the difference in diagnostic sensitivity between assays. References Ramachandran R, et al. Improved diagnostic accuracy for neuroendocrine neoplasms using two chromogranin A assays. Clin Endocrinol (Oxf). 2012;76:831–836 Baudin E, et al. Impact of chromogranin-A measurement in the work-up of neuroendocrine tumors. Ann Oncol 2001;12(Suppl 2): S79–S82 Stridsberg M, et al. A comparison between three commercial kits for chromogranin A measurements. Journal of Endocrinology 2003:177:337–341 Ardill JES. Circulating markers for endocrine tumours of the gastroenteropancreatic tract. Annals of Clinical Biochemistry 2008:45, 539–559 Disclosure of Interest None Declared.

Sa1935 Variation and Utility Ofchromogranin a Assays for Gastric Carcinoid Type 1

Introduction: Chromogranin A (CgA) is considered as the best and most sensitive general marker for the diagnosis and follow-up of neuroendocrine tumors (NETs) and is also of prognostic value. However, there are no available studies to date, which analysed the role of CgA as a predictor of radiological disease progression in all NETs. Aim: To investigate the prognostic value of CgA as a predictor of radiological disease progression in NET patients. Methods: Patients with metastatic NETs and evidence of Radiological Progression (RP) according to Radiological Evaluation Criteria In Solid Tumors (RECIST 1.1) were identified from our NETs database. Plasma CgA were measured 6 and 12 months before RP and at the event of RP. CgA was measured with the Supra-regional-Assay-Service radioimmunoassay (Hammersmith Hospital). In our laboratory, the reference value of CgA has been established as 20%). Results: 152 patients were evaluable including 91 midgut NETs (mNETs) and 61 pancreatic NETs (PNETs). Of these, 56 were G1 NETs, 65 G2, 10 G3, 21 of unknown histology. The majority of the patients (95.4%) had liver metastases, whereas bone and lung metastases were present in a smaller proportion of patients (27.6% and 9.9%, respectively). Median CgA for all NETs, 6 months before RP,

PWE-160 Interferon Alpha Therapy for Metastatic Neuroendocrine Tumours: A Retrospective Study

Introduction Interferon alpha has been used in the management of NETs for over 20 years. It has generally not been popular due to perceived lack of efficacy and due to toxicity profile. Currently molecular targeted medical therapies such as mTOR inhibitors and tyrosine kinase inhibitors are promoted but studies demonstrate only modest anti-tumour effect and time to progression (TTP) with not insignificant toxicity. Aim To perform a retrospective analysis of Interferon alpha (IFNα) in patients with metastatic NET and assess efficacy and toxicity. Methods We identified 37 patients treated with IFNα 3 – 5 million units x 3 per week between 2000–2012. Mean age 58.6 (24–88) years; 26:11 male:female; 21 midgut primary, 7 pancreatic, 1 hindgut, 1 bronchial, 1 thymic and 6 unknown. Histology: G1 49%; G2 41%; G3 5%: unknown 5%. 76% were also on somatostatin analogue. 65% had recorded progressive disease at disease onset. CT/MRI imaging; urine 5HIAA and plasma chromagranin A (CgA) and toxicities were recorded. Results 9 (24%) withdrew before 3 months because of toxicity, progressive disease or death. On intention to treat analysis: 1 (3%) had complete response; 1 (3%) partial response; 26 (70%) had at least 3 months of stable disease. The median TTP was 14 months. Median 5HIAA fell from 54 to 29 umol/24h at 6 months (NS) and CgA from 138 to 121pmol/l at 6 months (NS). 38% had WHO grade 1–2 haematological toxicity and 19% grade 3–4. The only other grade 3–4 toxicity was depression in 1 patient and 22% had grade 1–2 depression. Other grade 1–2 toxicities > 10% included flu-like symptoms 24%, fatigue 16%, hypothyroidism 11%, dry skin 14%. Conclusion Although there is toxicity which affects management in up to 1/3rd of patients the remaining patients tolerated therapy well. IFNα demonstrated efficacy in at least inducing or maintaining stable disease in most patients (76%). The median TTP is at least similar to other molecular targeted therapies. Those patients who were going to be intolerant or progress usually did so within the first 3 months of treatment. It would be appropriate to perform prospective randomised studies utilising IFNα and also better assess quality of life. Disclosure of Interest None Declared.

PTU-163 Depression and carcinoid syndrome: is there any relationship? A cross-sectional study

Introduction The relationship between brain serotonin and depression is well established. It is also widely accepted that serotonin hyperproduction in carcinoid syndrome does not cross the brain barrier. CNS serotonin is synthesised from tryptophan within serotonergic neurons and a deficiency of this precursor could be possible on carcinoid patients. In this cross-sectional study we evaluated, whether the feelings of depression are associated with neuroendocrine symptomatology. In addition, whether self-report of quality of life is associated with feelings of depression. Methods 47 patients with carcinoid syndrome completed a survey via clinic involving: QoL questionnaires and the Becks Depression Inventory-II (BDI-II). All questionnaires were counterbalanced. Results 45 out of 47 patients had low scores on the BDI-II and not likely to suffer from depression. Only two participants had moderate depression scores. These scores were negatively associated with self-report of QoL, r=−0.59, N=46, p<0.001. Interestingly, endocrine symptoms that is, flushing and night sweats, were not associated with depressive symptoms: r=0.22, N=44, p=0.15, whereas, gastrointestinal symptoms that is, diarrhoea, abdominal discomfort, bloatedness and indigestion, were strongly associated with depression scores: r=56, N=43, p<0.001. Conclusion Depressive scores in carcinoid patients are often attributed to the stress of diagnoses and adaptation to this chronic disease, however, although a causal relationship has not been established between carcinoid and depression, physicians should consider this possibility when psychological symptoms do not improve with conventional therapy. Further research is needed to understand why gastrointestinal, and not endocrine, symptoms were correlated with depressive symptoms. Competing interests None declared. References 1. Lapeire LD, Tansens A, Lemmens G, et al. Carcinoid encephalopathy: A single entity or a spectrum of different disorders. Acta Oncologica 2010;49:268–70. 2. Major LF, LaVonne Brown G, Wilson WP. Carcinoid and psychiatric symptoms. South Med J 1973;66:797–90. 3. Rosenthal MA. Carcinoid associated encephalitis successfully treated with tryptophan. J Clin Neurosci 2004;11:66–7. 4. Williams MD, Dolenic T. Selective serotonin reuptake inhibitors and patients with carcinoid tumor. Psychosomatics 2005;46:370–2.