Validation of the EORTC QLQ-GINET21 questionnaire for assessing quality of life of patients with gastrointestinal neuroendocrine tumours.

BACKGROUND: Quality of life is an important end point in clinical trials, yet there are few quality of life questionnaires for neuroendocrine tumours. METHODS: This international multicentre validation study assesses the QLQ-GINET21 Quality of Life Questionnaire in 253 patients with gastrointestinal neuroendocrine tumours. All patients were requested to complete two quality of life questionnaires - the EORTC Core Quality of Life questionnaire (QLQ-C30) and the QLQ-GINET21 - at baseline, and at 3 and 6 months post-baseline; the psychometric properties of the questionnaire were then analysed. RESULTS: Analysis of QLQ-GINET21 scales confirmed appropriate aggregation of the items, except for treatment-related symptoms, where weight gain showed low correlation with other questions in the scale; weight gain was therefore analysed as a single item. Internal consistency of scales using Cronbach's α coefficient was >0.7 for all parts of the QLQ-GINET21 at 6 months. Intraclass correlation was >0.85 for all scales. Discriminant validity was confirmed, with values <0.70 for all scales compared with each other.Scores changed in accordance with alterations in performance status and in response to expected clinical changes after therapies. Mean scores were similar for pancreatic and other tumours. CONCLUSION: The QLQ-GINET21 is a valid and responsive tool for assessing quality of life in the gut, pancreas and liver neuroendocrine tumours.

Discontinuation of proton pump inhibitors during assessment of chromogranin A levels in patients with neuroendocrine tumours.

BACKGROUND: The aim of this prospective study was to examine whether discontinuation of proton pump inhibitors (PPIs) or replacement by H(2)-receptor antagonists (H2RA) resulted in a decrease of chromogranin A (CgA) levels in 196 patients with well-differentiated neuroendocrine tumours (NETs). METHODS: Patients with an unexpectedly high CgA level not connected with NET disease discontinued PPIs, or used H2RA instead; 2 weeks later CgA level was measured again. RESULTS: In all, 19 out of 196 (10%) patients showed unexpected elevated CgA levels, they all used PPI. In 11 out of 19 patients with no evidence of the disease, median CgA decreased from 390 µg l(-1) during PPI treatment to 56 µg l(-1) after discontinuation (P=0.003). In 8 out of 19 patients with stable disease, median CgA decreased from 618 to 318 µg l(-1) (P=0.012). In 12 out of 19 patients who ceased all acid inhibition, CgA levels decreased by 82%, while in the seven patients who replaced PPI by H2RA, CgA decreased by 77% (P=0.967). CONCLUSION: Proton pump inhibitor use causes falsely elevated CgA levels in patients with NET. We recommend to stop, or replace PPI by H2RA, to obtain a reliable CgA value.

An elevated progastrin-releasing peptide level in patients with well-differentiated neuroendocrine tumours indicates a primary tumour in the lung and predicts a shorter survival.

BACKGROUND: Progastrin-releasing peptide (proGRP) is a recently identified biomarker of small-cell lung cancer. In well-differentiated neuroendocrine tumours (WDNETs), this study investigates the association between proGRP and tumour characteristics and the prognostic value of proGRP levels compared with chromogranin A (CgA) levels. PATIENTS AND METHODS: Serum samples were obtained in 282 patients with WDNET. The receiver operating characteristic (ROC) curve technique was used to assess specificity and sensitivity in the identification of a primary tumour location. Cox proportional hazards models and Kaplan-Meier curves were constructed to determine the association of patients' characteristics and tumour markers with survival. RESULTS: For proGRP, the ROC curve indicated a cut-off level of 90 ng/l (approximately twice the upper reference value), with a specificity of 99% and a sensitivity of 43% in distinguishing primary pulmonary tumours from other sites. In the multivariate Cox model, both proGRP and CgA were strongly associated with survival (P < 0.0001 for both variables). CONCLUSIONS: A high-risk proGRP level (more than twice the upper reference value) in patients with WDNETs is a strong indication for a primary tumour in the lung. Besides CgA, proGRP is a complementary tumour marker for prognosis and treatment monitoring in patients with neuroendocrine tumour.

Expression and ligand binding of bombesin receptors in pulmonary and intestinal carcinoids.

INTRODUCTION: Carcinoids are mainly found in the gastrointestinal (65%) and bronchopulmonary tract (25%). These neuroendocrine tumors secrete a wide range of bioactive peptides, including gastrin releasing peptide and neuromedin B, the mammalian analogs of bombesin. The purpose of this study was to investigate the quantity and localization of bombesin receptors in gastrointestinal and pulmonary carcinoids, and to reveal whether bombesin-like peptides (BLP) and their receptors are of any value in distinguishing pulmonary carcinoids from carcinoids of intestinal origin. METHODS: Carcinoid tumors with pulmonary (no.=9) or intestinal (no.=15) localizations were analyzed by immunohistochemistry, autoradiography, and radioimmunoassay, to examine the presence of bombesin receptor subtypes and determine BLP levels in these tumors. RESULTS: All 3 bombesin receptor subtypes (GRPR, NMBR, and BRS-3) were present on pulmonary and intestinal carcinoids by immunohistochemistry. In pulmonary carcinoids, low receptor ligand binding densities together with high and low BLP levels were found. Intestinal carcinoids showed predominantly high receptor ligand binding densities in combination with low BLP levels. CONCLUSIONS: The expression of bombesin receptor subtypes is independent from the carcinoid tumor origin, and is therefore not recommended as a distinction marker, although carcinoids of pulmonary and intestinal origin possess different receptor binding affinities for bombesin and dissimilar BLP levels. The combined presence of bombesin and its receptors might suggest the presence of a paracrine or autocrine growth loop in carcinoids.

Development of a disease-specific Quality of Life questionnaire module for patients with gastrointestinal neuroendocrine tumours.

Quality of life (QoL) measurements are increasingly being used as an end point in cancer clinical trials. Standard generic QoL questionnaires may not assess symptoms produced by neuroendocrine tumours. Here we report the development of a disease-specific quality of life score questionnaire for patients with neuroendocrine tumours of the gut to supplement the EORTC core cancer questionnaire, the QLQ-C30. Phases 1-3 of the EORTC quality of life group guidelines for module development were used to design the new questionnaire. Forty-one relevant issues (questions) were generated after an extensive literature search. Following interviews of 15 health care workers and 35 patients, a 35 question provisional questionnaire was constructed. This was translated into seven European languages and pre-tested in 180 patients resulting in a 21-item module that will be validated in an international clinical trial. The EORTC QLQ-NET21 provides a site-specific module to supplement the QLQ-C30 for patients with neuroendocrine tumours.

Developments in diagnosis and treatment of metastatic midgut carcinoid tumors. A review.

Carcinoids are neuroendocrine tumours derived from enterochromaffin cells which are widely distributed in the body and may, therefore, arise from any site. They are traditionally described as originating from the foregut, midgut and hindgut. Localisation in the gastrointestinal tract is the most frequent, among which the appendiceal involvement is often found at laparoscopy for appendicitis and the small bowel is known for the liver metastases with the production of serotonin causing the characteristic carcinoid syndrome with diarrhoea and flushes. The overall incidence of carcinoid disease has increased in the past decades, but whether this is a true increase or due to early detection or better recognition at pathology is not known. The prognosis of metastatic carcinoid tumours has improved during the last decade resulting in a 5 year survival of approximately 50% in the Netherlands. Due to a longer survival, complications such as carcinoid heart disease and new metastatic patterns like skin and bone metastases may become a more important feature in carcinoid disease. New developments are in the field of diagnostics (fine-tuning of the pathology, videocapsule endoscopy to find the primary tumour, positron emission tomography [PET] scanning) and treatment options (radiofrequency ablation, radioactive octreotide, meta-iodobenzylguanidine combinations). The new serum marker of carcinoid, chromogranin A, may play an important role in the follow-up and NT-proBNP for the detection of heart problems. Combining new diagnostic and treatment modalities in metastatic carcinoid patients may result in a better quality of life and a longer survival. The increasing number of therapeutic options and diagnostic procedures requires a multidisciplinary approach focused on tailor-made therapy based on patients' specific conditions preferably in specialised centres and in clinical studies.

Expression of oestrogen receptor and loss of E-cadherin are diagnostic for gastric metastasis of breast carcinoma.

AIMS: To investigate whether immunohistochemical staining for oestrogen receptor (ER)alpha, progesterone receptor (PgR) and E-cadherin might be useful to differentiate between metastatic breast carcinoma and primary gastric carcinoma. METHODS: Gastric biopsies of 75 patients containing adenocarcinoma were stained for ERalpha, PgR and E-cadherin. Included were: Group A, 28 patients with primary gastric cancer; Group B, 28 patients with an adenocarcinoma containing gastric biopsy and a clinical diagnosis of metastatic breast carcinoma; Group C, all consecutive patients with a positive gastric biopsy in 2001 (n = 19) without clinical history of breast carcinoma and not followed by gastric resection (control group). RESULTS: All ERalpha+ or PgR+ carcinomas (n = 20) were of patients with a previous or concurrent history of breast carcinoma: 19 in group B, one in group C. In addition, absence of E-cadherin staining was seen significantly more often in patients with metastatic breast carcinoma than in patients with primary gastric cancer (P < 0.001). CONCLUSION: Positive immunohistochemical staining for ERalpha or PgR of an adenocarcinoma in a gastric biopsy is diagnostic for metastatic breast carcinoma. Moreover, when carcinoma in a gastric biopsy is negative for E-cadherin staining, metastatic breast carcinoma should be considered.

Epidemiology of neuroendocrine tumours.

Neuroendocrine tumours account for only 0.5% of all malignancies. The incidence is approximately 2/100,000 with a female preponderance under the age of 50 years due to appendiceal location. The main primary sites are the gastrointestinal tract (62-67%) and the lung (22-27%). Presentation with metastatic disease accounts for 12-22%. In the last decades, the incidence has been rising. This might be due to more awareness, improved diagnostic tools or a change in definition. Most neuroendocrine tumours are mainly sporadic, but association with the multiple endocrine neoplasia type 1 syndrome and clustering within families is known. Also an increased risk of secondary cancers has been reported, but numbers are small. The 5-year survival is mainly associated with stage: 93% in local disease, 74% in regional disease and 19% in metastatic disease. In metastatic disease, survival increased since 1992, when treatment with octreotide became largely available in The Netherlands.

Interferon and meta-iodobenzylguanidin combinations in the treatment of metastatic carcinoid tumours.

Interferon (IFN) and meta-iodobenzylguanidin (MIBG) are active in metastatic carcinoids. In a phase II study, we evaluated the effect upon diagnostic 131I-MIBG uptake and the clinical response of the combination. 131I-MIBG scintigraphy was performed prior to treatment, after 8 weeks of IFN and after unlabelled MIBG. The tumour over non-tumour (T/NT) ratios were quantitatively determined by comparing counts in the centre of the tumour (liver metastases) with those in an adjacent area of normal liver uptake (T/NT1) and with abdominal background area (T/NT2). The T/NT1 ratio showed an increase of >10% in only four out of 21 patients (19%) after IFN (P = 0.178) and significantly more often in nine out of 18 patients (50%) after unlabelled MIBG (P = 0.016). The absolute uptake in tumour deposits was also increased if compared with the abdominal background (T/NT2: 23% increase after IFN and 83% increase after unlabelled MIBG). The combination produced 91% of patients with stable disease (using World Health Organisation criteria) at computed tomography scan and a biochemical response (a reduction of at least 50% in urinary 5-hydroxyindolacetic acid excretion) in 39%. IFN-alpha did not significantly improve tumour retention of 131I-MIBG. In contrast, unlabelled MIBG significantly improved biodistribution and tumour uptake in 83%. A synergistic effect was not seen.

Role of natriuretic peptides in the diagnosis and treatment of patients with carcinoid heart disease.

Carcinoid heart disease (CHD) occurs in 20-70% of the patients with metastatic well-differentiated neuroendocrine tumours (NET). We evaluated whether natriuretic peptides (ANP or NT-proBNP) are useful in early detection of CHD. Blood samples from 32 patients with NET were compared with cardiac ultrasound follow-up. CHD was defined as thickening of the tricuspid valve in the presence of grade III-IV/IV tricuspid valve regurgitation. CHD was found in nine out of 32 patients (28%), all with symptoms of the carcinoid syndrome compared to 65% in the 23 patients without CHD (P=0.04). Median levels of NT-proBNP and 5-HIAA were significantly higher in patients with CHD (894 ng l(-1) and 815 micromol 24 h(-1)) compared to those without (89 and 206 ng l(-1), P<0.001 and P=0.007). No significant differences were detected in ANP levels (P=0.11). Dilatation of the right atrium and ventricle as well as thickening of the tricuspid valve and degree of regurgitation were statistically significant correlated with NT-proBNP levels. The accuracy of NT-proBNP in the diagnosis of CHD was higher than that of ANP. A significantly better survival was observed in case of normal NT-proBNP values. In conclusion, NT-proBNP is helpful as a simple marker in the diagnosis of CHD. Survival is better in patients with normal levels of NT-proBNP.

Reactivity to human papillomavirus type 16 L1 virus-like particles in sera from patients with genital cancer and patients with carcinomas at five different extragenital sites.

A retrospective seroepidemiologic study was performed to examine the association between human papillomaviruses (HPV) 16 infection and carcinomas of the oropharynx, the oesophagus, penis and vagina. Sera were selected from the serum bank from the Antoni van Leeuwenhoek Hospital (Netherlands Cancer Institute) and the Slotervaart Hospital in Amsterdam, the Netherlands. Presence of HPV 16 specific antibody was assessed using HPV 16 L1 capsids. Sera positive for HPV 16 capsid antibody were further tested for antibody against HPV 16 E7 peptides. Prevalence of antibody against HPV 16 L1 capsids among both the negative control group without cancer and the negative control group with gastric cancer was 18%, while seroprevalence among the control group of patients with HPV-associated cervical squamous cell carcinoma was 47% (P<0.001). Among the patients with penile squamous cell carcinoma seroprevalence was 38% (P<0.001), among patients with oropharyngeal carcinoma 33% (P=0.04) and among patients with oesophageal squamous cell carcinoma 14% (P=0.7). The serological evidence for association between HPV 16 infection and both oropharyngeal carcinoma and penile carcinoma was established. The conclusion that no association was found between the presence of antibody against HPV 16 L1 capsids and oesophageal squamous cell carcinoma was in accordance with results of other studies carried out in the Netherlands using HPV DNA technology. In the subjects with HPV 16 L1 capsid antibody, no association was found between the antibody against HPV 16 E7 and clinical outcome.

Carcinoid heart disease: an update.

BACKGROUND: Carcinoid tumours are a poorly defined collection of lesions, histopathologically indistinguishable from gastroentero-pancreatic neuroendocrine tumours. In this report, we discuss epidemiology and survival, clinical presentation, carcinoid valvular heart disease (CVHD), histopathological considerations and treatment options. METHODS: Review and update of the literature. RESULTS: The term carcinoid suggests a disease entity, but with increasing knowledge it becomes progressively confusing. To avoid further confusion, it is advisable to define these tumours using differentiation, stage, primary site, known tumour products and an associated clinical syndrome. Incidence varies between 0.8 and 1.9/100,000 population. About 20% present with metastases, with a 5-year survival varying between 15% and 35%. Metastatic disease frequently accompanies the carcinoid syndrome (flushing, diarrhoea, wheezing and CVHD). CVHD incidence is about 50%, and seems unrelated to disease duration and tumour mass. An aetiological relation of CVHD with urinary 5-HIAA remains to be confirmed. Resection is the only curative option. Surgery can also offer prolonged palliation and is needed to restore bowel transit in obstructive/ischaemic bowel problems. Adequate palliation of hormone-related symptoms can also be achieved by somatostatin analogues, meta-iodo-benzyl-guanidine preparations and interferon-alpha formulations, all with a 70% response rate. Embolization of liver metastases has led to objective responses in about 50% of patients, but is accompanied by significant side effects. CONCLUSIONS: Most patients are cured by surgery. Symptom relief is the main target in metastatic disease and can be achieved by a range of equally potent biologically active medications, debulking surgery and hepatic embolization.

Pathogenesis and treatment of pain caused by skin metastases in neuroendocrine tumours.

BACKGROUND: Prognosis of neuroendocrine tumours has improved during the last decade and one might expect that more patients with (sub)cutaneous metastases will be seen in the future. We investigated the cause of pain in skin metastases and tried to give recommendations about treatment options. METHODS: We compared histology of (sub)cutaneous metastases in four patients, two with severely painful skin lesions and two without pain. RESULTS: On the pathological slides there were no differences in neuroinvasion, angioinvasion or mitosis between painful and non-painful metastases. However, the painful metastases rapidly multiplied, while the others remained indolent in nature. Pain was very difficult to manage and did not respond to analgesics, irradiation or systemic treatment with interferon or chemotherapy. Local excision was the only successful treatment option. CONCLUSION: Histology did not show differences between painful and non-painful skin metastases. Local excision is the treatment of choice.

A tumour with a neuroendocrine and papillary serous component: two or a pair?

AIMS: To examine the clonal origin of a tumour, made up of a neuroendocrine component and a papillary serous component by comparing the pattern of loss of heterozygosity (LOH) and the immunohistochemical protein expression of both components. METHODS/RESULTS: A 70 year old woman, known to have a metastasised neuroendocrine carcinoma, underwent resection of the distal part of the ileum because of obstruction by a mesenterial mass. The macroscopically homogeneous mesenterial mass consisted histologically of an admixture of a neuroendocrine component and a papillary serous carcinoma. Loss of heterozygosity (LOH) analysis of both components with a panel of 15 polymorphic microsatellite markers showed a distinctive pattern of LOH, and both components showed LOH on chromosome 4q and 17, but involving different alleles at the same locus. Moreover, both components showed different immunohistochemical staining patterns for neuroendocrine markers, cytokeratin 7, carcinoembryonic antigen, and CA125. CONCLUSION: Both LOH analysis of the neuroendocrine and papillary serous components of this tumour and the immunohistochemical profile of both components are consistent with a different clonal origin. The tumour is probably a collision tumour, in which the papillary serous carcinoma must have been of peritoneal origin because necropsy revealed a normal uterus and normal ovaries.

Evaluation of (111)In-pentetreotide, (131)I-MIBG and bone scintigraphy in the detection and clinical management of bone metastases in carcinoid disease.

Bone metastases are assumed to be rare in carcinoid disease and to be associated mainly with bronchial primaries. The aim of the present study was to evaluate the occurrence of bone metastases in patients with metastatic carcinoid tumours, and the role of various nuclear medicine modalities (bone scintigraphy, (111)In-pentetreotide and (131)I-MIBG) in its detection and clinical management. Nine (2 women, 7 men, median age 65 years) out of 86 consecutive carcinoid patients treated between 1987 and 1998 developed bone metastases (10%) with a median interval of 37 months between the diagnosis of metastatic carcinoid and bone metastases. Seven of them had non-bronchial primaries. (111)In-pentetreotide scintigraphy failed to detect the bone lesions in 50% of the cases, and (131)I-meta-iodobenzylguanidine(MIBG) scintigraphy in almost 80% of cases. Standard bone scintigraphy, however, was positive in all. Pain relief of bone metastases by means of radiation therapy was obtained in 5 of 6 patients. In another patient palliation of pain symptoms was obtained with Rhenium-186-hydroxyethylidene diphosphonate. Octreotide, Interferon of MIBG were ineffective for this purpose. It is concluded that bone metastases in carcinoid patients may be missed on (131)I-MIBG and (111)In-pentetreotide scintigraphy. Bone scintigraphy is a sensitive imaging technique. Diagnostic nuclear medicine modalities may be helpful in the clinical management of carcinoid disease.

Probabilities for a probabilistic network: a case study in oesophageal cancer.

With the help of two experts in gastrointestinal oncology from The Netherlands Cancer Institute, Antoni van Leeuwenhoekhuis, a decision-support system is being developed for patient-specific therapy selection for oesophageal cancer. The kernel of the system is a probabilistic network that describes the presentation characteristics of cancer of the oesophagus and the pathophysiological processes of invasion and metastasis. While the construction of the graphical structure of the network was relatively straightforward, probability elicitation with existing methods proved to be a major obstacle. To overcome this obstacle, we designed a new method for eliciting probabilities from experts that combines the ideas of transcribing probabilities as fragments of text and of using a scale with both numerical and verbal anchors for marking assessments. In this paper, we report experiences with our method in eliciting the probabilities required for the oesophagus network. The method allowed us to elicit many probabilities in reasonable time. To gain some insight in the quality of the probabilities obtained, we conducted a preliminary evaluation study of our network, using data from real patients. We found that for 85% of the patients, the network predicted the correct cancer stage.