- Email: [email protected]
Biomarkers in management of carcinoid tumours
Abstracts / Biomedicine & Pharmacotherapy 62 (2008) 513e525
Materials and methods From 1984 to 2007, 15 young patients underwent surgical treatment for DTC by the same surgeon at our Department. There were 11 females and 4 males; the mean age was 14.7 years (range 8-18) The follow up consisted of clinical examination, serum thyroglobulin measurement, antithyroglobulin antibody levels, high resolution US, and, when necessary, other imaging techniques in addition to I-131 Whole Body Scan, such as chest X-ray, liver US, Computed Tomography (CT) scan, and 18-Fluorodeoxyglucose PET/CT scanning, added in 1995. Results All patients underwent total thyroidectomy, node dissection was performed in all cases, of which central compartment in 12 cases (80%) and lateral compartment in 3 cases (20%). According to TNM staging system, 3 patients (20%) were T1, 3 (20%) were T2, 5 (33%) were T3 and 4 (27%) were T4; 2 patients (13%) were N0 and 13 (87%) were N1; 2 patients (13%) were M1 for pulmonary metastases; 13 cases (87%) were stage I and 2 (13%) were stage II. 131-I therapy was performed in all cases, due to pulmonary metastases in 2 (13%). At an average follow up of 133.85 months (range 5.58 to 420.69), all patients are alive; Thyroglobulin level is > 2 ng/ml in 5 cases. Discussion In children, DTC manifests itself with a high incidence of cervical node metastases, extra-thyroidal extent and distant metastases, the most common sites of which are the lungs and the bone (1-4). According to our experience, we suggest that total thyroidectomy, node dissection and 131-Iodine therapy may be proposed as the treatment of choice in childhood DTC, despite the positive biological behavior. References 1. Pazaitou-Panayiotou K. Differentiated thyroid carcinoma in children and adolescents: Clinical course and therapeutic approach. Pediatr Endocrinol Rev. 2004 Aug;1 Suppl 3:50812. Review. 2. Okada T, Sasaki F, Takahashi H et al. Management of childhood and adolescent thyroid carcinoma: long-term follow-up and clinical characteristics. Eur J Pediatr Surg. 2006 Feb;16(1):8-13. 3. Zimmerman D, Hay ID, Gough IR, Goellner JR, Ryan JJ, Grant CS, McConahey WM. Papillary thyroid carcinoma in children and adults: long term follow up of 1039 patients conservatively treated at one institution during three decades. Surgery 1988; 104(6):1157-66. 4. Grisby PW, Gal-Or A, Michalski JM, Doherty GM. Childood and adolescent thyroid carcinoma. Cancer 2002;95(4): 724-29. E-mail address: [email protected] (I.M. Boschin).
20 Biomarkers in management of carcinoid tumours Catharina M. Korse 1, Johannes M.G. Bonfrer 1, Babs G. Taal 2
523
1
Department of Clinical Chemistry, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands 2 Department of Medical Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
Background: Urinary 5-HIAA excretion is a well-known marker in neuroendocrine tumours (NET), but has a low sensitivity and the 24-hour collection is inconvenient for patients. In the last decade Chromogranin A (CgA) has been established as a marker for neuroendocrine tumours (NETs), but a thorough evaluation during follow-up is still lacking. Carcinoid heart disease (CHD) develops in 20-70% of patients with liver metastases and is a major cause of death in patients with carcinoid syndrome. An option to screen for cardiac dysfunction is the use of NT-proBNP, a useful marker for left ventricular dysfunction. The objective of the first, a longitudinal, study was to compare CgA and 5-HIAA with self-reported questionnaires during follow-up, and the objective of the second, a cross-sectional, study was to examine the combined diagnostic value of CgA and NTproBNP for CHD. Methods: Study 1:39 patients with metastatic gastrointestinal NET were monitored during treatment with the long-acting octreotide SandostatinLARÒ. A comparison was made between serum CgA and urinary 5-HIAA in relation to quality of life (HRQL) assessed by the EORTC QLQ-C30 questionnaire, supplemented with questions specific to carcinoid symptoms. Survival analyses were performed to examine the association between the markers and survival time. Study 2: From 102 NET-patients serum samples were obtained and cardiac ultrasound studies were performed. The measure for CHD was tricuspid regurgitation (TR) stage III/ IV. Logistic regression analyses were used to predict the presence of CHD and Cox regression analyses to investigate the relation between the markers and overall survival. Results Study 1:Correlations were found between CgA and physical functioning (p¼0.01) and quality of life (p¼0.03), while no significant correlations were observed between 5HIAA levels and any of the self-reported health outcomes. Cox regression showed an association between CgA levels and survival time (p¼0.02), while no significant association was observed between 5-HIAA levels and survival time. Study 2:Of 14 patients (14%) with CHD, 12 patients (86%) had elevated NT-proBNP levels, with a specificity of 80%. In the multiple logistic regression analysis NT-proBNP (p<0.001), carcinoid syndrome (p¼0.018) and gender (p¼0.046) were independent significant prognostic variables for CHD (p<0.001). CgA and NT-proBNP were independent prognostic parameters for overall survival (p<0.001 and p¼0.023 respectively). Conclusions: Stronger correlations of CgA compared to 5HIAA with physical functioning and well-being, the convenience of measuring in blood, as well as the prognostic value of CgA for survival, makes CgA the recommended marker in the management of patients with metastatic NET.
524
Abstracts / Biomedicine & Pharmacotherapy 62 (2008) 513e525
NT-proBNP is a helpful diagnostic marker for CHD in patients with NET. Patients with elevated NT-proBNP in addition to elevated CgA levels showed worse survival than patients with elevated CgA alone. E-mail address: [email protected] (C.M. Korse).
21 Positron emission tomography for functional imaging of neuroendocrine tumours Felix M. Mottaghy Department of Nuclear Medicine, University Hospital, Leuven Herestraat 49, 3000 Leuven, Belgium Neuroendocrine tumours (NET) have several distinct pathophysiological features that can be addressed by specific radiolabelled probes. An overview on the different radiopharmaceuticals that have been developed for positron emission tomography (PET) of neuroendocrine tumours will be presented. The focus will be on fluordeoxyglucose (FDG), biogenic amine precursors, somatostatin analogues and hormone syntheses markers. Due to the highly specific tracers lacking any clear anatomical landmarking the advantages of integrated functional and morphological imaging systems such as PET/ CT are obvious. Based on the up to now published literature and the own experience it is concluded that amine precursors (e.g. fluor-dihydroxyphenylalanin (FDOPA) and hydroxytryptophane (HTP)) should be employed in most gastroenteropancreatic NET, whereas FDG should be preserved for more aggressive less differentiated NETs. The different available somatostatin analogues are the most promising tracers, since they can improve dosimetry in cases were peptide receptor radiotherapies (PRRT) are planned. Of specific interest are the somatostatin analogues addressing several subtypes of the somatostatin receptor (e.g. DOTANOC) that allow detecting also subtypes not expressing the ’’classically‘‘ addressed subtype 2 and 5. Hormone syntheses markers have up to now only been used in few centres and their broad clinical value remains uncertain. Since neuroendocrine tumours have a high variety of different features the individual diagnostic approach using PET or integrated PET/CT should be tailored depending on the histological classification and the differentiation of the tumour. E-mail address: [email protected]
22 Peptide receptor radionuclide therapy with radiolabelled somatostatin analogues: ten years experience Lisa Bodei, Chiara M. Grana, Mirco Bartolomei, Silvia M. Baio, Maribel Lopera Sierra, Giovanni Paganelli Nuclear Medicine Division, European Institute of Oncology, Milano, Italy
Neuroendocrine tumours (NETs) are relatively rare tumours, mainly originating from the digestive system, able to produce a number of specific bioactive amines and hormones. Treatment of NETs is usually multidisciplinary and should be individualised according to the tumour type, burden, and symptoms. Therapeutic tools in NETs include surgery, interventional radiology and medical treatments such as somatostatin analogues, interferon, chemotherapy, new targeted drugs and peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues. NETs usually over-express somatostatin receptors on their cell surface, thus enabling the therapeutic use of somatostatin analogues, one of the basic tools for NETs. PRRT consists in the systemic administration of a synthetic hormone peptide analogue, such as a somatostatin analogue, radiolabelled with a suitable beta-emitting radionuclide. These compounds are able to irradiate tumours and their metastases via the internalization through a specific receptor subtype, generally over-expressed on the cell membrane. PRRT can deliver radiation doses to tumours, which are able to achieve significant volume reduction. Treatment with radiolabeled somatostatin analogues, such as [90Y-DOTA0,Tyr3]-octreotide (or 90Y-DOTATOC) and [177LuDOTA0,Tyr3,Thr8]-octreotide (or 177Lu-DOTATATE), is a valuable new tool in the management of patients with inoperable or metastasized gastro-entero-pancreatic (GEP) neuroendocrine tumours. Clinical trials performed in several countries over more than a decade showed complete and partial responses in 10 to 30% of patients for [90Y-DOTA0,Tyr3]-octreotide. In the clinical trial with [177Lu-DOTA0,Tyr3]-octreotate, 30% objective responses were registered, with a median survival time >48 months. Significant biochemical and symptomatic responses in functioning tumours were encountered for both radiopeptides. Toxicity is generally mild, if adequate protective measures are taken, and may involve kidneys and bone marrow. These data indicate that PRRT is a convincing option in the treatment scenario of GEP tumours. Newer peptides, with higher affinity for other somatostatin receptor subtypes, are presently under investigation and could extend PRRT to other endocrine as well as non-endocrine tumours. In the future, neuroendocrine tumours could be treated also with other radiolabelled peptides such as bombesin, gastrin, neurotensin, substance P, GLP-1, neuropeptide Y, and CRH analogues. Clinical experiences are ongoing with radiopeptides such as radiolabelled gastrin analogues in medullary thyroid carcinoma, substance-P analogues in high-grade glioma and bombesin analogues in hormone-refractory prostate carcinoma. E-mail address: [email protected] (L. Bodei). 23 PET TC for target therapy R.M. Moresco IBFM-CNR, Istituto Scientifico H San Raffaele, Unievrsita` degli Studi Milano Bicocca, Milan Italy
Materials and methods From 1984 to 2007, 15 young patients underwent surgical treatment for DTC by the same surgeon at our Department. There were 11 females and 4 males; the mean age was 14.7 years (range 8-18) The follow up consisted of clinical examination, serum thyroglobulin measurement, antithyroglobulin antibody levels, high resolution US, and, when necessary, other imaging techniques in addition to I-131 Whole Body Scan, such as chest X-ray, liver US, Computed Tomography (CT) scan, and 18-Fluorodeoxyglucose PET/CT scanning, added in 1995. Results All patients underwent total thyroidectomy, node dissection was performed in all cases, of which central compartment in 12 cases (80%) and lateral compartment in 3 cases (20%). According to TNM staging system, 3 patients (20%) were T1, 3 (20%) were T2, 5 (33%) were T3 and 4 (27%) were T4; 2 patients (13%) were N0 and 13 (87%) were N1; 2 patients (13%) were M1 for pulmonary metastases; 13 cases (87%) were stage I and 2 (13%) were stage II. 131-I therapy was performed in all cases, due to pulmonary metastases in 2 (13%). At an average follow up of 133.85 months (range 5.58 to 420.69), all patients are alive; Thyroglobulin level is > 2 ng/ml in 5 cases. Discussion In children, DTC manifests itself with a high incidence of cervical node metastases, extra-thyroidal extent and distant metastases, the most common sites of which are the lungs and the bone (1-4). According to our experience, we suggest that total thyroidectomy, node dissection and 131-Iodine therapy may be proposed as the treatment of choice in childhood DTC, despite the positive biological behavior. References 1. Pazaitou-Panayiotou K. Differentiated thyroid carcinoma in children and adolescents: Clinical course and therapeutic approach. Pediatr Endocrinol Rev. 2004 Aug;1 Suppl 3:50812. Review. 2. Okada T, Sasaki F, Takahashi H et al. Management of childhood and adolescent thyroid carcinoma: long-term follow-up and clinical characteristics. Eur J Pediatr Surg. 2006 Feb;16(1):8-13. 3. Zimmerman D, Hay ID, Gough IR, Goellner JR, Ryan JJ, Grant CS, McConahey WM. Papillary thyroid carcinoma in children and adults: long term follow up of 1039 patients conservatively treated at one institution during three decades. Surgery 1988; 104(6):1157-66. 4. Grisby PW, Gal-Or A, Michalski JM, Doherty GM. Childood and adolescent thyroid carcinoma. Cancer 2002;95(4): 724-29. E-mail address: [email protected] (I.M. Boschin).
20 Biomarkers in management of carcinoid tumours Catharina M. Korse 1, Johannes M.G. Bonfrer 1, Babs G. Taal 2
523
1
Department of Clinical Chemistry, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands 2 Department of Medical Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
Background: Urinary 5-HIAA excretion is a well-known marker in neuroendocrine tumours (NET), but has a low sensitivity and the 24-hour collection is inconvenient for patients. In the last decade Chromogranin A (CgA) has been established as a marker for neuroendocrine tumours (NETs), but a thorough evaluation during follow-up is still lacking. Carcinoid heart disease (CHD) develops in 20-70% of patients with liver metastases and is a major cause of death in patients with carcinoid syndrome. An option to screen for cardiac dysfunction is the use of NT-proBNP, a useful marker for left ventricular dysfunction. The objective of the first, a longitudinal, study was to compare CgA and 5-HIAA with self-reported questionnaires during follow-up, and the objective of the second, a cross-sectional, study was to examine the combined diagnostic value of CgA and NTproBNP for CHD. Methods: Study 1:39 patients with metastatic gastrointestinal NET were monitored during treatment with the long-acting octreotide SandostatinLARÒ. A comparison was made between serum CgA and urinary 5-HIAA in relation to quality of life (HRQL) assessed by the EORTC QLQ-C30 questionnaire, supplemented with questions specific to carcinoid symptoms. Survival analyses were performed to examine the association between the markers and survival time. Study 2: From 102 NET-patients serum samples were obtained and cardiac ultrasound studies were performed. The measure for CHD was tricuspid regurgitation (TR) stage III/ IV. Logistic regression analyses were used to predict the presence of CHD and Cox regression analyses to investigate the relation between the markers and overall survival. Results Study 1:Correlations were found between CgA and physical functioning (p¼0.01) and quality of life (p¼0.03), while no significant correlations were observed between 5HIAA levels and any of the self-reported health outcomes. Cox regression showed an association between CgA levels and survival time (p¼0.02), while no significant association was observed between 5-HIAA levels and survival time. Study 2:Of 14 patients (14%) with CHD, 12 patients (86%) had elevated NT-proBNP levels, with a specificity of 80%. In the multiple logistic regression analysis NT-proBNP (p<0.001), carcinoid syndrome (p¼0.018) and gender (p¼0.046) were independent significant prognostic variables for CHD (p<0.001). CgA and NT-proBNP were independent prognostic parameters for overall survival (p<0.001 and p¼0.023 respectively). Conclusions: Stronger correlations of CgA compared to 5HIAA with physical functioning and well-being, the convenience of measuring in blood, as well as the prognostic value of CgA for survival, makes CgA the recommended marker in the management of patients with metastatic NET.
524
Abstracts / Biomedicine & Pharmacotherapy 62 (2008) 513e525
NT-proBNP is a helpful diagnostic marker for CHD in patients with NET. Patients with elevated NT-proBNP in addition to elevated CgA levels showed worse survival than patients with elevated CgA alone. E-mail address: [email protected] (C.M. Korse).
21 Positron emission tomography for functional imaging of neuroendocrine tumours Felix M. Mottaghy Department of Nuclear Medicine, University Hospital, Leuven Herestraat 49, 3000 Leuven, Belgium Neuroendocrine tumours (NET) have several distinct pathophysiological features that can be addressed by specific radiolabelled probes. An overview on the different radiopharmaceuticals that have been developed for positron emission tomography (PET) of neuroendocrine tumours will be presented. The focus will be on fluordeoxyglucose (FDG), biogenic amine precursors, somatostatin analogues and hormone syntheses markers. Due to the highly specific tracers lacking any clear anatomical landmarking the advantages of integrated functional and morphological imaging systems such as PET/ CT are obvious. Based on the up to now published literature and the own experience it is concluded that amine precursors (e.g. fluor-dihydroxyphenylalanin (FDOPA) and hydroxytryptophane (HTP)) should be employed in most gastroenteropancreatic NET, whereas FDG should be preserved for more aggressive less differentiated NETs. The different available somatostatin analogues are the most promising tracers, since they can improve dosimetry in cases were peptide receptor radiotherapies (PRRT) are planned. Of specific interest are the somatostatin analogues addressing several subtypes of the somatostatin receptor (e.g. DOTANOC) that allow detecting also subtypes not expressing the ’’classically‘‘ addressed subtype 2 and 5. Hormone syntheses markers have up to now only been used in few centres and their broad clinical value remains uncertain. Since neuroendocrine tumours have a high variety of different features the individual diagnostic approach using PET or integrated PET/CT should be tailored depending on the histological classification and the differentiation of the tumour. E-mail address: [email protected]
22 Peptide receptor radionuclide therapy with radiolabelled somatostatin analogues: ten years experience Lisa Bodei, Chiara M. Grana, Mirco Bartolomei, Silvia M. Baio, Maribel Lopera Sierra, Giovanni Paganelli Nuclear Medicine Division, European Institute of Oncology, Milano, Italy
Neuroendocrine tumours (NETs) are relatively rare tumours, mainly originating from the digestive system, able to produce a number of specific bioactive amines and hormones. Treatment of NETs is usually multidisciplinary and should be individualised according to the tumour type, burden, and symptoms. Therapeutic tools in NETs include surgery, interventional radiology and medical treatments such as somatostatin analogues, interferon, chemotherapy, new targeted drugs and peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues. NETs usually over-express somatostatin receptors on their cell surface, thus enabling the therapeutic use of somatostatin analogues, one of the basic tools for NETs. PRRT consists in the systemic administration of a synthetic hormone peptide analogue, such as a somatostatin analogue, radiolabelled with a suitable beta-emitting radionuclide. These compounds are able to irradiate tumours and their metastases via the internalization through a specific receptor subtype, generally over-expressed on the cell membrane. PRRT can deliver radiation doses to tumours, which are able to achieve significant volume reduction. Treatment with radiolabeled somatostatin analogues, such as [90Y-DOTA0,Tyr3]-octreotide (or 90Y-DOTATOC) and [177LuDOTA0,Tyr3,Thr8]-octreotide (or 177Lu-DOTATATE), is a valuable new tool in the management of patients with inoperable or metastasized gastro-entero-pancreatic (GEP) neuroendocrine tumours. Clinical trials performed in several countries over more than a decade showed complete and partial responses in 10 to 30% of patients for [90Y-DOTA0,Tyr3]-octreotide. In the clinical trial with [177Lu-DOTA0,Tyr3]-octreotate, 30% objective responses were registered, with a median survival time >48 months. Significant biochemical and symptomatic responses in functioning tumours were encountered for both radiopeptides. Toxicity is generally mild, if adequate protective measures are taken, and may involve kidneys and bone marrow. These data indicate that PRRT is a convincing option in the treatment scenario of GEP tumours. Newer peptides, with higher affinity for other somatostatin receptor subtypes, are presently under investigation and could extend PRRT to other endocrine as well as non-endocrine tumours. In the future, neuroendocrine tumours could be treated also with other radiolabelled peptides such as bombesin, gastrin, neurotensin, substance P, GLP-1, neuropeptide Y, and CRH analogues. Clinical experiences are ongoing with radiopeptides such as radiolabelled gastrin analogues in medullary thyroid carcinoma, substance-P analogues in high-grade glioma and bombesin analogues in hormone-refractory prostate carcinoma. E-mail address: [email protected] (L. Bodei). 23 PET TC for target therapy R.M. Moresco IBFM-CNR, Istituto Scientifico H San Raffaele, Unievrsita` degli Studi Milano Bicocca, Milan Italy