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Health Technology Assessment... Feb 2019Medullary thyroid cancer (MTC) is a rare form of cancer that affects patients' health-related quality of life (HRQoL) and survival. Cabozantinib (Cometriq; Ipsen, Paris,...
BACKGROUND
Medullary thyroid cancer (MTC) is a rare form of cancer that affects patients' health-related quality of life (HRQoL) and survival. Cabozantinib (Cometriq; Ipsen, Paris, France) and vandetanib (Caprelsa; Sanofi Genzyme, Cambridge, MA, USA) are currently the treatment modality of choice for treating unresectable progressive and symptomatic MTC.
OBJECTIVES
(1) To evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. (2) To estimate the incremental cost-effectiveness of cabozantinib and vandetanib versus each other and best supportive care. (3) To identify key areas for primary research. (4) To estimate the overall cost of these treatments in England.
DATA SOURCES
Peer-reviewed publications (searched from inception to November 2016), European Public Assessment Reports and manufacturers' submissions.
REVIEW METHODS
A systematic review [including a network meta-analysis (NMA)] was conducted to evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. The economic analysis included a review of existing analyses and the development of a de novo model.
RESULTS
The systematic review identified two placebo-controlled trials. The Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial evaluated the efficacy and safety of cabozantinib in patients with unresectable locally advanced, metastatic and progressive MTC. The ZETA trial evaluated the efficacy and safety of vandetanib in patients with unresectable locally advanced or metastatic MTC. Both drugs significantly improved progression-free survival (PFS) more than the placebo ( < 0.001). The NMA suggested that, within the symptomatic and progressive MTC population, the effects on PFS were similar (vandetanib vs. cabozantinib: hazard ratio 1.14, 95% credible interval 0.41 to 3.09). Neither trial demonstrated a significant overall survival benefit for cabozantinib or vandetanib versus placebo, although data from ZETA were subject to potential confounding. Both cabozantinib and vandetanib demonstrated significantly better objective response rates and calcitonin (CTN) and carcinoembryonic antigen (CEA) response rates than placebo. Both cabozantinib and vandetanib produced frequent adverse events, often leading to dose interruption or reduction. The assessment group model indicates that, within the EU-label population (symptomatic and progressive MTC), the incremental cost-effectiveness ratios (ICERs) for cabozantinib and vandetanib are > £138,000 per quality-adjusted life-year (QALY) gained. Within the restricted EU-label population (symptomatic and progressive MTC with CEA/CTN doubling times of ≤ 24 months), the ICER for vandetanib is expected to be > £66,000 per QALY gained. The maximum annual budget impact within the symptomatic and progressive population is estimated to be ≈£2.35M for cabozantinib and ≈£5.53M for vandetanib. The costs of vandetanib in the restricted EU-label population are expected to be lower.
LIMITATIONS
The intention-to-treat populations of the EXAM and ZETA trials are notably different. The analyses of ZETA subgroups may be subject to confounding as a result of differences in baseline characteristics and open-label vandetanib use. Attempts to statistically adjust for treatment switching were unsuccessful. No HRQoL evidence was identified for the MTC population.
CONCLUSIONS
The identified trials suggest that cabozantinib and vandetanib improve PFS more than the placebo; however, significant OS benefits were not demonstrated. The economic analyses indicate that within the EU-label population, the ICERs for cabozantinib and vandetanib are > £138,000 per QALY gained. Within the restricted EU-label population, the ICER for vandetanib is expected to be > £66,000 per QALY gained.
FUTURE RESEARCH PRIORITIES
(1) Primary research assessing the long-term effectiveness of cabozantinib and vandetanib within relevant subgroups. (2) Reanalyses of the ZETA trial to investigate the impact of adjusting for open-label vandetanib use using appropriate statistical methods. (3) Studies assessing the impact of MTC on HRQoL.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42016050403.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Anilides; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Neuroendocrine; Cost-Benefit Analysis; England; Humans; Models, Economic; Piperidines; Pyridines; Quality-Adjusted Life Years; Quinazolines; Technology Assessment, Biomedical; Thyroid Neoplasms
PubMed: 30821231
DOI: 10.3310/hta23080 -
Endocrinology and Metabolism (Seoul,... Jun 2018Calcitonin measurement is pivotal in the management of medullary thyroid carcinoma (MTC), but several pitfalls can affect its reliability. Other potential markers have...
BACKGROUND
Calcitonin measurement is pivotal in the management of medullary thyroid carcinoma (MTC), but several pitfalls can affect its reliability. Other potential markers have been proposed, and procalcitonin (ProCT) has been reported as promising. The present study was undertaken to summarize the published data and provide more robust estimates on the reliability of ProCT as marker in the management of patients with MTC.
METHODS
The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The sources comprised studies published through May 2018. Journal Articles that reported series of MTC patients undergone ProCT during postoperative follow-up were searched. A random-effects model was used for statistical pooling of the data. The I² index was used to quantify the consistency among the studies. The Egger test evaluated the possible presence of significant publication bias. Quality assessment of the studies was performed according to Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2).
RESULTS
According to inclusion and exclusion criteria five papers, reporting 296 MTC patients undergone ProCT evaluation, were finally selected. The number of MTC with recurrence was 140. The pooled sensitivity of ProCT in detecting recurrence was 96% (95% confidence interval [CI], 92% to 99%), with neither heterogeneity (I²=0%) nor publication bias (Egger test, 3.16; P=0.99). The pooled specificity was 96% (95% CI, 87% to 100%) with mild heterogeneity (I²=66.6%), while Egger test was not calculable.
CONCLUSION
The present meta-analysis provides evidence that ProCT is reliable to manage MTC patients during their postoperative follow-up.
PubMed: 29947178
DOI: 10.3803/EnM.2018.33.2.204 -
Frontiers in Endocrinology 2018Vandetanib is the most largely used tyrosine kinase inhibitor (TKI) in patients with locally advanced and/or metastatic medullary thyroid cancer (MTC). Here, we...
BACKGROUND
Vandetanib is the most largely used tyrosine kinase inhibitor (TKI) in patients with locally advanced and/or metastatic medullary thyroid cancer (MTC). Here, we conducted a systematic review on its efficacy and attempted to perform a meta-analysis adopting standardized RECIST criteria as end-points.
METHODS
The terms "medullary thyroid" and "protein kinase inhibitor" (then including all TKIs) were searched in PubMed, ClinicalTrials.gov, and CENTRAL. Only original studies reporting the use of Vandetanib as single agent in MTC were included. The last search was performed on October 31, 2017 and registered in PROSPERO on December 12, 2017 (n = CRD42017081537).
RESULTS
The search revealed 487 articles, and, after removing duplicates, reading title and abstract, and screening the eligible papers, 10 studied were finally included. Two papers were randomized controlled trials and eight were observational longitudinal studies. No data were available for overall survival. No heterogeneity nor publication bias were recorded in the pooled rate of complete response (0.7%) and stable disease (47%). Mild to moderate heterogeneity were recorded in the pooled rate of other endpoints. Data of the studies did not allow to perform a meta-analysis of time-to-event outcomes.
CONCLUSION
Vandetanib should be considered as a promising treatment in advanced MTC. However, data based on RECIST endpoints do not currently provide high-level evidence on its efficacy.
PubMed: 29774010
DOI: 10.3389/fendo.2018.00224 -
European Thyroid Journal Jan 2018Positron emission tomography (PET) and PET/CT are functional imaging methods that are widely used in diagnostic procedures in oncology.
BACKGROUND
Positron emission tomography (PET) and PET/CT are functional imaging methods that are widely used in diagnostic procedures in oncology.
OBJECTIVES
The objective of this study was to assess the patient-relevant benefit of PET or PET/CT in patients with thyroid cancer based on a literature review and meta-analysis.
METHODS
A systematic review including studies that had been published until December 2013 was performed. To be included, studies had to prospectively investigate patients with thyroid cancer in a clinical setting of staging, restaging, or diagnosing tumour recurrence.
RESULTS
Out of 3,506 potentially relevant articles, 29 studies were included. No study directly evaluated the benefits of PET. Twenty-eight studies dealt with the diagnostic accuracy of PET or PET/CT, and 1 study evaluated the prognostic value of PET/CT. The authors showed that a positive result of PET/CT in restaging patients with differentiated thyroid cancer yielded a significant decrease in overall survival (hazard ratio, HR 5.01, CI 3.41-6.62). In patients with suspected recurrence of differentiated thyroid cancer, meta-analysis showed higher sensitivity of PET (89.7%, CI 78-99%) and PET/CT (94.3%, CI 87-97%) compared with conventional imaging (65.4%, CI 32-88%) and comparable results for specificity. Due to the low numbers of studies and patients, meta-analyses on medullary carcinoma did not produce meaningful results.
CONCLUSION
The patient-relevant benefits of PET or PET/CT in thyroid cancer could not be evaluated satisfactorily based on the included studies. It remains unclear whether higher diagnostic test accuracy leads to changes in therapeutic strategies and better patient-relevant outcomes.
PubMed: 29594049
DOI: 10.1159/000481707 -
Hormones (Athens, Greece) Oct 2017Several articles have demonstrated the high diagnostic performance of somatostatin receptor positron emission tomography (PET) in patients with neuroendocrine tumours... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Several articles have demonstrated the high diagnostic performance of somatostatin receptor positron emission tomography (PET) in patients with neuroendocrine tumours (NETs). On the other hand, only a few studies have evaluated the detection rate (DR) of this imaging method in recurrent medullary thyroid carcinoma (MTC). We aimed to perform a systematic review and a meta-analysis of the DR of somatostatin receptor PET or PET/CT in patients with recurrent MTC to add evidence-based data to this setting.
METHODS
A comprehensive computer literature search of studies published in PubMed/MEDLINE and the Cochrane Library Database through May 2017 and regarding somatostatin receptor PET or PET/CT in patients with recurrent MTC was carried out. DR was determined on a per patient-basis. A sub-analysis considering serum calcitonin (Ctn) values was also performed.
RESULTS
Nine studies on the diagnostic performance of somatostatin receptor PET or PET/CT in detecting recurrent MTC were discussed in the systematic review. The meta-analysis of these selected studies provided the following DR on a per patient-based analysis: 63.5% [95% confidence interval (95%CI): 49-77]. Heterogeneity among the selected studies was found. DR of somatostatin receptor PET or PET/CT increased in patients with higher serum Ctn levels (83% for Ctn >500 ng/L).
CONCLUSIONS
In patients with recurrent MTC, somatostatin receptor PET or PET/CT demonstrated a non-optimal DR which increased in patients with higher serum Ctn values. The diagnostic performance of somatostatin receptor PET or PET/CT in recurrent MTC is lower compared to that of the same imaging method in the majority of NETs.
Topics: Carcinoma, Neuroendocrine; Humans; Neoplasm Recurrence, Local; Positron-Emission Tomography; Receptors, Somatostatin; Thyroid Neoplasms
PubMed: 29518756
DOI: 10.14310/horm.2002.1756 -
OncoTargets and Therapy 2016Vandetanib is a promising anticancer targeted agent for treating advanced carcinomas, such as non-small-cell lung cancer, small-cell lung cancer, breast cancer,...
BACKGROUND AND PURPOSE
Vandetanib is a promising anticancer targeted agent for treating advanced carcinomas, such as non-small-cell lung cancer, small-cell lung cancer, breast cancer, malignant glioma, hepatocellular cancer, and unresectable, locally advanced, or metastatic medullary thyroid cancer. However, diarrhea is a frequently reported adverse event. The incidence of vandetanib-associated diarrhea varies extensively in different study populations and has not been carefully estimated. This systematic review and meta-analysis of clinical trials aims to figure out the overall risks of all-grade and high-grade diarrhea during vandetanib treatment and get a better understanding of its prediction and management.
MATERIALS AND METHODS
A comprehensive search was performed in EMBASE, PubMed, and Cochrane Library for clinical trials studying vandetanib and diarrhea prior to April 2015. Eligible articles were selected according to the inclusion criteria. Data were extracted to calculate the summary incidence of all-grade and high-grade diarrhea caused by vandetanib treatment.
RESULTS
Thirteen clinical trials that involved 3,264 patients were included in this meta-analysis. The overall incidences of all-grade and high-grade diarrhea caused by vandetanib treatment were 52.1% (95% confidence interval [CI], 48.3%-55.8%) and 5.6% (95% CI, 4.4%-76.7%), respectively. The risk ratios of the all-grade and high-grade diarrhea for vandetanib arm versus control arm were 1.932 (95% CI, 1.746-2.138; P<0.001) and 3.190 (95% CI, 2.061-4.938; P<0.001), respectively. Studies with small-cell lung cancer demonstrated the highest incidence of all-grade diarrhea (78.85%) and high-grade diarrhea (17.31%), whereas the lowest incidences of all-grade (42.11%) and high-grade (2.67%) diarrhea are seen in patients with hepatocellular carcinoma and non-small-cell lung cancer, respectively.
CONCLUSION
Our findings demonstrate that the administration of vandetanib leads to a significantly increased risk of diarrhea, which varies in different carcinoma patients. Early recognition and timely management may be key factors to avoid dose reduction, drug interruption, and drug discontinuation, which is significant to maximize the treatment benefits.
PubMed: 27382300
DOI: 10.2147/OTT.S96830 -
Thyroid : Official Journal of the... Aug 2016The 2015 American Thyroid Association (ATA) thyroid nodule guidelines recommend selecting nodules for biopsy based on a sonographic pattern classification. These... (Meta-Analysis)
Meta-Analysis Review
New American Thyroid Association Sonographic Patterns for Thyroid Nodules Perform Well in Medullary Thyroid Carcinoma: Institutional Experience, Systematic Review, and Meta-Analysis.
BACKGROUND
The 2015 American Thyroid Association (ATA) thyroid nodule guidelines recommend selecting nodules for biopsy based on a sonographic pattern classification. These patterns were developed based on features of differentiated thyroid cancer. This study aimed to evaluate the performance and the inter-observer agreement of this classification system in medullary thyroid carcinoma (MTC).
METHODS
The medical records of all patients with MTC evaluated at the authors' institution between 1998 and 2014 were retrospectively reviewed. Only patients with presurgical thyroid ultrasound available for review were included in the study. Five independent reviewers assessed the stored ultrasound images for composition, echogenicity, margins, presence of calcifications, and extrathyroidal extension for each nodule. The presence of suspicious lymph nodes was also evaluated when presurgical lateral neck ultrasound was available for review. Each nodule was classified according to the ATA sonographic patterns. Inter-observer agreement was calculated for each sonographic feature and for the sonographic patterns. To validate the findings, a systematic review of the literature and meta-analysis on the sonographic features of MTC was conducted.
RESULTS
In this institutional cohort, the inter-observer agreement for individual sonographic features was moderate to good (κ = 0.45-0.71), and for the ATA classification it was good (κ = 0.72). Ninety-seven percent (29/30) of the MTCs were classified in the intermediate or high suspicion patterns. A total of 249 MTCs were included in the meta-analysis. Based on pooled frequencies for solid composition and hypoechogenicity, >95% of MTCs would be classified at least in the intermediate suspicion pattern, warranting the lowest-size threshold for biopsy (≥1 cm).
CONCLUSIONS
The sonographic patterns proposed by the ATA perform well in MTC, and inter-observer agreement is good to very good.
Topics: Carcinoma, Medullary; Humans; Thyroid Gland; Thyroid Neoplasms; Thyroid Nodule; Ultrasonography; United States
PubMed: 27267210
DOI: 10.1089/thy.2016.0196 -
Endocrine-related Cancer Feb 2016In differentiated thyroid carcinoma refractory to radioactive iodine (CDT-RTI), chemotherapy has been considered for decades to be the only systemic therapy with... (Review)
Review
In differentiated thyroid carcinoma refractory to radioactive iodine (CDT-RTI), chemotherapy has been considered for decades to be the only systemic therapy with palliative purpose. Phase II studies assessing the efficacy of different chemotherapy outlines have been published. Nevertheless, phase III studies in these tumours have not been performed. Our objective is to evaluate the effectiveness of chemotherapy in patients with CDT-RTI by a systematic review of published studies. Systematic research of the literature in Medline and Embase databases (among others) was carried out. The full texts of selected references were analysed by two independent reviewers and then assessed for risk of bias in each study. We also extracted data using specifically designed questionnaires. Later, a qualitative synthesis of results was performed and pooled data were calculated. We found that 16 studies with 473 patients published in the last 40 years were included out of 509 identified references in databases. Thirteen studies (176 patients) included data on response to treatment and histology. Four studies included 70 patients only with well-differentiated non-medullary tumours. Response rate (RR) was 22.1% (0-57%) for 13 studies, 25% for the 176 patients and 27.1% for the 70 patients, with 2.5, 3.4 and 2.8% complete responses respectively. Survival times could not be assessed or pooled due to the lack of data and heterogeneity of the studies, and was determined to have a high risk of bias. Although it has not been possible to find solid evidence about the efficacy of chemotherapy, the results shown indicate that it may have some effectiveness, although this should be proven with well-designed studies using modern drugs.
Topics: Adenocarcinoma; Antineoplastic Agents; Disease Progression; Humans; Severity of Illness Index; Thyroid Neoplasms; Treatment Outcome
PubMed: 27064164
DOI: 10.1530/ERC-15-0194 -
The Oncologist Jul 2016Everolimus, an oral mTOR (mammalian target of rapamycin) inhibitor, is currently approved for the treatment of progressive pancreatic neuroendocrine tumors (NETs).... (Review)
Review
BACKGROUND
Everolimus, an oral mTOR (mammalian target of rapamycin) inhibitor, is currently approved for the treatment of progressive pancreatic neuroendocrine tumors (NETs). Although promising, only scattered data, often from nondedicated studies, are available for extrapancreatic NETs.
PATIENTS AND METHODS
A systematic review of the published data was performed concerning the use of everolimus in extrapancreatic NET, with the aim of summarizing the current knowledge on its efficacy and tolerability. Moreover, the usefulness of everolimus was evaluated according to the different sites of the primary.
RESULTS
The present study included 22 different publications, including 874 patients and 456 extrapancreatic NETs treated with everolimus. Nine different primary sites of extrapancreatic NETs were found. The median progression-free survival ranged from 12.0 to 29.9 months. The median time to progression was not reached in a phase II prospective study, and the interval to progression ranged from 12 to 36 months in 5 clinical cases. Objective responses were observed in 7 prospective studies, 2 retrospective studies, and 2 case reports. Stabilization of the disease was obtained in a high rate of patients, ranging from 67.4% to 100%. The toxicity of everolimus in extrapancreatic NETs is consistent with the known safety profile of the drug. Most adverse events were either grade 1 or 2 and easy manageable with a dose reduction or temporary interruption and only rarely requiring discontinuation.
CONCLUSION
Treatment with everolimus in patients with extrapancreatic NETs appears to be a promising strategy that is safe and well tolerated. The use of this emerging opportunity needs to be validated with clinical trials specifically designed on this topic.
IMPLICATIONS FOR PRACTICE
The present study reviewed all the available published data concerning the use of everolimus in 456 extrapancreatic neuroendocrine tumors (NETs) and summarized the current knowledge on the efficacy and safety of this drug, not yet approved except for pancreatic NETs. The progression-free survival rates and some objective responses seem promising and support the extension of the use of this drug. The site-by-site analysis seems to suggest that some subtypes of NETs, such as colorectal, could be more sensitive to everolimus than other primary NETs. No severe adverse events were usually reported and discontinuation was rarely required; thus, everolimus should be considered a valid therapeutic option for extrapancreatic NETs.
Topics: Adrenal Gland Neoplasms; Antineoplastic Agents; Carcinoma, Neuroendocrine; Colorectal Neoplasms; Disease-Free Survival; Everolimus; Humans; Ileal Neoplasms; Lung Neoplasms; Neuroendocrine Tumors; Pheochromocytoma; Stomach Neoplasms; Thyroid Neoplasms
PubMed: 27053503
DOI: 10.1634/theoncologist.2015-0420 -
The Journal of Clinical Endocrinology... Sep 2015Ectopic Cushing's Syndrome (ECS) can be a diagnostic challenge with the hormonal source difficult to find. This study analyzes the accuracy of imaging studies in ECS... (Review)
Review
CONTEXT
Ectopic Cushing's Syndrome (ECS) can be a diagnostic challenge with the hormonal source difficult to find. This study analyzes the accuracy of imaging studies in ECS localization.
EVIDENCE ACQUISITION
Systematic review of medical literature for ECS case series providing individual patient data on at least one conventional imaging technique (computed tomography [CT]/magnetic resonance imaging) and one of the following: 111In-pentetreotide (OCT), 131I/123I-metaiodobenzylguanidine, 18Ffluoro-2-deoxyglucose-positron emission tomography (FDG-PET), 18F-fluorodopa-PET (F-DOPA-PET), 68Ga- DOTATATE-PET/CT or 68Ga-DOTATOC-PET/CT scan (68Gallium-SSTR-PET/CT).
EVIDENCE SUMMARY
The analysis comprised 231 patients (females, 50.2%; age, 42.617 y). Overall, 52.4%(121/231) had "overt" ECS,18.6% had "occult" ECS, and 29% had "covert" ECS. Tumors were located in the lung (55.3%), mediastinum-thymus (7.9%), pancreas (8.5%), adrenal glands (6.4%), gastrointestinal tract (5.4%), thyroid (3.7%), and other sites (12.8%), and primary tumors were mostly bronchial neuroendocrine tumors (NETs) (54.8%), pancreatic NETs (8%), mediastinum-thymus NETs (6.9%), gastrointestinal NETs (5.3%), pheochromocytoma (6.4%), neuroblastoma (3.2%), and medullary thyroid carcinoma (3.2%). Tumors were localized byCTin66.2%(137/207), magnetic resonance imaging in 51.5% (53/103), OCT in 48.9% (84/172), FDG-PET in 51.7% (46/89), F-DOPAPET in 57.1% (12/21), 131/123I-metaiodobenzylguanidine in 30.8% (4/13), and 68Gallium-SSTRPET/CT in 81.8% (18/22) of cases. Molecular imaging discovered 79.1% (53/67) of tumors unidentified by conventional radiology, with OCT the most commonly used, revealing the tumor in 64%, followed by FDG-PET in 59.4%. F-DOPA-PET was used in only seven covert cases (sensitivity, 85.7%). Notably, 68Gallium-SSTR-PET/CT had 100% sensitivity among covert cases.
CONCLUSIONS
Nuclear medicine improves the sensitivity of conventional radiology when tumor site identification is problematic. OCT offers a good availability/reliability ratio, and FDG-PET was proven useful. 68Gallium-SSTR-PET/CT use was infrequent, despite offering the highest sensitivity.
Topics: Cushing Syndrome; Diagnostic Imaging; Humans; Nuclear Medicine; Reproducibility of Results
PubMed: 26158607
DOI: 10.1210/JC.2015-1589