Carcinoembryonic Antigen Doubling Time Research Articles

Usefulness of Carcinoembryonic Antigen Doubling Time in Prognosis Prediction after Curative Resection of Locally Recurrent Rectal Cancer: A Retrospective Study

Introduction: Given that doubling time is an indicator of tumor growth, we assessed the usefulness of carcinoembryonic antigen doubling time (CEA-DT) in prognosis prediction after curative resection for locally recurrent rectal cancer. Methods: During January 1986–December 2016, 33 patients with locally recurrent rectal cancer who underwent curative resection at our hospital were retrospectively reviewed. The primary endpoint was the 3-year recurrence-free survival (RFS) rate. The Kaplan-Meier method was used to compare RFS rates and evaluate univariate and multivariate analyses for factors associated with oncologic outcomes, including CEA-DT. CEA-DT was classified into 2 groups: the short and long CEA-DT groups. Results: The 3-year overall survival and RFS rates were 62.6% and 42.4%, respectively. In multivariate analyses, CEA-DT was an independent risk factor for poor RFS. The 3-year RFS rate was significantly better in the long CEA-DT group than in the short CEA-DT group (58.8% vs. 25.0%, p = 0.0063). Conclusion: CEA-DT is a useful prognostic factor that can be assessed before surgery for locally recurrent rectal cancer. Long CEA-DT may indicate a favorable prognosis. Contrarily, short CEA-DT is associated with poor prognosis; therefore, further treatment intervention is necessary for patients with short CEA-DT.

Prognostic significance of doubling time in patients undergoing radical surgery for metachronous peritoneal metastases of colorectal cancer.

The doubling times of tumor volume and tumor markers are associated with the prognosis of liver or lung metastases from colorectal cancer (CRC). However, no studies have assessed peritoneal metastases. Therefore, we aimed to elucidate the association between doubling time and the prognosis of patients who underwent radical surgery for metachronous peritoneal metastases of CRC. We calculated the tumor doubling times (TDT) of peritoneal metastases and serum carcinoembryonic antigen-doubling times (CEA-DT) in 33 consecutive patients who underwent radical surgery for metachronous peritoneal metastases between January 2006 and April 2017. The impact of short TDT and CEA-DT on overall survival (OS) and relapse-free survival (RFS) was retrospectively reviewed. In long TDT (> 137days) group, the 5-year OS rate was 74.1% and median OS time was 6.6years. In long CEA-DT (> 102days) group, the 5-year OS rate was 50.0% and median OS time was 5.6years. Conversely, in short TDT (≤ 137days) and CEA-DT (≤ 102days) group, the 5-year OS rates and median OS times were both 0.0% and 3.2years, respectively. In the multivariate analysis, short TDT was an independent risk factor for poor RFS (P = 0.006) and OS (P = 0.010). Similarly, short CEA-DT was also a poor risk factor for RFS (P < 0.001) and OS (P = 0.012). Short TDT and CEA-DT are independent risk factors for poor OS and RFS after surgery for metachronous peritoneal metastases of CRC. TDT and CEA-DT should be considered when selecting candidates for surgical resection.

68Ga-DOTANOC and 18F-FDG PET/CT in metastatic medullary thyroid carcinoma: novel correlations with tumoral biomarkers.

Metastatic disease is common in medullary thyroid carcinoma (MTC) and it is usually detected by raising calcitonin and carcinoembryonic antigen (CEA) levels. Nuclear medicine imaging has an important role in lesion identification/characterisation. We aim to compare 68Ga-DOTANOC PET/CT and 18F-FDG PET/CT performance and to explore the correlations between tumoral markers and functional imaging. This a retrospective cross-sectional study including 13 patients with MTC and high calcitonin/CEA levels that underwent both 68Ga-DOTANOC PET/CT and 18F-FDG PET/CT. 68Ga-DOTANOC PET/CT identified MTC metastases in 2twopatients that were 18F-FDG-negative (sensitivity of 69.2% vs. 53.9%, respectively). 68Ga-DOTANOC PET/CT also detected a higher number of lesions than 18F-FDG PET/CT in seven patients, with only one patient showing the opposite pattern. Both differences lacked statistical significance (p = 0.50 and p = 0.86, respectively) but 68Ga-DOTANOC PET/CT better performance allowed changes in patients' management. 68Ga-positive/18F-FDG-negative patients were the ones with the lowest calcitonin doubling time and presented a CEA doubling time >24 months, while the patient with more 18F-FDG-positive lesions was the one with the highest CEA/calcitonin ratio. The number of lesions found in 68Ga-DOTANOC PET/CT were correlated with calcitonin levels (r = 0.73; p < 0.01) but not with CEA ones (r = 0.42; p = 0.15). The number of 18F-FDG hypermetabolic focus were correlated with CEA levels (r = 0.60; p < 0.05) but not with calcitonin (r = 0.48; p = 0.09). This is the first study to describe a positive correlation between 68Ga-positive lesions and calcitonin levels and between 18F-FDG-positivity and CEA levels. Tumoral markers pattern in metastatic MTC could help clinicians to decide which exam to perform first.

18F-FDG PET-CT in Unknown-Source of Elevated Serum Carcinoembryonic Antigen (CEA) Level

To investigate the clinical value of 18F-FDG PET-CT in the diagnosis of malignant tumor when serum carcinoembryonic antigen (CEA) level is elevated for unknown primary lesion. A descriptive study. Department of Nuclear Medicine, Luoyang Central Hospital Affiliated to Zhengzhou University, Henan, China, from March 2015 to March 2017. A total of 120 cases of parallel 18F-FDG PET-CT examination with serum CEA level of patients with unexplained source examined were chosen. Those with a known disease or with incomplete record of clinical and/or relevant laboratory examinations were excluded. Pathological examination, results of clinical follow-up and other imaging tests constituted the clinical value of 18F-FDG PET-CT in the diagnosis of tumor. For patients who had underwent the determination of serum CEA more than twice, CEA doubling time (DT) was also calculated. The serum CEA level and CEA DT of benign versus malignant 18F-FDG PET-CT imaging results were compared. Thirty (25.00%) cases were finally diagnosed as malignant tumors, and 90 (75.00%) cases were excluded labelled benign condition. There was one false positive case and one false negative case each with 18F-FDG PET-CT diagnosis. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value were 96.7%, 98.9%, 98.3%, 96.7% and 98.9%, respectively. The serum CEA level of patients with positive 18F-FDG PET-CT imaging was higher than that of 18F-FDG PET-CT negative patients (p<0.001). The serum CEA DT of patients with positive 18F-FDG PET-CT imaging was shorter than that of 18F-FDG PET-CT negative patients (p<0.001). The receiver operating characteristic (ROC) curve analysis showed that the diagnostic efficacy of 18F-FDG PET-CT was best at serum CEA of 14.31 &mu;g/L. 18F-FDG PET-CT imaging has high diagnostic value for patients with elevated serum CEA. For patients with serum CEA over 14.31 &mu;g/L, the diagnostic value of 18F-FDG PET-CT for malignant tumors is more reliable.

Update on multiple endocrine neoplasia Type 1 and 2

Multiple endocrine neoplasia type 1 is a rare genetic syndrome, characterized by the co-occurrence, in the same individual or in related individuals of the same family, of hyperparathyroidism, duodenopancraetic neuroendocrine tumors, pituitary adenomas, adrenocortical tumors, and neuroendocrine tumors (carcinoids) in the thymus, the bronchi, or the stomach. Multiple endocrine neoplastic type 2 is a rare genetic syndrome, characterized by the familial occurrence of medullary thyroid carcinoma either isolated or associated with pheochromocytoma, primary hyperparathyroidism, or typical features (Marfanoid habitus, mucosal neuromas). Subjects with clinical MEN1 and those who carry a mutation in the MEN1 gene should be offered biochemical and imaging screening in order to detect tumors and evaluate their progression over time. Children with mutation in the RET gene should have prophylactic total thyroidectomy according to the category of aggressiveness of the detected mutation whereas those with clinical MEN2 should be operated on upon diagnosis. In MEN1 patients, special attention should be paid to evaluate the progression duodenopancraetic neuroendocrine tumors because of their malignant potential. Also, thymic neuroendocrine tumors should be detected as soon as possible because they represent the most lethal tumor. In MEN2, calcitonin and carcinoembryonic antigen (CEA) serve as excellent tumor markers for medullary thyroid carcinoma. Their preoperative levels are correlated with tumor size and predict postoperative cure. Moreover, calcitonin or CEA doubling time has important prognostic value. In both MEN syndromes, multidisciplinary approaches are very important in the care of affected patients. Moreover, those patients should be comprehensively informed and enabled to participate in the decision-making procedure. In addition to multidisciplinary approaches, every effort should be made to follow the recommendations and guidelines issued by national (the French Group of Endocrine Tumors) and international groups.

Predictive Value of 18F-FDG PET in Patients with Advanced Medullary Thyroid Carcinoma Treated with Vandetanib.

Therapeutic options in advanced medullary thyroid carcinoma (MTC) have markedly improved since the introduction of tyrosine kinase inhibitors (TKIs). We aimed to assess the role of metabolic imaging using 18F-FDG PET/CT shortly before and 3 mo after initiation of TKI treatment. Methods: Eighteen patients with advanced and progressive MTC scheduled for vandetanib treatment underwent baseline 18F-FDG PET/CT before and 3 mo after TKI treatment initiation. During follow-up, CT scans were obtained every 3 mo and analyzed according to RECIST. The predictive value for estimating progression-free survival (PFS) and overall survival (OS) was examined by investigating the 18F-FDG SUVmean/max of the metabolically most active lesion, as well as by analyzing clinical parameters (tumor marker doubling times [calcitonin, carcinoembryonic antigen], prior therapies, rearranged-during-transfection mutational status, and disease type). Results: Within a median follow-up of 5.2 y, 9 patients experienced disease progression after a median interval of 2.1 y, whereas the remainder had ongoing disease control (5 with a partial response and 4 with stable disease). Eight of the 9 patients with progressive disease died from MTC after a median of 3.5 y after TKI initiation. A pretherapeutic SUVmean of more than 4.0 predicted a significantly shorter PFS (1.9 y vs. 5.2 y, P = 0.04). Furthermore, sustained high 18F-FDG uptake at 3 mo with a SUVmean of more than 2.8 tended to portend an unfavorable prognosis, with a PFS of 1.9 y (vs. 3.5 y, P = 0.3). Prolonged carcinoembryonic antigen doubling times were significantly correlated with longer PFS (r = 0.7) and OS (r = 0.76, P < 0.01). None of the other clinical parameters had prognostic significance. Conclusion: Pretherapeutic 18F-FDG PET/CT provides prognostic information in patients with advanced MTC scheduled for treatment with the TKI vandetanib. A low tumor metabolism with an SUVmean of less than 4.0 before treatment predicts a longer PFS.

Outcomes of children with hereditary medullary thyroid carcinoma (MTC) treated with vandetanib.

10540 Background: Vandetanib is well tolerated and active in children with advanced or metastatic hereditary MTC (NCT00514046) [data cutoff 7/2011; Clin Cancer Res. 2013 Aug 1;19(15):4239-48]. We report outcomes as of 1/2017. Methods: We monitored toxicities, RECISTv1.0, carcinoembryonic antigen (CEA), and calcitonin (CT) response. Patients (pts) removed from the vandetanib trial were followed on a natural history study (NCT01660984). Results: Of 17 pts (8 male, age 13 years (9-17)*) enrolled, 1 was lost to follow-up. Of the 16 pts analyzed, 15 had a RET p.M918T germline mutation. The duration of vandetanib therapy was 5.6 years (0.1-9.2+) with treatment ongoing in 8 pts. Best response was partial response (PR) in 10, stable disease (SD) in 5, and progressive disease (PD) in 1 pt. Time to achieve PR (n = 10) was 0.6 years (0.4-2.4). Time to best response (n = 16) was 1.5 years (0.1-4.1). Duration of response was 5.1 years (1.3-8.6+) in pts with PR and 4.8 years (0.6-7.3+) in pts with SD. Seven of 8 pts with PD subsequently received sunitinib, sorafenib, and/or cabozantinib. Disease progression occurred as increase in target (n = 2), non-target/new lesions (n = 5), or CT/CEA (n = 1). Six pts died from disease 2.1 years (0.4-4.3) after stopping vandetanib. Progression free survival was 6.2 years (95% CI 3.0-na) and overall survival was 7.9 years (95% CI 5.9-na).Pts had no difference in enrollment age, baseline CT/CEA, or tumor size per response categories (n = 16). Rate of CEA/CT decrease during initial 4 months of treatment was not associated with PR/SD compared to PD (n = 16). While on vandetanib, 6 pts with PD had CEA or CT doubling time (DT) of &lt; 2 years within 1 year prior to PD. All pts with ongoing PR/SD had CEA and CT DT &gt; 2 years while on vandetanib. No pts came off treatment for toxicity. Dose reductions occurred in 8 pts for grade (gr) 2 weight loss (n = 2), palpitations (n = 1), arrhythmia (n = 1), elevated creatinine (n = 1), diarrhea (n = 2), and gr 3 constipation (n = 1). Conclusions: Many children with hereditary MTC sustained PR/SD on vandetanib. However, half ultimately developed PD and died from disease despite treatment with other targeted therapies. CEA/CT DT &lt; 2 years within 1 year of progression on vandetanib may be associated with PD. *Median (range)

PET imaging for thyroid cancers: Current status and future directions

Positron emission tomography–computed tomography (PET/CT) combines both functional and anatomic information and provides in vivo molecular information on biological processes that can be useful at different steps of evolution of thyroid cancers. 18Fluorodeoxyglucose being highly trapped in rapidly dividing cells makes 18F-FDG-PET recommended in the staging, prognostic evaluation and follow-up of metastatic and/or of poorly differentiated thyroid carcinomas. 18F-FDG PET/CT can help in the localization of persistent/recurrent disease. However, its sensitivity depends widely on tumor burden and histology. Iodine 124 (124I) is currently under evaluation for diagnosis and pretherapeutic dosimetry planning. PET/CT using 18F-FDOPA is the most sensitive radiopharmaceutical for localizing persistent/recurrent medullary thyroid carcinoma (MTC). However, its sensitivity depends on calcitonin levels, with a threshold value of around 150pg/mL. 18F-FDG PET/CT can also be used in MTC with short calcitonin or CEA doubling time.

Clinical Relevance of 18F-FDG PET and 18F-DOPA PET in Recurrent Medullary Thyroid Carcinoma

The transition from stable to progressive disease is unpredictable in patients with biochemical evidence of medullary thyroid carcinoma (MTC). Calcitonin and carcinoembryonic antigen (CEA) doubling times are currently the most reliable markers for progression, but for accurate determination, serial measurements, which need time, are required. We compared (18)F-FDG PET and (18)F-dihydroxyphenylanaline ((18)F-DOPA) PET with biochemical parameters and survival to assess whether these imaging modalities could be of value in detecting progressive disease. We evaluated the outcome of (18)F-FDG PET or (18)F-DOPA PET with calcitonin and CEA doubling times in 47 MTC patients. A subgroup of patients was included in the whole metabolic burden (WBMTB) analysis, with determination of standardized uptake values and number of lesions. WBMTB of (18)F-DOPA PET and (18)F-FDG PET was compared with biochemical parameters. Furthermore, survival was compared with (18)F-DOPA PET or (18)F-FDG PET positivity. Doubling times were available for 38 of 40 patients undergoing (18)F-FDG PET. There was a significant correlation with (18)F-FDG PET positivity. Doubling times were less than 24 mo in 77% (n = 10/13) of (18)F-FDG PET-positive patients, whereas 88% (n = 22/25) of (18)F-FDG PET-negative patients had doubling times greater than 24 mo (P < 0.001). Between doubling times and (18)F-DOPA PET positivity, no significant correlation existed. (18)F-DOPA PET detected significantly more lesions (75%, 56/75) than did (18)F-FDG PET (47%, 35/75) in the 21 patients included in WBMTB analysis (P = 0.009). Calcitonin and CEA levels correlated significantly with WBMTB on (18)F-DOPA PET, but doubling times did not. (18)F-FDG PET positivity was a more important indicator for poor survival in patients for whom both scans were obtained. (18)F-FDG PET is superior in detecting patients with biochemical progressive disease and identifying patients with poor survival. Although (18)F-DOPA PET has less prognostic value, it can more accurately assess the extent of the disease in patients with residual MTC. Hence, both scans are informative about tumor localization and behavior. On the basis of these results, we designed a clinical flow diagram for general practice in detecting recurrent MTC.

Phase II Trial of Anticarcinoembryonic Antigen Pretargeted Radioimmunotherapy in Progressive Metastatic Medullary Thyroid Carcinoma: Biomarker Response and Survival Improvement

The prognosis of medullary thyroid carcinoma (MTC) varies from long- to short-term survival based on such prognostic factors as serum calcitonin and carcinoembryonic antigen (CEA) doubling times (DTs). This prospective phase II multicenter trial evaluated the efficacy and safety of anti-CEA pretargeted radioimmunotherapy (pRAIT) in rapidly progressing metastatic MTC patients and also how serum biomarker DTs correlate with clinical outcome. From June 2004 to January 2008, 42 patients were treated with anti-CEA × anti-diethylenetriaminepentaacetic acid (DTPA) bispecific antibody (hMN-14 × m734) (40 mg/m(2)), followed by (131)I-di-DTPA-indium bivalent hapten (1.8 GBq/m(2)) 4-6 d later. The disease control rate (durable stabilization plus objective response) was 76.2%. Grade 3-4 hematologic toxicity was observed in 54.7% of patients and myelodysplastic syndrome in 2, including 1 heavily treated previously. After pRAIT, 21 of 37 assessed patients (56.7%) showed a significant impact on DT (≥100% increase of pre-pRAIT calcitonin or CEA DT or prolonged decrease of the biomarker concentration after pRAIT). Pre-pRAIT DT and post-pRAIT DT were significant independent predictors for overall survival (OS) from pRAIT (pre-pRAIT: hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.24-0.86; P = 0.016; and post-pRAIT: HR, 5.32; 95% CI, 1.63-17.36; P = 0.006) and OS from diagnosis (pre-pRAIT: HR, 0.21; 95% CI, 0.08-0.51; P = 0.001; and post-pRAIT: HR, 6.16; 95% CI, 1.81-20.98; P = 0.004). pRAIT showed antitumor activity, with manageable hematologic toxicity in progressive MTC. Increased biomarker DT after treatment correlated with increased OS.

Detection rate of recurrent medullary thyroid carcinoma using fluorine-18 fluorodeoxyglucose positron emission tomography: a meta-analysis

Several studies evaluated the diagnostic performance of fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET), and positron emission tomography/computed tomography (PET/CT) in detecting recurrent medullary thyroid carcinoma (MTC) with conflicting results. Aim of our study is to meta-analyze published data about this topic. A comprehensive computer literature search of studies published in PubMed/MEDLINE, Scopus, and Embase databases through December 2011 and regarding FDG PET or PET/CT in patients with suspected recurrent MTC was carried out. Pooled detection rate (DR) on a per patient-based analysis was calculated to measure the diagnostic performance of FDG PET and PET/CT in this setting. A sub-analysis considering PET device used, serum calcitonin, carcino-embryonic antigen (CEA), calcitonin doubling time (CTDT), and CEA doubling time (CEADT) values was also performed. Twenty-four studies comprising 538 patients with suspected recurrent MTC were included. DR of FDG PET or PET/CT in suspected recurrent MTC on a per patient-based analysis was 59 % (95 % confidence interval: 54-63 %). Heterogeneity between the studies was revealed. DR increased in patients with serum calcitonin ≥ 1,000 ng/L (75 %), CEA ≥ 5 ng/ml (69 %), CTDT <12 months (76 %), and CEADT <24 months (91 %). In patients with suspected recurrent MTC FDG PET and PET/CT are associated with a non-optimal DR since about 40 % of suspected recurrent MTC remain usually unidentified. However, FDG PET and PET/CT could modify the patient management in a certain number of recurrent MTC because these methods are often performed after negative conventional imaging studies. DR of FDG PET and PET/CT increases in patients with higher calcitonin and CEA values and lower CTDT and CEADT values, suggesting that these imaging methods could be very helpful in patients with more aggressive disease.

Medullary Thyroid Carcinoma Surgical Cytoreduction Induces an Increase in Serum Calcitonin and Carcinoembryonic Antigen Doubling Times

Serum calcitonin (Ct) and carcinoembryonic antigen (CEA) doubling times (DT) are considered to be strong prognostic markers in patients with medullary thyroid carcinoma (MTC). The Objective of this work is to study the effect of MTC debulking on Ct and CEA DTs. 4 patients with MTC are presented who after an initial neck operation had residual disease were followed-up with serial measurements of serum Ct and CEA for several years before and after a secondary incomplete removal of involved cervical lymph nodes. The patients received no other treatment for MTC. Ct and CEA DTs were determined after fitting the Ct or CEA values to an exponential growth equation. In patient A, Ct DT increased from 1.45 years (1.17-1.89, 95% CI) preoperatively, to 5.72 (3.22-25.77) postoperatively. In patient B, Ct DT was 1.63 years (1.36-2.02) preoperatively, and very long (serum Ct practically ceased increasing) postoperatively. In patient C, Ct DT was 4.03 years (2.22-21.58) before, and very long after the operation. In patient D, Ct DT from 1.16 years (0.82-1.99) before, increased to 4.21 years (3.04-6.86) after the operation. The changes in CEA DTs were similar to those of Ct DTs in 2 patients in whom the tumor was apparently producing the protein. In conclusion, surgical MTC cytoreduction in 4 patients caused an increase in the Ct and CEA DTs, and the patients could be reclassified in new Ct DT-based strata with better prognosis than before the operation. We hypothesize that such tumor burden reduction may slow the growth of any residual MTC and we discuss mechanisms that could be responsible for this phenomenon.

Complementary Roles of 18F-DOPA PET/CT and 18F-FDG PET/CT in Medullary Thyroid Cancer

Serum calcitonin and carcinoembryonic antigen (CEA) are markers of recurrent or persistent disease in medullary thyroid cancer (MTC). However, conventional imaging often fails to localize metastatic disease. Our aim was to compare fluorine-labeled dihydroxyphenylalanine ((18)F-DOPA) and (18)F-FDG PET/CT with multidetector CT (MDCT) and MRI in recurrent or persistent MTC. Nineteen MTC patients with increased calcitonin or CEA on follow-up (mean ± SD, 93 ± 91 mo; range, 4-300 mo) after primary therapy were prospectively imaged with 4 techniques: (18)F-DOPA PET/CT, (18)F-FDG PET/CT, MDCT, and MRI. Images were analyzed for pathologic lesions, which were surgically removed when possible. The correlation between the detection rate for each method and the calcitonin and CEA concentrations and histopathologic findings was investigated. On the basis of histology and follow-up, one or more imaging methods accurately localized metastatic disease in 12 (63%) of 19 patients. The corresponding figures for (18)F-DOPA PET/CT, (18)F-FDG PET/CT, MDCT, and MRI were 11 (58%) of 19, 10 (53%) of 19, 9 (47%) of 19, and 10 (59%) of 17, respectively. Calcitonin and CEA correlated with (18)F-DOPA PET/CT (P = 0.0007 and P = 0.0263, respectively) and (18)F-FDG PET/CT findings (both P < 0.0001). In patients with an unstable calcitonin doubling time (n = 8), (18)F-DOPA and (18)F-FDG PET/CT were equally sensitive. In contrast, for patients with an unstable CEA doubling time (n = 4), (18)F-FDG PET/CT was more accurate. For most MTC patients with occult disease, (18)F-DOPA PET/CT accurately detects metastases. In patients with an unstable calcitonin level, (18)F-DOPA PET/CT and (18)F-FDG PET/CT are complementary. For patients with an unstable CEA doubling time, (18)F-FDG PET/CT may be more feasible. MRI is sensitive but has the highest rate of false-positive results.

Prevalence of positive FDG-PET findings in patients with high CEA levels

The purpose of this study was to evaluate the prevalence of positive findings of positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose (FDG) in patients with high serum CEA levels. A total of 303 patients who had undergone an FDG-PET scan in our institution with high serum CEA levels were analyzed. The prevalence of positive PET findings was evaluated with regard to a previous history of malignancy, absolute value of CEA levels, and the time course of CEA levels (an increasing or decreasing pattern, a change divided by time (DeltaCEA) and doubling time of CEA). Of 303 patients, 232 were confirmed to have malignancy, and the patient-based sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of PET were 87, 86, 95, 66, and 86%, respectively. There was no statistically significant difference in positive rates according to the history of previous malignancy. The prevalence of PET-positive cases was higher with an increase in absolute CEA levels, and more than 90% of the patients were positive when CEA levels were more than 20 ng/ml. The DeltaCEA was significantly higher and the doubling time was significantly shorter in patients with positive results than those with negative results. A high value of serum CEA levels was correlated with a higher prevalence of positive PET findings. FDG-PET scans would be justified in patients with high serum CEA levels, regardless of whether there was or was not a previous history of malignancy.

Calcitonin and carcinoembryonic antigen doubling times as prognostic factors in medullary thyroid carcinoma: a structured meta‐analysis

In the management of patients with medullary thyroid carcinoma (MTC), calcitonin doubling time (dt) has gained interest as an independent predictor of recurrence and survival. To perform a structured meta-analysis of the diagnostic value of calcitonin dt, carcinoembryonic antigen (CEA) dt and the combination and to define dt strata with the highest predictive power. Design The study was a meta-analysis using individual data. Ten studies containing data on the post-operative kinetics of tumour marker(s) and (recurrence free) survival were included. Calcitonin- and CEA-dt are significant indicators for survival (hazard ratios (HR) 21.52 respectively infinite for dt 0-1 year compared to dt >1 year) and recurrence (HR 5.33 respectively 6.80 for dt 0-1 year compared to dt >1 year). The highest predictive power was found for the dt classification 0-1 year vs. >1 year. CEA dt has a higher predictive value than calcitonin dt in the subgroup of patients for which both parameters were available. The dts of both calcitonin and CEA are strong prognostic indicators for MTC recurrence and death. CEA dt has a higher predictive value than calcitonin dt and therefore measuring both tumour markers is essential for proper risk stratification.

Medullary thyroid carcinoma and biomarkers: past, present and future

The clinical management of patients with persistent or recurrent medullary thyroid carcinoma (MTC) is still under debate, because these patients either have a long-term survival, due to an indolent course of the disease, or develop rapidly progressing disease leading to death from distant metastases. At this moment, it cannot be predicted what will happen within most individual cases. Biomarkers, indicators which can be measured objectively, can be helpful in MTC diagnosis, molecular imaging and treatment, and/or identification of MTC progression. Several MTC biomarkers are already implemented in the daily management of MTC patients. More research is being aimed at the improvement of molecular imaging techniques and the development of molecular systemic therapies. Recent discoveries, like the prognostic value of plasma calcitonin and carcino-embryonic antigen doubling-time and the presence of somatic RET mutations in MTC tissue, may be useful tools in clinical decision making in the future. In this review, we provide an overview of different MTC biomarkers and their applications in the clinical management of MTC patients.

Diabetes insipidus and panhypopituitarism due to intrasellar metastasis from medullary thyroid cancer

Medullary thyroid cancer (MTC) commonly metastasizes to lymph nodes in the central and lateral neck, but spread to distant organs also occurs, typically involving lung, liver, and bone. Metastases to pituitary gland are rare for this tumor. We describe an unusual case and peculiar presentation of pituitary metastasis from MTC. We report clinical, genetic, and laboratory data of this patient. A young woman with multiple endocrine neoplasia type 2B was seen with recent onset of classic symptoms and signs of panhypopituitarism, mild diabetes insipidus, and optic chiasmatic compression. Transphenoidal resection of an intrapituitary mass confirmed the presence of metastatic MTC. MTC recurrence may present solely with subacute pituitary symptomatology, even in the context of a very lengthy interval after initial surgery, atypically low calcitonin plasma levels, carcinoembryonic antigen doubling times, and the concomitant absence of other tell-tale signs of disseminated metastatic disease.

Progression of medullary thyroid carcinoma: assessment with calcitonin and carcinoembryonic antigen doubling times

The progression of medullary thyroid cancer is difficult to assess with imaging modalities; we studied the interest of calcitonin and carcinoembryonic antigen (CEA) doubling times and of Ki-67 labeling and mitotic index (MI). Fifty-five consecutive medullary thyroid carcinoma (MTC) patients with elevated calcitonin levels underwent repeated imaging studies in order to assess tumor burden and progression status. We looked for relationships between tumor burden and levels of calcitonin and CEA and between progression status according to the response evaluation criteria in solid tumors (RECIST) and calcitonin and CEA doubling times, and Ki-67 labeling and MI. The calcitonin and CEA levels were correlated with tumor burden. Ten patients with calcitonin levels below 816 pg/ml had no imaged tumor foci. Among the 45 patients with imaged tumor foci, 19 had stable disease and 26 had progressive disease, according to the RECIST. The calcitonin and CEA doubling times were strongly related to disease progression, with very few overlaps: 94% of patients with doubling times shorter than 25 months had progressive disease and 86% of patients with doubling times longer than 24 months had stable disease. Ki-67 labeling and MI were not significantly associated with disease progression. For MTC patients, the doubling times of both calcitonin and CEA are efficient tools for assessing tumor progression.

Sensitivity and Prognostic Value of Positron Emission Tomography with F-18-Fluorodeoxyglucose and Sensitivity of Immunoscintigraphy in Patients with Medullary Thyroid Carcinoma Treated with Anticarcinoembryonic Antigen-Targeted Radioimmunotherapy

Patients with progressive medullary thyroid carcinoma (MTC) undergo multiple imaging procedures for diagnosis of relapse and staging. Our objective was to assess the sensitivity and prognostic value of 18F-2-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET)/computed tomography (CT), and the imaging sensitivity of pretargeted iodine-131-radioimmunotherapy (RIT) in patients with progressive MTC. We performed a prospective multicenter study in high-risk patients with rapidly progressing MTC enrolled in a phase-II pretargeted RIT study, as documented by short serum calcitonin (Ct) or carcinoembryonic antigen (CEA) doubling time (DT). INTERVENTIONS/MAIN OUTCOME MEASURES: Patients underwent neck-thoracic-abdominal CT, spine and pelvic magnetic resonance imaging, whole-body post-RIT immunoscintigraphy (IS) with iodine-131, and whole-body 18F-FDG-PET/CT imaging. Imaging sensitivity and the correlation between FDG uptake and biomarkers DT were evaluated. A total of 33 patients with mean CEA and Ct DTs of 1.90 yr (range 0.21-8.50) and 1.52 yr (range 0.09-6.01), respectively, were evaluated. Sensitivity of FDG-PET/CT was 83% for neck, 85% for mediastinal, 75% for lung, 60% for liver, and 67% for bone metastases; overall sensitivity was 76%. Median standardized uptake value (SUVmax) was 5.23 (2.06-13.90). SUVmax correlated significantly with Ct DT (P = 0.011) and minimal DT (minimal value between CEA DT and Ct DT) (P = 0.027). Overall sensitivity of post-RIT IS, CT, and bone magnetic resonance imaging were 94, 74, and 85%, respectively. These results demonstrate the value of FDG-PET/CT for staging of patients with progressive MTC, especially in the neck and mediastinum, with possible prognostication by SUV quantification. Post-RIT IS was the most sensitive of the imaging modalities studied prospectively.

Chronomodulated Irinotecan, Oxaliplatin, and Leucovorin-Modulated 5-Fluorouracil as Ambulatory Salvage Therapy in Patients with Irinotecan- and Oxaliplatin-Resistant Metastatic Colorectal Cancer

To evaluate the activity and tolerability of salvage chronomodulated chemotherapy combining irinotecan (I), 5-fluorouracil/leucovorin (5-FU/LV), and oxaliplatin (O) (chronoIFLO) in patients with metastatic colorectal cancer (MCRC) and prior progression on four drugs. Seventy-seven nonhospitalized MCRC patients received chronoIFLO every 3 weeks, with day 1: I (180 mg/m2 over 6 hours, with peak infusion rate at 05:00) and days 2-5: 5-FU/LV (700/300 mg/m2 per day over 12 hours, with peak flow rate at 04:00), and O (20 mg/m2 per day over 12 hours, with peak flow rate at 16:00). Toxicity and response were assessed every 3 weeks and every 2 months, respectively. RESULTS. Three or more prior chemotherapy lines were given to 75% of the patients. Two or more organs had metastatic disease in 65% of the patients. A median number of six courses of chronoIFLO was given. The main grade 3-4 toxicities were diarrhea (39% of the patients, 9% of the courses) and neutropenia (30% of the patients and 7% of the courses). Grade 3 peripheral sensory neuropathy occurred in 14% of the patients. Two patients achieved a partial response and 61 had stable disease, resulting in disease control for 82% of the patients. The median time to progression (TTP) was 5.5 months (95% confidence interval, 3.7-6.0). The median overall survival time was 14.2 months (9.8-17.3). Baseline performance status, serum carcinoembryonic antigen (CEA) level, and CEA doubling time were independent prognostic factors of TTP. ChronoIFLO safely and durably halted tumor progression in most extensively pretreated MCRC patients.