Sophie Leboulleux

Strategies of Radioiodine Ablation in Patients with Low-Risk Thyroid Cancer

BACKGROUND It is not clear whether the administration of radioiodine provides any benefit to patients with low-risk thyroid cancer after a complete surgical resection. The administration of the smallest possible amount of radioiodine would improve care. METHODS In our randomized, phase 3 trial, we compared two thyrotropin-stimulation methods (thyroid hormone withdrawal and use of recombinant human thyrotropin) and two radioiodine ((131)I) doses (i.e., administered activities) (1.1 GBq and 3.7 GBq) in a 2-by-2 design. Inclusion criteria were an age of 18 years or older; total thyroidectomy for differentiated thyroid carcinoma; tumor-node-metastasis (TNM) stage, ascertained on pathological examination (p) of a surgical specimen, of pT1 (with tumor diameter ≤1 cm) and N1 or Nx, pT1 (with tumor diameter >1 to 2 cm) and any N stage, or pT2N0; absence of distant metastasis; and no iodine contamination. Thyroid ablation was assessed 8 months after radioiodine administration by neck ultrasonography and measurement of recombinant human thyrotropin-stimulated thyroglobulin. Comparisons were based on an equivalence framework. RESULTS There were 752 patients enrolled between 2007 and 2010; 92% had papillary cancer. There were no unexpected serious adverse events. In the 684 patients with data that could be evaluated, ultrasonography of the neck was normal in 652 (95%), and the stimulated thyroglobulin level was 1.0 ng per milliliter or less in 621 of the 652 patients (95%) without detectable thyroglobulin antibodies. Thyroid ablation was complete in 631 of the 684 patients (92%). The ablation rate was equivalent between the (131)I doses and between the thyrotropin-stimulation methods. CONCLUSIONS The use of recombinant human thyrotropin and low-dose (1.1 GBq) postoperative radioiodine ablation may be sufficient for the management of low-risk thyroid cancer. (Funded by the French National Cancer Institute [INCa] and the French Ministry of Health; ClinicalTrials.gov number, NCT00435851; INCa number, RECF0447.).

Combination chemotherapy in advanced adrenocortical carcinoma

BACKGROUND Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment. METHODS We randomly assigned 304 patients with advanced adrenocortical carcinoma to receive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival. RESULTS For first-line therapy, patients in the EDP-mitotane group had a significantly higher response rate than those in the streptozocin-mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P=0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP-mitotane group and 2.2 months in the streptozocin-mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments. CONCLUSIONS Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival. (Funded by the Swedish Research Council and others; FIRM-ACT ClinicalTrials.gov number, NCT00094497.).

The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas.

CONTEXT Germline mutations in SDHx genes cause hereditary paraganglioma. OBJECTIVE The aim of the study was to assess the indications for succinate dehydrogenase (SDH) genetic testing in a prospective study. DESIGN A total of 445 patients with head and neck and/or thoracic-abdominal or pelvic paragangliomas were recruited over 5 yr in 20 referral centers. In addition to classical direct sequencing of the SDHB, SDHC, and SDHD genes, two methods for detecting large genomic deletions or duplications were used, quantitative multiplex PCR of short fluorescent fragments (QMPSF) and multiplex ligation-dependent probe amplification (MLPA). RESULTS A large variety of SDH germline mutations were found by direct sequencing in 220 patients and by QMPSF and MLPA in 22 patients (9.1%): 130 in SDHD, 96 in SDHB, and 16 in SDHC. Mutation carriers were younger and more frequently had multiple or malignant paraganglioma than patients without mutations. A head and neck paraganglioma was present in 97.7% of the SDHD and 87.5% of the SDHC mutation carriers, but in only 42.7% of the SDHB carriers. A thoracic-abdominal or pelvic location was present in 63.5% of the SDHB, 16.1% of the SDHD, and in 12.5% of the SDHC mutation carriers. Multiple paragangliomas were diagnosed in 66.9% of the SDHD mutation carriers. A malignant paraganglioma was documented in 37.5% of the SDHB, 3.1% of the SDHD, and none of the SDHC mutation carriers. CONCLUSIONS SDH genetic testing, including tests for large genomic deletions, is indicated in all patients with head and neck and/or thoracic-abdominal or pelvic paraganglioma and can be targeted according to clinical criteria.

Prophylactic Lymph Node Dissection for Papillary Thyroid Cancer Less Than 2 cm: Implications for Radioiodine Treatment

OBJECTIVE Prophylactic neck dissection for small papillary carcinoma remains controversial. Radioiodine ablation is not recommended for tumors less than 10 mm and depends on various factors for tumors between 10 and 20 mm. The aim was to determine the effect of lymph node (LN) staging on the indication for treatment with radioiodine. PATIENTS AND METHODS We conducted a retrospective study of 115 patients presenting with papillary thyroid carcinoma less than 2 cm without ultrasonographically detectable cervical LN treated by total thyroidectomy and complete selective dissection of the central and lateral compartment. Radioiodine treatment was based on definitive pathology (tumor and LN). Follow-up was based on neck ultrasound and thyroglobulin levels. RESULTS LN were found for 41.7% of cases. Radioiodine was not used for 42% of patients with tumors less than 20 mm and no metastatic LN. Fifty-eight percent of patients were treated with radioiodine due to LN metastasis, extracapsular thyroid invasion, or unfavorable histological subtype. LN status affected the indication for radioiodine in 30.5% of cases classified as T1, 12 cases with tumors less than 10 mm but with LN metastases (who received radioiodine), and 13 cases with tumors between 10 and 20 mm but without LN metastases (who did not receive radioiodine). Definitive vocal fold paralysis and hypoparathyroidism each occurred in 0.9% of cases. At 1 yr, ultrasound was normal in all patients, and recombinant human TSH-stimulated thyroglobulin was undetectable for 97% of the patients. CONCLUSION Precise LN staging by prophylactic neck dissection for tumors initially staged T1N0 modified the indication for radioiodine ablation for 30% of patients.

Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial

BACKGROUND No effective standard treatment exists for patients with radioiodine-refractory, advanced differentiated thyroid carcinoma. We aimed to assess efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signalling, in this setting. METHODS In this randomised, double-blind, phase 2 trial, we enrolled adults (aged ≥18 years) with locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated) at 16 European medical centres. Eligible patients were sequentially randomised in a 1:1 ratio with a standard computerised scheme to receive either vandetanib 300 mg per day (vandetanib group) or matched placebo (placebo group), balanced by centre. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population based on investigator assessment. This study is registered with ClinicalTrials.gov, number NCT00537095. FINDINGS Between Sept 28, 2007, and Oct 16, 2008, we randomly allocated 72 patients to the vandetanib group and 73 patients to the placebo group. By data cutoff (Dec 2, 2009), 113 (78%) patients had progressed (52 [72%] patients in the vandetanib group and 61 [84%] in the placebo group) and 40 (28%) had died (19 [26%] patients in the vandetanib group and 21 [29%] in the placebo group). Patients who received vandetanib had longer PFS than did those who received placebo (hazard ratio [HR] 0·63, 60% CI 0·54-0·74; one-sided p=0·008): median PFS was 11·1 months (95% CI 7·7-14·0) for patients in the vandetanib group and 5·9 months (4·0-8·9) for patients in the placebo group. The most common grade 3 or worse adverse events were QTc prolongation (ten [14%] of 73 patients in the vandetanib group vs none in the placebo group), diarrhoea (seven [10%] vs none), asthenia (five [7%] vs three [4%]), and fatigue (four [5%] vs none). Two patients in the vandetanib group and one in the placebo group died from treatment-related serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group). INTERPRETATION Vandetanib is the first targeted drug to show evidence of efficacy in a randomised phase 2 trial in patients with locally advanced or metastatic differentiated thyroid carcinoma. Further investigation of tyrosine-kinase inhibitors in this setting is warranted. FUNDING AstraZeneca.

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

OBJECTIVE 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). PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION For MTC patients, the doubling times of both calcitonin and CEA are efficient tools for assessing tumor progression.

Staging of peritoneal carcinomatosis: enhanced CT vs. PET/CT.

PurposeTo assess and compare the performance of CT and 18F-FDG-PET/CT in the evaluation of peritoneal carcinomatosis (PC).Method and materialsThirty consecutive patients with PC and scheduled for a surgery underwent a CT of the abdomen and pelvis and a whole-body 18F-FDG PET/CT. The extent of PC was assessed precisely using the peritoneal cancer index combining the distribution of tumor throughout 11 abdominopelvic regions with a lesion size score. CT and PET/CT imaging results were compared in all patients with intraoperative findings using an interclass correlation test.ResultsThe presence of PC was correctly determined on CT and PET/CT in 23/28 and 16/28 patients, respectively. The extent of PC was understaged with CT and PET/CT in 27 patients and overstaged with CT and PET/CT in 1 and 2 patients, respectively. The interclass correlation was 0.53 (moderate) between CT and surgery and 0.12 (low) between PET/CT and surgery. The interclass correlation was higher for mucinous tumor (0.63) than for non-mucinous (0.16) on CT imaging whereas no difference was found in PET/CT.ConclusionThe intraperitoneal assessment of the extent of carcinomatosis, necessary to assess prognosis and treatment planning, is not accurate enough with CT and PET/CT imaging.

Mitotane, Metyrapone, and Ketoconazole Combination Therapy as an Alternative to Rescue Adrenalectomy for Severe ACTH-Dependent Cushing's Syndrome

CONTEXT Mitotane is highly effective in the long-term management of Cushings syndrome but has a slow onset of action. Mitotane combined with fast-acting steroidogenesis inhibitors might avoid the need for emergency bilateral adrenalectomy in patients with severe hypercortisolism. OBJECTIVE Our objective was to assess the efficacy and safety of combination therapy with mitotane, metyrapone, and ketoconazole in severe ACTH-dependent Cushings syndrome. PATIENTS, DESIGN, AND SETTING Eleven patients with severe Cushings syndrome participated in this follow-up study in a tertiary referral hospital. INTERVENTIONS High-dose therapy combining mitotane (3.0-5.0 g/24 h), metyrapone (3.0-4.5 g/24 h), and ketoconazole (400-1200 mg/24 h) was initiated concomitantly. Twenty-four-hour urinary free cortisol (UFC) excretion (normal values 10-65 μg/24 h) was monitored. RESULTS Data are reported as medians (range). All 11 patients experienced a marked clinical improvement. UFC excretion fell rapidly from 2737 μg/24 h (range 853-22,605) at baseline to 50 μg/24 h (range 18-298) (P = 0.001) within 24-48 h of treatment initiation and remained low to normal on the combination therapy. In seven patients, metyrapone and ketoconazole were discontinued after 3.5 months (range 3.0-6.0) of combination therapy, and UFC excretion remained controlled by mitotane monotherapy (UFC 17 μg/24 h, range 5-85; P = 0.016). Five patients became able to undergo etiological surgery and are presently in remission. Four of them recovered normal adrenal function after mitotane discontinuation. Adverse effects were tolerable, consisting mainly of gastrointestinal discomfort and a significant rise in total cholesterol and γ-glutamyl transferase levels (P = 0.012 and P = 0.002, respectively). CONCLUSIONS When surgical treatment for severe ACTH-dependent Cushings syndrome is not feasible, combination therapy with mitotane, metyrapone, and ketoconazole is an effective alternative to bilateral adrenalectomy, a procedure associated with significant morbidity and permanent hypoadrenalism.

Are G3 ENETS neuroendocrine neoplasms heterogeneous

The new WHO classification of gastroenteropancreatic (GEP) neuroendocrine tumors (NET) implies that G3 neoplasms with mitotic index >20 and/or Ki67 index >20% are neuroendocrine carcinomas (NEC), described as poorly differentiated, small or large cell types, by analogy with lung NEC. To characterize the subgroup of non-small-cell-type GEP and thoracic NET with mitotic index >20 and/or Ki67 >20% according to their pathological features, response to cisplatin and overall survival (OS). We reviewed pathological and clinical presentation of G3 non-small-cell-type NET referred to our institution for 5 years. Data from 166 patients with metastatic thoracic and GEP-NET were collected. Twenty-eight patients (17%) fulfill the inclusion criteria. Tumors were classified as well-differentiated NET (G3-WDNET) in 42.8% of cases and poorly differentiated, large-cell NEC (G3-LCNEC) in 57.2% of cases. Plasma chromogranin A or neuron-specific enolase were elevated in 42 and 25% respectively of G3-WDNET and 31 and 50% of G3-LCNEC. Somatostatin receptor scintigraphy was positive in 88 and 50% of G3-WDNET or G3-LCNEC respectively. Complete or partial response to cisplatin was observed in 31% of cases, all classified as G3-LCNEC. The median OS was 41 months for G3-WDNET but 17 months for G3-LCNEC (P=0.34). Short survival was observed in 25% of G3-WDNET but 62.5% of G3-LCNEC patients (P=0.049). G3 ENETS GEP and thoracic neuroendocrine neoplasms (NEN) could constitute a heterogeneous subgroup of NEN as regards diagnosis, prognosis, and treatment. If confirmed, future classifications may consider splitting them into two groups according to their morphological differentiation.

Definition and management of radioactive iodine-refractory differentiated thyroid cancer.

356 www.thelancet.com/diabetes-endocrinology Vol 2 May 2014 ALT reduction when liver fat content is reduced, even without improvement in hepatic infl ammation. Finally, although patients with non-alcoholic steatohepatitis can have increased urinary free cortisol, data for increased 11-βHSD1 hepatic expression is confl icting, thus questioning the relevance of this protein as a therapeutic target. Stefan and colleagues’ carefully conducted trial shows benefi cial eff ects of 11-βHSD1 inhibition on body and liver fat in overweight, insulin-resistant patients with liver steatosis. Unfortunately, data suggestive of effi cacy in patients with non-alcoholic steatohepatitis cannot be inferred from this report and need to be obtained from future, liver-oriented trials with relevant histological endpoints.