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Sophie Mauclère-Denost, Sophie Leboulleux, Isabelle Borget, Angelo Paci, Jacques Young, Abir Al Ghuzlan, Desiree Deandreis, Laurence Drouard, Antoine Tabarin, Philippe Chanson, Martin Schlumberger, and Eric Baudin

Background

The benefit-to-risk ratio of a high-dose strategy at the initiation of mitotane treatment of adrenocortical carcinoma (ACC) remains unknown.

Methods

To evaluate the performance of a high-dose strategy, defined as the highest tolerated dose administered within 2 weeks and maintenance therapy over 4 weeks, we conducted a single-center, prospective study with two main objectives: to evaluate the percentage of patients who achieve a plasma mitotane level above 14 mg/l and to evaluate the tolerance of mitotane within the first 3 months of treatment. Plasma mitotane levels were measured monthly using HPLC.

Results

Twenty-two patients with ACC were prospectively enrolled. The high-dose mitotane strategy (4 g/day or more in all patients, with a median of 6 g/day within 2 weeks) enabled to reach the therapeutic threshold of >14 mg/l at 1, 2, or 3 months in 6/22 patients (27%), 7/22 patients (32%), and 7/22 patients (32%) respectively. In total, a therapeutic plasma mitotane level was reached in 14 out of 22 patients (63.6%) during the first 3 months in ten patients, and after 3 months in four patients. Grade 3–4 neurological or hematological toxicities were observed in three patients (13.6%).

Conclusion

Employing a high-dose strategy at the time of mitotane initiation enabled therapeutic plasma levels of mitotane to be reached within 1 month in 27% of the total group of patients. If this strategy is adopted, we suggest that mitotane dose is readjusted according to plasma mitotane levels at 1 or/and 2 months and patient tolerance.

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Livia Lamartina, Sophie Bidault, Julien Hadoux, Joanne Guerlain, Elizabeth Girard, Ingrid Breuskin, Marie Attard, Voichita Suciu, Eric Baudin, Abir Al Ghuzlan, Sophie Leboulleux, and Dana Hartl

Objective

The presence of extrathyroidal extension (ETE) is generally considered an indication for total thyroidectomy for differentiated thyroid cancer. The accuracy of neck ultrasound for the diagnosis of ETE is controversial. The aim of this study was to assess the diagnostic accuracy of preoperative ultrasound evaluation of ETE.

Methods

Retrospective and observational study of consecutive patients operated between 2016 and 2019 for cytologically suspicious or indeterminate thyroid nodules. US images obtained preoperatively were retrospectively reviewed to identify signs of minimal or gross ETE. Histology was considered the gold standard for diagnosis of ETE. The sensitivity, specificity, positive (PPV) and negative predictive values (NPV), and accuracy of US were evaluated.

Results

A cohort of 305 patients (75% females, median age 48 years) with 378 nodules (median size 18 mm) was studied. Seventy-five percent of the nodules (n=228) were malignant on histology and ETE was present in 106 cases (28%): 83 minimal ETE and 23 gross ETE. Suspicion of minimal ETE on preoperative ultrasound was found in 50 (13%) with a sensitivity of 30%, a specificity of 93%, a PPV 62% and a NPV of 78%, with an accuracy of 76%. Gross ETE on ultrasound was found in 19 (5%) nodules with a sensitivity of 78%, a specificity of 99.7% a PPV 94.7% an NPV of 98.6% and an accuracy of 98%.

Conclusions

Preoperative US is very specific and accurate in diagnosing gross ETE which impacts the extent of initial surgery for thyroid cancers.

Free access

Anne Laure Giraudet, Abir Al Ghulzan, Anne Aupérin, Sophie Leboulleux, Ahmed Chehboun, Frédéric Troalen, Clarisse Dromain, Jean Lumbroso, Eric Baudin, and Martin Schlumberger

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.

Free access

Charlotte Lepoutre-Lussey, Audrey Rousseau, Abir Al Ghuzlan, Laurence Amar, Chantal Hignette, Angela Cioffi, Franck Zinzindohoué, Sophie Leboulleux, and Pierre-François Plouin

Context

Primary adrenal angiosarcoma is an extremely rare neoplasm, as are combined tumors within a given adrenal lesion.

Clinical presentation and intervention

A 35-year-old man presented with hypokalemic hypertension leading to the discovery of a 6 cm diameter malignant-appearing right adrenal tumor. The lesion displayed marked 18F-fluorodeoxyglucose uptake on positron emission tomography scanning. Endocrine investigations revealed secretion of both cortisol and aldosterone by the neoplasm. The entire right adrenal gland along with the periadrenal fat tissue was removed during laparoscopic surgery.

Results

Histological examination revealed two intermingled tumor cell proliferations, namely an angiosarcoma and an adrenocortical adenoma. An extensive post-operative search revealed no other primary tumor site, nor metastases. The lesion was then considered to be a primary adrenal angiosarcoma combined with a secreting adrenocortical adenoma. The patient received four cycles of chemotherapy (adriamycin/ifosfamide). At 2-year follow-up, he is alive and well, with no sign of relapse.

Conclusion

To the best of our knowledge, this is the first case of an adrenal neoplasm combining a primary angiosarcoma and a functioning adrenocortical adenoma.

Free access

Thierry de Baere, Frederic Deschamps, Lambros Tselikas, Michel Ducreux, David Planchard, Ernesto Pearson, Amandine Berdelou, Sophie Leboulleux, Dominique Elias, and Eric Baudin

Neuroendocrine tumors from gastro-pancreatic origin (GEP-NET) can be responsible for liver metastases. Such metastases can be the dominant part of the disease as well due to the tumor burden itself or the symptoms related to such liver metastases. Intra-arterial therapies are commonly used in liver only or liver-dominant disease and encompass trans-arterial chemoembolization (TACE), trans-arterial embolization (TAE), and radioembolization (RE). TACE performed with drug emulsified in Lipiodol has been used for the past 20 years with reported overall survival in the range of 3–4 years, with objective response up to 75%. Response to TACE is higher when treatment is used as a first-line therapy and degree of liver involvement is lower. Benefit of TACE over TAE is unproven in randomized study, but reported in retrospective studies namely in pancreatic NETs. RE provides early interesting results that need to be further evaluated in terms of benefit and toxicity. Radiofrequency ablation allows control of small size and numbered liver metastases, with low invasiveness. Ideal metastases to target are one metastasis <5 cm, or three metastases <3 cm, or a sum of diameter of all metastases below 8 cm. Ablation therapies can be applied in the lung or in the bones when needed, and more invasive surgery should be probably saved for large-size metastases. Even if the indication of image-guided therapy in the treatment of GEP-NET liver metastases needs to be refined, such therapies allow for manageable invasive set of treatments able to address oligometastatic patients in liver, lung, and bones. These treatments applied locally will save the benefit and the toxicity of systemic therapy for more advanced stage of the disease.

Free access

Sylvie Salenave, Valérie Bernard, Christine Do Cao, Laurence Guignat, Anne Bachelot, Sophie Leboulleux, Céline Droumaguet, Hélène Bry-Gauillard, Peggy Pierre, Lise Crinière, Pietro Santulli, Philippe Touraine, Philippe Chanson, Martin Schlumberger, Dominique Maiter, Eric Baudin, and Jacques Young

Context

Mitotane is an adrenolytic and anticortisolic drug used in adrenocortical carcinoma (ACC), Cushing's disease (CD), and ectopic ACTH syndrome. Its effects on the ovaries are unknown.

Objective

To evaluate the ovarian and gonadotrope effects of mitotane therapy in premenopausal women.

Patients

We studied 21 premenopausal women (ACC: n=13; CD: n=8; median age 33 years, range 18–45 years) receiving mitotane at a median initial dose of 3 g/day (range 1.5–6 g/day).

Methods

Gynecological history was collected and ovarian ultrasound was performed. Four women also underwent ovarian CT or magnetic resonance imaging. Serum gonadotropin, estradiol (E2), androgens, sex hormone-binding globulin (SHBG), and circulating mitotane levels were determined at diagnosis and during mitotane therapy.

Results

In the women included, ovarian macrocysts (bilateral in 51%) were detected after a median 11 months (range: 3–36) of mitotane exposure. The median number of macrocysts per woman was two (range: 1–4) and the median diameter of the largest cysts was 50 mm (range: 26–90). Menstrual irregularities and/or pelvic pain were present in 15 out of 21 women at macrocyst diagnosis. In two women, the macrocysts were revealed by complications (ovarian torsion and hemorrhagic macrocyst rupture) that required surgery. Mitotane therapy was associated with a significant decrease in androstenedione and testosterone levels and a significant increase in LH levels. Serum FSH and E2 levels were also increased, and SHBG levels rose markedly.

Conclusions

Mitotane therapy causes significant morphological and ovarian/gonadotrope hormonal abnormalities in premenopausal women. Follicular thecal steroid synthesis appears to be specifically altered and the subsequent increase in gonadotropins might explain the development of macrocysts. The mechanisms underlying these adverse effects, whose exact prevalence in this population still needs to be determined, are discussed.

Free access

Marie-Hélène Massicotte, Maryse Brassard, Médéric Claude-Desroches, Isabelle Borget, Françoise Bonichon, Anne-Laure Giraudet, Christine Do Cao, Cécile N Chougnet, Sophie Leboulleux, Eric Baudin, Martin Schlumberger, and Christelle de la Fouchardière

Objective

Tyrosine kinase inhibitors (TKIs) are used to treat patients with advanced thyroid cancers. We retrospectively investigated the efficacy of TKIs administered outside of clinical trials in metastatic sites or locally advanced thyroid cancer patients from five French oncology centers.

Design and methods

There were 62 patients (37 men, mean age: 61 years) treated with sorafenib (62%), sunitinib (22%), and vandetanib (16%) outside of clinical trials; 22 had papillary, five had follicular, five had Hürthle cell, 13 had poorly differentiated, and 17 had medullary thyroid carcinoma (MTC). Thirty-three, 25, and four patients were treated with one, two, and three lines of TKIs respectively. Primary endpoints were objective tumor response rate and progression-free survival (PFS). Sequential treatments and tumor response according to metastatic sites were secondary endpoints.

Results

Among the 39 sorafenib and 12 sunitinib treatments in differentiated thyroid carcinoma (DTC) patients, partial response (PR) rate was 15 and 8% respectively. In the 11 MTC patients treated with vandetanib, 36% had PR. Median PFS was similar in second-line compared with first-line sorafenib or sunitinib therapy (6.7 vs 7.0 months) in DTC patients, but there was no PR with second- and third-line treatments. Bone and pleural lesions were the most refractory sites to treatment.

Conclusions

This is the largest retrospective study evaluating TKI therapies outside of clinical trials. DTC patients treated with second-line therapy had stable disease as best response, but had a similar median PFS compared with the first-line treatment.

Free access

Eric Baudin, Mouhammed Amir Habra, Frederic Deschamps, Gilbert Cote, Frederic Dumont, Maria Cabanillas, J Arfi-Roufe, A Berdelou, Bryan Moon, Abir Al Ghuzlan, Shreyaskumar Patel, Sophie Leboulleux, and Camilo Jimenez

Metastatic pheochromocytomas and paragangliomas (MPPs) present clinicians with three major challenges: scarcity, complexity of characterization, and heterogeneous behavior and prognosis. As with the treatment for all neuroendocrine tumors, the control of hormonal symptoms and tumor growth is the main therapeutic objective in MPP patients. A significant number of MPP patients still die from uncontrolled hormone secretion. In addition, the management of MPPs remains palliative. Steps forward include proper characterization of MPP patients at large cancer referral centers with multidisciplinary teams; improved strategies to stratify patients prognostically; and implementation of trials within national and international networks. Progress in the molecular characterization and staging of MPPs constitutes the basis for significant treatment breakthroughs.

Free access

Alfredo Berruti, Paola Sperone, Anna Ferrero, Antonina Germano, Arianna Ardito, Adriano Massimiliano Priola, Silvia De Francia, Marco Volante, Fulvia Daffara, Daniele Generali, Sophie Leboulleux, Paola Perotti, Eric Baudin, Mauro Papotti, and Massimo Terzolo

Background

There is a strong rationale in the use of antiangiogenic therapy in the management of adrenocortical carcinoma (ACC). Metronomic administration of chemotherapy and antiangiogenic drugs can be synergistic in targeting endothelial cells.

Objective

We assessed the activity of sorafenib plus metronomic paclitaxel as second/third-line therapy in advanced ACC patients. We also tested the activity of sorafenib and paclitaxel against NCI-H295R in vitro.

Design

Multicenter, prospective phase II trial.

Setting

Referral centers for ACC.

Methods

Twenty-five consecutive metastatic ACC patients who progressed after mitotane plus one or two chemotherapy lines were planned to be enrolled. The patients received a combination of i.v. paclitaxel (60 mg/m2 every week) and oral sorafenib (400 mg twice a day) till progression. The primary aim was to measure the progression-free survival rate after 4 months and the secondary aims were to assess the objective response rate and toxicity.

Results

Tumor progression was observed in nine evaluable patients at the first assessment. These results led to the premature interruption of the trial. The treatment was well tolerated. The most relevant toxicities were fatigue, being grade 2 or 3 in four patients, and hypophosphatemia, being grade 3 in three patients. In the in vitro study, sorafenib impaired the viability of H295R cells with dose–response and time–response relationships. The in vitro sorafenib activity was not increased in combination with paclitaxel.

Conclusions

Despite the in vitro activity, sorafenib plus weekly paclitaxel is an inactive salvage treatment in patients with advanced ACC and should not be recommended.