Prognostic value of total, free and lipoprotein fraction-bound plasma mitotane levels in advanced adrenocortical carcinoma: a prospective study of the ENDOCAN-COMETE-Cancer network-Reference-Cited by-同舟云学术

Prognostic value of total, free and lipoprotein fraction-bound plasma mitotane levels in advanced adrenocortical carcinoma: a prospective study of the ENDOCAN-COMETE-Cancer network

Published:2023-07-14 Issue: Volume: Page:
ISSN:
Container-title:
language:
Short-container-title:

Author:

Faron Matthieu¹^ORCID,NAMAN Annabelle¹,Delahousse Julia¹,Hescot Segolene²,Hadoux Julien¹,Castinetti Frederic³,DRUI Delphine⁴,Renoult-Pierre Peggy⁵,Libe Rossella⁶,Lamartina Livia¹,Leboulleux Sophie¹,Ghuzlan Abir Al¹,Lombes Marc⁷,Paci Angelo¹,Baudin Eric¹

Affiliation:

1. Gustave Roussy

2. Institut Curie

3. Hopital de la Conception Service d'Endocrinologie Diabete Maladies Metaboliques

4. CHU Nantes: Centre Hospitalier Universitaire de Nantes

5. Bretonneau Hospital: Hopital Bretonneau

6. Hôpital Cochin: Hopital Cochin

7. Université Paris-Sud: Universite Paris-Saclay

Abstract

Abstract Purpose Mitotane is the only approved treatment for metastatic adrenocortical carcinoma (ACC). Monitoring plasma levels is recommended, but its positive predictive value is insufficient. Methods This prospective study of the French ENDOCAN-COMETE network aimed to investigate the prognostic role of early plasma mitotane levels pharmacokinetics and free or bound to lipoprotein fraction dosages during six consecutive months. Lipoprotein fractions were isolated by ultracentrifugation, and mitotane level was determined by HPLC-UV. Total, free, and lipoprotein fraction bound plasma mitotane were monitored every two months for six months with a clinical and morphological assessment. The primary endpoint was overall survival (OS) since the initiation of mitotane. Results Twenty-one patients with metastatic ACC and at least two measurements of mitotane level during the MITOLIPO period were included. Median overall survival was 23 months. The median free mitotane level per patient was 12% (± 7%), and the majority (88%) was bound to lipoprotein fractions. Several pharmacokinetics measures of total mitotane were related to OS: the first level at one month (p: 0.047), the mean level (p: 0.082), and the area under the curve (AUC) (p: 0.089), with higher exposure associated to longer OS. Free mitotane (not bounded) and mitotane bounded to lipoprotein subfraction added no prognostic values. The relationship between the mitotane level and OS suggested a minimum "effective" threshold of 10-15mg/L or an area under the curve above 100mg/L/month with no individualized maximum value. Conclusion This prospective study did not identify any added prognostic value of free mitotane level over the total level. Early total mitotane level measurements (before 3–6 months) were related to OS with a higher and faster exposure related to more prolonged survival.

Publisher

Research Square Platform LLC

Reference35 articles.

1. R. Libé, I. Borget, C.L. Ronchi, B. Zaggia, M. Kroiss, T. Kerkhofs, J. Bertherat, M. Volante, M. Quinkler, O. Chabre, M. Bala, A. Tabarin, F. Beuschlein, D. Vezzosi, T. Deutschbein, F. Borson-Chazot, I. Hermsen, A. Stell, C. Fottner, S. Leboulleux, S. Hahner, M. Mannelli, A. Berruti, H. Haak, M. Terzolo, M. Fassnacht, E. Baudin, and ENSAT network, Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 26, 2119 (2015)

2. Guidelines Committee. Electronic address: clinicalguidelines@esmo.org;Fassnacht M;Ann. Oncol. Off J. Eur. Soc. Med. Oncol.,2020

3. A. Naing, F. Meric-Bernstam, B. Stephen, D.D. Karp, J. Hajjar, J. Rodon Ahnert, S.A. Piha-Paul, R.R. Colen, C. Jimenez, K.P. Raghav, R. Ferrarotto, S.-M. Tu, M. Campbell, L. Wang, S.H. Sabir, C. Tapia, C. Bernatchez, M. Frumovitz, N. Tannir, V. Ravi, S. Khan, J.M. Painter, A. Abonofal, J. Gong, A. Alshawa, L.M. McQuinn, M. Xu, S. Ahmed, V. Subbiah, D.S. Hong, S. Pant, T.A. Yap, A.M. Tsimberidou, E.E.I. Dumbrava, F. Janku, S. Fu, R.M. Simon, K.R. Hess, G.R. Varadhachary, and M. A. Habra, J. Immunother. Cancer 8, (2020)

4. M. Fassnacht, O. Dekkers, T. Else, E. Baudin, A. Berruti, R.R. de Krijger, H.R. Haak, R. Mihai, G. Assie, M. Terzolo, Eur. J. Endocrinol. (2018)

5. H.R. Haak, J. Hermans, C.J. Velde, E.G. Lentjes, B.M. Goslings, G.J. Fleuren, H.M. Krans, Br. J. Cancer. 69, 947 (1994)