Achievementoftherapeuticmitotaneconcentrationsinmanagementofadvancedadrenocorticalcancer-BES2018.pdf (200.17 kB)
Achievement of therapeutic mitotane concentrations in management of advanced adrenocortical cancer: a single centre experience in 47 patients
journal contribution
posted on 2018-06-14, 19:12 authored by Mohamed Bakhit, Benjamin C Whitelaw, Jackie Gilbert, Patsy Coskeran, Salvador J. Diaz-CanoSalvador J. Diaz-Cano, David R Taylor, Norman T Taylor, Lea Ghatore, Dylan Lewis, Gillian Vivian, Debashis Sarker, Paul Ross, Laura May Davis, Jennifer Clough, Johnathan G Hubbard, Gabriele Galata, Andreas Prachalias, Klaus-Martin Schulte, Simon J B AylwinIntroduction:
Multi-modal therapy for adrenocortical carcinoma (ACC) includes
surgery, therapy with the adrenolytic agent mitotane and systemic
chemotherapy. Achievement of therapeutic mitotane concentrations (≥14
mg/l) has been related to improved outcomes.
Aim: To evaluate the effectiveness of a defined* high dose protocol
mitotane therapy in patients with advanced ACC (stages III and IV).
Methods: Review of patients presenting to KCH with stage III or IV ACC
and the mitotane concentration achieved through the Lysosafe monitoring
service.
Results: N=57 patients were referred and first diagnosed with ACC
(2008-17) of whom 44 patients had stage III or IV disease at diagnosis
and were managed actively with surgery and/or mitotane therapy. 40/44
patients underwent surgical resection of the primary tumour;11/22
patients with stage IV disease subsequently received systemic
chemotherapy [10 patients received a combination of etoposide,
doxorubicin and cisplatin (EDP) and 1 patient received a combination of
carboplatin and etoposide]. 38/44 patients were initiated on mitotane
therapy. The median overall survival of patients with stage IV disease
was 25.3 months. The median survival for stage III has not been reached.
An additional 9 patients had prior management, including surgery,
elsewhere and were referred for mitotane initiation. A total of 47
patients were therefore included in the mitotane pharmacokinetic
analysis. Six patients were excluded: 3 patients died shortly after
mitotane initiation, 1 patient withdrew due to a severe reaction and 2
patients had not completed 12 weeks therapy at the time of submission.
Of the remaining 41 patients, 33 commenced the ‘high dose’ protocol and
the remainder the ‘low dose’ protocol. For patients on the high dose
protocol, 25/33 (76%) reached a mitotane concentration ≥14 mg/l within
12 weeks of initiation of therapy, compared to 3 patients from the low
dose protocol group (P=0.084). In the high dose protocol group, 21
patients (84%) maintained therapeutic drug concentrations in ≥50% of the
subsequent follow-up samples and 12 patients (48%) maintained
therapeutic drug concentrations in ≥75% of subsequent samples.
Conclusion: The use of high dose protocol mitotane therapy is a
successful strategy to achieve and maintain therapeutic drug
concentrations when treating patients with advanced ACC (stages III and
IV). In combination with an assertive surgical approach and optimal
chemotherapy, this has resulted in outcomes that compare favourably
(median OS 25.5 months in stage IV disease) with previously published
series which describe a median OS <12 months.