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A case report of a TDM-guided optimization of mitotane for a safe and effective long-term treatment
Antonello Di Paolo, Laura Ciofi, Alessandra Bacca & Giampaolo Bernini
To cite this article: Antonello Di Paolo, Laura Ciofi, Alessandra Bacca & Giampaolo Bernini (2019): A case report of a TDM-guided optimization of mitotane for a safe and effective long-term treatment, Journal of Chemotherapy, DOI: 10.1080/1120009X.2018.1552502
To link to this article: https://doi.org/10.1080/1120009X.2018.1552502
Published online: 04 Mar 2019.
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Case Report
A case report of a TDM-guided optimization of mitotane for a safe and effective long-term treatment
Antonello Di Paolo1,2 D, Laura Ciofi1,2, Alessandra Bacca1,3, Giampaolo Bernini1,3
ªDepartment of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; bClinical Pharmacology Unit, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy; “First Internal Medicine Unit, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
A 43-years old woman was diagnosed an adrenocortical carcinoma (AC) that was excised, whereas two lung metastases were un-operable. Mitotane 6g/day was started as standard therapy but it was responsible for severe central nervous system (CNS) and gastrointestinal toxicities associated with a 10kg body weight loss. A therapeutic drug monitoring (TDM) protocol demonstrated that mitotane plasma concentrations (>30 mg/L) exceeded the therapeutic range (14-20mg/L) and increased even when drug daily dose was reduced by 50%. The increase in drug plasma concentrations was probably due to body slimming. Under continuous TDM control, a reduced mitotane dose (1.5 g/day) was definitively administered and it proved to be tolerable and effective. Indeed, lung metastases were excised and two years later there was no evidence of other neo- plastic lesions. In conclusion, the adoption of therapeutic mitotane monitoring allowed the treatment of an AC patient with a reduced, tolerable and effective dose.
Keywords: Mitotane; Therapeutic drug monitoring; Dose optimization; Toxicity
Introduction
Mitotane finds its selective use in the treatment of adrenocortical carcinoma (AC), against which the drug is effective alone or in combination with other pharmacological agents.1 Indeed, in adjuvant set- ting, mitotane significantly improves the disease- free survival at the cost of moderate toxicities.2 In advanced disease, mitotane shows to control dis- ease progression with a median overall survival of 12-14.8 months depending on the combination regimen.3 Even in that setting, the administration of mitotane may be associated with neurological and gastrointestinal toxicities that may require a decrease in daily dosage or the discontinuation of therapy.4 In the latter case, the patient may lose the therapeutic benefit of drug administration.
Being a highly lipophilic drug, mitotane has a wide tissue distribution and a long terminal half- life, so that the steady state may be achieved after several weeks of therapy.5 Furthermore, clinical studies have demonstrated that the patients may achieve the best therapeutic benefit when minimum
plasma concentrations (Cmin) of the drug are within the range 14-20 mg/L.2,6 However, the long ter- minal half-life explains the delay by which every modification in plasma levels occurs after a change in drug dosage, even if the timing of blood with- drawal should be carefully considered because plasma concentrations of mitotane display wide fluctuation after drug intake.6 For all of these rea- sons, the therapeutic drug monitoring (TDM) may improve the management of AC patients both in adjuvant and palliative settings.
Case presentation
A 43-year-old woman referred to our unit com- plained a body weight increase (56 vs. 53 kg), hir- sutism, polymenorrhea and menorrhagia, hypertension (range 140-160 mmHg for systolic and 85-100 mmHg for diastolic blood pressure) and headache. The clinical history did not reveal any particular cause; hence, the physician pre- scribed a estro-progestinic therapy (May 2013) that did not ameliorate the symptoms. At next follow- up visit (November 2013), the examination returned the following data: body weight 56 kg,
Correspondance to: Antonello Di Paolo, Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy. Email: antonello.dipaolo@med.unipi.it
body mass index 21, persistence of hirsutism and hypertension (150/90 mmHg, 70 bpm), appearance of arm and leg ecchymoses. Laboratory analyses (including serum creatinine, transaminases and gamma-glutamyltransferase) were within normal ranges, but abdominal echography revealed a suprarenal mass of 6 cm in diameter. Computerized tomography (CT) scan showed the presence of the mass (55 × 48 × 60 mm) together with two lung masses (17 × 11 and 8 x 8 mm), a finding confirmed by 18F-fluorodeoxyglucose positron emission tom- ography (18F-FDG PET) on 2 December 2013). At that time, the estro-progestinic therapy was defini- tively suspended and the patient was free from drugs. Hormonal evaluation showed the presence of a highly vascularized suprarenal mass producing sexual hormones (dihydroepiandrostenedione 334 µg/dL, estradiol 519 pg/mL and estrone >2000 pg/mL), mineralocorticoids (aldosterone 32 ng/dL and plasma renin activity 1.2 ng/ml/h) and free urine cortisol (38.7 µg/dL). The patient under- went surgery and the neoplasm was excised (December 10th, 2013). Histological diagnosis con- firmed the AC (stage IV UICC/WHO 2004 and ENSAT 2008) with Ki-67 protein proliferation index of 15%.
As per guidelines, mitotane (Lysodren®) 3 g/day was started on January 4th, 2014 and dose was increased up to achieve a daily dose of 6g in the next six days. This treatment was associated with cortisol replacement therapy (hydrocortison acetate - 37.5 mg/day) to maintain an adequate hemo- dynamic and electrolytic balance together with flu- orohydrocortisone 0.1 mg twice a week. No further drugs were administered to the patient.
Methods
Informed consent
Informed and written consent was obtained from the patient.
Evaluation of treatment efficacy and tolerability
The efficacy of mitotane was evaluated by CT scan and 18F-FDG PET as per guidelines, while toxic effects induced by mitotane were assessed on a monthly base and scored according to the common toxicity criteria-adverse events, version 4.03.
Measurement of plasma concentrations of mitotane
Blood samples were obtained early in the morning before drug intake in order to minimize errors.6 They were collected in tubes containing lithium- heparin and sent immediately to the laboratory for
6
Mitotane dose (g/day)
4.5
50
3
3
1.5
1
1.5
[Mitotane] mg/L
40
+
30
+
+
20
Diagnosis
Surgery
Treatment start
+
10
+
+
+
Toxicities
0
12-NOV-13
5-DEC-13
04-JAN-14
10-JAN-14
02-FEB-14
25-FEB-14
20-MAR-14
29-APR-14
12-JUN-14
11-SEP-14
03-DEC-14
08-JUN-15
09-DEC-15
18-APR-16
14-DEC-16
Time
processing. Samples were centrifuged at 5000 rpm for 10 min and resulting plasma was stored at 4℃ until the measurement was performed within the next hour. Plasma concentrations of mitotane were assessed by a validated high-performance liquid chromatography method with ultraviolet detection as previously described.7
Results
After three weeks of treatment, moderate-to-severe toxicities occurred, mainly related to central ner- vous system (CNS; confusion, absences and somno- lence) and gastrointestinal symptoms (nausea, diarrhea and anorexia) that were accompanied by a decrease in body weight (43 kg). Because of the per- sistent CNS symptoms, mitotane dose was reduced to 4.5 g/day (2 February 2014) then a TDM proto- col was started to check whether drug plasma levels were within the therapeutic range. Results of TDM revealed a Cmin value of 30.7 mg/L (25 February 2014) and the dose was promptly reduced to 3 g/ day (Figure 1).
One month later (March 20th, 2014), the next measurement of drug plasma concentrations gave a result of 36.2 mg/L that immediately required a fur- ther decrease in mitotane dose to 1.5 g/day. At that time neurological symptoms improved, whereas nausea and diarrhea still persisted. However, des- pite the decrease in daily dose, mitotane Cmin value was still higher than the therapeutic range (33.0 mg/L on April 29th, 2014), so that physicians reduced the dose to 1 g/day (May 7th, 2014). Toxic
effects progressively improved, despite a body weight reduction, mild diarrhea and muscular stiff- ness were still present. CT scan confirmed disease stabilization of the lung metastases without any further sign of the disease, hence the daily dose of 1 g was maintained. On June 12th, 2014, for the first time since the beginning of chemotherapy, mitotane plasma concentration was 20mg/L. At that follow-up visit, the patient referred a further improvement in symptoms and physical examin- ation showed a blood pressure of 120/70 mmHg, absence of postural hypotension and normal results from lab analyses except for a normocytic anemia. Hirsutism, polymenorrhea and menorrhagia disappeared.
On September 11th, 2014, Cmin value of mitotane accounted for 7.7 mg/L, well below the therapeutic range. Therefore, the dose was increased to 1.5 g/ day and a closer monitoring was performed on December 2014, when Cmin value was 11.7mg/L. On January 2015 the two little lung metastases were surgically removed and plasma concentrations of mitotane were measured over the next two years, ranging from 9.4mg/L (December 2014) up to 14.7 mg/L (April 2016, Figure 1). During that time interval, mitotane dose was maintained at 1.5 g/ day. At this regimen the drug was well tolerated with occasional tiredness and tachycardia. Blood pressure was normal (120/80 mmHg), body weight recovered (58 kg) and gastrointestinal and neuro- logical symptoms disappeared. CT scans (January and July 2016) did not show recurrence of disease or metastases. On December 2016, mitotane plasma concentration was 9.4 mg/L, while 5 months later (May 2017) 18F-FDG PET did not show any abnormal uptake of the radiotracer. Of note, dur- ing the entire follow up described above, findings of laboratory exams were within normal ranges.
Discussion
The present case report supports early TDM proto- cols for mitotane in order to optimize the dose of the drug8 and to confirm dose appropriateness when changes in dosage were adopted. Indeed, mitotane was able to arrest disease progression even at a reduced but tolerable dose, as previously demonstrated.9 More interestingly, during the first four months of treatment, plasma concentrations of mitotane not only did not reduce, but they even increased despite the tapering daily dose. That sur- prising finding could be explained by the extensive accumulation of mitotane, a highly lipophilic drug, in several tissues, such as adipose tissue.5 As a con- sequence, the rapid and evident body weight loss (10 kg, approximately 18% of initial body weight at
the beginning of chemotherapy) could be respon- sible for the release of the mitotane stored within tissues, making it newly available in plasma for redistribution processes. In the absence of TDM, it is likely that the patient had to discontinue mito- tane intake due to intolerable toxicity at standard doses. On the contrary, the measurement of drug plasma concentrations demonstrated that a 75% dose reduction was not only tolerable in long term treatment, but also effective. Indeed, it was possible to excise the two lung metastases without the evi- dence of new lesions in the next two years of fol- low-up.
Undoubtedly, the present case report opens to other cogent points of discussion. The analysis of patient’s genotype for those polymorphisms known to affect mitotane disposition, as well as those belonging to cyp2b6 and abcb1 genes, could exped- ite the achievement of plasma concentrations within the established therapeutic range and predict the risk of drug-drug interactions.10 Indeed, many drugs can act as inducers of inhibitors of cyto- chrome isoforms and/or transmembrane transport- ers.11,12 Moreover, although the therapeutic range of mitotane is known (Cmin 14-20 mg/L), the strati- fication of patients according to plasma concentra- tions of both drug and its active metabolite (o,p- DDA) significantly improved the performance of the test.8,13 This approach could turn into an increased percentage of patients with effective drug plasma concentration, because the low bioavailabil- ity of mitotane and its high lipophilicity are responsible for subtherapeutic concentrations in more than 50% of patients. Therefore, according to all evidences, mitotane TDM could be considered for all patients,8 especially in the first weeks of treatment in order to maximize therapeutic efficacy and minimize the incidence and severity of toxic- ities, as adopted in the present clinical case. Then, repetitive TDM should be prescribed in the pres- ence of changes in drug dosage or toxic effects.
To conclude, the present case report demon- strates the usefulness of mitotane TDM to indi- vidualize drug dosage, demonstrating all TDM benefits for the patients and the caregivers.
Acknowledgments
We thank the patient for her permission to report the present findings.
Conflict of interest
No potential conflict of interest was reported by the authors.
Notes on contributors
Prof. Di Paolo is an associate professor of Pharmacology at the University of Pisa, being mainly involved in the pharmacokinetics of drugs and their therapeutic drug monitoring. Prof. Bernini is an associate professor of Internal Medicine, being his main areas of interest endocri- nopathies and hypertension. Dr Bacca was a recipi- ent of an Internal Medicine fellowship, while Dr. Ciofi is a technician at the Clinical Pharmacology Unit, Pisa University Hospital.
ORCID
Antonello Di Paolo (D http://orcid.org/0000-0002- 2661-6183
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