CASE REPORT
Mitotane-induced dyspnoea: an unusual side effect
Ali U Farooq,1 Waseem Amjad,2 Tanureet Kochar,3 Subash Adhikari3
1Department of Cardiovascular Medicine, Charleston Area Medical Center, Charleston, South Carolina, USA 2Department of Digestive Diseases, Mercy Medical Center, Baltimore, Maryland, USA 3Department of Internal Medicine, Charleston Area Medical Center, Charleston, South Carolina, USA
Correspondence to
Dr Waseem Amjad, waseemonline001@gmail.com
Accepted 15 August 2018
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C BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.
To cite: Farooq AU, Amjad W, Kochar T, et al. BMJ Case Rep Published Online First: [please include Day Month Year]. doi:10.1136/bcr-2018- 225490
SUMMARY
Mitotane is a cytostatic antineoplastic agent that is used in the treatment of adrenocortical carcinoma and Cushing’s syndrome. The commonly reported side effects associated with mitotane are anorexia, nausea, vomiting, diarrhoea, decreased memory, rash, gynaecomastia, arthralgias and leucopenia. We present a case of a 68-year-old female who developed gradual dyspnoea concurrent with the use of mitotane for the treatment of adrenocortical carcinoma. To the best of our knowledge and literate review, this is the first reported case of dyspnoea associated with the use of this medication. The purpose of this case report is to raise awareness about this uncommon adverse effect of mitotane that may have gone unrecognised on postmarketing surveillance because of under-reporting, lack of case follow-up or other comorbidities masking shortness of breath.
BACKGROUND
Adrenocortical carcinoma (ACC) is a rare but aggressive tumour of the adrenal gland that effects only 0.72 per one million population per year.1 About 50% of patients present with features of hormone excess, whereas 30% present with mani- festations of mass effect, abdominal pain and early satiety.2-4 Twenty per cent of cases of ACC are inci- dental findings on imaging performed for other medical issues.5 Complete surgical resection of the tumour is the treatment of choice for localised ACC (stages I -III). In stage IV disease, mitotane alone or in combination with etoposide-cisplatin-doxoru- bicin is the treatment of choice.6
Mitotane has a very narrow therapeutic index. Even minimal variation in the drug dosage or medi- cation interactions with other drugs could cause adverse effects. The most common adverse effects of mitotane are gastrointestinal disturbances and central nervous system toxicity. Other reported side effects include skin rash, arthralgias and leucopenia. To date, dyspnoea has not been reported as a side effect of mitotane. We report the first case of mito- tane-induced dyspnoea in a patient with ACC.
CASE PRESENTATION
A 68-year-old female patient was hospitalised for 2 months of progressively worsening dyspnoea. She had been diagnosed with adrenal carcinoma 2 years earlier and had undergone left adrenalectomy. Mitotane was initiated as neoadjuvant therapy at 10g/day. However, the patient developed short- ness of breath shortly thereafter, for which she underwent extensive yet inconclusive evaluation for pulmonary disease. Her dose of mitotane was
reduced to 2g/day with marked improvement in her dyspnoea. Following detection of subthera- peutic serum mitotane levels on routine follow-up with her oncologist, her dose was increased to 4 g/ day, following which dyspnoea recurred. Her symp- toms progressed to the point that she was unable to perform her activities of daily living. At the time of presentation, her physical examination was unremarkable.
INVESTIGATIONS
Haematological evaluation revealed a white cell count of 6.2×109/L, and a haemoglobin level of 11.6g/dL which was at baseline. Serum mitotane level was 14.9 ug/mL (therapeutic range 14-20 µg/ mL), troponin I was <0.04 ng/ml, and Brain natri- uretic peptide (BNP) was 209 pg/mL. No ST-seg- ment or T-wave changes were detected on ECG. Computed Tomography Angiography (CTA) chest revealed mild bibasilar subsegmental atel- ectasis (figure 1), with no evidence of pulmonary embolism. Echocardiogram revealed normal left ventricular ejection fraction (55%-60%), normal PA pressure and no wall motion abnormalities. Pulmonary function testing revealed a forced expi- ratory volume in 1 s/forced vital capacity ratio 85% and no evidence of obstructive or restrictive lung disease. Respiratory cultures and viral respiratory PCR panel were negative.
DIFFERENTIAL DIAGNOSIS
Differentials were pneumonia, pulmonary embo- lism, congestive heart failure and ischaemic heart disease. The patient was afebrile and did not have leucocytosis. CTA chest was negative for thrombo- embolism. ECG was normal, and troponins were negative. The onset of symptoms with initiation of mitotane and improvement with a decrease in the dose strongly suggest drug-induced aetiology.
TREATMENT
The patient’s shortness of breath was attributed to mitotane. The Naranjo adverse drug reaction probability scale indicated a definite relationship (score of 9) between the patient’s development of dyspnoea and mitotane.7 Discontinuation of mito- tane therapy led to marked improvement in her symptoms. She was gradually restarted on mitotane and was discharged on the tolerated dose of 2.5 g/ day. On 2-month follow-up, the patient reported improvement in her dyspnoea.
OUTCOME AND FOLLOW-UP
Dyspnoea improved gradually after stopping mito- tane. The patient was discharged after 4 days of
Unexpected outcome (positive or negative) including adverse drug reactions
hospitalisation on the tolerated dose of mitotane 2.5 g/day. On 2-month follow-up, mitotane serum level was 14.8 mL (thera- peutic range 14-20 µg/mL). The patient has remained on mito- tane 2.5 g/day for 3 months, and she is tolerating it very well.
DISCUSSION
Mitotane is a steroidogenesis inhibitor and a cytostatic anti- neoplastic agent that was introduced in 1960 for the treatment of ACC but has also been used in the treatment of Cushing’s syndrome.8 The recommended initial dose of mitotane for the treatment of ACC is 2-6g orally in three to four daily divided doses, with gradual increase in dose as tolerated based on plasma mitotane levels to achieve a therapeutic serum concentration of 14-20 µg/mL.9 10
Mitotane has a very narrow therapeutic index, and small changes in the dosage or interactions with other drugs could cause adverse effects. Currently, mitotane is the only cytotoxic agent for which regular pharmacokinetic-guided dosing is recom- mended to maintain therapeutic plasma levels, and a significant increase in previously recognised adverse effects is reported with plasma levels >20 µg/mL.2 The commonly reported side effects of mitotane include anorexia and nausea (88%), diarrhoea (38%), vomiting (23%), decreased memory and inability to concentrate (50%), rash (23%), gynaecomastia (50%), arthralgia (19%) and leucopenia (7%).11
Dyspnoea is a relatively unknown side effect of mitotane. To our knowledge, dyspnoea has not been reported as a side effect of mitotane. This would be the first case of mitotane-induced dyspnoea with a definite relationship between adverse effect and exposure to the medicine.
In this case, severe dyspnoea occurred at the therapeutic range of mitotane and was not associated with alteration in pulmo- nary function. The mechanism of mitotane-induced dyspnoea is unknown, but the association of increased dose with increase
in the intensity of the adverse reaction suggests a cumulative toxicity.
Learning points
Physicians should consider mitotane as possible cause of dyspnoea in the adrenocortical cancer patients who have symptoms without obvious cause.
We recommend that mitotane should be started at the lower end of the dosage spectrum and be titrated up to achieve a therapeutic level.
Clinical evaluation and appropriate imaging testing are warranted to evaluate for alternative causes.
Appropriate alternative agent should be started if dyspnoea becomes intolerable at the lowest effective dose of mitotane.
Acknowledgements The authors would like to thank Frank H Annie, Charleston Area Medical Center Health Education and Research Insitute, for research support as well as Abhishek Bhagat, Charleston Area Medical Center Department of Internal Medicine and Fatima Ahmed, Charleston Area Medical Center Department of Internal Medicine for general support for this project.
Contributors AUF: designed the study, drafted the manuscript, revised the manuscript and did literature review, obtained the consent. TK: contributed to case presentation. WA: performed the literature review. SA: reviewed the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
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Unexpected outcome (positive or negative) including adverse drug reactions
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