Pregnancy in a Patient With Adrenal Carcinoma Treated With Mitotane: A Case Report and Review of Literature
Liana Tripto-Shkolnik, Zeev Blumenfeld, Moshe Bronshtein, Asher Salmon, and Anat Jaffe
Diabetes and Endocrinology Unit (L.T.S., A.J.), Hillel Yaffe Medical Center, Hadera 38100, Israel; Reproductive Endocrinology (Z.B.), Department of Obstetrics and Gynecology, RAMBAM Health Care Campus, Rappaport Institute and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31097, Israel; Faculty of Social Welfare and Health Sciences (M.B.), University of Haifa, Haifa 31095, Israel; and Sharett Institute of Oncology (A.S.), Hadassah University Hospital, Jerusalem 91120, Israel
Context: Adrenocortical carcinoma (ACC) affects patients in a broad age group, including young women. Mitotane, an adrenolytic agent, is the mainstay of treatment after surgical removal of the tumor. There is extreme paucity of information regarding the effect of mitotane on childbearing potential and pregnancy outcome.
Objective: The aim of the study was to describe and discuss the case of an ACC patient who conceived while on mitotane treatment. Current literature is reviewed.
Patient and Methods: A 33-year-old woman received mitotane treatment for 4 years due to met- astatic ACC. Despite nearly therapeutic blood levels of the drug, the patient had regular menstru- ation and was able to conceive. Mitotane was stopped at gestation week 6. Although the drug continued to be detected in considerable amounts, the fetus developed normally, including mor- phologically intact adrenal glands. At gestation week 21, pregnancy was terminated due to ACC recurrence. Mitotane levels were undetectable in fetal cord blood and amniotic fluid.
Conclusion: Our report suggests that mitotane, despite its action as an endocrine disruptor, does not affect normal gonadal function or an ability to conceive. The concern of placental transfer by this hydrophobic compound is not supported by our findings. However, we do not recommend drawing conclusions regarding the safety of mitotane in pregnancy, based on 1 or several case reports. Until more data are available, pregnancy should be avoided in women being treated with mitotane for ACC. (J Clin Endocrinol Metab 98: 443-447, 2013)
T he patient first presented in 2005, at the age of 29 years, with rapid development of facial and ankle edema, hirsutism, supraclavicular fat pads, and easy bruis- ing. Cushing’s syndrome was diagnosed by 9 times the upper limit of normal urinary free cortisol and abnormal overnight dexamethasone suppression test. ACTH was un- detectable. Abdominal computer tomography revealed a right adrenal mass measuring 7.5 cm in its longest diameter, with baseline Hounsfield unit density of 30, undergoing con- trast enhancement to 66 and no contrast washout on late
10-minute scan. According to the above parameters, adrenal carcinoma was suspected. No metastases were seen on ab- dominal and lung computer tomography scan and on fluo- rodeoxyglucose (FDG)-positron emission tomography (PET). Electrolytes were normal at presentation, but over a period of 10 days, hypokalemia evolved, indicating overt hypercortisolism. It responded to treatment with aldospi- rone. At this point, ketoconazole was administered.
Urinary free cortisol had fallen from 1018 to 313 mg/d after 2 days of therapy and to 130 mg/d after 4 days.
Abbreviations: ACC, Adrenal cortical carcinoma; FDG, fluorodeoxyglucose; PET, positron emission tomography; US, ultrasound.
The patient underwent surgery and the mass, measur- ing 8 × 6 × 5 centimeters and weighing 165 grams, was excised. The pathologist concluded that the lesion was adrenocortical carcinoma (ACC) with abundant necrosis, vascular invasion, and Ki-67 of 30-40%.
The patient started mitotane treatment immediately af- ter surgery and continued treatment at a dose of 1.5-3 g/d with plasma mitotane level monitoring (Table 1). Plasma levels were measured by Lysosafe service provided by HPA Pharma (www.lysosafe.com).
Further dose escalation was prevented by gastrointes- tinal intolerance.
One year after the surgery, follow-up FDG-PET scan revealed disseminated disease with lung, liver, and lymph node metastases.
The patient started chemotherapy according to EDP (etoposide, doxorubicin, and cisplatin) protocol (1). Prior to chemotherapy initiation, and monthly for the duration, GnRH analog treatment was given for fertility preserva- tion (2, 3).
After 4 courses of chemotherapy, the patient preferred to stop the treatment. She continued mitotane, glucocor- ticoid and mineralocorticoid replacement, and oral con- traceptive pills.
Mitotane level reached the therapeutic target after 18 months of therapy (Table 1).
Serial FDG-PET scans were negative.
One and a half years after cessation of chemotherapy, the patient chose to stop oral contraceptives, regular men- strual periods were resumed, and hormonal profile was of the ovulating type.
After 3 months the patient learned that she was pregnant.
At this point she was strongly advised to terminate the pregnancy. The patient was determined to continue.
The patient decided to stop mitotane at 6-week gesta- tion due to her desire not to harm the fetus. Blood levels
| Clinical Context | Mitotane Dose, g/d | Mitotane Level, mg/L | Months After Diagnosis |
|---|---|---|---|
| Treatment started | 2.5-3 | 1.6-6.6 | 2-11 |
| First recurrence | 3.5 | 7.8 | 12 |
| EDP chemotherapy | 3 | 13.4 | 17 |
| Serial FDG-PET negative | 1.5-3 | 13.2-20.6 | 20-27 |
| Contraceptive stopped | 1.5 | 13.2 | 34 |
| 6 wk pregnantª | 1.5 | 9.8 | 40 |
| Second recurrence | 0 | 5.99 | 42 |
| Pregnancy terminated | 0 | 4.2 | 45 |
Abbreviation: EDP, etoposide, doxorubicin, and cisplatin. a Mitotane stopped at 6 weeks gestation.
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were monitored (Table 1). Those continued to be measur- able 5 months after discontinuation. She continued glucocorticoid supplementation with hydrocortisone. Change of supplemental glucocorticoid to dexamethasone was considered, in the face of possible placental transfer of mitotane and, thus, fetal hypoadrenalism that might have been addressed with dexamethasone replacement.
Fetal ultrasound (US) at week 16 revealed a morpho- logically normal female fetus, no intrauterine growth re- tardation, and normal appearing adrenals (Figure 1).
At gestation week 18, the patient presented with a clin- ical picture compatible with rapid evolvement of Cush- ing’s syndrome. Hypercortisolism was biochemically con- firmed-loss of diurnal variation, and urinary free cortisol elevated to 9 times normal.
Abdominal US and magnetic resonance imaging dem- onstrated a large 8-centimeter liver metastasis, and lung computer tomography revealed a 2-centimeter metastasis of left lung base.
Since the patient preferred the effort to spare the preg- nancy, right hepatectomy was attempted but was unsuc- cessful due to profuse bleeding from a severely congested liver.
At 21-week gestation, the pregnancy was terminated. Prior to the procedure, amniotic fluid and fetal cord blood were drawn for mitotane level; in both samples, the drug was undetectable. Blood levels 2 weeks before the proce- dure and 10 days afterward were 5.99 and 4.2 mg/L, respectively.
The patient resumed chemotherapy, and the liver mass shrank but remained detectable on imaging.
Six months after the pregnancy termination, the patient underwent surgery to remove the liver lesion. Immediately after the procedure, the patient suffered a refractory shock. As part of resuscitation efforts, reexploration of the
surgery site was undertaken, but no bleeding was found. The patient died on the operating table. It was suspected that she might have suffered a massive pulmonary embo- lism, but a postmortem investigation was not performed.
Discussion
ACC is a rare neoplasm with a high mortality rate. The disease has bimodal age distribution with a first peak in childhood and a second peak in ages 40s and 50s. ACC is slightly more prevalent in women (4). More than half of the cases are hormone secreting -most commonly cortisol and androgens (5).
Mitotane [o,p’ dichlorodiphenyl dichloroethane (o,p’ DDD)] (Lysodren; HRA Pharma, Paris, France; Bristol Meyers Squibb, New York, New York) is a derivate of p,p’ dichlorodiphenyl trichloroethane (p,p’ DDT), a common insecticide.
Mitotane’s adrenolytic activity has been known since the late 1950s and has been used in the treatment of en- dogenous hypercortisolism and adrenal carcinoma (6). Recent data suggest that treatment with mitotane might prolong recurrence-free survival in patients with ACC (7). Blood level monitoring is recommended. The target blood concentration is 14-20 mg/L (4). Given the young age of diagnosis in some patients and the need for prolonged if not lifelong treatment, questions do arise concerning the
feasibility of pregnancy on mitotane therapy as well as mutagenic potential of the compound.
ACC diagnosed during pregnancy has been reported with grave maternal and fetal outcomes; several reports have been published recently (8-10).
There is an extreme paucity of data regarding the effect of mitotane on the human fetus. The suspicion of the abil- ity of this hydrophobic compound to cross the placenta comes from the observation that p,p’ DDT, the morpho- logically similar insecticide, is found in cord blood of in- fants in DDT-exposed areas (11). Given the adrenolytic activity of the drug, teratogenic effect is feared.
However, very few reports regarding humans address this issue. Those are summarized in Table 2.
In 1973, Luton et al (12) published a paper describing several patients treated with mitotane for Cushing’s dis- ease. Among them, one patient gave birth to a normal infant after being treated throughout her pregnancy.
In 1978, Leiba et al (13) reported a case of a 38-year-old woman treated with mitotane 5 g/d for 100 days for hy- percortisolism due to Cushing’s disease 8 years before pregnancy. She delivered a normal female baby.
In 1989, Leiba et al (14) reported a case of a 30-year-old woman treated with mitotane 1.5-4 g/d (1.5 g during month 1 of pregnancy). Mitotane was stopped on week 4, and the pregnancy was terminated on week 6. Histopatho- logical examination of the embryo revealed a dysmorpho-
| Authors | Year of Publication | Patient's Age | Diagnosis | Mitotane Dose | Blood Level Monitoring During Pregnancy | Timing of Mitotane Cessation | Fetal Outcome | Patient's Outcome | Additional Information |
|---|---|---|---|---|---|---|---|---|---|
| Luton et al (12) | 1973 | ND | CD | ND | ND | Continued throughout pregnancy | Normal infant | ND | |
| Leiba et al (13) | 1978 | 38 | CD | 5 g/d | ND | 8 y before pregnancy | Normal female infant | ND | |
| Leiba et al (14) | 1989 | 30 | CD | 1.5 g/d | ND | 4 wk gestation | Pregnancy termination on wk 6 | ND | Pycnotic sympathoblasts in cortical primordia |
| Gerl et al (15) | 1992 | 28 | CD | 1-1.5 g/d | 3.9-4.7 mg/L | 34 wk gestation | Healthy male infant on wk 38 | ND | Cord blood mitotane 1.4 mg/L, equal to maternal blood at birth |
| Baszko-Blaszyk et al (16) | 2011 | 28 | ACC | ND | 12.5 mg/L on conception | Continued | Spontaneous abortion on wk 10, twins | 6 mo later, no evidence of ACC | |
| Kojori et al (17) | 2011 | 28 | ACC | 1 g/d | ND | Continued throughout | Premature delivery | ACC recurred shortly after delivery | Normal child's growth and development at 1 y follow-up |
| pregnancy | on wk 31 due to maternal | ||||||||
| HELLP | |||||||||
| syndrome, no evidence of AI | |||||||||
| Current case | 2012 | 33 | ACC | 1.5 g/d | 9.8-4.2 mg/L | 6 wk gestation | Pregnancy | Passed away | Visualization of fetal |
| termination on wk 21 due to dramatic ACC recurrence | 6 mo later | adrenal on US, morphologically normal fetus, mitotane <1 mg/L in cord blood or AF |
Abbreviations: CD, Cushing’s disease; ND, no details; HELLP, hemolytic anemia, elevated liver enzymes, and low platelet count; Al, adrenal insufficiency; AF, amniotic fluid.
genic event in the cortical primordia characterized by py- cnotic sympathoblasts.
Among the very few references mentioning mitotane treatment during pregnancy in more detail is a German publication by Gerl et al (15) reporting a case of a 28- year-old woman with Cushing’s syndrome treated by 1.5 g/d for 18 months before pregnancy. Dose was reduced to 1 g/d during pregnancy. Mitotane blood levels were 3.9- 4.7 mg/L. Mitotane was stopped at 34 weeks, and delivery was at 38 weeks. Cord blood mitotane concentration at birth was 1.4 mg/L- equal to maternal blood level.
This patient delivered a healthy baby boy. The new- born’s ACTH measured 3 hours postpartum was 1533 pg/ml (10 times higher than normal), yet the baby’s blood cortisol was normal (15).
The two most recent reports, and the only two discuss- ing patients with ACC, were published in 2011 by Polish (16) and Canadian (17) groups. In the report by Baszko- Błaszyk et al (16), a 27-year-old patient with a virilizing adrenal carcinoma was treated with surgical excision in 2008 and subsequently with mitotane. The patient con- ceived twins while on mitotane, with a blood level of 12.5 mg/L. On week 10 gestation, spontaneous abortion oc- curred (16). Kojori et al (17) presented a patient of the same age with ACC who became pregnant while treated with mitotane and hydrocortisone replacement. She was switched to dexamethasone on gestation week 17. Mito- tane blood level monitoring was not reported. On the 29th week, US demonstrated normal fetal growth but suggested hypoplastic adrenal glands. Despite that, the baby had intact adrenal function at birth and was growing and de- veloping normally at 1-year follow-up (17).
It is important to note that the mother presented with disease recurrence shortly after birth.
Our report contributes several discussion points, bear- ing in mind natural limitations since it is only based on one case.
First, mitotane treatment at a dose achieving nearly therapeutic blood level did not interfere with normal ovu- latory gonadal function in our patient and her ability to conceive. Second, although mitotane treatment was dis- continued at gestation week 6, the blood concentration of the drug continued to be measurable (Table 1). Despite this, the fetus developed normally, including morpholog- ically normal adrenals, viewed by sonography (Figure 1). Previous experience supports the ability of high resolution US to accurately diagnose adrenal pathology such as agen- esia, tumors, hypoplasia, hyperplasia, and gross morpho- logical abnormalities (18). It should be highlighted that the pregnancy was terminated at week 21; thus, fetal anomaly that might have occurred later cannot be ex- cluded. Third, the patient received hydrocortisone sup-
plementation, a substrate to placental inactivation by 11ß- hydroxysteroid dehydrogenase. Thus, if mitotane had caused fetal hypoadrenalism, and since the fetus did not “receive” glucocorticoid replacement, one could expect intrauterine growth retardation. This, however, was not evident.
Fourth, fetal cord blood and amniotic fluid drug levels were undetectable, whereas the patient’s blood concen- tration was between 4 and 6 mg/L, further supporting the assumption that the placental transfer may be less than expected from the compound’s chemical properties. The lower detection limit of the assay is 1 mg/L, far below the patient’s blood level at the time. Since fat serves as a res- ervoir for mitotane accumulation, it might have been use- ful to examine the drug presence in fetal fat tissue, but that was not performed.
Fifth, the disease recurred drastically during pregnancy in our patient. Pregnancy itself and mitotane withdrawal could have been implicated as possible accelerators.
Thus, both the Canadian patient who experienced ACC recurrence shortly after giving birth (despite being treated with mitotane throughout the pregnancy) (17) and our patient whose outcome was so grave should lead to the conclusion that feasibility of pregnancy in an ACC patient needs to be seriously weighed against the possible negative effect on disease progression.
In summary, there are very few reports discussing preg- nancy in patients on mitotane. This is a detailed case pre- sentation of a patient with ACC who conceived while on mitotane treatment and who maintained the pregnancy up to week 21, with sonographic confirmation of a morpho- logically normal fetus, including intact adrenal glands vi- sualization and no evidence of mitotane transfer to the amniotic fluid and cord blood. However, we do not rec- ommend, based on our case and the scant current litera- ture, concluding that pregnancy is safe in women treated with mitotane. Until further knowledge is available, ef- fective contraception should be recommended to such pa- tients, and pregnancy should be avoided.
Acknowledgments
This article is dedicated to D.S.P., a beautiful woman, a remark- able person, and an outstandingly courageous patient.
The authors thank Prof. David Schneider, Asaf Ha-Rofe Medical Center, Sackler Faculty of Medicine, Tel Aviv Univer- sity, for his help with the amniotic fluid and fetal cord blood samples. We also thank Mrs. Ariela Ehrlich, MLS, for the revi- sion and proofreading.
Address all correspondence and requests for reprints to: Liana Tripto Shkolnik, MD, MMedSc, Diabetes and Endocrinology
Unit, Hillel Yaffe Medical Center, POB 169, Hadera 38100, Israel. E-mail: lianatrish@gmail.com.
Disclosure Summary: The authors have nothing to disclose.
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