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Adrenocortical Carcinoma and the Mitotane Morass: A Physician/Patient Perspective
David A. Goodkin, MD
*
Bellevue, Washington
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ARTICLE INFO
Article history: Received 6 September 2024 Accepted 13 September 2024 Available online 16 September 2024
Adrenocortical carcinoma (ACC) was diagnosed when I was 65 years old. The presentation was unusual: peripheral edema due to compression of the inferior vena cava.1 I underwent tumor resec- tion, hepatic lobectomy, and nephrectomy. The 27-cm tumor had a satellite lesion and a Ki67 proliferation index of 22% (worse prog- nosis associated with values >10%; far worse for values >20%). My prognosis is probably worse than the 5-year survival of 24% typi- cally associated with stage 3 disease.2
My expert endocrinologists recommended adjuvant mitotane chemotherapy. As a nephrologist and clinical researcher myself, I am data driven; thus, I sought information on the benefits and risks of mitotane.
I cannot find any published animal survival study of implanted ACC tumors treated with mitotane versus control. There is a paucity of research to even establish the drug’s mechanism of action. An in vitro metabolomic/lipidomic study suggests mitochondrial damage to human adrenocortical tumor cells.”
I cannot find any randomized controlled trials demonstrating that the insecticide derivative mitotane is efficacious in people. The ADIUVO study was a randomized comparison of the effects of mitotane versus no treatment on recurrence-free survival among patients with ACC with stage 1 to 3 disease and a Ki67 proliferation index of ≤10%.4 It is the only randomized trial, and it showed no significant benefit from adjuvant mitotane. The most-cited mito- tane study was a retrospective observational exercise that found that 47 patients treated with adjuvant mitotane in Italy had better outcomes than 55 Italian and 75 German patients at different centers who did not receive mitotane.5 The participants ranged from stage 1 to stage 4 diseases, with the majority in stage 2. The
authors concluded that “Adjuvant mitotane may prolong recur- rence-free survival in patients with radically resected adrenocor- tical carcinoma.” However, factors other than mitotane may have differed between centers and confounded the outcomes. A meta- analysis based on retrospective studies reported that only 3 of 5 studies showed a significant mitotane benefit on recurrence-free survival and only 1 of 4 studies showed a significant benefit on overall survival, concluding that “current evidence suggests adju- vant mitotane significantly decreases the recurrence rate and mortality after resection of ACC in patients without distant metastasis, but these findings need further demonstration from prospective controlled trials.”6
The package insert for mitotane (Lysodren) lists 43 potential adverse reactions to the drug, including central nervous system toxicity, adrenal insufficiency, liver damage, kidney damage, depression, and retinopathy. A seminal review of the experiences of patients treated with mitotane noted that “All of our patients found it unpleasant to take.” The drug also increases cholesterol levels and is a strong inducer of hepatic CYP3A4 enzymes, necessitating dose adjustment for many other medications.
My inclination was not to take a toxic medication of unproven effectiveness. Ultimately, I opted to see if I could tolerate the drug, following the unanimous recommendation of my endocrinologists, an oncologist, my wife (a physician), and consensus guidelines.8
The drug took a major toll, including unrelenting sleepiness (2 naps a day), fatigue, malaise, irritability, cloudy thinking, rash, and breast pain. I am haunted by the possibility that I sacrificed 2 years of quality life out of perhaps ≤4 years of survival, with no compelling reason to believe the medicine prolonged my life. My tumor has recurred.
I am unaware of other nonhormonal adjuvant chemotherapy regimens that require 2 years of treatment or stipulate uninter- rupted daily dosing. Most adjuvant treatments entail only several 1- to 2-week cycles of therapy. Although my side effects did not grade highly on the Common Terminology Criteria for Adverse Events, mitotane made me feel sick constantly, month after month, in contrast to rough cytotoxic chemotherapies that often entail only limited episodes of vomiting and neutropenia. There are sporadic reports of tumor regression on mitotane; however, convincing ev- idence of efficacy is lacking. Furthermore, there are no persuasive data to support a given target serum drug concentration (and,
Abbreviation: ACC, adrenocortical carcinoma.
* Address correspondence to Dr David A. Goodkin, 3807 134th Ave NE, Bellevue, WA, 98005.
therefore, dosing) or an appropriate duration of treatment. The literature consensus suggests a target serum level of 14 to 20 µg/ mL; however, I cannot find supportive randomized studies. I was unable to withstand >9 ug/mL. Finally, as an oral chemotherapeutic, the drug falls into an unusual high-cost specialty tier that permits Medicare prescription drug plans to deny coverage of the medicine, costing the patient thousands of dollars each year.
The ADIUVO-2 trial is enrolling. It compares mitotane alone versus mitotane plus cisplatin and etoposide after surgery in pa- tients with high-risk of ACC recurrence. The assumption that mitotane is efficacious is implicit, despite the negative result of the first ADIUVO trial of patients at lower risk of recurrence. In my opinion, high-risk patients would benefit much more from a ran- domized controlled study of mitotane alone versus placebo. I believe that even a study of different mitotane blood levels or of varying durations of mitotane therapy would provide more valu- able information than the cisplatin/etoposide comparison study. I have been told informally by leadership of the ADIUVO-2 trial that they feared that they would be unable to enroll a placebo- controlled mitotane trial for this rare disease and that some in- vestigators believe it would be unethical not to prescribe mitotane. I would argue that such a trial is feasible and necessary, and it is less ethical not to include a placebo arm. I would gladly have enrolled in such a trial to inform treatment of future patients. I would not have been upset if randomized to placebo because equipoise exists as to whether there is any benefit associated with toxic mitotane. The first ADIUVO study was able to enroll patients, even though it included a no treatment arm. In my observation, endocrinologists are the gentlest and kindest of internists; however, endocrinology researchers should emulate colleagues such as oncologists and cardiologists and see that assertive, factual persuasion is some- times needed to enroll patients in clinical trials.
In conclusion, I found mitotane to be a miserable experience, and I cannot find convincing data that it works. Patients with bad diseases desire treatment, and clinicians want to prescribe
something; however, in the case of mitotane, there is a desperate need for placebo-controlled prospective studies to prove that it is worthwhile. No such trials are underway. I fear that a decade from now, patients will continue to be poisoned with mitotane, without solid justification.
Disclosure
The author has no conflicts of interest to disclose.
References
1. Goodkin DA. Massive adrenocortical carcinoma presenting as peripheral edema: a case report. J Med Case Rep. 2022;16(1):249. https://doi.org/10.1186/s13256- 022-03397-5
2. Fay AP, Elfiky A, Telo GH, et al. Adrenocortical carcinoma: the management of metastatic disease. Crit Rev Oncol Hematol. 2014;92(2):123-132. https://doi.org/ 10.1016/j.critrevonc.2014.05.009
3. Hescot S, Amazit L, Lhomme M, et al. Identifying mitotane-induced mitochon- dria-associated membranes dysfunctions: metabolomic and lipidomic ap- proaches. Oncotarget. 2017;8(66):109924-109940. https://doi.org/10.18632/ oncotarget.18968
4. Terzolo M, Fassnacht M, Perotti P, et al. Results of the ADIUVO study, the first randomized trial on adjuvant mitotane in adrenocortical carcinoma patients. J Endocr Soc. 2021;5(suppl 1):A166-A167. https://doi.org/10.1210/jendso/ bvab048.336
5. Terzolo M, Angeli A, Fassnacht M, et al. Adjuvant mitotane treatment for adre- nocortical carcinoma. N Engl J Med. 2007;356(23):2372-2380. https://doi.org/ 10.1056/NEJMoa063360
6. Tang Y, Liu Z, Zou Z, Liang J, Lu Y, Zhu Y. Benefits of adjuvant mitotane after resection of adrenocortical carcinoma: a systematic review and meta-analysis. Biomed Res Int. 2018;2018:9362108. https://doi.org/10.1155/2018/9362108
7. Hoffman DL, Mattox VR. Treatment of adrenocortical carcinoma with o,p’-DDD. Med Clin North Am. 1972;56(4):999-1012. https://doi.org/10.1016/s0025- 7125(16)32365-3
8. Fassnacht M, Dekkers OM, Else T, et al. European Society of Endocrinology clinical practice guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2018;179(4):G1-G46. https://doi.org/10.1530/EJE-18- 0608