Treatment advances in adrenocortical carcinoma

teaser

Justine Bacchetta
Fellow

Jean-Pierre Droz
MD PhD
Head of Department
Department of Medical Oncology
Centre Leon Berard
Lyon
France
E:[email protected]

Adrenocortical carcinoma incidence is less than 1/1,000,000. It has poor outcome(1) and may be associated with cancer predisposition (eg, Li-Fraumeni syndrome). The standard treatment is radical surgery, consisting of en-bloc resection of the adrenal gland tumour with kidney and adjacent organs. Overall survival is 20–40%. The major prognostic factor is the histocytological score of Weiss.(2) Advanced and metastatic disease is incurable, with a median survival of one year. Surgical excision of metastases, o,p’DDD (1,1-dichloro-2-(p-chlorophenyl)-2-(o-chlorophenyl)-ethane) and chemotherapy are the most important treatments at this stage.

o,p’DDD

Discovery, mode of action and formulation
The insecticide o,p’DDD has adrenolytic properties in dogs.(3) It induces necrosis of both fascicular and reticular zones of the gland. It inhibits the 11β-hydroxy­lation of the S component, ­desoxycorticosterone and corticosterone. It also induces the cleavage of the cholesterol chain, which leads to inhibition of cortisol and aldosterone chains.(4) Finally, o,p’DDD inhibits mitochondrial metabolism and induces apoptosis.(5) The result is also adrenocortical insufficiency and inhibition of tumour hormone secretion (observed in 80% of cases) in two-thirds of patients.(6) However, the objective response rate in measurable tumours is only 10–40%.(7) It is interesting to note that o,p’DDD inhibits the multidrug resistance (MDR) protein P.(8) Thus, it may potentiate the action of anthracyclines, taxanes and mitosis-targeting drugs. No cisplatin potentiation has been observed, and no information is available on the induction of carcinogenesis, ­teratogenicity and excretion in human milk during lactation. Only one formulation of o,p’DDD, Lysodren(®), is available (Mitotane(®) is no longer produced). It is presented as a white granular solid composed of colourless crystals. o,p’DDD is mixed with polyethylene glycol; it is soluble in ethanol, isooctane and carbon tetrachloride. The dosage is 500mg of o,p’DDD per tablet.

Pharmacology
o,p’DDD has a high affinity to lipids; thus, it strongly binds to low-density lipoproteins, very low-density lipoproteins and chylomicrons. It has a large diffusion in lipid-rich organs such as the adrenal glands and the central nervous system (CNS), which explains the CNS toxicity associated with the drug. Plasma levels are measured by gas chromatography(9) or high-performance liquid chromatography (HPLC).(10) A detectable plasma level is obtained after several weeks, after the patient has received an initial high dose of 2–12g/day. The bioavailability through oral intake is around 40%. Urinary metabolite excretion represents 10% of the dose, and biliary excretion is low; around 50% of the drug is stored in the lipid compartments of the body. The plasma terminal half-life has been estimated to be 20–160 days,(11) the drug being undetectable after two to three months after the end of the treatment.(12)

Toxicity
The major clinical toxicities are gastrointestinal (nausea and vomiting in 80% of patients), asthenia and CNS toxicities. The symptoms are confusion, malaise, vertigo and somnolence, observed in 40% of patients.(12) These side-effects are reversible when treatment is stopped.

Other symptoms are skin rash (20%), cystitis, retinopathy and, rarely, hypersensitivity. Biological side-effects are hypercholesterolaemia, hyper‑triglyceridaemia, low serum uric acid level and infrequent myelosuppression, with the most common adverse effect being abnormalities of hepatic enzymes. Serum alanine aminotransferase and aspartate aminotransferase and γ-glutamyl ­transferase levels are increased in almost all patients; this represents the true cytolytic liver toxicity and a sign of o,p’DDD liver storage, respectively.(13) Finally, the drug has an aspirin-like effect on blood clotting and increases hepatic microsomal enzyme induction. Coumarin anticoagulants must not be used at the same time as o,p’DDD.

Monitoring o,p’DDD plasma levels
Different studies have focused on the importance of monitoring o,p’DDD plasma levels.(12,14,15) A retrospective study has shown that patients with plasma drug level >14mg/l and <14mg/l have 59% and 0% objective response rates, respectively. Moreover, plasma drug level is a strong prognostic factor for survival. This has been confirmed prospectively using both Mitotane(15) and Lysodren.(12) The same studies demonstrated that plasma o,p’DDD level >20mg/l is correlated with excessive CNS toxicities.

Practical mode of administration
Lysodren is given at an initial daily dose of 2g, with a 1g dose increase until the maximal tolerated dose is obtained, at the earliest possible time, to reach a daily dose of 9–10g after three weeks of treatment. The drug is given as three or four divided daily doses during meals. The meal would contain normal salt amount and be poor in milk and lipids to avoid excessive binding with the drug. However, previous data suggested better intestinal absorption with lipid intake.(11) Plasma samples are collected on sodium heparin, then centrifuged and stored at –20°C. Plasma drug level is determined by HPLC. Dosages are repeated monthly to obtain plasma levels of 14–20mg/l. When the activity threshold has been reached, the daily dose must be decreased by 1–2g, with further dosage adjustments. Lysodren is continued until failure or disease progression. All patients will obtain a plasma drug level within the recommended limits after a time interval of three to four months.(12) Patients receive hydrocortisone supplementation at a daily dose of 30mg, which must be increased in the case of an intercurrent problem (such as infection, diarrhoea, surgical intervention or wound). Mineralocorticoids may be warranted in such ­intercurrent situations (for example, fludrocortisone 25–100μg daily, depending on the clinical issue). Patients receiving Lysodren should receive written information regarding treatment, toxicities and medical contacts in case of emergency. They must also be aware of the risk of driving a car or using dangerous machinery, due to somnolence. The biological follow-up must include a monthly control of CBC (complete blood count), hepatic enzymes, blood electrolytes, total cholesterol and triglycerides. A close clinical monitoring is required, mainly during treatment administration. Lysodren must be interrupted until recovery when National Cancer Institute – Common Toxicity Criteria (NCI-CTC)(16) grade 3 or 4 CNS and gastrointestinal toxicities are observed, and when surgical procedure is needed. Therefore, drug dosage is decreased by 1 or 2g, as for grade 1 or 2 toxicities. Hepatic toxicity does not justify drug dosage adaptation.(13)

Chemotherapy
The results of phase II trials of chemotherapy in adreno‑
cortical carcinoma are shown in Table 1,(17–25) with response rates of 20–30%. Two trials are currently ongoing in this tumour model.(26,27) Chemotherapy is only indicated in the advanced disease stage, generally in combination with o,p’DDD. A combination of etoposide and cisplatin,(21) possibly in combination with doxorubicin,(22) is routinely used. Other drugs such as paclitaxel or temozolomide,(28) and targeted drugs such as inhibitors of the insulin growth factor receptor family or binding proteins(29) warrant further investigations.

[[HPE23_table1_79]]

Conclusion
Surgery remains the major treatment in adrenocortical carcinoma, and o,p’DDD is a major option in the adjuvant and advanced disease settings. Chemotherapy and new drugs require further studies.

The authors would like to thank Marie-Dominique Reynaud for editorial assistance

References

1. Ann Oncol 1997;8:423-7.
2. Am J Surg Pathol 1989;13:202-6.
3. Arch Pathol 1949;48:387.
4. Endocrinol Metab Clin North Am 1994;23:571-84.
5. J Clin Endocrinol Metab 1997;82:1317-24.
6. N Engl J Med 1990;322:1195-201.
7. World J Surg 2001;25:927-33.
8. Cancer 1993;71:2900-1.
9. J Chromatograph 1987;417:287-94.
10. Ther Drug Monit 1999;21:355-9.
11. Cancer Chemother Pharmacol 1981;7:51-4.
12. J Clin Endocrinol Metab 2000;85:2234-8.
13. Therapie 2001;56:793-7.
14. Eur J Cancer Clin Oncol 1984;20:47-53.
15. Cancer 2001;92:1385-92.
16. European Organisation for Research and Treatment of Cancer. Available from: http://www.eortc.be/Services/Doc/ctc
17. Ann Oncol 2000;11:1281-7.
18. J Clin Oncol 1993;11:161-5.
19. Surgery 1991;110:1006-13.
20. Ann Oncol 2002;13:1806-7.
21. Br J Cancer 1998;78:546-9.
22. Cancer 1998;83:2194-200.
23. Cancer 1991;67:2997-3000.
24. Cancer 1993;72:3145-55.
25. Cancer 2002;94:2333-43.
26. FIRM-ACT. http://cancer.gov/clinicaltrials
27. Tarquiridar, mitotane, doxorubicin, vincristine and etoposide plus surgery. http://cancer.gov/clinicaltrials
28. Endocr Res 1996;22:709-15.
29. Endocrinology 2000;141:3165-71.