1. Adrenal Carcinoma Dr. D.W. Daugherty

2. Epidemiology Estimated incidence of 0.5-2 per 10 6 patients per year Estimated incidence of 0.5-2 per 10 6 patients per year Peaks of age distribution at age <5 and in the 4 th and 5 th decades Peaks of age distribution at age <5 and in the 4 th and 5 th decades Scattered reports of gene associations, but rarity of lesion limits studies – no clear associations Scattered reports of gene associations, but rarity of lesion limits studies – no clear associations

3. Functioning Lesions 60-65% of adrenocortical carcinomas are functioning lesions 60-65% of adrenocortical carcinomas are functioning lesions Cushings Cushings Virilization Virilization Feminization Feminization Hyperaldosteronism Hyperaldosteronism

4. Diagnostics Hormonal studies can be a first diagnostic test which confirms ectopic steroid hormone secretion, leading to an imaging and tissue diagnosis. Hormonal studies can be a first diagnostic test which confirms ectopic steroid hormone secretion, leading to an imaging and tissue diagnosis. They also can be a “tumor marker” which can be useful for monitoring response to therapy and suspicion of recurrence. They also can be a “tumor marker” which can be useful for monitoring response to therapy and suspicion of recurrence.

5. Hypercortisolism 24 hour urinary cortisol exrection 24 hour urinary cortisol exrection More than 90% of Cushinoid patients have free cortisol levels greater than 200mcg/ 24 hours. 97% of normals have levels less than 100mcg/ 24 hours More than 90% of Cushinoid patients have free cortisol levels greater than 200mcg/ 24 hours. 97% of normals have levels less than 100mcg/ 24 hours ACTH measured with serum cortisol will demonstrate ACTH independent nature of hypercortisolism.

6. Other Steroids Other steroids are elevated: Other steroids are elevated: androstenediol and adrosetenedione androstenediol and adrosetenedione DHEA and DHEA-S DHEA and DHEA-S 11- deoxycortisol 11- deoxycortisol urinary 17- ketosteroids urinary 17- ketosteroids aldosterone aldosterone Many intermediate enzymes are defective or dysregulated, leading to inefficient steroid production and precursor accumulation Many intermediate enzymes are defective or dysregulated, leading to inefficient steroid production and precursor accumulation

8. Potential Functional Assays Serum Testosterone Serum Testosterone Serum DHEA and DHEA-S Serum DHEA and DHEA-S 24 hour urinary ketosteroids 24 hour urinary ketosteroids Plasma estradiol and/ or estrone Plasma estradiol and/ or estrone Plasma aldosterone/ renin Plasma aldosterone/ renin Urinary catecholamines/ metanephrines in all patients Urinary catecholamines/ metanephrines in all patients

9. Imaging CT detects 98% of adrenal carcinomas CT detects 98% of adrenal carcinomas MRI scanning can also provide vascular invasion/ tumor thrombosis information. MRI scanning can also provide vascular invasion/ tumor thrombosis information. Many incidental findings? Many incidental findings? Malignant lesions tend to be > 5cm, have irregular shapes/ blurred margins, and be heterogeneously enhancing. Malignant lesions tend to be > 5cm, have irregular shapes/ blurred margins, and be heterogeneously enhancing.

10. Staging Hormonal studies directed at symptoms Hormonal studies directed at symptoms 24h urine studies to r/o pheochromocytoma 24h urine studies to r/o pheochromocytoma CT scanning to determine extent and resectability of lesion CT scanning to determine extent and resectability of lesion MRI may clarify vascular invasion; right sided lesions have a propensity to form venous tumor emboli MRI may clarify vascular invasion; right sided lesions have a propensity to form venous tumor emboli

11. Staging Stage I — Disease confined to the adrenal gland and <5 cm in diameter (approx 20%) Stage I — Disease confined to the adrenal gland and <5 cm in diameter (approx 20%) Stage II — Disease confined to the adrenal gland and >5 cm in diameter (approx 20%) Stage II — Disease confined to the adrenal gland and >5 cm in diameter (approx 20%) Stage III — Local invasion that does not involve adjacent organs or regional lymph nodes (approx 20%) Stage III — Local invasion that does not involve adjacent organs or regional lymph nodes (approx 20%) Stage IV — Distant metastases or invasion into adjacent organs plus regional lymph nodes (approx 40%) Stage IV — Distant metastases or invasion into adjacent organs plus regional lymph nodes (approx 40%)

12. Surgery Complete surgical resection is the primary treatment modality

13. Post- Resection Survival Complete resection is the strongest predictor of survival

14. Incomplete resection is associated with a uniformly poor prognosis, with less than a 1 year median survival

15. Resectability Unresectable tumors include those that invade the celiac plexus/ vascular structures/ SMA/ aorta Unresectable tumors include those that invade the celiac plexus/ vascular structures/ SMA/ aorta

16. Prognostic factors In a case review of 46 patients at MSKCC, 3 histologic factors correlated with survival: In a case review of 46 patients at MSKCC, 3 histologic factors correlated with survival: Tumor > 12cm Tumor > 12cm 6 or more mitotic figures/ 10hpf 6 or more mitotic figures/ 10hpf presence of histologic evidence of intra-tumoral hemorrhage presence of histologic evidence of intra-tumoral hemorrhage 5 year survivals: 5 year survivals: 0 factors: 83% 0 factors: 83% 1 factor: 42% 1 factor: 42% 2 factors: 33% 2 factors: 33%

17. Treatment Adrenalectomy Adrenalectomy Prednisone for steroid replacement Prednisone for steroid replacement Patients with glucocorticoid producing tumors postoperatively will need replacement due to suppression of the remaining adrenal Patients with glucocorticoid producing tumors postoperatively will need replacement due to suppression of the remaining adrenal

18. Radiation Approach There are emerging case reports demonstrating improved outcomes when palliative XRT used for localized lesions There are emerging case reports demonstrating improved outcomes when palliative XRT used for localized lesions

19. Chemotherapeutic Approach Emerging case reports, retrospective treatment data, and reviews are beginning to support this approach. Emerging case reports, retrospective treatment data, and reviews are beginning to support this approach.

20. Mitotane 1,1- dichloro-2-(o-chlorophenyl) ethane (o,p- DDD). 1,1- dichloro-2-(o-chlorophenyl) ethane (o,p- DDD). Chemical relative to DDT Chemical relative to DDT Found to have adrenolytic activity in dogs in vivo (selectively destroyed the zonae reticularis and fasciculata) Found to have adrenolytic activity in dogs in vivo (selectively destroyed the zonae reticularis and fasciculata)

21. Mitotane inhibits the mitochondrial conversion of cholesterol to pregnenolone and the conversion of 11-deoxycortisol to cortisol (11B- hydroxylation). It produces selective adrenocortical necrosis in both the adrenal tumor and metastases inhibits the mitochondrial conversion of cholesterol to pregnenolone and the conversion of 11-deoxycortisol to cortisol (11B- hydroxylation). It produces selective adrenocortical necrosis in both the adrenal tumor and metastases

22. Mitotane Side effects are major and frequent, including: Side effects are major and frequent, including: CNS disturbance (vertigo, somnolence, ataxia) CNS disturbance (vertigo, somnolence, ataxia) Liver Toxicity Liver Toxicity Renal Toxicity Renal Toxicity Nausea, Vomiting Nausea, Vomiting Diarrhea Diarrhea Rash Rash

23. Selected Mitotane Studies

24. Other symptom- palliative Options Metyrapone (11B hydroxylase inhibitor) Metyrapone (11B hydroxylase inhibitor) Ketoconazole Ketoconazole Aminoglutehamide Aminoglutehamide

25. Cytotoxics Various systemic cytotoxics have been used for advanced disease, usually for those failing mitotane. Various systemic cytotoxics have been used for advanced disease, usually for those failing mitotane. Most studied have been Etoposide, cisplatin, and adriamycin. Most studied have been Etoposide, cisplatin, and adriamycin. Paclitaxel and Temozolamide have recently demonstrated antitumor activity in vitro Paclitaxel and Temozolamide have recently demonstrated antitumor activity in vitro

26. Combos Original studies utilized Cisplatin and Doxorubicin with Cyclophosphamide or 5-FU. RR was 20% Original studies utilized Cisplatin and Doxorubicin with Cyclophosphamide or 5-FU. RR was 20% Cisplatin/ Etoposide reported to have an 11% response rate Cisplatin/ Etoposide reported to have an 11% response rate

27. Overview of Chemo Trials

28. MDR issues P-Glycoprotein (Pgp) is expressed widely in normal adrenal and adrenocortical carcinoma cells P-Glycoprotein (Pgp) is expressed widely in normal adrenal and adrenocortical carcinoma cells In vitro, mitotane inhibits the Pgp efflux pump at concentrations achieved with mitotane therapy In vitro, mitotane inhibits the Pgp efflux pump at concentrations achieved with mitotane therapy

29. EDP-M Italian study Italian study 28 patients enrolled 28 patients enrolled Etoposide (100mg/ m 2 ) d5-7; Doxorubicin (20mg/ m 2 ) d1,8; Cisplatin (40mg/ m 2 ) d1,9 every 4 weeks Etoposide (100mg/ m 2 ) d5-7; Doxorubicin (20mg/ m 2 ) d1,8; Cisplatin (40mg/ m 2 ) d1,9 every 4 weeks Concomitant mitotane up to 4g/ day Concomitant mitotane up to 4g/ day

30. EDP-M CR in 2 patients CR in 2 patients PR in 13 patients PR in 13 patients Overall response of 54% Overall response of 54% Stable disease in 8, progessive in 5 Stable disease in 8, progessive in 5 Median TTP of 24 months in responders Median TTP of 24 months in responders

31. Recurrences Recurrences that are amenable to re- operation may be resected for long term survival Recurrences that are amenable to re- operation may be resected for long term survival 5 year survivals compare from 57% in those amenable to resection to 0% for those who are not 5 year survivals compare from 57% in those amenable to resection to 0% for those who are not

32. Recurrences Italian registry: 140 resections Italian registry: 140 resections Recurrences in 52 (37%) Recurrences in 52 (37%) Locally in 13 Locally in 13 Distant in 25 Distant in 25 Local + Distant in 14 Local + Distant in 14 20 patients underwent re- resection 20 patients underwent re- resection 5 yr survival of 50% in those resected 5 yr survival of 50% in those resected 5 yr survival of 8% in those not resected 5 yr survival of 8% in those not resected

33. Recurrences MSKCC: 47 patients with recurrent/ metastatic disease MSKCC: 47 patients with recurrent/ metastatic disease Patients who had a complete second resection had a median survival of 74 months (5-year survival, 57%), whereas those with incomplete second resection had a median survival of 16 months (5-year survival, 0%).

34. Summary Adrenocortical carcinoma is a rare disease that often presents late Adrenocortical carcinoma is a rare disease that often presents late Primary curative therapy is surgical Primary curative therapy is surgical No role for adjuvant chemotherapy has been definitively demonstrated to date No role for adjuvant chemotherapy has been definitively demonstrated to date Palliative therapy with mitotane may be useful; its palliative effect may be entirely due to adrenolytic effect Palliative therapy with mitotane may be useful; its palliative effect may be entirely due to adrenolytic effect

35. Summary Re-operation appears to be the only long term curative option in recurrent cases Re-operation appears to be the only long term curative option in recurrent cases Cytotoxic chemotherapy in the advanced/ metastatic setting has not been definitively demonstrated to be useful in controlled trials Cytotoxic chemotherapy in the advanced/ metastatic setting has not been definitively demonstrated to be useful in controlled trials EDP-M may be useful in metastatic settings; evaluation is ongoing EDP-M may be useful in metastatic settings; evaluation is ongoing

36. Thank You