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Adrenal Carcinoma

Adrenal Carcinoma. Dr. D.W. Daugherty. Epidemiology. 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 Scattered reports of gene associations, but rarity of lesion limits studies – no clear associations.

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Adrenal Carcinoma

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  1. Adrenal Carcinoma Dr. D.W. Daugherty

  2. Epidemiology • Estimated incidence of 0.5-2 per 106 patients per year • Peaks of age distribution at age <5 and in the 4th and 5th decades • 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 • Cushings • Virilization • Feminization • Hyperaldosteronism

  4. Diagnostics • 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.

  5. Hypercortisolism • 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 ACTH measured with serum cortisol will demonstrate ACTH independent nature of hypercortisolism.

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

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

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

  9. Staging • Hormonal studies directed at symptoms • 24h urine studies to r/o pheochromocytoma • 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

  10. Staging • 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 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%)

  11. Surgery • Complete surgical resection is the primary treatment modality

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

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

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

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

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

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

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

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

  20. Mitotane • inhibits the mitochondrialconversion of cholesterol to pregnenolone and the conversionof 11-deoxycortisol to cortisol (11B- hydroxylation). It produces selective adrenocorticalnecrosis in both the adrenal tumor and metastases

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

  22. Selected Mitotane Studies

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

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

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

  26. Overview of Chemo Trials

  27. MDR issues • 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

  28. EDP-M • Italian study • 28 patients enrolled • Etoposide (100mg/ m2) d5-7; Doxorubicin (20mg/ m2) d1,8; Cisplatin (40mg/ m2) d1,9 every 4 weeks • Concomitant mitotane up to 4g/ day

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

  30. Recurrences • 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

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

  32. Recurrences • 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%).

  33. Summary • Adrenocortical carcinoma is a rare disease that often presents late • Primary curative therapy is surgical • 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

  34. Summary • 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 • EDP-M may be useful in metastatic settings; evaluation is ongoing

  35. Thank You

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