Contemporary management of adrenocortical carcinoma Review Article

Cancer Therapy Vol 6, page 597 Cancer Therapy Vol 6, 597-602, 2008 Contemporary management of adrenocortical carcinoma Review Article Troy Guthrie Jr, Nikesh Jasani* Research and Education Baptist Cancer Institute, Jacksonville, FL, USA *Correspondence: Nikesh Jasani MD Fellow University of Florida/Shands Jacksonville, FL, USA; Tel: 904-891-7065; Fax: 904-244- 1681; e-mail: nikjasani@gmail.com Key words: adrenocortical carcinoma, Epidemiology, molecular pathogenesis, Clinical presentation, Diagnosis, Treatment, Prognosis Abbreviations: Adrenocortical carcinoma, (ACC); cisplatin, doxorubicin, etoposide, (EDP); computerized tomography, (CT); dehydroepiandrosterone sulfate, (DHEAS); F-fluorodeoxyglucose positron emission tomography, (FDG-PET); First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment, (FIRM-ACT) Received: 7 April 2008; Revised: 12 June 2008 Approved: 15 June 2008; electronically published: September 2008 Summary Adrenocortical carcinoma is a rare malignancy with a high mortality rate. Management of adrenocortical carcinoma has evolved with most advances occuring in the past decade. This review will touch on the pathogenesis, epidemiology and diagnosis of adrenocortical carcinoma. The article will focus on treatment and review surgical, radiation and chemotherapeutic indications in the managment of this lethal disease. I. Introduction Adrenocortical carcinoma (ACC) is a rare and heterogeneous malignancy with generally poor outcomes. Increasing use of imaging techniques have led to the discovery of silent adrenal tumors that may have malignant potential. Molecular pathogenesis still remains a mystery and is relatively poorly understood. Treatment options for advanced ACC are limited. II. Epidemiology and molecular pathogenesis Benign Adrenocortical masses are common with a prevalence of 3% in people above age of 50 (National Institutes of Health, 2002; Grumbach et al, 2003). Actual adrenocortical carcinoma, however is quite rare having an incidence of 1-2 per million population. The age distribution is bimodal with a peak in childhood and second higher peak in fourth and fifth decade (Wajchenberg et al, 2000; NG and Libertino, 2003). Women are more commonly affected than men. TP53 is a tumor-suppressor gene located at 17p13, and controls cell proliferation (Allolio and Fassnacht, 2006). This acquired mutation is involved in pathogenesis of many types of cancer. TP53 mutations can be found in only 25% of sporadic ACC cases (Libe and Bertherat, 2005). The IGF- II gene located at 11p15 encodes for a fetal growth factor. IGF-II is dependant on IGF-I which are both present in adrenal tissue and leads to cell line proliferation in ACC (Libe and Bertherat, 2005). Despite progress in genetics of ACC there are no conclusive pathways that have been identified that lead to ACC and much remains to be done. III. Clinical presentation Patients present with either adrenal steroid hormone excess symptoms or symptoms from local tumor invasion. Rapidly progressing Cushing syndrome with or without virilization is often an initial presentation. A review of the German ACC registry showed 60% of cases had cortisol secretion based on pre-surgery hormone levels (Koschker et al, 2006). ACC can also lead to release of androgens which in females can cause hirsutism and virilization. In males estrogen secreting tumors can cause gynecomastia and testicular atrophy (Fassnacht et al, 2004). Rarely aldosterone producing tumors cause hypertension with hypokalemia. Hormonally inactive tumors present usually with abdominal discomfort or back pain from mass effect. Hemorrhage within tumor can also happen resulting in acute abdominal pain. IV. Diagnosis A. Imaging Imaging using computerized tomography (CT), magnetic resonance imaging (MRI) and F- fluorodeoxyglucose positron emission tomography (FDG- 597

Guthrie: Contemporary management of adrenocortical carcinoma PET) are being used to asses adrenal tumors. ACC have irregular borders and irregular areas of enhancement after intravenous contrast when using CT scanning. Imaging of the chest and abdomen is essential since liver and lung are the two most common sites of metastases. Recently a new imaging process using C-metomidate-PET has been used. This incorporates metomidate which binds to 11Bhydoxylase and can help distinguish lesions of adrenocortical origin from others (Khan et al, 2003). Benign adrenal tumors found on imaging present a diagnostic challenge to clinicians. Tumors larger than 6cm are usually resected due to a higher chance for malignancy in these larger size masses. Tumors between 3 and 6 cm are more difficult to separate benign versus malignant and should be observed with follow-up imaging every 3-12 months. B. Laboratory work up It is necessary to obtain a complete blood count and serum chemistries. If signs of excess sex hormone secretion exist, then a hormonal laboratory evaluation should be completed. Hormonal evaluation includes random plasma rennin activity, plasma aldosterone concentration, ACTH, serum cortisol and 24 hour urine for creatinine, free cortisol, catecholamines, metanephrines and VMA (Kantarjian et al, 2006). Testosterone levels should also be measured as dehydroepiandrosterone sulfate (DHEAS) and estradiol. C. Staging Staging for adrenocortical carcinoma is most often based on the Sullivan modification of the Macfarlane system (Macfarlane, 1958; Sullivan et al, 1978) (Figure 1). V. Treatment A. Early stage disease (stage I-III) Surgery is the mainstay of treatment and complete resection by skilled surgeon is the best chance for cure (Icard et al, 1992; Dackiw et al, 2001). R0 (no residual microscopic or macroscopic disease left behind) resection is goal of surgery involving en bloc resection of involved organs and lymphadenectomy. It is important to leave the tumor capsule in place thus reducing the risk of local recurrences (Dackiw et al, 2001). The use of laparoscopic adrenalectomy for ACC has been evaluated and found inferior to an open adrenalectomy approach in ACC that invades adjacent organs, having clinically enlarged lymph nodes or tumors greater than 10cm (Saunders and Doherty, 2004; Schteingart et al, 2005; Shen et al, 2005). Adjuvant medical therapy with Mitotane an oral adrenal-specific drug has been studied in ACC. Mitotane specifically has cytotoxic effect on adrenalcortical cells mainly in the reticular zone. Impairment of steroidgenesis is due to direct inhibition of steroidogenic enzymes (Hahner and Fassnacht, 2005). Mitotane causes adrenal insufficiency due to adrenolytic effect and increased clearance of glucocorticoids (Hague et al, 1989). Glucocorticoid replacement (in the range of 50mg hydrocortisone) is needed. Mitotane as adjuvant therapy was initially based on two retrospective studies which suggested improved survival compared to historical survival rates (Venkatesh et al, 1989). A recent publication by Terzolo and colleagues was a retrospective study looking at 177 patients with ACC who completed radical surgery which demonstrated that mitotane may prolong recurrence-free survival (Terzolo et al, 2007). Figure 1. Staging adrenocortical carcinoma. 598

Cancer Therapy Vol 6, page 599 Although this retrospective literature suggest a role for mitotane in the adjuvant setting may exist firm recommendations await randomized trial. No role for cytotoxic chemotherapy in the adjuvant setting has been defined. There is limited data in the use of radiation therapy in the adjuvant setting. Based on data from small retrospective trials no role for adjuvant radiation therapy to a adequately excised postoperative tumor bed exists and anectdotal evidence supports offering adjuvant radiation in stage III or high risk stage II disease (King and Lack, 1979; Magee et al, 1987; Markoe et al, 1991; Allolio and Fassnacht, 2006). B. Unresectable locally advanced disease and metastatic disease When a complete surgical resection is not attainable, the mainstay of treatment involves the use of mitotane, cytotoxic chemotherapy and radiation in various combinations. One large study by Lubitz and colleagues showed response rate of 61% in patients with measurable disease treated with mitotane (Lubitz et al, 1973). However Numerous retrospective and prospective studies involving mitotane monotherapy have shown average response rates of 25% in advanced ACC. Complete responses have been reported with the use of mitotane in advanced ACC (Becker and Schumacher, 1975; Boven et al, 1984; Krzisnik et al, 1988; Remond et al, 1992; Ilias et al, 2001). Mitotane is associated with severe toxicities at adequate therapeutic doses. There are no large randomized trials to date that have incorporated mitotane therapy. Cytotoxic chemotherapy using cisplatin in combination with etoposide and/or doxorubicin has shown activity in advanced ACC. The largest prospective trial to date by Berruti and colleagues involved 72 patients with advanced ACC and showed a 49% response rate with 5 complete remissions using cisplatin, doxorubicin, etoposide (EDP) and mitotane (Berruti et al, 2005). Median overall survival was 28 months (Berruti et al, 2005). Another prospective trial by Khan and colleagues demonstrated the combination of streptozotocin and mitotane had improved disease free survival in metastatic ACC compared to historical controls (Khan et al, 2000). Based on the above prospective trials and these promising results a large phase III trial is underway FIRM-ACT (First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment) and will compare EDP and mitotane versus streptozocin and mitotane chemotherapy in terms of survival and response rate. Until the results from FIRM- ACT trial are available, locally advanced or metastatic ACC patients should be treated with either EDP plus mitotane or streptozotocin and mitotane (Table 1). Radiation therapy as a single treatment modality has shown response rates of up to 42% (Percarpio and Knowlton, 1976; Magee et al, 1987; Markoe et al, 1991). Radiation therapy can be used in locally advanced disease not amenable to surgery. Surgery for recurrent metastatic disease has been incorporated in the management of ACC. There are small retrospective studies showing that surgical resection for recurrent disease had survival rates that equal those patients without recurrent disease who were just observed (Jensen et al, 1991; Bellantone et al, 1997; Schulick and Brennan, 1999). C. Management of hormone excess ACC is frequently associated with hormone excess syndromes such as Cushing s syndrome, excess androgen secretion and hyperaldosteronemia. This may result in hypokalemia, hypertension, osteoporosis, and infectous complications. Drugs such as ketoconazole, metypraone, aminoglutethimide and etomidate have been used to suppress steroid formation within the adrenal gland (Feldman, 1986; Miller and Crapo, 1993). The management of hormone excess in ACC should be monitored by experienced endocrinologist. Table 1. Role of chemotherapy in adrenalcortical carcinoma Series Year Institution Regimen Number Response Berrutti(31) 2005 Italy MEDP 72 35 PR, 5CR Khan(32) 2000 EATSMRC MS 40 4 PR, 1CR Williamson(33) 2000 SWOG EPM 45 5 PR Abraham(34) 1999 NCI MEDV 28 4 PR, 1CR Zidan(35) 1996 Israel EP 1 1 PR Bukowski(36) 1993 SWOG MP 37 11 PR Berruti(37) 1992 Italy EDP 2 2 PR cisplatin, (P); complete response, (CR); doxorubicin, (D); Endocrine Abdominal Tumors of the Swedish Medical Research Council, (EATSMRC); etoposide, (E); mitotane, (M); National Cancer Institute, (NCI); partial response, (PR); Southwest Oncology Group, (SWOG); streptozocin, (S); vincristine, (V) 599

Guthrie: Contemporary management of adrenocortical carcinoma VI. Prognosis Various prognostic markers have been associated with poor survival outcomes. Large tumors greater than 12 cm, high mitotic rates, high Ki67 immunohistochemical staining and mutated P53 are some factors associated with poor prognosis in ACC (Harrison et al, 1999; Stojadinovic et al, 2002). The two major predictors of survival in metastatic ACC were found to be number of tumoral organs at the time of first metastasis and mitotic index (Assié et al, 2007). Median 5 yr survival for stage I disease has been reported around 60%, stage II 58%, stage III 24%. Median survival for stage IV disease is less than 12 months (Allolio and Fassnacht, 2006). VII. Conclusions and future The mangement of ACC has evolved through retrospective and prospective trials resulting in a multimodality approach to treatment of this rare malignancy. Surgical resection remains the cornerstone to curative treatment for ACC. Adjuvant therapy with mitotane is still not conclusive and this should be individually discussed with high risk patients until prospective clinical trial are available. Adjuvant radiation therapy to postoperative tumor bed can be used in high risk stage II or stage III disease. Unresectable locally advanced disease should be treated with cytotoxic chemotherapy consisting of EDP plus mitotane or streptozotocin and mitotane with radiation. Metastatic or recurrent disease should be treated with either above chemotherapy regimen and surgical resection of solitary metastasis should be pursued. Hormonal excess should be managed by experienced endocrinologist. Future advances in the pathogenesis and therapeutic management of ACC will depend on clinical trials. The FIRM-ACT trial is a multinational prospective trial and will be the first ever phase III trial in ACC. It will determine the standard cytotoxic chemotherapy for ACC. This trial randomizes patients to either the Berruti protocol (EDP plus mitotane) or the one by Khan (streptozotocin and mitotane) and intends to enroll 300 patients. This trial as well as other phase II trials will not only lead to advancement in the treatment of ACC but also stimulate research into the pathogenesis of the disease. References Abraham J, Bakke S, Rutt A, Meadows B, Merino M, Alexander R, Schrump D, Bartlett D, Choyke P, Robey R, Hung E, Steinberg SM, Bates S, Fojo T (2002) A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma: continuous infusion doxorubicin, vincristine, and etoposide with daily mitotane as a P-glycoprotein antagonist Cancer 94, 2333-43. Allolio B, Fassnacht M (2006) Adrenocortical carcinoma: clinical update J Clin Endocrinol Metab 91, 2027-2037. Assié G, Antoni G, Tissier F, Caillou B, Abiven G, Gicquel C, Leboulleux S, Travagli JP, Dromain C, Bertagna X, Bertherat J, Schlumberger M, Baudin E (2007) Prognostic Parameters of Metastatic Adrenocortical Carcinoma J Clin Endocrinol Metab 92, 148-154. Becker D, Schumacher OP (1975) o,p DDD therapy in invasive adrenocortical carcinoma Ann Intern Med 82, 677-679. Bellantone R, Ferrante A, Boscherini M, Lombardi CP, Crucitti P, Crucitti F, Favia G, Borrelli D, Boffi L, Capussotti L, Carbone G, Casaccia M, Cavallaro A, Del Gaudio A, Dettori G, Di Giovanni V, Mazziotti A, Marrano D, Masenti E, Miccoli P, Mosca F, Mussa A, Petronio R, Piat G, Marazano L, et al (1997) Role of reoperation in recurrence of adrenal cortical carcinoma: results from 188 cases collected in the Italian National Registry for Adrenal Cortical carcinoma Surgery 122, 1212-1218. Berruti A, Terzolo M, Paccotti P, Veglio F, Pia A, Dogliotti L, Angeli A (1992) Favorable response of metastatic adrenocortical carcinoma to etoposide, adriamycin and cisplatin (EAP) chemotherapy Report of two cases Tumori 78, 345-8. Berruti A, Terzolo M, Sperone P, Pia A, Casa SD, Gross DJ, Carnaghi C, Casali P, Porpiglia F, Mantero F, Reimondo G, Angeli A, Dogliotti L (2005) Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large phase II prospective trial Endocr Relat Cancer 12, 657-666. Boven E, Vermorken JB, van Slooten H, Pinedo HM (1984) Complete response of metastasized adrenal cortical carcinoma with o,p -DDD Cancer 53, 26-29. Bukowski RM, Wolfe M, Levine HS, Crawford DE, Stephens RL, Gaynor E, Harker WG (1993) Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: a southwest Oncology group Study L Clin Oncol 11, 161-5. Dackiw AP, Lee JE, Gagel RF, Evans DB (2001) Adenal cortical carcinoma World J Surg 25, 914-926. Fassnacht M, Kenn W, ALlolio B (2004) Adrenal tumors: how to establish malignancy? J Endocrinol Invest 27, 387-399. Feldman D (1986) Ketoconazole and other imidazole derivatives as inhibitors of steroidogenesis Endocr Rev 7, 409-420. Grumbach MM, Biller BM, Braunstein GD, Campbell KK, Carney JA, Godley PA, Harris EL, Lee JK, Oertel YC, Posner MC, Schlechte JA, Wieand HS (2003) Management of the clinically inapparent adrenal mass Ann Intern Med 138, 424-429. Hague RV, May W, Cullen DR (1989) Hepatic microsomal enzyme induction and adrenal crisis due to o,p DDD therapy for metastatic adrenocortical carcinoma Clin Endocrinol (Oxf) 31, 51-57. Hahner S, Fassnacht M (2005) Mitotane for adrenocortical carcinoma treatment Curr Opin Investig Drugs 6, 386-394. Harrison LE, Gaudin PB, Brennan MF (1999) Pathologic features of prognostic significance for adrenocortical carcinoma after curative resection Arch Surg 134, 181-185. Icard P, Chapuis Y, Andreassian B, Bernard A, Proye C (1992) Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery Surgery 112, 972-979. Ilias I, Alevizaki M, Philippou G, Anastasiou E, Souvatzoglou A (2001) Sustained remission of metastatic adrenal carcinoma during long-term administration of low dose mitotane J Endocrinol Invest 24, 532-535. Jensen JC, Pass HI, Sindelar WF, Norton JA (1991) Recurrent or metastatic disease in select patients with adrenalcortical carcinoma Aggressive resection vs chemotherapy Arch Surg 126, 457-461. Kantarjian MH, Wolff AR, Koller AC (2006) Adrenocortical Carcinoma MD Anderson Manual of Medical Oncology 4, 841-847. Khan TS, Imam H, Juhlin C, Skogseid B, Gröndal S, Tibblin S, Wilander E, Oberg K, Eriksson B (2000) Streptozocin and o,p DDD in the treatment of adrenal cortical cancer patients: long-term survival in its adjuvant use Ann Oncol 11, 1281-1287. 600

Cancer Therapy Vol 6, page 601 Khan TS, Sundin A, Juhlin C, Långström B, Bergström M, Eriksson B (2003) 11C-Metomidate PET imaging of adrenocortical cancer Eur J Nucl Med Mol imaging 30, 403-410. King DR, Lack EE (1979) Adrenal cortical carcinoma: a clinical and pathological study of 49 cases Cancer 44, 239-244. Koschker AC, Fassnacht M, Hahner S, Weismann D, Allolio B (2006) Adrenocortical carcinoma: improving patient care by establishing new structures Exp Clin Endocrinol Diabetes 114, 45-51. Krzisnik C, Petric G, Jereb B (1988) Complete response of metastatic adrenal cortical carcinoma to o,p -DDD in a child Pediatr Hematol Oncol 5, 65-69. Libe R, Bertherat J (2005) Molecular Genetic of adrenocortical tumors, from familial to sporadic diseases Eur J Endocrinol 153, 477-487. Lubitz JA, Freeman L, Okun R (1973) Mitotane use in inoperable adrenal cortical carcinoma JAMA 223, 1109-1112. Macfarlane DA (1958) Cancer of the adarenal cortex: the natural history, prognosis and treatment in a study of fifty-five cases Ann R C Surg Engl 23, 155-186. Magee BJ, Gattamaneni HR, Pearson D (1987) Adrenal cortical carcinoma: survival after radiotherapy Clin Radiol 38, 587-588. Markoe AM, Serber W, Micaily B, Brady LW (1991) Radiation therapy for adjunctive treatment of adrenal cortical carcinoma Am J Clin Oncol 14, 170-174. Miller JW, Crapo L (1993) The medical treatment of Cushing s syndrome Endocr Rev 14, 443-458. National Institutes of Health (2002) NIH state-of-science statement on management of the clinically inapparent adrenal mass NIH Consens State Sci Statements 19, 1-25. NG L, Libertino JM (2003) Adrenocortical carcinoma: diagnosis, evaluation and treatment J Urol 169, 5-11. Percarpio B, Knowlton AH (1976) Radiation therapy of adrenal cortical carcinoma Acta Radiol Ther Phys Biol 15, 288-292. Remond S, Bardet S, Charbonnel B (1992) Complete and lasting remission of a metastatic malignant adrenocortical carcinoma under treatment with o,p DDD alone Presse Med 1,4756944. Saunders BD, Doherty GM (2004) Laparoscopic adrenalectomy for malignant disease Lancet Oncol 5, 718-726. Schteingart DE, Doherty GM, Gauger PG, Giordano TJ, Hammer GD, Korobkin M, Worden FP (2005) Management of patients with adrenal cancer: recommendations of an international consensus conference Endocr Relat Cancer 12, 667-680. Schulick RD, Brennan MF (1999) Long-term survival after complete resection and repeat resection in patients with adrenocortical carcinoma Ann Surg Oncol 6, 719-726. Shen WT, Sturgeon C, Duh QY (2005) From incidentaloma to adrenocortical carcinoma: the surgical management of adrenal tumors J Surg Oncol 89, 186-192. Stojadinovic A, Ghossein RA, Hoos A, Nissan A, Marshall D, Dudas M, Cordon-Cardo C, Jaques DP, Brennan MF (2002) Adrenocortical carcinoma: clinical, morphologic, and molecular characterization J Clin Oncol 941-950. Sullivan M, Boileau M, Hodges CV (1978) Adrenal cortical carcinoma J Urol 120, 660-665. Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, Rossetto R, Buci L, Sperone P, Grossrubatscher E, Reimondo G, Bollito E, Papotti M, Saeger W, Hahner S, Koschker AC, Arvat E, Ambrosi B, Loli P, Lombardi G, Mannelli M, Bruzzi P, Mantero F, Allolio B, Dogliotti L, Berruti A (2007) Adjuvant mitotane treatment for adrenalcortical carcinoma N Engl J Med 356, 2372-2380. Venkatesh S, Hickey RC, Sellin RV, Fernandez JF, Samaan NA (1989) Adrenal cortical carcinoma Cancer 64, 765-769. Wajchenberg BL, Albergaria Pereira MA, Medonca BB, Latronico AC, Campos Carneiro P, Alves VA, Zerbini MC, Liberman B, Carlos Gomes G, Kirschner MA (2000) Adrenocortical carcinoma: clinical laboratory observations Cancer 88, 711-736. Williamson SK, Lew D, Miller GJ, Balcerzak SP, Baker LH, Crawford ED (2000) Phase II evaluation of cisplatin and etoposide followed by mitotane at disease progression in patients with locally advanced or metastatic adrenocortical carcinoma: a Southwest Oncology Group Study Cancer 88, 1159-65. Zidan J, Shpendler M, Robinson E (1996) Treatment of metastatic adrenal cortical carcinoma with etoposide (VP-16) and cisplatin after failure with o,p DDD Clinical case reports Am J Clin Oncol 19, 229-31. Nikesh Jasani 601

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