Case Report
Metastatic Adrenocortical Carcinoma Treated with Sunitinib: A Case Report
Jeong-Ok Lee1, Keun-Wook Lee1, Chung-Jong Kim1, Yu Jung Kim1, Hee Eun Lee2, Haeryoung Kim2, Jee Hyun Kim1, Soo-Mee Bang1, Jae-Sung Kim3 and Jong Seok Lee1
1Department of Internal Medicine, 2Department of Pathology and 3Department of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
Received July 30, 2008; accepted November 30, 2008; published online January 24, 2009
Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. Palliative che- motherapy can be considered in patients with metastatic disease. Although mitotane- or cisplatin-based chemotherapy regimens are widely used, the effects of these agents have been limited. We have experienced a case that showed a partial response with sunitinib after failure of mitotane-based cytotoxic chemotherapy. The clinical benefit from sunitinib persisted 7.5 months in this case. To our knowledge, this is the first reported case showing the effects of sunitinib on metastatic ACC.
Key words: adrenocortical carcinoma - chemotherapy - sunitinib
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare malignancy, accounting annually for 0.02% of all cancers reported, with dismal prognosis (1,2). Complete surgical resection of the tumor can offer the best chance for cure, but has high recur- rence rate (3). Although mitotane has been widely used for adjuvant chemotherapy, the effectiveness of adjuvant therapy after resection has remained controversial (4). In recurrent or metastatic cases, mitotane- or cisplatin-based chemotherapeutic regimens are widely used. The combi- nation of etoposide, doxorubicin, cisplatin and mitotane showed a response rate (RR) of 49% in advanced ACC (5). Streptozotocin plus mitotane chemotherapy also yielded positive results (RR = 36%) (6). However, as these clinical trials were small-sized and no results of prospective random- ized trials have been available, the chemotherapeutic regimen for recurred or metastatic ACC has not been stan- dardized (7). Especially, patients with advanced ACC resist- ant to mitotane or cytotoxic chemotherapy have few treatment options. Here, we report a case of recurred ACC
that showed a partial response (PR) to sunitinib treatment after mitotane-based cytotoxic chemotherapy failure.
CASE REPORT
A 21-year-old male presented with pain and a palpable mass in the right upper quadrant (RUQ) of the abdomen. A com- puted tomography (CT) scan of the abdomen showed a 21 x 16 × 14 cm mass in the right adrenal gland (Fig. 1). There was no evidence of distant metastasis and right adrenalect- omy and nephrectomy were performed. The pathologic evaluation confirmed an ACC with capsular and angiolym- phatic invasion which had extensive necrosis and hemor- rhage (Fig. 2A). The cancer cells had marked nuclear polymorphism and high mitotic rate (Fig. 2B). The immuno- histologic staining for vascular endothelial growth factor (VEGF) was focal positive in tumor cells (Fig. 2C). He received adjuvant radiation therapy (RT) of 45 Gy delivered to the tumor bed. Six months after surgery, a CT scan of the chest showed multiple lung metastases and the patient and his family declined chemotherapy. Eleven months after surgery, periumbilical abdominal pain developed and a CT scan showed bulky hepatic and aortocaval lymph node metastases. After palliative RT to the aortocaval lymph nodes for pain control, etoposide, doxorubicin, cisplatin and
Feb-2006
mitotane chemotherapies were initiated. However, after three cycles of chemotherapy, he developed RUQ abdominal pain and a follow-up CT scan showed progressive disease (PD). Palliative RT was directed to the increased hepatic mass for symptom control, after which he received sunitinib (50 mg/ day) in 6-week cycles (4 weeks of treatment and 2 weeks off of treatment). The sunitinib dose was decreased to 37.5 mg/ day due to combined toxicities of neutropenia and fatigue. The sizes of the metastatic pulmonary nodules decreased in 6 weeks after the initiation of sunitinib and a PR was achieved in 4 months (Fig. 3A and B). The clinical benefit of sunitinib continued for 7.5 months. After 7.5 months of sunitinib treatment, however, the sizes of the pulmonary metastatic nodules increased and PD was confirmed. Then, he received mitotane and streptozotocin chemotherapies, but a follow-up CT scan showed PD. He is now receiving supportive care only.
DISCUSSION
Mitotane and/or cytotoxic chemotherapies are treatment schemes most frequently used in advanced ACC, with limited efficacy. Based on the recent availability of molecu- larly targeted agents for the treatment of several tumors, there has been an attempt to use new targeted agents to treat ACC.
Imatinib is not effective in patients with ACC expressing c-kit and/or platelet derived growth factor (PDGF) receptor (8). However, a recent study showed that patients with ACC had significantly higher serum levels of circulating VEGF than those with benign adrenal tumors or normal subjects (9). Some studies have correlated the serum levels of VEGF with adrenal tumor aggressiveness and clinical outcome (10). Although there are few data on ACC treated with anti- angiogenic drugs, thalidomide, which is a strong anti- angiogenic agent, showed a PR in a patient with ACC that
(A)
(B)
(C)
failed to respond to conventional mitotane-based chemother- apy (11). These findings suggest that angiogenesis is an important mechanism related to tumorigenesis of ACC, and thus targeting angiogenesis may have therapeutic effects on ACC.
(A)
4.8 cm
July-2007
(B)
3.1 cm
Dec-2007
Sunitinib is an oral multi-targeted tyrosine kinase inhibitor with anti-tumor and anti-angiogenic activities, which has been successfully used in the treatment of metastatic renal cell carcinoma and gastrointestinal stromal tumor (12,13). Until now, no data exists on sunitinib in ACC. Our report shows a clinical benefit from sunitinib in a patient with ACC who failed previous cytotoxic chemotherapy. Currently, a phase II study [Sunitinib in Refractory ACC (SIRAC)] is recruiting patients with advanced ACC that has progressed after previous cytotoxic chemotherapy. This phase II study is
expected to demonstrate the effects of sunitinib on ACC and the results of this study are eagerly awaited.
In conclusion, sunitinib showed a significant anti-tumor activity in our case with chemo-refractory advanced ACC.
Conflict of interest statement
None declared.
References
1. Roman S. Adrenocortical carcinoma. Curr Opin Oncol 2006;18:36-42.
2. Allolio B, Fassnacht M. Clinical review: adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 2006;91:2027-37.
3. Stojadinovic A, Ghossein RA, Hoos A, Nissan A, Marshall D, Dudas M, et al. Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. J Clin Oncol 2002;20:941-50.
4. Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, et al. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 2007;356:2372-80.
5. Berruti A, Terzolo M, Sperone P, Pia A, Casa SD, Gross DJ, et al. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer 2005;12:657-66.
6. Khan TS, Imam H, Juhlin C, Skogseid B, Grondal S, Tibblin S, et al. Streptozocin and o,p’DDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use. Ann Oncol 2000;11:1281-7.
7. van Ditzhuijsen CI, van de Weijer R, Haak HR. Adrenocortical carcinoma. Neth J Med 2007;65:55-60.
8. Gross DJ, Munter G, Bitan M, Siegal T, Gabizon A, Weitzen R, et al. The role of imatinib mesylate (Glivec) for treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R. Endocr Relat Cancer 2006;13:535-40.
9. Zacharieva S, Atanassova I, Orbetzova M, Nachev E, Kalinov K, Kirilov G, et al. Circulating vascular endothelial growth factor and active renin concentrations and prostaglandin E2 urinary excretion in patients with adrenal tumours. Eur J Endocrinol 2004;150:345-9.
10. Kolomecki K, Stepien H, Bartos M, Kuzdak K. Usefulness of VEGF, MMP-2, MMP-3 and TIMP-2 serum level evaluation in patients with adrenal tumours. Endocr Regul 2001;35:9-16.
11. Chacon R, Tossen G, Loria FS, Chacon M. CASE 2. Response in a patient with metastatic adrenal cortical carcinoma with thalidomide. J Clin Oncol 2005;23:1579-80.
12. Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006;368:1329-38.
13. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115-24.