Urological Notes
Sunitinib monotherapy instead of mitotane combination therapy for the treatment of refractory adrenocortical carcinoma
Jintao Zhuang M.D., Ph.D., Daohu Wang M.D., Ph.D., Rongpei Wu M.D., Ph.D., Xiangan Tu M.D., Ph.D., Yu Chen M.D. and Shaopeng Qiu M.D., Ph.D.
Abbreviations & Acronyms ACC = adrenocortical carcinoma CT = computed tomography CYP3A4 = cytochrome P450, family 3, subfamily A, polypeptide 4 TKI = tyrosine kinase inhibitor VEGF = vascular endothelial growth factor VEGFR = vascular endothelial growth factor receptor
Department of Urology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
DOI: 10.1111/iju.12903
ACC is a rare malignancy with a poor prognosis. Only complete surgical resection can offer the potential for cure; however, even after successful excision, local recurrences and distant metastases frequently occur.1 Thus, adjuvant therapy options need to be considered for advanced ACC, but the effectiveness remains controversial. As is well known, mitotane is the only recognized adrenal cytotoxic agent currently available, and might prolong progression- free survival. However, the objective response rate was just 23%, and long-term disease con- trol was achieved in <15% of patients.2 Therefore, several studies have investigated targeted therapies, such as imatinib, erlotinib, sorafenib and sunitinib, in patients with ACC, but the responses have been disappointing.3
Here, we report a case of refractory ACC that showed a good response to sunitinib treat- ment. A 33-year-old woman presented to First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, with a palpable mass in her right upper quadrant of the abdomen. CT scan showed a 13.8 x 10.4-cm mass in the right adrenal gland and liver involvement; a tumor thrombus in the inferior vena cava and lung metastases were also found (Fig. S1a,b). Endocrine examination was almost normal. She was diagnosed with advanced ACC and received surgical resection in March 2011. The pathological evaluation confirmed an ACC with liver invasion, and immunohistochemical staining for VEGF was positive in the tumor cells. The Weiss score was nine (Fig. S1c-f). Then she received adjuvant chemotherapy. Mito- tane plus etoposide, doxorubicin and cisplatin chemotherapies were initiated, but failed after two cycles of chemotherapy. After the failure of mitotane-based cytotoxic chemotherapy, tar- geted therapy with sunitinib was chosen after careful discussion with the patient’s family. She received sunitinib plus mitotane treatment from August 2011. However, after 8 months of sunitinib treatment, the patient developed a severe cough, and a CT scan showed progressive disease in April 2012. Her entire lungs were bestrewn with increasing pulmonary nodules (Fig. 1a,b). Because of the disease progression and adverse events, mitotane was withdrawn in May 2012 and sunitinib monotherapy was continued. In May 2013, a CT scan showed a significant remission (Fig. 1c,d) and the patient’s condition improved. In May 2014, a further CT scan showed that there were fewer metastatic pulmonary nodules and their sizes were smaller (Fig. le,f). The patient’s condition stabilized and she survived postoperatively for 4 years.
Sunitinib is an oral multitargeted tyrosine kinase inhibitor that targets VEGFR1, VEGFR2, c-KIT and Fms-like tyrosine kinase 3, and thus combines direct antitumor effects with antian- giogenic activity.4 The results of a phase II study in patients progressing after mitotane and one to three cytotoxic chemotherapies showed that sunitinib had modest activity in advanced refractory ACC. Furthermore, the results were highly suggestive of a negative impact of con- comitant mitotane therapy on the outcome.3
Fortunately, we have gained great encouragement from our successful experience with that refractory ACC patient. After the failure of mitotane-based chemotherapy, we continued her treatment with a combination of sunitinib and mitotane, but the tumor still progressed. This result was in good agreement with published data.3 Mitotane was then withdrawn and suni- tinib monotherapy was continued. A year later, unexpected results were observed. A CT scan showed that the patient’s metastatic pulmonary nodules had nearly disappeared and her condi- tion stabilized. The clinical benefit of sunitinib has persisted until the present time. However, the present results again suggest that a drug interaction between sunitinib and mitotane might have a major influence on their effects.
The pharmacokinetic properties of the two drugs could be the reason for this interaction. It is well established that sunitinib is metabolized in the liver and intestine by CYP3A4 monooxygenase to its active metabolite SU12662, which is then inactivated in a second step by CYP3A4 monooxygenase.5 However, mitotane is an extraordinarily strong inducer of CYP3A4, which will markedly increase the inactivation of sunitinib, and therefore reduce
(a)
(b)
L
(c)
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serum concentrations of the active drug.6 This could also explain the relatively low toxicity of sunitinib administered concomitantly with mitotane.
As a targeted therapy, sunitinib appears to be an attractive and promising option in the management of refractory ACC. It should be noted that sunitinib should not be used in combi- nation with mitotane because of a potential drug interaction. This warrants verification in further investigations.
Acknowledgments
The authors thank Contact Ed Net, Shanghai Co. Ltd for pro- viding editorial assistance with the manuscript. This work was supported by research grant number 81272809 and 81172432 of the National Natural Science Foundation of China.
Conflict of interest
None declared.
References
1 Stojadinovic A, Ghossein RA, Hoos A et al. Adrenocortical carcinoma: clini- cal, morphologic, and molecular characterization. J. Clin. Oncol. 2002; 20: 941-50.
2 Fassnacht M, Terzolo M, Allolio B et al. Combination chemotherapy in advanced adrenocortical carcinoma. N. Engl. J. Med. 2012; 366: 2189-97.
3 Kroiss M, Quinkler M, Johanssen S et al. Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm, open-label trial. J. Clin. Endocrinol. Metab. 2012; 97: 3495-503.
4 Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N. Engl. J. Med. 2007; 356: 115-24.
5 van Erp NP, Gelderblom H, Guchelaar HJ. Clinical pharmacokinetics of tyro- sine kinase inhibitors. Cancer Treat. Rev. 2009; 35: 692-706.
6 van Erp NP, Guchelaar HJ, Ploeger BA, Romijn JA, Hartigh JD, Gelderblom H. Mitotane has a strong and a durable inducing effect on CYP3A4 activity. Eur. J. Endocrinol. 2011; 164: 621-6.
Supporting information
Additional Supporting Information may be found in the online version of this article at the publisher’s web-site:
Fig. S1. (a,b) CT scans at the time of the initial diagnosis. (a) A 13.8 × 10.4-cm sized mass in the right adrenal gland with tumor extension into the liver and inferior vena cava (arrow). (b) Multiple bilateral pulmonary metastases. (c,d,e,f) Pathological evaluation after surgical resection. (c) Gross specimen appeared as multiple ashen irregular tubercles. (d)
The tumor cells with nest-like distribution and necrosis were present (hematoxylin-eosin stain, magnification: ×100). (e) The tumor cells showed marked nuclear pleomorphism and high mitotic rate (hematoxylin-eosin stain, magnification: ×400). (f) Immunohistochemical staining for VEGF was pos- itive (magnification: ×100).
Angiomyolipoma with epithelial cysts: Add one to the differential of cystic renal lesions
Michael A Gorin M.D.,1 Steven P Rowe M.D., Ph.D.,2 Mohamad E Allaf M.D.1 and Pedram Argani M.D.3
Abbreviations & Acronyms
AMLEC = angiomyolipoma with epithelial cysts
1The James Buchanan Brady Urological Institute and Department of Urology, 2The Russell H. Morgan Department of Radiology and Radiological Science, 3Departments of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA mgorin1@jhmi.edu DOI: 10.1111/iju.12908
Cystic lesions of the kidney are a common finding in patients undergoing abdominal imaging. Although the vast majority of lesions are benign epithelial-lined cysts, on occasion cystic lesions are malignant and thus necessitate surgical resection. First described in 1986, the Bos- niak classification system includes five categories (I, II, IIF, III and IV), and was designed to aid clinicians in the risk stratification and management of patients presenting with renal cysts.1 Class I and II lesions are either simple or minimally complex, and almost always rep- resent benign cysts. In contrast, class III and IV lesions are more complex, the majority of which are cystic renal cell carcinomas. Finally, IIF lesions are indeterminate, and should be followed for interval growth and/or increasing complexity.
In a contemporary report of 133 patients from our institution, who underwent resection of a cystic lesion of the kidney, 91 procedures were carried out for Bosniak class III-IV cysts.2 Of these, 71 (78%) were found to be malignant on final surgical pathology. Benign lesions included a combination of simple cysts and mixed epithelial and stromal tumor family lesions (which include adult multilocular cystic nephromas). Among malignant tumors, clear cell renal cell carcinoma was the most prevalent histological type (47% of all class III-IV lesions and 61% of malignant lesions). These data are consistent with other reports, and support the classic dictum that the differential diagnosis for complex cystic tumors of the kidney (i.e. Bosniak class III-IV lesions) should include renal cell carcinoma, mixed epithelial and stromal tumor family lesions, and benign cysts.3
Adding to the list of differential diagnostic considerations, a cystic variant of angiomyolipoma, termed AMLEC, has been described.4 These “fat-poor” tumors are histolog- ically distinct from classic angiomyolipomas, and are composed of a characteristic triphasic architecture that includes: (i) an epithelium composed of predominantly cuboidal renal tubular cells, representing entrapped renal tubular epithelium which label for cytokeratin 7 and PAX8; (ii) a cellular subepithelial stroma resembling endometrium that consists of bland spin- dle cells with minimal cytoplasm that stain intensely for estrogen receptor and melanocytic markers, such as HMB45, and focally for muscle markers, such as smooth muscle actin; and (iii) an outer, “pinker,” area composed of bundles of irregular smooth muscle-like cells and dysplastic vessels typical of stromal-predominant angiomyolipomas. This third layer labels diffusely for muscle markers, such as smooth muscle actin, and focally for estrogen receptor and for melanocytic markers, such as HMB45. In the English literature, <20 AMLECs have been reported. To our knowledge, just three have included a description of their radiographic appearance.5-7 Of these lesions, one presented as a Bosniak III cyst, another as a Bosniak IV and the third as a primarily solid mass with a cystic component. All three AMLECs were resected for the presumption of cancer.
To contribute to the existing literature on this rare tumor, we present representative radiol- ogy and pathology images of two complex cystic renal lesions detected incidentally on work- up for non-urological complaints and later diagnosed as AMLECs after surgical excision (Fig. 1). The first lesion was diagnosed in a 50-year-old man who presented with 3.0-cm Bos- niak III cyst characterized by thick visibly enhancing septations. The second lesion was found in a 53-year-old woman who presented with a 2.0-cm Bosniak IV lesion with a discrete enhancing mural nodule comprising approximately 50% of the lesion. Both patients success-