SUSTAINED REMISSION WITH THE KINASE INHIBITOR SORAFENIB IN STAGE IV METASTATIC ADRENOCORTICAL CARCINOMA
Charles Butler, MD1; William M. Butler, MD, FACP2; Ali A. Rizvi, MD, FACP3
ABSTRACT
Objective: To report our experience using kinase in- hibition therapy with sorafenib in a patient with advanced adrenocortical carcinoma.
Methods: We describe the clinical, laboratory, and ra- diologic findings of the study patient and discuss the clini- cal course with sorafenib therapy.
Results: A 56-year-old woman presented with rapid development of virilization, cushingoid features, hyper- tension, weight gain, and abdominal distension. An 8-cm left adrenal lesion was found on computed tomography, re- moved surgically, and confirmed as adrenal carcinoma on pathologic examination. Postoperative scanning revealed metastases to both lungs and the liver that were confirmed by fine-needle biopsy, thus establishing stage IV disease. Treatment with the adrenolytic agent mitotane failed to halt disease progression. A trial of sorafenib resulted in regres- sion and eventual resolution of bilateral metastatic lung lesions, reduction in size of the hepatic lesion, normaliza- tion of androgen hypersecretion, and marked clinical im- provement. The radiologic and biochemical remission on sorafenib has continued for 28 months.
Conclusion: Multiple kinase inhibitors such as sorafenib provide targeted oncologic treatment and may be effective in treating advanced adrenal cancer. (Endocr Pract. 2010;16:441-445)
Accepted for publication November 18, 2009
From the 1Division of Oncology, Medical University of South Carolina,
Charleston, South Carolina; 2South Carolina Oncology Associates, Columbia, South Carolina; 3Department of Internal Medicine, Division of Endocrinology, University of South Carolina School of Medicine, Columbia, South Carolina.
Address correspondence and reprint requests to Dr. Ali A. Rizvi, Two Medical Park, Suite 502, Columbia, SC, 29203. E-mail: Ali.Rizvi@uscmed. sc.edu.
Published as a Rapid Electronic Article in Press at http://www. endocrine practice.org on November 26, 2009. DOI: 10.4158/EP09295.CR @ 2010 AACE.
Abbreviations:
CT = computed tomography; VEGF = vascular endo- thelial growth factor
INTRODUCTION
Adrenocortical cancer is an uncommon malignancy that has a poor prognosis. Most affected patients present with advanced disease. Surgery followed by a combination regimen with the adrenolytic agent mitotane and cytotoxic drugs is the mainstay of therapy. Unfortunately, long-term remission is unusual and the 5-year survival rate in stage IV disease (invasion of adjacent structures or metastatic spread) is dismally low. The invariably fatal nature of ad- vanced adrenocortical carcinoma has spurred efforts to evaluate the best possible therapeutic regimen for this tu- mor. Treatments with novel mechanisms of action are be- ing assessed in the management of many cancers. Tumors that express a variety of angiogenetic and cellular growth factors may respond to agents that block tissue prolifera- tion, potentially offering a unique treatment approach (tar- geted oncology). Sorafenib tosylate is a multiple protein kinase inhibitor that has had recent success in the manage- ment of advanced renal cell and hepatic carcinomas. We describe a case of advanced adrenocortical cancer with a large primary lesion and multiple metastases that failed to show satisfactory response to traditional treatment, but had a remarkable and sustained response to sorafenib admin- istration. Details of the case and a brief discussion of the place of kinase inhibition in the therapeutic armamentari- um against adrenal carcinoma are presented.
CASE REPORT
A 56-year-old African American woman was seen in endocrine consultation for a 6-month history of new- onset hypertension, increased facial hair, acne, deepening of voice, weight gain, anxiety, palpitations, and fatigue.
Her medical problems included primary hypothyroidism, reflux disorder, and dyslipidemia for which she was taking levothyroxine, esomeprazole, and rosuvastatin, respective- ly. The following medications had been prescribed by her primary care physician and gynecologist soon after the on- set of the above-mentioned symptoms: metoprolol, isradip- ine, irbesartan, furosemide, oral potassium supplements, and zolpidem. The patient drank alcohol sparingly and did not use tobacco. Her weight was 83.9 kg, body mass index was 32.3 kg/m2, blood pressure was 172/94 mm Hg, and heart rate was 86 beats/min. She appeared anxious and in general distress. Physical examination revealed a receding hairline with male-pattern alopecia, facial acne, and termi- nal hair growth on the chin. A well-developed upper body musculature was noted. The abdomen was distended with generalized mild tenderness. There was pitting edema of the distal lower extremities and prominent clitoromegaly on genitourinary examination.
Laboratory investigation showed a random plasma glucose concentration of 136 mg/dL and a potassium con- centration of 3.5 mEq/L. Hormone evaluation revealed the following values: plasma total testosterone, 913 ng/dL (ref- erence range 14-76 ng/dL); dehydroepiandrosterone sul- phate, 416 ug/dL (reference range, 26-200 ug/dL); andro- stenedione, 3641 ng/dL (reference range, 47-268 ng/dL); corticotropin <5 pg/mL (reference range, 9-52 pg/mL); and 9 AM serum cortisol, 18 ug/dL (reference range, 6-25 ug/ dL). A 24-hour urine collection revealed the following val- ues: 17-ketosteroids, 64.4 ug/24 h (reference range 6-15 ug/24 h); 17-hydroxycorticosteroids, 33.1 mg/24 h (ref- erence range, 2-6 mg/24 h); norepinephrine, 115 ug/24 h (reference range 15-100 µg/24 h); dopamine, 671 ug/24 h (reference range, 52-480 ug/24 h); normetanephrine, 475 ug/24 h (reference range, 52-310 ug/24 h); and urinary free cortisol, 532.9 ug/24 h (reference range 4-50 µg/24 h). The clinical impression was that of severe hypertension, Cushing syndrome, hyperandrogenism, and virilization. Computed tomography (CT) revealed an 8-cm left adrenal tumor (Fig. 1, Panel A).
One month later the patient underwent surgical treat- ment with laparoscope-assisted removal of the lesion. Although the likelihood of a pheochromocytoma was low, she was treated with the a-adrenergic blocker phenoxy- benzamine before surgery because of mildly elevated cat- echolamines and hypertension. Surgical pathologic exami- nation showed a left adrenal gland lesion measuring 9.6 x 6.8 × 5.7 cm (Fig. 1, Panel B). Microscopic examination revealed nearly solid sheets of cells with zones of coagula- tive necrosis, some cortical-type cells focally arranged in a trabecular fashion, and mitotic count ranging from 5 to 25/high-powered field (Fig. 1, Panel C). Extension beyond the external adrenal gland capsule was not seen. The pa- tient did remarkably well in the postoperative period. She felt much better, became normotensive, and the abdomi- nal distension and the lower extremity edema were greatly ameliorated. The patient lost more than 13.6 kg during her 5-day hospital stay. Androgen levels decreased consider- ably but did not normalize (Table 1). The adrenolytic agent mitotane was begun at a dosage of 1 g twice daily.
Despite the patient’s improvement, CT imaging 1 week after operation revealed bilateral lung lesions (Fig. 2, Panel A), and fine-needle biopsy of 1 lesion confirmed metastatic disease. The mitotane dosage was increased to 2 g twice daily. Several months later, the pulmonary involve- ment had persisted, and new lesions developed in the right lobe of the liver and the right adrenal gland (Fig. 2, Panels B and C). Concurrently, testosterone and androstenedione levels started to rise again (Table 1), and the patient report- ed increasing tiredness. Initiation of standard chemother- apy was considered in view of radiologic, hormonal, and clinical parameters denoting progression of the disease. However, because of the vascular appearance of the tumor on imaging and data suggesting high levels of vascular en- dothelial growth factor (VEGF) in adrenal tumors, a trial of the kinase inhibitor sorafenib was initiated at a dosage of 400 mg twice daily. CT performed 8 weeks later showed uniform regression in the size of all metastatic lesions. Sorafenib was continued, although eventually the dosage
5 07-358
A
B
C
| Table 1 Patient's Clinical Course With Results of Investigations and Therapeutic Interventions | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Time point | |||||||||||
| Variable | 0 Week | 1 Week | 3 Months | 5 Months | 7 Months | 9 Months | 11 Months | 15 Months | 20 Months | 26 Months | 32 Months |
| Treatment changes | Surgical removal; mitotane started, 1 g twice daily | Mitotane dosage increased to 2 g twice daily | Therapeutic trial of sorafenib, 400 mg twice daily | Sorafenib, 400 mg twice daily continued | Sorafenib reduced to 200 mg twice daily | Sorafenib, 200 mg | twice daily | continued | |||
| Total testosterone, ng/dLa | 913 | 156 | 450 | 97 | 30 | 11 | <20 | <20 | <20 | 20 | 23 |
| DHEA-S, ug/dLb | 416 | 85 | 77 | <15 | <15 | <15 | <15 | <15 | <15 | <15 | <15 |
| Androstenedione, ng/dLc | 3641 | 969 | 1297 | 320 | 45 | 17 | 5 | <5 | <5 | 21 | 18 |
| Computed tomography | 8-cm left adrenal lesion | Bilateral lung lesions; biopsy confirms metastases | Pulmonary lesions persist; new ones develop in liver and right adrenal | Metastatic lesions are smaller | Lesions are smaller | ... | Stable, improve- ment | Lung and right adrenal lesions undetectable; liver lesion smaller | ... | ... | No detectable metastases except unchanged liver lesion |
| Abbreviation: DHEA-S, dehydroepiandrosterone sulfate. a Reference range, 14-76 ng/dL. b Reference range, 26-200 ug/dL. c Reference range, 47-268 ng/dL. | |||||||||||
was reduced to 200 mg twice daily because of diarrhea and the development of mild palmar-plantar erythrodysesthesia (“hand-foot syndrome”). At the time of writing, the patient is doing well on sorafenib therapy 32 months after initial diagnosis. Hormone levels have remained suppressed, and the most recent CT evaluation showed resolution of the lung and right adrenal lesions, decrease in size of the liver lesion, and no discernible appearance of new lesions (Fig. 3). A summary of the clinical course with laboratory and CT findings and treatment interventions is outlined in Table 1.
DISCUSSION
Adrenocortical carcinoma is a rare endocrine malig- nancy with an overall age-adjusted incidence of 0.72 per
million individuals (1). Females are affected more fre- quently than males (2). Clinical features include fatigue, hypertension, abdominal distension and tenderness, fluid retention, and weight gain. About 60% of affected individ- uals have hormonal excess, with Cushing syndrome being the most common. Androgen hypersecretion in women can cause masculinization and virilization. CT and magnetic resonance imaging are useful for anatomic confirmation and localization. According to the TNM classification, invasion of adjacent organs or distant metastases denotes stage IV disease (3), which carries a 5-year survival rate of 0% (3). Clinical management consists of surgical removal or debulking followed by adjuvant treatment with mitotane, an adrenolytic agent that leads to tumor regression in 25% of cases and control of hormonal excess in most patients (4). If disease progression is evident while on mitotane,
A
B
C
A
B
C
cytotoxic drugs are added (5). Although long-term survival is possible, cure is rare. Prognosis depends on tumor stage, with size and mitotic activity also correlating with survival. One-third of patients with adrenocortical carcinoma present with distant metastases (5). Presence of extensive advanced disease is uniformly fatal. Management in this stage is gen- erally palliative rather than curative. The low incidence of adrenal cancer has hampered research and the development of efficacious treatment regimens. Mitotane given alone or combined with chemotherapy is a recommended first-line treatment for advanced adrenocortical carcinoma. The ac- cepted chemotherapeutic options are limited, have signifi- cant toxicities, and offer minimal survival benefit. An on- going randomized international trial aims to define the cri- terion standard chemotherapy protocol by comparing the 2 most promising drug combinations investigated in phase II trials (6). Unfortunately, most patients continue to have progressive disease despite treatment with these regimens (7). Because of the extremely grim prognosis and lack of effective therapies, efforts are underway to devise novel methods of achieving long-term remission and improving the survival rate. A recent report of salvage chemotherapy using erlotinib plus gemcitabine in patients with advanced adrenal malignancy was disappointing (8). Morphologic parameters, as well as a variety of chromosomal, genetic, molecular, and immunohistochemical markers, are being identified for their diagnostic and prognostic implications and as possible therapeutic targets (9).
The role of kinase inhibitors in cancer therapy has received attention recently. Kinases are found on various levels in intracellular signaling transduction pathways and have key roles in communication networks (10). These pathways are important in the development of tumor vas- culature and in the proliferation of tumor cells. Receptor tyrosine kinases are found in tumor vessels and neoplas- tic cells, while serine/threonine kinases are located down- stream in the signaling pathways (11). Blocking these pro- teins may retard tumor growth and proliferation. A recent report described “a partial response” to the kinase inhibitor sunitinib that persisted for 7 months in a patient with meta- static adrenocortical carcinoma (12).
Sorafenib (Nexavar; Bayer HealthCare Pharmaceuticals, Inc, Wayne, New Jersey) is an oral multiple kinase inhibi- tor, working at different points to simultaneously decrease both angiogenesis and tumor cell proliferation (11). It blocks the receptor for the 2 tyrosine kinases VEGF re- ceptor and platelet-derived growth factor receptor and the serine/threonine kinases along the RAF/MEK/ERK path- way. It has demonstrated efficacy in the treatment of pa- tients with advanced renal cell carcinoma and unresectable hepatocellular carcinoma. Sorafenib significantly doubled progression-free survival in renal cell carcinoma and ex- tended overall survival and time to progression in patients with unresectable hepatocellular carcinoma, leading to US Food and Drug Administration approval for treating both conditions (13,14).
Our patient had a very large primary adrenocortical lesion and distant metastases in the lung and liver. Her prognosis was extremely poor because of progression of metastatic disease despite standard treatment with mito- tane. Remarkably, however, regression of metastatic de- posits was noted soon after initiation of sorafenib. Ultimate disappearance of most of the tumor burden and normaliza- tion of androgen hormone levels was achieved with ongo- ing sorafenib therapy. The rather dramatic improvement in clinical, biochemical, and radiologic parameters has been sustained for more than 28 months. The temporal associa- tion makes it very likely that the patient’s improvement has been a result of sorafenib administration. Of note, al- though sorafenib is currently under investigation as a therapeutic option in adrenocortical carcinoma (5), our ex- tensive search of the medical literature revealed no reports regarding its use or efficacy in treating this malignancy. Therefore, we believe that our case is the first to show the effectiveness of sorafenib in adrenal carcinoma.
Knowledge of genomic, proteomic, and angiogenetic characteristics of certain cancers can be used for devising new types of treatments. Although VEGF messenger RNA is found in normal adrenal cells, patients with adrenal car- cinoma have significantly elevated VEGF levels (15,16). Expression of angiogenetic markers have been shown to correlate with genotypic alterations in adrenocortical
tumors (17). The presence of increased serum VEGF in patients with adrenal carcinomas makes protein kinase in- hibitors that target VEGF receptors an intriguing treatment modality. Measurement of tumor kinases may therefore predict a favorable response of adrenocortical carcinoma to kinase inhibitors and possibly assist in choice of thera- peutic agents in individual patients (18,19). Trials are cur- rently in progress evaluating unconventional and targeted therapies in advanced adrenal cancer (7,19). Our report is limited by the fact that it describes a single-patient experi- ence. However, the extraordinary response observed in this patient is encouraging and offers potential for sorafenib and similar treatments based on tumor kinase inhibition and targeted oncology.
CONCLUSION
Advanced adrenocortical carcinoma is a neoplasm that carries a poor prognosis and a very high 5-year mortality rate. Current treatment regimens may prolong survival, but are ineffective in producing sustained remission or cure. Kinase inhibitors are novel therapeutic agents that are ca- pable of achieving tumor regression by targeting growth factors involved in angiogenesis and cellular proliferation. We report dramatic long-term clinical improvement with the multiple kinase inhibiting agent sorafenib in a patient with metastatic adrenocortical cancer. Further research will prove useful in delineating the efficacy of targeted inhibi- tion of tumor vasculature and cell growth.
DISCLOSURE
The authors have no multiplicity of interest to disclose.
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