Case Report
Abiraterone—What Is Wrong With the Adrenal Glands? Sabine Schmid,1 Jürgen Fornaro,2 Christian Rothermundt,1 Aurelius Omlin,1 Michael Brändle,3 Niels J. Rupp,4 Silke Gillessen1 Clinical Practice Points Abiraterone acetate (AA) is an antihormonal treatment
in metastatic castration-resistant prostate cancer showing overall survival benefit in docetaxel-naive and docetaxel-treated patients in 2 large phase III trials. After the case of a patient who developed biopsy proven prostate cancer metastases in the left adrenal gland during AA treatment, we reviewed all patients
receiving AA and found significant ( 20%) increase in the volume of the adrenal glands in 50% of the patients. This can lead to a diagnostic dilemma because standard imaging cannot easily differentiate between benign and malignant lesions. With the approval of AA before and after docetaxel chemotherapy this diagnostic difficulty will be of increasing importance.
Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Abiraterone acetate, Adrenal gland metastases, Metastatic castration-resistant prostate cancer, Steroid switch, Visceral disease
Case Report We report on a patient who developed a biopsy proven prostate cancer (PC) metastasis in the adrenal gland during abiraterone acetate (AA) treatment and a series of 26 patients treated with AA for metastatic castration-resistant PC (mCRPC) with radiological review of the adrenal glands. The 64-year-old patient was diagnosed with PC with multiple bone metastases in 2009 and androgen deprivation therapy was initiated. In 2011, the patient developed progressive castrationresistant disease with a prostate-specific antigen (PSA) increase (Fig. 1), new bone metastases, and clinical deterioration and was subsequently treated with docetaxel. He had an excellent clinical and PSA response to chemotherapy. Three months after stopping chemotherapy, PSA increased rapidly again and treatment with AA at the standard dose of 1000 mg per day with prednisone 5 mg twice daily was started.
1
Department of Medical Oncology Department of Radiology 3 Department of Endocrinology, Diabetology, and Osteology 4 Department of Pathology Kantonsspital St Gallen, St Gallen, Switzerland 2
Submitted: Nov 21, 2013; Revised: Jan 21, 2014; Accepted: Jan 23, 2014 Address for correspondence: Sabine Schmid, MD, Kantonsspital St Gallen, Department of Medical Oncology, Rorschacherstrasse 95, CH-9007 St Gallen, Switzerland Fax: þ41-71-494-63-25; e-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2014.01.008
After 3 months of therapy with AA a nodular lesion in the left adrenal gland was seen on computed tomography (CT) scan and after another 3 months (total 6 months of therapy) progressive nodular formations in both adrenal glands were observed (Fig. 2A and B). No other soft tissue metastases were observed and there was only a slight increase in PSA; bone metastases were stable according to bone scan as per PC Working Group criteria 2.1 The patient showed no clinical signs of adrenal insufficiency. On CT and magnetic resonance scans the adrenal glands showed diffuse hypertrophy, but the nodular lesions showed no lipid content and therefore were considered indeterminate. Yet, with CT perfusion imaging the lesions showed a relative and absolute washout on delayed scanning of > 40% and > 60% respectively, consistent with benign adenomas according to Dunnick and Korobkin (Fig. 3).2 For definitive diagnosis we conducted CT-guided core needle biopsy (Fig. 4A and B) of the nodular formation of the left adrenal gland (maximum diameter, 2 cm), which rather surprisingly showed PC metastasis (Fig. 4C and D). Because the patient was feeling well, we continued therapy with AA, but switched from prednisone to dexamethasone (2 mg, orally per day continuously for 3 weeks, then reduced to 1.5 mg for 1 week and subsequently 1 mg per day), which has been shown to have positive effects on PSA values in some patients.3 Using this modified treatment a good PSA response was seen and rather unexpectedly a significant reduction in size of the adrenal metastasis and the adrenal glands in general (Fig. 2C).
Clinical Genitourinary Cancer Month 2014
-1
Abiraterone—What Is Wrong With the Adrenal Glands? Figure 1 Anticancer Treatments and History of PSA Changes
Abbreviations: LHRH ¼ luteinizing hormone-releasing hormone; PSA ¼ prostate-specific antigen.
Discussion Adrenal masses discovered during imaging investigations for nonadrenal disorders are called incidentalomas. With the widespread use of CT scans these have become increasingly common. The prevalence is up to 4.4% with an increase in elderly patients and patients with cancer.4 Adrenal gland tumors in the general population are most often benign and nonsecreting adenomas, followed by hormone secreting
adenomas (cortisol, aldosterone), pheochromocytomas, adrenal gland metastases, and adrenocortical carcinomas.5 Until now, adrenal metastases have rarely been described in PC. In one retrospective analysis of CT scans of 508 PC patients, adrenal gland metastases were present in only 1 patient (0.2%).6 In a large autopsy study published at approximately the same time, the incidence of adrenal gland metastases in 1500 PC patients was 13%, suggesting that they are more frequent than clinically suspected.7
Figure 2 Computed Tomography Scans of the Adrenal Glands at Start and During AA Treatment. Green Arrows Mark the Right Adrenal Gland; Red Arrows Mark the Left Adrenal Gland. (A) CT Scan of the Adrenal Glands Before AA Administration. (B) CT Scan of the Adrenal Glands After 6 Months of AA/Prednisone Therapy. (C) CT Scan of the Adrenal Glands 3 Months After Switching Therapy From AA/Prednisone to AA/Dexamethasone
2
-
Abbreviations: AA ¼ abiraterone acetate; CT ¼ computed tomography.
Clinical Genitourinary Cancer Month 2014
Sabine Schmid et al Figure 3 Computed Tomography Scans of the Adrenal Glands Showing Diffuse Thickening. Computed Tomography Scans of the Adrenal Glands in the (A) Native, (B) Enhanced, and (C) Delayed Phases Showing Diffuse Thickening of the Glands and a Nodular Lesion in the Left Side at the Same Time Point as in Figure 1B. An Absolute Wash out of 67% and a Relative Wash out of 49% was Computed From the ROI Measurements of the Nodular Lesion in the Left Adrenal Gland
Abbreviation: ROI ¼ region of interest.
Figure 4 Computed Tomography-Guided Biopsy of the Left Adrenal Gland. (A) and (B): CT-Guided Biopsy of Left Adrenal Gland. CT Fluoroscopy Images: (A) Head Slice, and (B) Center Slice Show a 20-Gauge Biopsy Needle (Arrow) Advanced in an Anterior Caudocranial Direction Into a Nodular Lesion (Arrowhead) of the Left Adrenal Gland. (C) and (D): Biopsy Specimen From the Left Adrenal Gland Shows Glandular and Partially Solid Growing Adenocarcinoma With Prominent Nucleoli (Arrowheads) in Conventional (H & E) Histological Staining. Immunohistochemical Staining for PSA Results in Robust Positivity Within the Tumor Cells (D), Consistent With Metastatic Infiltrates of Acinar Prostate Adenocarcinoma (Scale bar, 100 mm)
Abbreviations: CT ¼ computed tomography; H & E ¼ hematoxylin and eosin; PSA ¼ prostate-specific antigen.
Clinical Genitourinary Cancer Month 2014
-3
Abiraterone—What Is Wrong With the Adrenal Glands? Figure 5 Waterfall Plot With Percentage Change of Adrenal Gland Size. Each Patient Is Represented by 2 Side Bars (Yellow [ Right Adrenal Gland; Blue [ Left Adrenal Gland). Red Line Indicates a 20% Increase in Size
100
80
60
40
20
0
-20
-40
-60
4
-
More recently, Vinjamoori et al analyzed CT scans of 620 consecutive patients with PC and identified 82 cases with visceral metastases among which 12 (2%) had adrenal gland involvement.8 In a very recent analysis of castration-resistant PC (CRPC) patients, adrenal gland metastases have been found in 10% of the patients.9 Because we had observed a seemingly unusually high incidence of enlarged adrenal glands in our CRPC patients treated with AA, we conducted a retrospective evaluation of all of our patients who had begun treatment with AA for mCRPC between July 2010 and June 2012 who had CT scans available for review. In this cohort of 26 patients, we found an increase in the volume of the adrenal glands of more than 20% according to Response Evaluation Criteria in Solid Tumours 1.110 (range, 24%-103%) in 13 patients (50%) in comparison of the baseline CT scan with the scan at the end of treatment (Fig. 5). Mean time from start of AA treatment to CT scan evaluation (end of treatment in 24 patients) was 6.3 months (range, 2.2-20.9 months), mean time from start of AA to CT scan evaluation in the 13 patients with a significant increase in adrenal gland size was 7.6 months (range, 2-21 months). At that time point in these 13 patients hypokalemia as an early sign of mineralocorticoid excess was seen in only 3 cases. After 3 months of therapy only 2 of 13 patients (15%) with a CT scan at that time point had an increase in volume of the adrenal glands of 20%. The increase in size was bilateral in all 13 cases. In 3 patients, nodular formations were seen whereas in the other 10 patients only an increase in volume was documented. Unfortunately, we have no biopsy evaluation in these patients. These findings have led to the hypothesis that treatment with AA seems to have an effect on adrenal gland growth and that this effect might be dependent on the duration of treatment. Abiraterone acetate is a small molecule that binds irreversibly at the active site of cytochrome P450 17A1 (CYP17), a key enzyme
Clinical Genitourinary Cancer Month 2014
in the steroidogenic pathway with 17a-hydroxylase and 17, 20-lyase activity.11 Mutations of P450c17a are associated with 17a hydroxylase- and 17a hydroxylase/17, 20-lyase deficiency, and represent a rare form of congenital adrenal hyperplasia.12 The 17a-hydroxylase defect results in reduced cortisol production and a consecutive increase in adrenocorticotropic hormone (ACTH) secretion with increased production of mineralocorticoids (corticosterone and deoxycorticosterone) and leads to mineralocorticoid excess with volume expansion, hypertension, hypokalemia, and alkalosis. A defect in 17a-hydroxylation in the adrenal cortex and the gonads leads to a combined androgen and estrogen deficiency with an increase in follicle stimulating hormone and luteinizing hormone concentrations. This defect causes diffuse or nodular cortical hyperplasia of the adrenal glands.13,14 Treatment is based on sodium restriction and glucocorticoid supplementation, preferentially with dexamethasone, to decrease the excess ACTH secretion to restore blood pressure and potassium concentration to normal.12,13,15 Abiraterone acetate affects the same pathway. In the phase I trial conducted by Attard et al, endocrine studies showed that at all dose levels, treatment was associated with an increase in ACTH levels and increased steroid precursors upstream of CYP17 (corticosterone and deoxycorticosterone).11 Administration of dexamethasone resulted in suppression of ACTH and a decrease in upstream steroid levels to baseline levels. Steroids upstream of CYP17 maintained glucocorticoid activity and caused a syndrome of mineralocorticoid excess. This was reversible with application of eplerenone or with low doses of glucocorticoids to suppress the ACTH drive.11 Considering the almost identical metabolic situation in patients with inherited CYP17 deficiencies and patients undergoing therapy with AA it seems reasonable that adrenal hyperplasia would be found. In contrast to the treatment of congenital adrenal gland hyperplasia, in which patients receive mostly low-dose dexamethasone, in patients with AA treatment prednisone is typically used, which has a relevantly shorter biological half-life (12-36 hours compared with 36-72 hours). One could postulate that treatment with prednisone lessens ACTH-drive to high-normal levels and prevents symptoms of mineralocorticoid excess as intended, but there is still a chronic ACTH overstimulation of the adrenal glands. Optimal glucocorticoid supplementation in patients with AA treatment could potentially decrease the incidence of adrenal gland hyperplasia. This could be helpful, since differentiation between benign adenomas and metastases seems difficult with standard imaging procedures. This differentiation could gain more importance in the future since we might see more patients with adrenal metastases. The reason being that on one hand, owing to new treatment options for PC, longer overall survival can be achieved.16 Thus, with a longer course of disease more sites of metastases may occur. A trend to increased rates of visceral metastases in patients with mCRPC has already been described.17 On the other hand there is a possibility that changes in the microenvironment of the adrenals induced by AA might facilitate prostate cancer dissemination into this organ. Our observation of enlarged adrenal glands in patients with mCRPC treated with AA and prednisone has to be confirmed in larger series and more of the lesions have to be histologically
Sabine Schmid et al evaluated. This might also confirm our hypothesis of an increase in adrenal gland metastases. It has been recognized that the kind and dose of the concomitant glucocorticoid could be of importance and a trial investigating the role of AA with different doses of prednisolone or dexamethasone is currently recruiting patients (NCT 01867710). At least in our patient described here, the steroid switch has been successful and resulted in a significant decline in PSA and decrease in size of the adrenal gland metastasis. In conclusion, we would like to raise awareness to the endocrine and morphologic features of the adrenal glands in patients treated with AA and to the difficulty in differentiation between benign and malignant morphology with current imaging procedures.
References 1. Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008; 26:1148-59. 2. Dunnick NR, Korobkin M. Imaging of adrenal incidentalomas: current status. AJR Am J Roentgenol 2002; 179:559-68. 3. Lorente D, Weatherstone K, Omlin A, et al. Tumor responses after steroid switch of prednisolone (P) to dexamethasone (D) in castration-resistant prostate cancer (CRPC) patients (pts) on abiraterone acetate (AA) (abstract 2918). Presented at the European Cancer Conference; September 27-October 1, 2013; Amsterdam, Netherlands. 4. Mansmann G, Lau J, Balk E, et al. The clinically inapparent adrenal mass: update in diagnosis and management. Endocr Rev 2004; 25:309-40.
5. Mantero F, Terzolo M, Arnaldi G, et al. A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab 2000; 85:637-44. 6. Long MA, Husband JE. Features of unusual metastases from prostate cancer. Br J Radiol 1999; 72:933-41. 7. Bubendorf L, Schopfer A, Wagner U, et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol 2000; 31:578-83. 8. Vinjamoori AH, Jagannathan JP, Shinagare AB, et al. Atypical metastases from prostate cancer: 10-year experience at a single institution. AJR Am J Roentgenol 2012; 199:367-72. 9. Pezaro CJ, Omlin A, Lorente D, et al. Visceral Disease in Castration-resistant Prostate Cancer. Eur Urol 2014; 65:270-3. 10. Eisenhauer EA, Therasse P, Bogaerts J, et al. New Response Evaluation Criteria in Solid Tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47. 11. Attard G, Reid AH, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol 2008; 26:4563-71. 12. Goldsmith O, Solomon DH, Horton R. Hypogonadism and mineralocorticoid excess. The 17-hydroxylase deficiency syndrome. N Engl J Med 1967; 277: 673-7. 13. Yanase T, Simpson ER, Waterman MR. 17 alpha-hydroxylase/17,20-lyase deficiency: from clinical investigation to molecular definition. Endocr Rev 1991; 12: 91-108. 14. Perez EG, del Rincon LG, Loza OT, et al. P450C17 (CYP17) deficiency in native Mexican patient with a novel CYP17A1 mutation. Endocr Pract 2011; 17: 99-103. 15. Auchus RJ. The genetics, pathophysiology, and management of human deficiencies of P450c17. Endocrinol Metab Clin North Am 2001; 30: 101-19, vii. 16. Omlin A, Pezaro C, Mukherji D, et al. Improved survival in a cohort of trial participants with metastatic castration-resistant prostate cancer demonstrates the need for updated prognostic nomograms. Eur Urol 2013; 64:300-6. 17. Doctor S, Tsao CK, Godbold JH, et al. Evolving patterns of metastatic disease in castration-resistant prostate cancer (CRPC) reported in clinical trials from 1990 to 2011. J Clin Oncol 2013; 31 (abstract 5015).
Clinical Genitourinary Cancer Month 2014
-5
Abiraterone—What Is Wrong With the Adrenal Glands? Sabine Schmid,1 Jürgen Fornaro,2 Christian Rothermundt,1 Aurelius Omlin,1 Michael Brändle,3 Niels J. Rupp,4 Silke Gillessen1 Clinical Practice Points Abiraterone acetate (AA) is an antihormonal treatment
in metastatic castration-resistant prostate cancer showing overall survival benefit in docetaxel-naive and docetaxel-treated patients in 2 large phase III trials. After the case of a patient who developed biopsy proven prostate cancer metastases in the left adrenal gland during AA treatment, we reviewed all patients
receiving AA and found significant ( 20%) increase in the volume of the adrenal glands in 50% of the patients. This can lead to a diagnostic dilemma because standard imaging cannot easily differentiate between benign and malignant lesions. With the approval of AA before and after docetaxel chemotherapy this diagnostic difficulty will be of increasing importance.
Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Abiraterone acetate, Adrenal gland metastases, Metastatic castration-resistant prostate cancer, Steroid switch, Visceral disease
Case Report We report on a patient who developed a biopsy proven prostate cancer (PC) metastasis in the adrenal gland during abiraterone acetate (AA) treatment and a series of 26 patients treated with AA for metastatic castration-resistant PC (mCRPC) with radiological review of the adrenal glands. The 64-year-old patient was diagnosed with PC with multiple bone metastases in 2009 and androgen deprivation therapy was initiated. In 2011, the patient developed progressive castrationresistant disease with a prostate-specific antigen (PSA) increase (Fig. 1), new bone metastases, and clinical deterioration and was subsequently treated with docetaxel. He had an excellent clinical and PSA response to chemotherapy. Three months after stopping chemotherapy, PSA increased rapidly again and treatment with AA at the standard dose of 1000 mg per day with prednisone 5 mg twice daily was started.
1
Department of Medical Oncology Department of Radiology 3 Department of Endocrinology, Diabetology, and Osteology 4 Department of Pathology Kantonsspital St Gallen, St Gallen, Switzerland 2
Submitted: Nov 21, 2013; Revised: Jan 21, 2014; Accepted: Jan 23, 2014 Address for correspondence: Sabine Schmid, MD, Kantonsspital St Gallen, Department of Medical Oncology, Rorschacherstrasse 95, CH-9007 St Gallen, Switzerland Fax: þ41-71-494-63-25; e-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2014.01.008
After 3 months of therapy with AA a nodular lesion in the left adrenal gland was seen on computed tomography (CT) scan and after another 3 months (total 6 months of therapy) progressive nodular formations in both adrenal glands were observed (Fig. 2A and B). No other soft tissue metastases were observed and there was only a slight increase in PSA; bone metastases were stable according to bone scan as per PC Working Group criteria 2.1 The patient showed no clinical signs of adrenal insufficiency. On CT and magnetic resonance scans the adrenal glands showed diffuse hypertrophy, but the nodular lesions showed no lipid content and therefore were considered indeterminate. Yet, with CT perfusion imaging the lesions showed a relative and absolute washout on delayed scanning of > 40% and > 60% respectively, consistent with benign adenomas according to Dunnick and Korobkin (Fig. 3).2 For definitive diagnosis we conducted CT-guided core needle biopsy (Fig. 4A and B) of the nodular formation of the left adrenal gland (maximum diameter, 2 cm), which rather surprisingly showed PC metastasis (Fig. 4C and D). Because the patient was feeling well, we continued therapy with AA, but switched from prednisone to dexamethasone (2 mg, orally per day continuously for 3 weeks, then reduced to 1.5 mg for 1 week and subsequently 1 mg per day), which has been shown to have positive effects on PSA values in some patients.3 Using this modified treatment a good PSA response was seen and rather unexpectedly a significant reduction in size of the adrenal metastasis and the adrenal glands in general (Fig. 2C).
Clinical Genitourinary Cancer Month 2014
-1
Abiraterone—What Is Wrong With the Adrenal Glands? Figure 1 Anticancer Treatments and History of PSA Changes
Abbreviations: LHRH ¼ luteinizing hormone-releasing hormone; PSA ¼ prostate-specific antigen.
Discussion Adrenal masses discovered during imaging investigations for nonadrenal disorders are called incidentalomas. With the widespread use of CT scans these have become increasingly common. The prevalence is up to 4.4% with an increase in elderly patients and patients with cancer.4 Adrenal gland tumors in the general population are most often benign and nonsecreting adenomas, followed by hormone secreting
adenomas (cortisol, aldosterone), pheochromocytomas, adrenal gland metastases, and adrenocortical carcinomas.5 Until now, adrenal metastases have rarely been described in PC. In one retrospective analysis of CT scans of 508 PC patients, adrenal gland metastases were present in only 1 patient (0.2%).6 In a large autopsy study published at approximately the same time, the incidence of adrenal gland metastases in 1500 PC patients was 13%, suggesting that they are more frequent than clinically suspected.7
Figure 2 Computed Tomography Scans of the Adrenal Glands at Start and During AA Treatment. Green Arrows Mark the Right Adrenal Gland; Red Arrows Mark the Left Adrenal Gland. (A) CT Scan of the Adrenal Glands Before AA Administration. (B) CT Scan of the Adrenal Glands After 6 Months of AA/Prednisone Therapy. (C) CT Scan of the Adrenal Glands 3 Months After Switching Therapy From AA/Prednisone to AA/Dexamethasone
2
-
Abbreviations: AA ¼ abiraterone acetate; CT ¼ computed tomography.
Clinical Genitourinary Cancer Month 2014
Sabine Schmid et al Figure 3 Computed Tomography Scans of the Adrenal Glands Showing Diffuse Thickening. Computed Tomography Scans of the Adrenal Glands in the (A) Native, (B) Enhanced, and (C) Delayed Phases Showing Diffuse Thickening of the Glands and a Nodular Lesion in the Left Side at the Same Time Point as in Figure 1B. An Absolute Wash out of 67% and a Relative Wash out of 49% was Computed From the ROI Measurements of the Nodular Lesion in the Left Adrenal Gland
Abbreviation: ROI ¼ region of interest.
Figure 4 Computed Tomography-Guided Biopsy of the Left Adrenal Gland. (A) and (B): CT-Guided Biopsy of Left Adrenal Gland. CT Fluoroscopy Images: (A) Head Slice, and (B) Center Slice Show a 20-Gauge Biopsy Needle (Arrow) Advanced in an Anterior Caudocranial Direction Into a Nodular Lesion (Arrowhead) of the Left Adrenal Gland. (C) and (D): Biopsy Specimen From the Left Adrenal Gland Shows Glandular and Partially Solid Growing Adenocarcinoma With Prominent Nucleoli (Arrowheads) in Conventional (H & E) Histological Staining. Immunohistochemical Staining for PSA Results in Robust Positivity Within the Tumor Cells (D), Consistent With Metastatic Infiltrates of Acinar Prostate Adenocarcinoma (Scale bar, 100 mm)
Abbreviations: CT ¼ computed tomography; H & E ¼ hematoxylin and eosin; PSA ¼ prostate-specific antigen.
Clinical Genitourinary Cancer Month 2014
-3
Abiraterone—What Is Wrong With the Adrenal Glands? Figure 5 Waterfall Plot With Percentage Change of Adrenal Gland Size. Each Patient Is Represented by 2 Side Bars (Yellow [ Right Adrenal Gland; Blue [ Left Adrenal Gland). Red Line Indicates a 20% Increase in Size
100
80
60
40
20
0
-20
-40
-60
4
-
More recently, Vinjamoori et al analyzed CT scans of 620 consecutive patients with PC and identified 82 cases with visceral metastases among which 12 (2%) had adrenal gland involvement.8 In a very recent analysis of castration-resistant PC (CRPC) patients, adrenal gland metastases have been found in 10% of the patients.9 Because we had observed a seemingly unusually high incidence of enlarged adrenal glands in our CRPC patients treated with AA, we conducted a retrospective evaluation of all of our patients who had begun treatment with AA for mCRPC between July 2010 and June 2012 who had CT scans available for review. In this cohort of 26 patients, we found an increase in the volume of the adrenal glands of more than 20% according to Response Evaluation Criteria in Solid Tumours 1.110 (range, 24%-103%) in 13 patients (50%) in comparison of the baseline CT scan with the scan at the end of treatment (Fig. 5). Mean time from start of AA treatment to CT scan evaluation (end of treatment in 24 patients) was 6.3 months (range, 2.2-20.9 months), mean time from start of AA to CT scan evaluation in the 13 patients with a significant increase in adrenal gland size was 7.6 months (range, 2-21 months). At that time point in these 13 patients hypokalemia as an early sign of mineralocorticoid excess was seen in only 3 cases. After 3 months of therapy only 2 of 13 patients (15%) with a CT scan at that time point had an increase in volume of the adrenal glands of 20%. The increase in size was bilateral in all 13 cases. In 3 patients, nodular formations were seen whereas in the other 10 patients only an increase in volume was documented. Unfortunately, we have no biopsy evaluation in these patients. These findings have led to the hypothesis that treatment with AA seems to have an effect on adrenal gland growth and that this effect might be dependent on the duration of treatment. Abiraterone acetate is a small molecule that binds irreversibly at the active site of cytochrome P450 17A1 (CYP17), a key enzyme
Clinical Genitourinary Cancer Month 2014
in the steroidogenic pathway with 17a-hydroxylase and 17, 20-lyase activity.11 Mutations of P450c17a are associated with 17a hydroxylase- and 17a hydroxylase/17, 20-lyase deficiency, and represent a rare form of congenital adrenal hyperplasia.12 The 17a-hydroxylase defect results in reduced cortisol production and a consecutive increase in adrenocorticotropic hormone (ACTH) secretion with increased production of mineralocorticoids (corticosterone and deoxycorticosterone) and leads to mineralocorticoid excess with volume expansion, hypertension, hypokalemia, and alkalosis. A defect in 17a-hydroxylation in the adrenal cortex and the gonads leads to a combined androgen and estrogen deficiency with an increase in follicle stimulating hormone and luteinizing hormone concentrations. This defect causes diffuse or nodular cortical hyperplasia of the adrenal glands.13,14 Treatment is based on sodium restriction and glucocorticoid supplementation, preferentially with dexamethasone, to decrease the excess ACTH secretion to restore blood pressure and potassium concentration to normal.12,13,15 Abiraterone acetate affects the same pathway. In the phase I trial conducted by Attard et al, endocrine studies showed that at all dose levels, treatment was associated with an increase in ACTH levels and increased steroid precursors upstream of CYP17 (corticosterone and deoxycorticosterone).11 Administration of dexamethasone resulted in suppression of ACTH and a decrease in upstream steroid levels to baseline levels. Steroids upstream of CYP17 maintained glucocorticoid activity and caused a syndrome of mineralocorticoid excess. This was reversible with application of eplerenone or with low doses of glucocorticoids to suppress the ACTH drive.11 Considering the almost identical metabolic situation in patients with inherited CYP17 deficiencies and patients undergoing therapy with AA it seems reasonable that adrenal hyperplasia would be found. In contrast to the treatment of congenital adrenal gland hyperplasia, in which patients receive mostly low-dose dexamethasone, in patients with AA treatment prednisone is typically used, which has a relevantly shorter biological half-life (12-36 hours compared with 36-72 hours). One could postulate that treatment with prednisone lessens ACTH-drive to high-normal levels and prevents symptoms of mineralocorticoid excess as intended, but there is still a chronic ACTH overstimulation of the adrenal glands. Optimal glucocorticoid supplementation in patients with AA treatment could potentially decrease the incidence of adrenal gland hyperplasia. This could be helpful, since differentiation between benign adenomas and metastases seems difficult with standard imaging procedures. This differentiation could gain more importance in the future since we might see more patients with adrenal metastases. The reason being that on one hand, owing to new treatment options for PC, longer overall survival can be achieved.16 Thus, with a longer course of disease more sites of metastases may occur. A trend to increased rates of visceral metastases in patients with mCRPC has already been described.17 On the other hand there is a possibility that changes in the microenvironment of the adrenals induced by AA might facilitate prostate cancer dissemination into this organ. Our observation of enlarged adrenal glands in patients with mCRPC treated with AA and prednisone has to be confirmed in larger series and more of the lesions have to be histologically
Sabine Schmid et al evaluated. This might also confirm our hypothesis of an increase in adrenal gland metastases. It has been recognized that the kind and dose of the concomitant glucocorticoid could be of importance and a trial investigating the role of AA with different doses of prednisolone or dexamethasone is currently recruiting patients (NCT 01867710). At least in our patient described here, the steroid switch has been successful and resulted in a significant decline in PSA and decrease in size of the adrenal gland metastasis. In conclusion, we would like to raise awareness to the endocrine and morphologic features of the adrenal glands in patients treated with AA and to the difficulty in differentiation between benign and malignant morphology with current imaging procedures.
References 1. Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008; 26:1148-59. 2. Dunnick NR, Korobkin M. Imaging of adrenal incidentalomas: current status. AJR Am J Roentgenol 2002; 179:559-68. 3. Lorente D, Weatherstone K, Omlin A, et al. Tumor responses after steroid switch of prednisolone (P) to dexamethasone (D) in castration-resistant prostate cancer (CRPC) patients (pts) on abiraterone acetate (AA) (abstract 2918). Presented at the European Cancer Conference; September 27-October 1, 2013; Amsterdam, Netherlands. 4. Mansmann G, Lau J, Balk E, et al. The clinically inapparent adrenal mass: update in diagnosis and management. Endocr Rev 2004; 25:309-40.
5. Mantero F, Terzolo M, Arnaldi G, et al. A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab 2000; 85:637-44. 6. Long MA, Husband JE. Features of unusual metastases from prostate cancer. Br J Radiol 1999; 72:933-41. 7. Bubendorf L, Schopfer A, Wagner U, et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol 2000; 31:578-83. 8. Vinjamoori AH, Jagannathan JP, Shinagare AB, et al. Atypical metastases from prostate cancer: 10-year experience at a single institution. AJR Am J Roentgenol 2012; 199:367-72. 9. Pezaro CJ, Omlin A, Lorente D, et al. Visceral Disease in Castration-resistant Prostate Cancer. Eur Urol 2014; 65:270-3. 10. Eisenhauer EA, Therasse P, Bogaerts J, et al. New Response Evaluation Criteria in Solid Tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47. 11. Attard G, Reid AH, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol 2008; 26:4563-71. 12. Goldsmith O, Solomon DH, Horton R. Hypogonadism and mineralocorticoid excess. The 17-hydroxylase deficiency syndrome. N Engl J Med 1967; 277: 673-7. 13. Yanase T, Simpson ER, Waterman MR. 17 alpha-hydroxylase/17,20-lyase deficiency: from clinical investigation to molecular definition. Endocr Rev 1991; 12: 91-108. 14. Perez EG, del Rincon LG, Loza OT, et al. P450C17 (CYP17) deficiency in native Mexican patient with a novel CYP17A1 mutation. Endocr Pract 2011; 17: 99-103. 15. Auchus RJ. The genetics, pathophysiology, and management of human deficiencies of P450c17. Endocrinol Metab Clin North Am 2001; 30: 101-19, vii. 16. Omlin A, Pezaro C, Mukherji D, et al. Improved survival in a cohort of trial participants with metastatic castration-resistant prostate cancer demonstrates the need for updated prognostic nomograms. Eur Urol 2013; 64:300-6. 17. Doctor S, Tsao CK, Godbold JH, et al. Evolving patterns of metastatic disease in castration-resistant prostate cancer (CRPC) reported in clinical trials from 1990 to 2011. J Clin Oncol 2013; 31 (abstract 5015).
Clinical Genitourinary Cancer Month 2014
-5
