RESEARCH LETTER
Response of adrenocortical carcinoma liver metastases to hepatic artery infusion floxuridine
Introduction
Adrenocortical carcinoma (ACC) is a rare malignancy with an incidence of 1-2 million cases per year. For patients with limited recurrent local or distant metastatic disease, resection is the most effective therapy and is associated with 5-year overall survival (OS) rates of up to 41%.2 However, for patients with advanced ACC not amenable to resection, outcome is typically poor, with low objective response rates (ORR; 14-23%) and median OS (14-25 months) to available chemotherapy regimens including immunotherapy or mitotane with multi-agent cyto- toxic chemotherapy.1,3
Unfortunately, the burden of metastases is often too extensive for resection, particularly in the liver. Hepatic artery infusion chemotherapy (HAIC) achieves high intrahepatic concentrations of chemotherapy with reduced systemic toxicity due to near- complete first-pass metabolism of drugs such as floxuridine (FUDR) by the liver.4 This therapy has been used primarily for colorectal liver metastases (CLM) and more recently for locally advanced unresectable intrahepatic cholangiocarcinoma (IHC), achieving ORR of approximately 90% and 58%, respectively. Based on the known activity of 5-FU-containing regimens in ACC5 (FUDR is pro-drug of 5-FU), we sought to evaluate the feasibility and efficacy of HAI FUDR in two patients with high- volume liver metastases and limited systemic therapy options.
Methods
After discussion of limited available systemic therapy options, informed consent was obtained. HAI pumps (HAIPs) were implanted in standard surgical fashion,4 with concomitant resection or ablation of metastatic liver lesions, either near- complete, or left-sided lesions only (planned two-stage proced- ure). HAIC was administered for 6 cycles postoperatively, paired with systemic therapy. Restaging imaging was performed in parallel with serial biochemical monitoring if hormone- secreting, and if not, with circulating tumor DNA (ctDNA) using Signatera™M.
Results
The first case was a 43-year-old female with a large left ACC with extensive liver metastases and hypercortisolemia. She was treated
with etoposide, doxorubicin, cisplatin, and mitotane, followed by pembrolizumab after progression, yet there was continued pro- gression of liver metastases and symptomatic hypercortisolemia persisted despite a maximum dose ketoconazole and metyr- apone. Given the lack of effective standard of care palliative chemotherapy options and the presence of liver-confined disease (Fig. 1a and b), she underwent en bloc resection of the left ad- renal gland, kidney, and portion of left diaphragm, resection/ ablation of amenable liver lesions, and HAIP implantation (Intera 3000) for treatment of residual unresectable disease. A total of 5 lesions were resected, and 2 were ablated. There were two macroscopic residual lesions that were not resected or ab- lated given their proximity to major portal inflow structures deep within the liver parenchyma (Fig. 1c) and innumerable radio- graphically occult smaller lesions. Pathology revealed pT2pN0pM1 ACC with negative margins. After 6 cycles of HAI FUDR and systemic mitotane, restaging imaging revealed no residual or recurrent disease (Fig. 1d), and serum cortisol normalized (Fig. 2a). Further therapy was held and there was no evidence of disease 14 months after initiating HAI FUDR.
The second case was a 46-year-old male with a biochemically inactive 13.2 × 9.6 cm left ACC which grew from a 1.5 x 2.7 cm left adrenal nodule within a three-month period. The patient underwent en bloc radical resection of the left adrenal gland, kidney, tail of pancreas, spleen, and a portion of the diaphragm, with final pathology revealing high grade ACC (pT3pN0cM0) with negative margins. Adjuvant external beam radiation (4500 Gy) was administered to the adrenalectomy bed along with 4 cycles of cisplatin, etoposide, and mitotane. Ten months after surgery, surveillance imaging revealed fifteen bilobar liver me- tastases (Fig. 1e and f). Given the extent of disease and the poor expected response to available systemic therapy, he underwent HAIP implantation (Medtronic Synchromed II™ pump/ Codman™ vascular catheter) and concomitant clearance of the left liver (microwave ablation x 4, partial hepatectomy x 2), with pathology showing metastatic ACC. After 6 cycles of HAI FUDR with systemic 5-FU and mitotane, restaging liver MRI showed near-complete response with only two small residual liver de- posits and no other measurable disease (Fig. 1g and h). Circu- lating tumor DNA (ctDNA) had been detected at his initial recurrence (192 MTM/mL) and was undetectable after 6 cycles (Fig. 2b).6 He continued the same regimen, however, at his next imaging, ctDNA was detected at a low level, and two new liver
a
b
C
d
e
f
g
h
lesions were subsequently visualized. He subsequently under- went resection and ablation of these lesions.
Discussion
We present the first cases to our knowledge of HAIP for ACC liver metastases. Our two patients had either a near-complete or complete radiographic response to HAI FUDR after six cycles of treatment. Responses were durable and even allowed for com- plete second stage resection of a small amount of residual disease (case 2). ACC liver metastases exhibit a particularly aggressive biology, with higher growth rates than that of metastases to other sites.7 Thus, control of liver metastases is paramount, yet
currently available systemic therapy regimens have low response rates.1 While multiple studies have documented benefit to local control either via metastasectomy or ablation for mACC to the liver, the disease burden is usually too high, presenting an unmet need.8,9 With report of these two cases, we introduce the possi- bility of HAIC as an additional tool in the management of high- volume ACC liver metastases in highly selected patients.
Serum biomarkers have proven useful for monitoring disease status in other solid malignancies, however for biochemically inactive ACC, there are no known tumor markers to follow treatment response in conjunction with imaging. Circulating tumor DNA (ctDNA) has previously been detected in ACC, and is increasingly being applied in solid cancers for detection of
a
Cortisol Levels, Case 1
30
Cortisol Level (ug/dL)
20
10
0
Diagnosis
After Ketoconazole initiation
After Metyrapone Initiation
6 months after diagnosis
Preoperative
3 months Postoperative
15 months Postoperative
b
ctDNA, Case 2
200
Surgery*
150
MTM/mL
FUDR HAIC
100
Surgery **
Ablation*
50
Progression*
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Months Following Recurrence
radiographically occult recurrent or residual disease, and for monitoring response to treatment when imaging is equivocal.6 Here we used serial Signatera™ assays to follow case 2, who did not exhibit adrenocortical hormone elevation. Based on this case, further study of ctDNA for monitoring disease burden in ACC should be undertaken.
Based on these results, a phase II study of HAI FUDR in ACC liver metastases is planned at the National Cancer Institute (IRB approval pending). Given the rapid recent expansion of HAIP programs in the last 5 years,10 further evidence from this upcoming trial could have rapid impact in this rare, deadly malignancy.
Funding sources
This research was supported by NIH T32CA60003 [HGM] and the intramural research program of the National Institutes of Health [LS, JDR, JMH].
Conflict of interest
None to declare.
Hannah G. McDonald* Department of Surgery, University of Kentucky College of Medicine, Lexington, KY, USA
Amber Leila Sarvestani*
Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Joseph W. Owen
Department of Radiology, University of Kentucky College of Medicine, Lexington, KY, USA
Justin Rueckert
Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY, USA
Margaret E. Wierman
Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine at Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
Research Service Veterans Affairs Medical Center, Denver, CO, 80220, USA
Katja Kiseljak-Vassiliades
Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine at Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA
Research Service Veterans Affairs Medical Center, Denver, CO, 80220, USA
Prakash K. Pandalai Department of Surgery, University of Kentucky College of Medicine, Lexington, KY, USA
Carleton S. Ellis College of Pharmacy, University of Kentucky, Lexington, KY, USA
Reema A. Patel Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, KY, USA
Jaydira del Rivero
Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Jonathan M. Hernandez
Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Michael J. Cavnar Department of Surgery, University of Kentucky College of Medicine, Lexington, KY, USA
Correspondence: Michael Cavnar, Department of Surgery, University of Kentucky, 800 Rose Street, Lexington, KY, 40508, USA. E-mail: michael.cavnar@uky.edu (M.J. Cavnar)
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