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Transarterial Chemoembolization vs Radioembolization for Neuroendocrine Liver Metastases: A Multi-Institutional Analysis
Journal Pre-proof Transarterial Chemoembolization vs Radioembolization for Neuroendocrine Liver Metastases: A Multi-Institutional Analysis Michael E. Egger, MD, MPH, FACS, Emily Armstrong, BS, Robert CG. Martin, II, MD, PhD, FACS, Charles R. Scoggins, MD, MBA, FACS, Prejesh Philips, MD, FACS, Manisha Shah, MD, Bhavana Konda, MD, MPH, Mary Dillhoff, MD, FACS, Timothy M. Pawlik, MD, MPH, PhD, FACS, Jordan M. Cloyd, MD PII:
S1072-7515(20)30113-7
DOI:
https://doi.org/10.1016/j.jamcollsurg.2019.12.026
Reference:
ACS 9722
To appear in:
Journal of the American College of Surgeons
Received Date: 16 December 2019 Accepted Date: 16 December 2019
Please cite this article as: Egger ME, Armstrong E, Martin II RC, Scoggins CR, Philips P, Shah M, Konda B, Dillhoff M, Pawlik TM, Cloyd JM, Transarterial Chemoembolization vs Radioembolization for Neuroendocrine Liver Metastases: A Multi-Institutional Analysis, Journal of the American College of Surgeons (2020), doi: https://doi.org/10.1016/j.jamcollsurg.2019.12.026. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc. on behalf of the American College of Surgeons.
Transarterial Chemoembolization vs Radioembolization for Neuroendocrine Liver Metastases: A Multi-Institutional Analysis Michael E Egger, MD, MPH, FACS1, Emily Armstrong, BS2, Robert CG Martin II, MD, PhD, FACS1, Charles R Scoggins, MD, MBA, FACS1, Prejesh Philips, MD, FACS1, Manisha Shah, MD3, Bhavana Konda, MD, MPH3, Mary Dillhoff, MD, FACS2, Timothy M. Pawlik, MD, MPH, PhD, FACS2, Jordan M Cloyd, MD2 1
Hiram C Polk Jr, MD Department of Surgery, University of Louisville, Louisville, KY Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 3 Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 2
Disclosure Information: Nothing to disclose. Presented at the Southern Surgical Association 131st Annual Meeting, Hot Springs, VA, December 2019. Corresponding Author: Jordan Cloyd, MD Assistant Professor of Surgery Division of Surgical Oncology The Ohio State University Wexner Medical Center 410 W 10th Ave, N-907 Doan Hall Columbus, OH 43210 Phone: 614-293-4583 Fax: 614-366-0003 Email: [email protected]
Abbreviated title: Therapy for Neuroendocrine Liver Metastases
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Background: Liver-directed hepatic arterial therapies are associated with improved survival and effective symptom control for patients with unresectable neuroendocrine liver metastases (NELM). Whether transarterial chemoembolization (TACE) or transarterial radioembolization (TARE) with yttrium-90 (y-90) are associated with improved short- or long-term outcomes is unknown.
Methods: A retrospective review of all patients with NELM at two academic medical centers undergoing transarterial therapies from 2000-2018 was performed. Postoperative morbidity, radiographic response according to RECIST criteria, and long-term outcomes were compared between patients who underwent TACE versus TARE.
Results: Among 248 patients with NELM, 197 (79%) received TACE while 51 (21%) received TARE. While patients who underwent TACE were more likely to have carcinoid syndrome, larger tumors, and have higher chromogranin A levels, there was no difference in tumor differentiation, primary site, bilobar disease, or synchronous presentation. Nearly all TARE treatments (92%) were performed as an outpatient while 99% of TACE patients spent at least one night in the hospital. There were no differences in overall morbidity (TARE 13.7% vs TACE 22.6%, p = 0.17), grade III/IV complications (5.9% vs 9.2%, p=0.58), or 90-day mortality. The disease control rate (DCR) on first post-treatment imaging (RECIST partial/complete response or stable disease) was greater for TACE compared with TARE (96% vs 83%, p<0.01). However, there was no difference in median OS (35.9 months vs 50.1 months, p=0.3) or PFS (15.9 months vs 19.9 months, p=0.37).
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Conclusions: In this retrospective multi-institutional analysis, both TACE and TARE with Y-90 were safe and effective liver-directed therapies for unresectable NELM. Although TARE was associated with a shorter length of hospital stay, TACE demonstrated improved short term DCR, and both resulted in comparable long term outcomes.
Key words: carcinoid, TACE, y-90, radioembolization, neuroendocrine liver metastases; selective internal radiation therapy
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Introduction Neuroendocrine tumors (NETs) are a diverse group of neoplasms whose clinical presentation, behavior, and prognosis are heterogeneous1. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) frequently metastasize to the liver2. In fact, 60-90% of patients with small bowel NETs will develop neuroendocrine liver metastases (NELM) during their lifetime3. The presence of NELM is not only an important negative prognostic factor but is also associated with worse quality of life (QOL) due to the frequent development of carcinoid syndrome3–5. As such, liverdirected therapies are an important component of the multidisciplinary management of patients with metastatic NETs. While surgical resection of NELMs affords the best long-term outcomes and only potential for cure6,7, only a minority of patients are candidates for surgery due to the diffuse bilobar nature of metastatic disease, prohibitive patient comorbidities, or the presence of extrahepatic disease8. For patients with advanced NELM not amenable to surgical resection, a variety of liver-directed therapies exist. Transarterial embolization (TAE)9, chemoembolization (TACE)10 or radioembolization (TARE) with yittrium-90 (y-90)11 are most commonly employed given their ability to treat multiple tumors concurrently and reproducibly12,13. The use of liver-directed intra-arterial therapies (IAT) has been associated with improved locoregional control, overall survival duration, and effective symptom control12,13. While IATs have been incorporated into consensus guidelines for the management of NELM, there has been insufficient evidence to suggest the superiority of one modality over others13–15. Few studies have directly compared the results of TAE, TACE, and TARE and most are limited by their single-institution design, small sample size, and disparate results. The purpose therefore of the 4
current study was to directly compare the outcomes of patients with NELM undergoing TACE vs TARE at two high-volume NET institutions.
Methods Study Cohort A retrospective review of all adult patients with NELM at two academic medical centers (The Ohio State University and the University of Louisville) who underwent any IAT between 20002018 were retrospectively reviewed. No additional exclusion criteria were applied. The decision to administer IAT was made after individual discussion at a multidisciplinary tumor board conference that included surgical oncologists, medical oncologists, nuclear medicine physicians, and interventional radiologists. In general, patients were selected for IAT if they had progressive liver metastases, uncontrolled symptoms, or significant tumor burden. Eligibility criteria included unresectable disease based on surgical evaluation, minimal or no extrahepatic disease, and adequate liver function and performance status to recover safely from liver-directed therapy. For patients with bilobar NELM, staged procedures approximately 4-8 weeks apart were performed. The decision to perform TACE (Ohio State) versus TARE (Louisville) was largely based on institutional preference. Variables and Outcomes Demographic and clinical information were directly abstracted from the electronic medical chart: age, patient comorbidities, primary tumor location, presentation (synchronous vs metachronous), tumor grade, prior surgery of the primary or liver metastases, prior systemic therapy, presence of
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extrahepatic disease, distribution of liver metastases (bilobar vs unilobar), and size of largest metastasis. Periprocedural information including type of IAT, extent of treatment (bilobar, lobar, selective), dose and agents used for TACE, pre- and post-treatment laboratory values, length of in-hospital stay (LOS), and the occurrence of any 30-day complication. Complications were graded according to Clavien-Dindo scale.16 The size of the largest lesion following liver-directed therapy on triple-phase computed tomography scan within six months of the index procedure was recorded. Response to TACE or TARE was calculated based on RECIST 1.1 criteria using the largest liver metastasis. In general, patients were followed every 6 months with computed tomography, tumor markers, and clinical examination. The radiographic development of a new liver or extrahepatic lesion with characteristics consistent with neuroendocrine metastasis or the interval growth of a previously treated lesion were defined as progression. Progression-free survival (PFS) and overall survival (OS) were calculated based on the date of the liver-directed therapy; patients were censored at the time of their last clinical follow-up. Intra-arterial Therapies For patients undergoing TACE, all patients were placed on continuous intravenous octreotide to prevent periprocedural carcinoid crisis. Preoperative antibiotics were usually administered. After gaining access to the femoral artery, an initial visceral angiogram was performed to detail hepatic arterial anatomy. Selective hepatic artery cannulation was performed and chemoembolic agents were administered. The chemotherapy agents utilized varied throughout the study period but most commonly included doxorubicin, mitomycin, and cisplatin. Embolic particles (typically 6
ioxaglate sodium and ethiodized oil 37%) were infused until arterial stasis was achieved. Patients were observed overnight and routinely discharged on post-procedural day 1 following 24 h of continuous octreotide infusion. For patients undergoing TARE, all patients initially underwent an outpatient mesenteric angiography to assess arterial anatomy and to determine hepatopulmonary shunting. This was performed using a 100 megabecquerel (MBq) dose of 99mTc-labeled macroaggregated albumin infused into the hepatic artery. Shunt fractions were assessed using planar scintigraphy. If shunt fractions were acceptable for TARE (<15%), the patient was scheduled for an outpatient treatment with y-90 10-14 days later. The TARE y-90 treatment consisted of percutaneous femoral artery access and visceral angiography, followed by treatment of the involved lobe with y-90, dosed according to liver volume. If bilobar disease was present, the contralateral lobe was treated in a similar fashion 4 weeks later. The delivery agent of y-90 used for nearly all of the patients undergoing TARE was Therasphere (BTG). Most patients were discharged to home on the same day of TARE. Statistical Analysis Descriptive statistics were summarized for each treatment regimen and compared. Categorical variables were compared using chi-square test or Fisher’s exact test, as appropriate. Continuous variables were compared using the nonparametric Wilcoxon rank-sum test. Missing data were excluded on a per-variable basis. Kaplan-Meier analysis was used to illustrate OS and PFS for each group. For OS, an event was considered death from any cause and patients were censored at the time of last follow-up if still alive. For PFS, an event was considered at time of documented progression or death, and patients were censored at the time of last follow-up if they
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were alive without evidence of progression. Survival was compared using the log rank test. All statistical analyses were performed using SAS 9.4 (SAS, Cary, NC). Results Among 248 patients with NELM who underwent IAT during the study period, 197 (79%) received TACE while 51 (21%) received TARE. The demographic and clinical information of all patients are reported in Table 1. The median age of the cohort was 60 years and 44.8% were male. The most common primary tumor location was small bowel (35.5%) followed by pancreas (25.0%). While there were no significant differences in primary tumor location, proportion of patients with an intact primary tumor, or tumor differentiation between patients who underwent TACE versus TARE, patients who received TACE were more likely to present with synchronous disease (85.8% vs 70.6%, p<0.05) and have carcinoid syndrome (58.4% vs 23.5%, p<0.0001). Tumor grade was higher among patients treated with TARE. While a similar proportion of patients had bilobar disease and underwent staged bilateral procedures, patients who underwent TACE had larger maximum sized liver metastases (median 4.9 cm vs 3.3 cm, p<0.001) and a higher pre-treatment chromogranin A level (1475 vs 193 ng/mL, p<0.0001). Peri-procedural outcomes of IAT are reported in Table 2. The median LOS following TARE was shorter than TACE (0 vs 1, p<0.0001). Nearly all TARE treatments (92%) were performed as an outpatient while 99% of TACE patients spent at least one night in the hospital. There were no differences in overall complications (TARE 13.7% vs TACE 22.6%, p = 0.17), grade III/IV complications (5.9% vs 9.2%, p=0.58), or 30-day mortality (2.0% vs 3.1%, p=1.0). Figure 1 shows the median percentage change in relevant laboratory values following IAT. Patients who underwent TACE experienced a significantly greater increase in their post8
procedure bilirubin (+55% vs 0%, p<0.0001) and creatinine (+12% vs -13%, p<0.0001) but a greater decrease in their median chromogranin A levels (-43% vs -16%, p=0.07) and decrease in the size of the largest liver metastasis (-19% vs -9%, p=0.05). Complete radiographic data was available for 184 patients. The disease control rate (DCR) on first post-treatment imaging (RECIST partial/complete response or stable disease) was greater for TACE compared with TARE (96% vs 83%, p=0.004). The RECIST response rates are summarized in Figure 2. Median follow-up for the entire cohort was 34 months. Comparing patients who underwent TARE vs TACE, there was no significant difference in median OS (35.9 months vs 50.1 months, p=0.3) or PFS (15.9 months vs 19.9 months, p=0.37) (Figure 3). The 5yr OS rates for patients who underwent TACE vs TARE were 42% vs 35%, respectively. In a sensitivity analysis of only patients with well-differentiated grade 1/2 tumors, median PFS (18.4 months vs 20.6 months, p=0.29) and OS (35.9 months vs 50.7 months, p=0.27) remained not significantly different. Discussion The incidence of GEP-NETs is increasing and a majority of patients will develop NELM in their lifetime. As most patients with NELM will have unresectable disease, an improved understanding of the short- and long-term outcomes of liver-directed therapies is imperative. Among IATs, TAE, TACE, and TARE have been performed for several decades largely based on institutional preference and few comparative effectiveness studies have been conducted. In the current bi-institutional analysis of TACE versus TARE, we found that both approaches resulted in safe, effective control of unresectable NELM. Both modalities were well tolerated, with no difference in peri-procedural complications between the two. Radiographic response based on the initial follow-up imaging suggested improved outcomes with TACE compared to 9
TARE but at the expense of a longer hospital length of stay. Most importantly, no differences in long-term outcomes, either PFS or OS, were observed among patients receiving TACE or TARE. Because of the hypervascular nature of NELM, there is a rational physiologic basis for the use of IAT for unresectable NELM. TACE theoretically provides two mechanisms of action against NELM; one is a simple embolization of the tumor that reduces vascularity, and a second is localized delivery of cytotoxic chemotherapy. Multiple reports of TACE for unresectable NELM have shown favorable results. Short term DCR (i.e. at least stable disease without progression) appears to be on the order of 85-95%10,17,18. The procedure is safe and welltolerated, with reported peri-procedural complication rates of approximately 10-20% and shortterm mortality rates of 2-5%10,17,19,20 Early radiographic response rates and peri-procedural morbidity and mortality of TACE reported in the current study are consistent with these previously published results, confirming the safety and efficacy of TACE for NELM. An alternative IAT for NELM is TARE, sometimes referred to as selective internal radiotherapy (SIRT). TARE is less embolic than TARE, utilizing smaller β-radiation emitting particles (y-90) that deliver high-dose, localized radiotherapy to NELM. TARE has some theoretic advantages over TACE, including the ability to diffuse into the entire hemi-liver to treat miliary disease as well as less initial liver toxicity. Short term radiographic DCR >90% have been reported in the literature11,21-23. Minor side effects that are commonly reported include fatigue and nausea, but the rate of major complications is low11,18,23,24. The low rate of complications with TARE in this study compares favorably to rates previously reported. The radiographic DCR of 83% is somewhat lower than what most studies report which may be due to the inclusion of a higher proportion of poorly differentiated tumors in the TARE group (~10%).
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The current study found that early radiographic and biochemical response seemed to favor TACE compared with TARE, but potentially at the expense of a longer hospital LOS and greater toxicity. There were statistically significant increases in bilirubin and creatinine in patients undergoing TACE compared to TARE. While this may represent an increase in serologic toxicity in TACE compared to TARE, the actual clinical relevance of these minor laboratory changes are likely minimal especially given the lack of differences in overall or major complications. Most importantly, there were no significant differences in PFS or OS between the two treatment groups. While direct comparisons of long-term efficacy should be interpreted cautiously outside of a randomized controlled trial, these findings suggest that both TACE and TARE are acceptable forms of IAT for NELM. TACE and TARE have not been directly compared in a randomized clinical trial though a few retrospective studies have been previously performed. Chen et al in a retrospective, multicenter study evaluated 155 patients with NELM treated with TACE (n=50), TARE (n=64), or TAE (n=41)25. In a propensity score matched analysis, there was no difference in PFS or OS among the three treatments. Minh et al also used a propensity score matched model to compare TACE and TARE in a retrospective study of 192 patients with NELM26. The authors reported that conventional TACE was associated with significantly improved OS and PFS compared to TACE with drug-eluting beads or TARE. When therapies are equally effective, the question of cost, convenience, and patient-reported outcomes must be considered. Each therapy has a unique cost structure and burden on the healthcare system. TACE is typically performed with an overnight hospitalization while TARE is usually an outpatient procedure. On the other hand, TARE involves an additional mapping procedure and other physician services (radiation oncology). Whitney et al performed a 11
multicenter, international evaluation of TACE and TARE for NELM27. In this study, both TARE and TACE appeared to be equally effective, but TARE was associated with nearly twice the cost of TACE. An important limitation of the current study is the lack of data on healthcare associated costs as well as QOL scores between the two groups. As healthcare systems continue to prioritize value and patient-centered outcomes, a more thorough analysis of costs and QOL outcomes will be required. In evaluating the results of this study, several limitations should be acknowledged. This is a retrospective analysis and treatment decisions were not made randomly. Indeed, differences in several clinical and pathologic factors between the TARE and TACE groups were observed. Furthermore, while the bi-institutional nature of the study is regarded as a strength in terms of generalizability, the evaluation, periprocedural management, and follow-up, including timing of imaging and laboratory tests, of patients were not standardized across the institutions. As a result, some laboratory and imaging data were missing. For radiographic response, RECIST criteria were used though modified RECIST criteria, which takes into account the degree of arterial enhancement, may provide a more accurate assessment of response to therapy given the highly vascular nature of NELM. In addition, radiographic response was measured at one early time point; given that additional downstaging may occur over time, the current study may underestimate the true RECIST response rates, particularly in the TARE group. Also, the number of patients in the TARE cohort was relatively small and may have limited the power to detect significant differences. Finally, the current study focused on short-term toxicities and long-term survival outcomes. In addition to costs and QOL measures, late-term toxicities were not reported. Given the increased awareness of late-onset hepatoxicitiy following TARE28,29, this should be included in future comparative analyses. 12
Conclusions In conclusion, both TACE and TARE with y-90 are safe and effective liver-directed therapies for unresectable NELM. Although TARE was associated with a shorter length of hospital stay, TACE demonstrated improved short term DCR, and both resulted in comparable long-term outcomes. Given the heterogeneity of GEP-NETs and the emergence of novel systemic therapies, future prospective comparative effectiveness trials are needed to identify the optimal indications for these liver-directed therapies. Author Contribution: M Egger, E Armstrong, RCG Martin, C Scoggins, P Philips, K McMasters, M Shah, B Konda, A Ejaz, A Tsung, M Dillhoff, TM Pawlik and J. M. Cloyd have contributed to the design, analysis, interpretation of data, and drafting of the manuscript. All authors have approved the final version of the manuscript and are accountable for all aspects of the work. The authors have no conflicts of interest or financial ties to disclose.
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Table 1: Clinical Characteristics of Patients with Neuroendocrine Liver Metastases Undergoing Transarterial Radioembolization and Transarterial Chemoembolization Characteristic TARE (n=51) TACE (n=197) p Value Demographic Sex, male, n (%) 19 (37.3) 92 (46.7) 0.23 Age, y, median 60 (56, 70) 60 (51, 67) 0.052 (IQR) BMI, kg/m2, 25.7 (21.3, 29.9) 27.5 (23.6, 32.5) 0.021 median (IQR) Clinical Primary site, n (%) 0.15 Unknown 8 (15.7) 54 (27.4) Pancreas 16 (31.4) 46 (23.4) Colon/appendix 3 (5.9) 10 (5.1) Small bowel 19 (37.3) 69 (35.0) Rectum 0 (0) 3 (1.5) Stomach 3 (5.9) 3 (1.5) Lung 2 (3.9) 12 (6.1) Primary intact, n 26 (52.0) 94 (48.5) 0.65 (%) Synchronous 36 (70.6) 169 (85.8) 0.0106 metastatic disease, n (%) Carcinoid 12 (23.5) 115 (58.4) <0.0001 symptoms, n (%) Differentiation, n (%) Well46 (90.2) 191 (97.0) 0.052 differentiated Poor 5 (9.8) 6 (3.0) Grade, n (%) 0.0124 1 20 (60.6) 139 (75.5) 2 8 (24.2) 39 (21.1) 3 5 (15.2) 6 (3.3) Size of largest 3.3 (2.2, 5.3) 4.9 (3.5. 7.0) 0.0013 lesion, cm, median (IQR) Pretreatment 193 (93, 1645) 1475 (298, 6500) 0.0001 chromogranin A (ng/mL), median (IQR) Staged bilateral 28 (58.3) 110 (57.6) 0.92 treatment, n (%) IQR, interquartile range; TACE, transarterial chemoembolization; TARE, transarterial radioembolization 19
Table 2: Periprocedural Outcomes after Transarterial Chemoembolization vs Transarterial Radioembolization among Patients with Neuroendocrine Liver Metastases Outcome TARE (n=51) TACE (n=197) p Value Length of stay, d, median 0 (0, 0) 1 (1,1) <0.0001 (IQR) Any complication, n (%) 7 (13.7) 44 (22.6) 0.17 Major complication, n (%) 3 (5.9) 18 (9.2) 0.58 30-day mortality, n (%) 1 (2.0) 6 (3.1) 1.0 90-day mortality, n (%) 5 (9.8) 10 (5.2) 0.21 Laboratory, median (IQR) Bilirubin change, 0 (-0.3, +0.1) +0.4 (+0.1, +0.8) <0.0001 mg/dL Platelet change, 103/µL -29 (-78, +19) -42 (-82, -4) 0.31 INR change +0.1 (-0.1, +0.3) +0.2 (+0.1, +0.3) 0.07 Creatinine change, -0.1 (-0.2, 0) +0.1 (0, +0.2) <0.0001 mg/dL % chromogranin -16 (-64, +49) -43 (-77, -4) 0.07 change Radiographic % change in size, -9 (0, -27) -19 (-6, -34) 0.051 median (IQR) RECIST response, n 0.0002 (%) Complete response 2 (4.4) 5 (3.6) Partial response 9 (19.6) 37 (26.6) Stable disease 27 (58.7) 92 (66.2) Progressive disease 8 (17.4) 5 (3.6) IQR, interquartile range; INR, international normalized ratio; TACE, transarterial chemoembolization; TARE, transarterial radioembolization; RECIST, response evaluation criteria in solid tumors.
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Figure Legends Figure 1: Median percentage relative change in relevant laboratory values after transarterial chemoembolization (TACE) vs transarterial radioembolization (TARE), error bars denote interquartile range (IQR). * p<0.05. INR, international normalized ratio. Figure 2: Waterfall plot of radiographic response of patients with neuroendocrine liver metastases undergoing (A) transarterial radioembolization (TARE) vs (B) transarterial chemoembolization (TACE). CR, complete response; PD, progressive disease; PR, partial response; RECIST, response evaluation criteria in solid tumors; SD, stable disease. Figure 3: (A) Overall survival and (B) progression-free survival of patients with neuroendocrine liver metastases undergoing transarterial chemoembolization (TACE) vs transarterial radioembolization (TARE)
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Precis:
In a multi-institutional analysis of patients with neuroendocrine liver metastases treated with liver-directed therapy, both transarterial chemoembolization and transarterial radioembolization were safe and effective. Long-term overall and progression-free survival were similar.
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S1072-7515(20)30113-7
DOI:
https://doi.org/10.1016/j.jamcollsurg.2019.12.026
Reference:
ACS 9722
To appear in:
Journal of the American College of Surgeons
Received Date: 16 December 2019 Accepted Date: 16 December 2019
Please cite this article as: Egger ME, Armstrong E, Martin II RC, Scoggins CR, Philips P, Shah M, Konda B, Dillhoff M, Pawlik TM, Cloyd JM, Transarterial Chemoembolization vs Radioembolization for Neuroendocrine Liver Metastases: A Multi-Institutional Analysis, Journal of the American College of Surgeons (2020), doi: https://doi.org/10.1016/j.jamcollsurg.2019.12.026. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc. on behalf of the American College of Surgeons.
Transarterial Chemoembolization vs Radioembolization for Neuroendocrine Liver Metastases: A Multi-Institutional Analysis Michael E Egger, MD, MPH, FACS1, Emily Armstrong, BS2, Robert CG Martin II, MD, PhD, FACS1, Charles R Scoggins, MD, MBA, FACS1, Prejesh Philips, MD, FACS1, Manisha Shah, MD3, Bhavana Konda, MD, MPH3, Mary Dillhoff, MD, FACS2, Timothy M. Pawlik, MD, MPH, PhD, FACS2, Jordan M Cloyd, MD2 1
Hiram C Polk Jr, MD Department of Surgery, University of Louisville, Louisville, KY Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 3 Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 2
Disclosure Information: Nothing to disclose. Presented at the Southern Surgical Association 131st Annual Meeting, Hot Springs, VA, December 2019. Corresponding Author: Jordan Cloyd, MD Assistant Professor of Surgery Division of Surgical Oncology The Ohio State University Wexner Medical Center 410 W 10th Ave, N-907 Doan Hall Columbus, OH 43210 Phone: 614-293-4583 Fax: 614-366-0003 Email: [email protected]
Abbreviated title: Therapy for Neuroendocrine Liver Metastases
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Background: Liver-directed hepatic arterial therapies are associated with improved survival and effective symptom control for patients with unresectable neuroendocrine liver metastases (NELM). Whether transarterial chemoembolization (TACE) or transarterial radioembolization (TARE) with yttrium-90 (y-90) are associated with improved short- or long-term outcomes is unknown.
Methods: A retrospective review of all patients with NELM at two academic medical centers undergoing transarterial therapies from 2000-2018 was performed. Postoperative morbidity, radiographic response according to RECIST criteria, and long-term outcomes were compared between patients who underwent TACE versus TARE.
Results: Among 248 patients with NELM, 197 (79%) received TACE while 51 (21%) received TARE. While patients who underwent TACE were more likely to have carcinoid syndrome, larger tumors, and have higher chromogranin A levels, there was no difference in tumor differentiation, primary site, bilobar disease, or synchronous presentation. Nearly all TARE treatments (92%) were performed as an outpatient while 99% of TACE patients spent at least one night in the hospital. There were no differences in overall morbidity (TARE 13.7% vs TACE 22.6%, p = 0.17), grade III/IV complications (5.9% vs 9.2%, p=0.58), or 90-day mortality. The disease control rate (DCR) on first post-treatment imaging (RECIST partial/complete response or stable disease) was greater for TACE compared with TARE (96% vs 83%, p<0.01). However, there was no difference in median OS (35.9 months vs 50.1 months, p=0.3) or PFS (15.9 months vs 19.9 months, p=0.37).
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Conclusions: In this retrospective multi-institutional analysis, both TACE and TARE with Y-90 were safe and effective liver-directed therapies for unresectable NELM. Although TARE was associated with a shorter length of hospital stay, TACE demonstrated improved short term DCR, and both resulted in comparable long term outcomes.
Key words: carcinoid, TACE, y-90, radioembolization, neuroendocrine liver metastases; selective internal radiation therapy
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Introduction Neuroendocrine tumors (NETs) are a diverse group of neoplasms whose clinical presentation, behavior, and prognosis are heterogeneous1. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) frequently metastasize to the liver2. In fact, 60-90% of patients with small bowel NETs will develop neuroendocrine liver metastases (NELM) during their lifetime3. The presence of NELM is not only an important negative prognostic factor but is also associated with worse quality of life (QOL) due to the frequent development of carcinoid syndrome3–5. As such, liverdirected therapies are an important component of the multidisciplinary management of patients with metastatic NETs. While surgical resection of NELMs affords the best long-term outcomes and only potential for cure6,7, only a minority of patients are candidates for surgery due to the diffuse bilobar nature of metastatic disease, prohibitive patient comorbidities, or the presence of extrahepatic disease8. For patients with advanced NELM not amenable to surgical resection, a variety of liver-directed therapies exist. Transarterial embolization (TAE)9, chemoembolization (TACE)10 or radioembolization (TARE) with yittrium-90 (y-90)11 are most commonly employed given their ability to treat multiple tumors concurrently and reproducibly12,13. The use of liver-directed intra-arterial therapies (IAT) has been associated with improved locoregional control, overall survival duration, and effective symptom control12,13. While IATs have been incorporated into consensus guidelines for the management of NELM, there has been insufficient evidence to suggest the superiority of one modality over others13–15. Few studies have directly compared the results of TAE, TACE, and TARE and most are limited by their single-institution design, small sample size, and disparate results. The purpose therefore of the 4
current study was to directly compare the outcomes of patients with NELM undergoing TACE vs TARE at two high-volume NET institutions.
Methods Study Cohort A retrospective review of all adult patients with NELM at two academic medical centers (The Ohio State University and the University of Louisville) who underwent any IAT between 20002018 were retrospectively reviewed. No additional exclusion criteria were applied. The decision to administer IAT was made after individual discussion at a multidisciplinary tumor board conference that included surgical oncologists, medical oncologists, nuclear medicine physicians, and interventional radiologists. In general, patients were selected for IAT if they had progressive liver metastases, uncontrolled symptoms, or significant tumor burden. Eligibility criteria included unresectable disease based on surgical evaluation, minimal or no extrahepatic disease, and adequate liver function and performance status to recover safely from liver-directed therapy. For patients with bilobar NELM, staged procedures approximately 4-8 weeks apart were performed. The decision to perform TACE (Ohio State) versus TARE (Louisville) was largely based on institutional preference. Variables and Outcomes Demographic and clinical information were directly abstracted from the electronic medical chart: age, patient comorbidities, primary tumor location, presentation (synchronous vs metachronous), tumor grade, prior surgery of the primary or liver metastases, prior systemic therapy, presence of
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extrahepatic disease, distribution of liver metastases (bilobar vs unilobar), and size of largest metastasis. Periprocedural information including type of IAT, extent of treatment (bilobar, lobar, selective), dose and agents used for TACE, pre- and post-treatment laboratory values, length of in-hospital stay (LOS), and the occurrence of any 30-day complication. Complications were graded according to Clavien-Dindo scale.16 The size of the largest lesion following liver-directed therapy on triple-phase computed tomography scan within six months of the index procedure was recorded. Response to TACE or TARE was calculated based on RECIST 1.1 criteria using the largest liver metastasis. In general, patients were followed every 6 months with computed tomography, tumor markers, and clinical examination. The radiographic development of a new liver or extrahepatic lesion with characteristics consistent with neuroendocrine metastasis or the interval growth of a previously treated lesion were defined as progression. Progression-free survival (PFS) and overall survival (OS) were calculated based on the date of the liver-directed therapy; patients were censored at the time of their last clinical follow-up. Intra-arterial Therapies For patients undergoing TACE, all patients were placed on continuous intravenous octreotide to prevent periprocedural carcinoid crisis. Preoperative antibiotics were usually administered. After gaining access to the femoral artery, an initial visceral angiogram was performed to detail hepatic arterial anatomy. Selective hepatic artery cannulation was performed and chemoembolic agents were administered. The chemotherapy agents utilized varied throughout the study period but most commonly included doxorubicin, mitomycin, and cisplatin. Embolic particles (typically 6
ioxaglate sodium and ethiodized oil 37%) were infused until arterial stasis was achieved. Patients were observed overnight and routinely discharged on post-procedural day 1 following 24 h of continuous octreotide infusion. For patients undergoing TARE, all patients initially underwent an outpatient mesenteric angiography to assess arterial anatomy and to determine hepatopulmonary shunting. This was performed using a 100 megabecquerel (MBq) dose of 99mTc-labeled macroaggregated albumin infused into the hepatic artery. Shunt fractions were assessed using planar scintigraphy. If shunt fractions were acceptable for TARE (<15%), the patient was scheduled for an outpatient treatment with y-90 10-14 days later. The TARE y-90 treatment consisted of percutaneous femoral artery access and visceral angiography, followed by treatment of the involved lobe with y-90, dosed according to liver volume. If bilobar disease was present, the contralateral lobe was treated in a similar fashion 4 weeks later. The delivery agent of y-90 used for nearly all of the patients undergoing TARE was Therasphere (BTG). Most patients were discharged to home on the same day of TARE. Statistical Analysis Descriptive statistics were summarized for each treatment regimen and compared. Categorical variables were compared using chi-square test or Fisher’s exact test, as appropriate. Continuous variables were compared using the nonparametric Wilcoxon rank-sum test. Missing data were excluded on a per-variable basis. Kaplan-Meier analysis was used to illustrate OS and PFS for each group. For OS, an event was considered death from any cause and patients were censored at the time of last follow-up if still alive. For PFS, an event was considered at time of documented progression or death, and patients were censored at the time of last follow-up if they
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were alive without evidence of progression. Survival was compared using the log rank test. All statistical analyses were performed using SAS 9.4 (SAS, Cary, NC). Results Among 248 patients with NELM who underwent IAT during the study period, 197 (79%) received TACE while 51 (21%) received TARE. The demographic and clinical information of all patients are reported in Table 1. The median age of the cohort was 60 years and 44.8% were male. The most common primary tumor location was small bowel (35.5%) followed by pancreas (25.0%). While there were no significant differences in primary tumor location, proportion of patients with an intact primary tumor, or tumor differentiation between patients who underwent TACE versus TARE, patients who received TACE were more likely to present with synchronous disease (85.8% vs 70.6%, p<0.05) and have carcinoid syndrome (58.4% vs 23.5%, p<0.0001). Tumor grade was higher among patients treated with TARE. While a similar proportion of patients had bilobar disease and underwent staged bilateral procedures, patients who underwent TACE had larger maximum sized liver metastases (median 4.9 cm vs 3.3 cm, p<0.001) and a higher pre-treatment chromogranin A level (1475 vs 193 ng/mL, p<0.0001). Peri-procedural outcomes of IAT are reported in Table 2. The median LOS following TARE was shorter than TACE (0 vs 1, p<0.0001). Nearly all TARE treatments (92%) were performed as an outpatient while 99% of TACE patients spent at least one night in the hospital. There were no differences in overall complications (TARE 13.7% vs TACE 22.6%, p = 0.17), grade III/IV complications (5.9% vs 9.2%, p=0.58), or 30-day mortality (2.0% vs 3.1%, p=1.0). Figure 1 shows the median percentage change in relevant laboratory values following IAT. Patients who underwent TACE experienced a significantly greater increase in their post8
procedure bilirubin (+55% vs 0%, p<0.0001) and creatinine (+12% vs -13%, p<0.0001) but a greater decrease in their median chromogranin A levels (-43% vs -16%, p=0.07) and decrease in the size of the largest liver metastasis (-19% vs -9%, p=0.05). Complete radiographic data was available for 184 patients. The disease control rate (DCR) on first post-treatment imaging (RECIST partial/complete response or stable disease) was greater for TACE compared with TARE (96% vs 83%, p=0.004). The RECIST response rates are summarized in Figure 2. Median follow-up for the entire cohort was 34 months. Comparing patients who underwent TARE vs TACE, there was no significant difference in median OS (35.9 months vs 50.1 months, p=0.3) or PFS (15.9 months vs 19.9 months, p=0.37) (Figure 3). The 5yr OS rates for patients who underwent TACE vs TARE were 42% vs 35%, respectively. In a sensitivity analysis of only patients with well-differentiated grade 1/2 tumors, median PFS (18.4 months vs 20.6 months, p=0.29) and OS (35.9 months vs 50.7 months, p=0.27) remained not significantly different. Discussion The incidence of GEP-NETs is increasing and a majority of patients will develop NELM in their lifetime. As most patients with NELM will have unresectable disease, an improved understanding of the short- and long-term outcomes of liver-directed therapies is imperative. Among IATs, TAE, TACE, and TARE have been performed for several decades largely based on institutional preference and few comparative effectiveness studies have been conducted. In the current bi-institutional analysis of TACE versus TARE, we found that both approaches resulted in safe, effective control of unresectable NELM. Both modalities were well tolerated, with no difference in peri-procedural complications between the two. Radiographic response based on the initial follow-up imaging suggested improved outcomes with TACE compared to 9
TARE but at the expense of a longer hospital length of stay. Most importantly, no differences in long-term outcomes, either PFS or OS, were observed among patients receiving TACE or TARE. Because of the hypervascular nature of NELM, there is a rational physiologic basis for the use of IAT for unresectable NELM. TACE theoretically provides two mechanisms of action against NELM; one is a simple embolization of the tumor that reduces vascularity, and a second is localized delivery of cytotoxic chemotherapy. Multiple reports of TACE for unresectable NELM have shown favorable results. Short term DCR (i.e. at least stable disease without progression) appears to be on the order of 85-95%10,17,18. The procedure is safe and welltolerated, with reported peri-procedural complication rates of approximately 10-20% and shortterm mortality rates of 2-5%10,17,19,20 Early radiographic response rates and peri-procedural morbidity and mortality of TACE reported in the current study are consistent with these previously published results, confirming the safety and efficacy of TACE for NELM. An alternative IAT for NELM is TARE, sometimes referred to as selective internal radiotherapy (SIRT). TARE is less embolic than TARE, utilizing smaller β-radiation emitting particles (y-90) that deliver high-dose, localized radiotherapy to NELM. TARE has some theoretic advantages over TACE, including the ability to diffuse into the entire hemi-liver to treat miliary disease as well as less initial liver toxicity. Short term radiographic DCR >90% have been reported in the literature11,21-23. Minor side effects that are commonly reported include fatigue and nausea, but the rate of major complications is low11,18,23,24. The low rate of complications with TARE in this study compares favorably to rates previously reported. The radiographic DCR of 83% is somewhat lower than what most studies report which may be due to the inclusion of a higher proportion of poorly differentiated tumors in the TARE group (~10%).
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The current study found that early radiographic and biochemical response seemed to favor TACE compared with TARE, but potentially at the expense of a longer hospital LOS and greater toxicity. There were statistically significant increases in bilirubin and creatinine in patients undergoing TACE compared to TARE. While this may represent an increase in serologic toxicity in TACE compared to TARE, the actual clinical relevance of these minor laboratory changes are likely minimal especially given the lack of differences in overall or major complications. Most importantly, there were no significant differences in PFS or OS between the two treatment groups. While direct comparisons of long-term efficacy should be interpreted cautiously outside of a randomized controlled trial, these findings suggest that both TACE and TARE are acceptable forms of IAT for NELM. TACE and TARE have not been directly compared in a randomized clinical trial though a few retrospective studies have been previously performed. Chen et al in a retrospective, multicenter study evaluated 155 patients with NELM treated with TACE (n=50), TARE (n=64), or TAE (n=41)25. In a propensity score matched analysis, there was no difference in PFS or OS among the three treatments. Minh et al also used a propensity score matched model to compare TACE and TARE in a retrospective study of 192 patients with NELM26. The authors reported that conventional TACE was associated with significantly improved OS and PFS compared to TACE with drug-eluting beads or TARE. When therapies are equally effective, the question of cost, convenience, and patient-reported outcomes must be considered. Each therapy has a unique cost structure and burden on the healthcare system. TACE is typically performed with an overnight hospitalization while TARE is usually an outpatient procedure. On the other hand, TARE involves an additional mapping procedure and other physician services (radiation oncology). Whitney et al performed a 11
multicenter, international evaluation of TACE and TARE for NELM27. In this study, both TARE and TACE appeared to be equally effective, but TARE was associated with nearly twice the cost of TACE. An important limitation of the current study is the lack of data on healthcare associated costs as well as QOL scores between the two groups. As healthcare systems continue to prioritize value and patient-centered outcomes, a more thorough analysis of costs and QOL outcomes will be required. In evaluating the results of this study, several limitations should be acknowledged. This is a retrospective analysis and treatment decisions were not made randomly. Indeed, differences in several clinical and pathologic factors between the TARE and TACE groups were observed. Furthermore, while the bi-institutional nature of the study is regarded as a strength in terms of generalizability, the evaluation, periprocedural management, and follow-up, including timing of imaging and laboratory tests, of patients were not standardized across the institutions. As a result, some laboratory and imaging data were missing. For radiographic response, RECIST criteria were used though modified RECIST criteria, which takes into account the degree of arterial enhancement, may provide a more accurate assessment of response to therapy given the highly vascular nature of NELM. In addition, radiographic response was measured at one early time point; given that additional downstaging may occur over time, the current study may underestimate the true RECIST response rates, particularly in the TARE group. Also, the number of patients in the TARE cohort was relatively small and may have limited the power to detect significant differences. Finally, the current study focused on short-term toxicities and long-term survival outcomes. In addition to costs and QOL measures, late-term toxicities were not reported. Given the increased awareness of late-onset hepatoxicitiy following TARE28,29, this should be included in future comparative analyses. 12
Conclusions In conclusion, both TACE and TARE with y-90 are safe and effective liver-directed therapies for unresectable NELM. Although TARE was associated with a shorter length of hospital stay, TACE demonstrated improved short term DCR, and both resulted in comparable long-term outcomes. Given the heterogeneity of GEP-NETs and the emergence of novel systemic therapies, future prospective comparative effectiveness trials are needed to identify the optimal indications for these liver-directed therapies. Author Contribution: M Egger, E Armstrong, RCG Martin, C Scoggins, P Philips, K McMasters, M Shah, B Konda, A Ejaz, A Tsung, M Dillhoff, TM Pawlik and J. M. Cloyd have contributed to the design, analysis, interpretation of data, and drafting of the manuscript. All authors have approved the final version of the manuscript and are accountable for all aspects of the work. The authors have no conflicts of interest or financial ties to disclose.
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Table 1: Clinical Characteristics of Patients with Neuroendocrine Liver Metastases Undergoing Transarterial Radioembolization and Transarterial Chemoembolization Characteristic TARE (n=51) TACE (n=197) p Value Demographic Sex, male, n (%) 19 (37.3) 92 (46.7) 0.23 Age, y, median 60 (56, 70) 60 (51, 67) 0.052 (IQR) BMI, kg/m2, 25.7 (21.3, 29.9) 27.5 (23.6, 32.5) 0.021 median (IQR) Clinical Primary site, n (%) 0.15 Unknown 8 (15.7) 54 (27.4) Pancreas 16 (31.4) 46 (23.4) Colon/appendix 3 (5.9) 10 (5.1) Small bowel 19 (37.3) 69 (35.0) Rectum 0 (0) 3 (1.5) Stomach 3 (5.9) 3 (1.5) Lung 2 (3.9) 12 (6.1) Primary intact, n 26 (52.0) 94 (48.5) 0.65 (%) Synchronous 36 (70.6) 169 (85.8) 0.0106 metastatic disease, n (%) Carcinoid 12 (23.5) 115 (58.4) <0.0001 symptoms, n (%) Differentiation, n (%) Well46 (90.2) 191 (97.0) 0.052 differentiated Poor 5 (9.8) 6 (3.0) Grade, n (%) 0.0124 1 20 (60.6) 139 (75.5) 2 8 (24.2) 39 (21.1) 3 5 (15.2) 6 (3.3) Size of largest 3.3 (2.2, 5.3) 4.9 (3.5. 7.0) 0.0013 lesion, cm, median (IQR) Pretreatment 193 (93, 1645) 1475 (298, 6500) 0.0001 chromogranin A (ng/mL), median (IQR) Staged bilateral 28 (58.3) 110 (57.6) 0.92 treatment, n (%) IQR, interquartile range; TACE, transarterial chemoembolization; TARE, transarterial radioembolization 19
Table 2: Periprocedural Outcomes after Transarterial Chemoembolization vs Transarterial Radioembolization among Patients with Neuroendocrine Liver Metastases Outcome TARE (n=51) TACE (n=197) p Value Length of stay, d, median 0 (0, 0) 1 (1,1) <0.0001 (IQR) Any complication, n (%) 7 (13.7) 44 (22.6) 0.17 Major complication, n (%) 3 (5.9) 18 (9.2) 0.58 30-day mortality, n (%) 1 (2.0) 6 (3.1) 1.0 90-day mortality, n (%) 5 (9.8) 10 (5.2) 0.21 Laboratory, median (IQR) Bilirubin change, 0 (-0.3, +0.1) +0.4 (+0.1, +0.8) <0.0001 mg/dL Platelet change, 103/µL -29 (-78, +19) -42 (-82, -4) 0.31 INR change +0.1 (-0.1, +0.3) +0.2 (+0.1, +0.3) 0.07 Creatinine change, -0.1 (-0.2, 0) +0.1 (0, +0.2) <0.0001 mg/dL % chromogranin -16 (-64, +49) -43 (-77, -4) 0.07 change Radiographic % change in size, -9 (0, -27) -19 (-6, -34) 0.051 median (IQR) RECIST response, n 0.0002 (%) Complete response 2 (4.4) 5 (3.6) Partial response 9 (19.6) 37 (26.6) Stable disease 27 (58.7) 92 (66.2) Progressive disease 8 (17.4) 5 (3.6) IQR, interquartile range; INR, international normalized ratio; TACE, transarterial chemoembolization; TARE, transarterial radioembolization; RECIST, response evaluation criteria in solid tumors.
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Figure Legends Figure 1: Median percentage relative change in relevant laboratory values after transarterial chemoembolization (TACE) vs transarterial radioembolization (TARE), error bars denote interquartile range (IQR). * p<0.05. INR, international normalized ratio. Figure 2: Waterfall plot of radiographic response of patients with neuroendocrine liver metastases undergoing (A) transarterial radioembolization (TARE) vs (B) transarterial chemoembolization (TACE). CR, complete response; PD, progressive disease; PR, partial response; RECIST, response evaluation criteria in solid tumors; SD, stable disease. Figure 3: (A) Overall survival and (B) progression-free survival of patients with neuroendocrine liver metastases undergoing transarterial chemoembolization (TACE) vs transarterial radioembolization (TARE)
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Precis:
In a multi-institutional analysis of patients with neuroendocrine liver metastases treated with liver-directed therapy, both transarterial chemoembolization and transarterial radioembolization were safe and effective. Long-term overall and progression-free survival were similar.
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