TY - JOUR
T1 - Representativeness of the Index Lymph Node for Total Nodal Basin in Pathologic Response Assessment after Neoadjuvant Checkpoint Inhibitor Therapy in Patients with Stage III Melanoma
AU - Reijers, Irene L. M.
AU - Rawson, Robert V.
AU - Colebatch, Andrew J.
AU - Rozeman, Elisa A.
AU - Menzies, Alex M.
AU - van Akkooi, Alexander C. J.
AU - Shannon, Kerwin F.
AU - Wouters, Michel W.
AU - Saw, Robyn P. M.
AU - van Houdt, Winan J.
AU - Zuur, Charlotte L.
AU - Nieweg, Omgo E.
AU - Ch'Ng, Sydney
AU - Klop, W. Martin C.
AU - Spillane, Andrew J.
AU - Long, Georgina V.
AU - Scolyer, Richard A.
AU - van de Wiel, Bart A.
AU - Blank, Christian U.
N1 - Funding Information:
Funding/Support: This work was supported by a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1093017) (to Drs Scolyer and Long). Dr Scolyer is supported by a National Health and Medical Research Council of Australia (NHMRC) Program Grant and Practitioner Fellowship (APP1141295). Support from Deborah McMurtrie and John McMurtrie AM, The CLEARbridge Foundation, The Cameron Family, as well as from colleagues at Melanoma Institute Australia and Royal Prince Alfred Hospital is also gratefully acknowledged. Dr Menzies is supported by Nicholas and Helen Moore and Melanoma Institute Australia. Dr Saw is supported by Melanoma Institute Australia.
Funding Information:
reported receiving personal fees from the Bristol-Myers Squibb (BMS) advisory board, personal fees from Merck Sharp & Dohme (MSD) advisory board, from Novartis advisory board, from Roche advisory board, from Pierre-Fabre advisory board, and from Qbiotics advisory board outside the submitted work. Dr van Akkooi reported receiving advisory board and consulting honoraria grants from Amgen, from BMS, from Novartis, from MSD-Merck, from Merck-Pfizer, from Pierre Fabre, from Sanofi, from Sirius Medical, and from 4SC outside the submitted work. Dr Saw reported receiving personal fees for advisory board participation and speaking honoraria from Novartis, from MSD, from Qbiotics, and speaking honoraria from BMS outside the submitted work. Dr van Houdt reported receiving personal fees from Amgen, from Sanofi, from Belpharma, from MSD, and from Novartis outside the submitted work. Dr Long reported receiving personal fees as consultant advisor from Aduro Biotech Inc, from Amgen Inc, from Array Biopharma Inc, from Boehringer Ingelheim International GmbH, from BMS, from Evaxion Biotech A/S, from Hexal AG, from Highlight Therapeutics S.L, from MSD, from Novartis Pharma AG, from OncoSec, from Pierre Fabre, from QBiotics Group Limited, from Regeneron Pharmaceuticals Inc, from SkylineDX BV, and from Specialised Therapeutics Australia Pty Ltd outside the submitted work. Dr Scolyer reported receiving grants from National Health and Medical Research Council of Australia Program and from National Health and Medical Research Council of Australia Fellowship during the conduct of the study; personal fees from Evaxion, from Provectus Biopharmaceuticals Australia, from Qbiotics, from Novartis, from Merck Sharp & Dohme, from NeraCare, from AMGEN Inc, from BMS, from Myriad Genetics, and from GlaxoSmithKline outside the submitted work. Dr Blank reported receiving grants from an advisory role for BMS, MSD, Roche, Novartis, GlaxoSmithKline, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures and receiving research funding: BMS, Novartis, and NanoString; having stock ownership in 4SC; being a cofounder of Immagene BV; all grants and funding were paid to the institute, except for the funding from Third Rock Ventures and Immagene. No other disclosures were reported.
Funding Information:
Additional Contributions: We thank all patients and their families for participation in the clinical trials and the participating study teams in the Netherlands Cancer Institute, Melanoma Institute Australia, and Karolinska Institute. Financial support for the conduct of the OpACIN and OpACIN-neo studies was provided by BMS. The authors gratefully acknowledge the support of colleagues at the pathology departments of the Netherlands Cancer Institute and Melanoma Institute Australia.
Publisher Copyright:
© 2022 American Medical Association. All rights reserved.
PY - 2022/4
Y1 - 2022/4
N2 - Importance: Neoadjuvant checkpoint inhibition in patients with high-risk stage III melanoma shows high pathologic response rates associated with a durable relapse-free survival. Whether a therapeutic lymph node dissection (TLND) can be safely omitted when a major pathologic response in the largest lymph node metastasis at baseline (index lymph node; ILN) is obtained is currently being investigated. A previous small pilot study (n = 12) showed that the response in the ILN may be representative of the pathologic response in the entire TLND specimen. Objective: To assess the concordance of response between the ILN and the total lymph node bed in a larger clinical trial population. Design, Setting, and Participants: Retrospective pathologic response analysis of a multicenter clinical trial population of patients from the randomized Study to Identify the Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab in Melanoma Patients (OpACIN) and Optimal Neo-Adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) trials. Included patients were treated with 6 weeks neoadjuvant ipilimumab plus nivolumab. Patient inclusion into the trials was conducted from August 12, 2015, to October 24, 2016 (OpACIN), and November 24, 2016, and June 28, 2018 (OpACIN-neo). Data were analyzed from April 1, 2020, to August 31, 2021. Main Outcomes and Measures: Concordance of the pathologic response between the ILN and the TLND tumor bed. The pathologic response of the ILN was retrospectively assessed according to the International Neoadjuvant Melanoma Consortium criteria and compared with the pathologic response of the entire TLND specimen. Results: A total of 82 patients treated with neoadjuvant ipilimumab and nivolumab followed by TLND (48 [59%] were male; median age, 58.5 [range, 18-80] years) were included. The pathologic response in the ILN was concordant with the entire TLND specimen response in 81 of 82 patients (99%) and in 79 of 82 patients (96%) concordant when comparing the ILN response with the response in every individual lymph node. In the single patient with a discordant response, the ILN response (20% viable tumor, partial pathologic response) underestimated the entire TLND specimen response (5% viable, near-complete pathologic response). Two other patients each had 1 small nonindex node that contained 80% viable tumor (pathologic nonresponse) whereas all other lymph nodes (including the ILN) showed a partial pathologic response. In these 2 patients, the risk of regional relapse might potentially have been increased if TLND had been omitted. Conclusions and Relevance: The results of this study suggest that the pathologic response of the ILN may be considered a reliable indicator of the entire TLND specimen response and may support the ILN response-directed omission of TLND in a prospective trial.
AB - Importance: Neoadjuvant checkpoint inhibition in patients with high-risk stage III melanoma shows high pathologic response rates associated with a durable relapse-free survival. Whether a therapeutic lymph node dissection (TLND) can be safely omitted when a major pathologic response in the largest lymph node metastasis at baseline (index lymph node; ILN) is obtained is currently being investigated. A previous small pilot study (n = 12) showed that the response in the ILN may be representative of the pathologic response in the entire TLND specimen. Objective: To assess the concordance of response between the ILN and the total lymph node bed in a larger clinical trial population. Design, Setting, and Participants: Retrospective pathologic response analysis of a multicenter clinical trial population of patients from the randomized Study to Identify the Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab in Melanoma Patients (OpACIN) and Optimal Neo-Adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) trials. Included patients were treated with 6 weeks neoadjuvant ipilimumab plus nivolumab. Patient inclusion into the trials was conducted from August 12, 2015, to October 24, 2016 (OpACIN), and November 24, 2016, and June 28, 2018 (OpACIN-neo). Data were analyzed from April 1, 2020, to August 31, 2021. Main Outcomes and Measures: Concordance of the pathologic response between the ILN and the TLND tumor bed. The pathologic response of the ILN was retrospectively assessed according to the International Neoadjuvant Melanoma Consortium criteria and compared with the pathologic response of the entire TLND specimen. Results: A total of 82 patients treated with neoadjuvant ipilimumab and nivolumab followed by TLND (48 [59%] were male; median age, 58.5 [range, 18-80] years) were included. The pathologic response in the ILN was concordant with the entire TLND specimen response in 81 of 82 patients (99%) and in 79 of 82 patients (96%) concordant when comparing the ILN response with the response in every individual lymph node. In the single patient with a discordant response, the ILN response (20% viable tumor, partial pathologic response) underestimated the entire TLND specimen response (5% viable, near-complete pathologic response). Two other patients each had 1 small nonindex node that contained 80% viable tumor (pathologic nonresponse) whereas all other lymph nodes (including the ILN) showed a partial pathologic response. In these 2 patients, the risk of regional relapse might potentially have been increased if TLND had been omitted. Conclusions and Relevance: The results of this study suggest that the pathologic response of the ILN may be considered a reliable indicator of the entire TLND specimen response and may support the ILN response-directed omission of TLND in a prospective trial.
UR - https://www.scopus.com/pages/publications/85125073765
U2 - 10.1001/jamasurg.2021.7554
DO - 10.1001/jamasurg.2021.7554
M3 - Article
C2 - 35138335
SN - 2168-6254
VL - 157
SP - 335
EP - 342
JO - JAMA surgery
JF - JAMA surgery
IS - 4
ER -
SDG 3 Good Health and Well-being