Multimodal CEA-targeted fluorescence and radioguided cytoreductive surgery for peritoneal metastases of colorectal origin
Jan Marie de Gooyer, Fortuné M K Elekonawo, Andreas J A Bremers, Otto C Boerman, Erik H J G Aarntzen, Philip R de Reuver, Iris D Nagtegaal, Mark Rijpkema, Johannes H W de Wilt, Jan Marie de Gooyer, Fortuné M K Elekonawo, Andreas J A Bremers, Otto C Boerman, Erik H J G Aarntzen, Philip R de Reuver, Iris D Nagtegaal, Mark Rijpkema, Johannes H W de Wilt
Abstract
In patients with colorectal peritoneal metastases scheduled for cytoreductive surgery, accurate preoperative estimation of tumor burden and subsequent intraoperative detection of all tumor deposits remains challenging. In this study (ClinicalTrials.gov NCT03699332) we describe the results of a phase I clinical trial evaluating [111In]In-DOTA-labetuzumab-IRDye800CW, a dual-labeled anti-carcinoembryonic antigen (anti-CEA) antibody conjugate that enables both preoperative imaging and intraoperative radioguidance and fluorescence imaging. Primary study outcomes are safety and feasibility of this multimodal imaging approach. Secondary outcomes are determination of the optimal dose, correlation between tracer uptake and histopathology and effects on clinical strategy. Administration of [111In]In-DOTA-labetuzumab-IRDye800CW is well-tolerated and enables sensitive pre- and intraoperative imaging in patients who receive 10 or 50 mg of the tracer. Preoperative imaging revealed previously undetected lymph node metastases in one patient, and intraoperative fluorescence imaging revealed four previously undetected metastases in two patients. Alteration of clinical strategy based on multimodal imaging occurred in three patients. Thus, multimodal image-guided surgery after administration of this dual-labeled tracer is a promising approach that may aid in decision making before and during cytoreductive surgical procedures.
Conflict of interest statement
The authors declare no competing interests
© 2022. The Author(s).
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References
- Segelman J, et al. Incidence, prevalence and risk factors for peritoneal carcinomatosis from colorectal cancer. Br. J. Surg. 2012;99:699–705. doi: 10.1002/bjs.8679.
- Verwaal VJ, Bruin S, Boot H, van Slooten G, van Tinteren H. 8-year follow-up of randomized trial: cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy in patients with peritoneal carcinomatosis of colorectal cancer. Ann. Surg. Oncol. 2008;15:2426–2432. doi: 10.1245/s10434-008-9966-2.
- Hallam S, Tyler R, Price M, Beggs A, Youssef H. Meta-analysis of prognostic factors for patients with colorectal peritoneal metastasis undergoing cytoreductive surgery and heated intraperitoneal chemotherapy. BJS Open. 2019;3:585–594. doi: 10.1002/bjs5.50179.
- Quénet F, et al. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22:256–266. doi: 10.1016/S1470-2045(20)30599-4.
- Jacquet P, Sugarbaker PH. Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis. Cancer Treat. Res. 1996;82:359–374. doi: 10.1007/978-1-4613-1247-5_23.
- Elias D, et al. Peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy: retrospective analysis of 523 patients from a multicentric French study. J. Clin. Oncol.: Off. J. Am. Soc. Clin. Oncol. 2010;28:63–68. doi: 10.1200/JCO.2009.23.9285.
- Elekonawo FMK, et al. Can [(18)F]F-FDG PET/CT be used to assess the pre-operative extent of peritoneal carcinomatosis in patients with colorectal cancer? Abdom. Radio. 2020;45:301–306. doi: 10.1007/s00261-019-02268-w.
- Koh JL, Yan TD, Glenn D, Morris DL. Evaluation of preoperative computed tomography in estimating peritoneal cancer index in colorectal peritoneal carcinomatosis. Ann. Surgical Oncol. 2009;16:327–333. doi: 10.1245/s10434-008-0234-2.
- Iversen LH, Rasmussen PC, Laurberg S. Value of laparoscopy before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis. Br. J. Surg. 2013;100:285–292. doi: 10.1002/bjs.8908.
- Pomel C, Appleyard TL, Gouy S, Rouzier R, Elias D. The role of laparoscopy to evaluate candidates for complete cytoreduction of peritoneal carcinomatosis and hyperthermic intraperitoneal chemotherapy. Eur. J. Surgical Oncol.: J. Eur. Soc. Surgical Oncol. Br. Assoc. Surgical Oncol. 2005;31:540–543. doi: 10.1016/j.ejso.2005.01.009.
- Marmor RA, Kelly KJ, Lowy AM, Baumgartner JM. Laparoscopy is safe and accurate to evaluate peritoneal surface metastasis prior to cytoreductive surgery. Ann. Surgical Oncol. 2016;23:1461–1467. doi: 10.1245/s10434-015-4958-5.
- van Oudheusden TR, et al. Peritoneal cancer patients not suitable for cytoreductive surgery and HIPEC during explorative surgery: risk factors, treatment options, and prognosis. Ann. Surgical Oncol. 2015;22:1236–1242. doi: 10.1245/s10434-014-4148-x.
- Hentzen, J. et al. Diagnostic laparoscopy as a selection tool for patients with colorectal peritoneal metastases to prevent a non-therapeutic laparotomy during cytoreductive surgery. Ann. Surgical Oncol.10.1245/s10434-019-07957-w (2019).
- Hekman MC, et al. Tumor-targeted dual-modality imaging to improve intraoperative visualization of clear cell renal cell carcinoma: a first in man study. Theranostics. 2018;8:2161–2170. doi: 10.7150/thno.23335.
- van Dam GM, et al. Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-alpha targeting: first in-human results. Nat. Med. 2011;17:1315–1319. doi: 10.1038/nm.2472.
- Boogerd, L. S. F. et al. Safety and effectiveness of SGM-101, a fluorescent antibody targeting carcinoembryonic antigen, for intraoperative detection of colorectal cancer: a dose-escalation pilot study. Lancet10.1016/s2468-1253(17)30395-3 (2018).
- Harlaar NJ, et al. Molecular fluorescence-guided surgery of peritoneal carcinomatosis of colorectal origin: a single-centre feasibility study. Lancet Gastroenterol. Hepatol. 2016;1:283–290. doi: 10.1016/S2468-1253(16)30082-6.
- Tiernan JP, et al. Carcinoembryonic antigen is the preferred biomarker for in vivo colorectal cancer targeting. Br. J. cancer. 2013;108:662–667. doi: 10.1038/bjc.2012.605.
- Hoogstins CE, et al. In search for optimal targets for intraoperative fluorescence imaging of peritoneal metastasis from colorectal cancer. Biomark. Cancer. 2017;9:1179299x17728254. doi: 10.1177/1179299X17728254.
- Boonstra MC, et al. Selecting targets for tumor imaging: an overview of cancer-associated membrane proteins. Biomark. Cancer. 2016;8:119–133. doi: 10.4137/BIC.S38542.
- Dotan E, et al. Phase I/II trial of labetuzumab govitecan (anti-CEACAM5/SN-38 antibody-drug conjugate) in patients with refractory or relapsing metastatic colorectal cancer. J. Clin. Oncol.: Off. J. Am. Soc. Clin. Oncol. 2017;35:3338–3346. doi: 10.1200/JCO.2017.73.9011.
- Hajjar G, et al. Phase I radioimmunotherapy trial with iodine-131—labeled humanized MN-14 anti-carcinoembryonic antigen monoclonal antibody in patients with metastatic gastrointestinal and colorectal cancer. Clin. Colorectal Cancer. 2002;2:31–42. doi: 10.3816/CCC.2002.n.009.
- Rijpkema M, et al. SPECT- and fluorescence image-guided surgery using a dual-labeled carcinoembryonic antigen-targeting antibody. J. Nucl. Med.: Off. Publ., Soc. Nucl. Med. 2014;55:1519–1524. doi: 10.2967/jnumed.114.142141.
- Elekonawo FMK, et al. Ex vivo assessment of tumor-targeting fluorescent tracers for image-guided surgery. Cancers. 2020;12:987. doi: 10.3390/cancers12040987.
- ICRP. ICRP, 1992. Radiological Protection in Biomedical Research. ICRP Publication 62. Ann. ICRP 22 (1992).
- Boogerd LS, et al. Biomarker expression in rectal cancer tissue before and after neoadjuvant therapy. Onco Targets Ther. 2018;11:1655–1664. doi: 10.2147/OTT.S145473.
- de Gouw, D. et al. Identifying biomarkers in lymph node metastases of esophageal adenocarcinoma for tumor-targeted imaging. Mol. Diagn. Ther. 10.1007/s40291-020-00448-9 (2020).
- Brouwer NPM, et al. Clinical lymph node staging in colorectal cancer; a flip of the coin? Eur. J. Surgical Oncol.: J. Eur. Soc. Surgical Oncol. Br. Assoc. Surgical Oncol. 2018;44:1241–1246. doi: 10.1016/j.ejso.2018.04.008.
- Kawai K, et al. Prediction of pathological complete response using endoscopic findings and outcomes of patients who underwent watchful waiting after chemoradiotherapy for rectal cancer. Dis. Colon Rectum. 2017;60:368–375. doi: 10.1097/DCR.0000000000000742.
- Kuijpers AM, et al. Implementation of a standardized HIPEC protocol improves outcome for peritoneal malignancy. World J. Surg. 2015;39:453–460. doi: 10.1007/s00268-014-2801-y.
- de Boer, N. L. et al. The accuracy of the surgical peritoneal cancer index in patients with peritoneal metastases of colorectal Cancer. Dig Surg. 1–7,10.1159/000513353 (2021).
- Lu G, et al. Co-administered antibody improves penetration of antibody-dye conjugate into human cancers with implications for antibody-drug conjugates. Nat. Commun. 2020;11:5667. doi: 10.1038/s41467-020-19498-y.
- Marshall MV, Draney D, Sevick-Muraca EM, Olive DM. Single-dose intravenous toxicity study of IRDye 800CW in Sprague-Dawley rats. Mol. Imaging Biol.: MIB: Off. Publ. Acad. Mol. Imaging. 2010;12:583–594. doi: 10.1007/s11307-010-0317-x.
- EMA. the EMA directives in: Radiopharmaceuticals based on Monoclonal Antibodies Directives 65/65/EEC, 75/318/EEC as amended, Directive 89/343/EEC, 3AQ21A).
- Linssen MD, et al. Roadmap for the development and clinical translation of optical tracers cetuximab-800CW and trastuzumab-800CW. J. Nucl. Med.: Off. Publ., Soc. Nucl. Med. 2019;60:418–423. doi: 10.2967/jnumed.118.216556.
- van Eden WJ, et al. Treatment of isolated peritoneal recurrences in patients with colorectal peritoneal metastases previously treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Ann. Surg. Oncol. 2018;25:1992–2001. doi: 10.1245/s10434-018-6423-8.
- Schindelin J, et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods. 2012;9:676–682. doi: 10.1038/nmeth.2019.
- Castor, E. D. C. Castor Electronic Data Capture, <> (2019).
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