To identify the optimal dosing strategy for fluorescence-guided surgery in patients with head and neck squamous cell carcinoma, we conducted a dose-ranging study evaluating the anti-epidermal growth factor receptor (EGFR) therapeutic antibody, panitumumab, that was fluorescently labeled with the near-infrared dye IRDye800CW.
Patients (n = 24) received either 0.5 or 1.0 mg/kg panitumumab-IRDye800CW in the weight-based dosing group or 25 or 50 mg panitumumab-IRDye800CW in the fixed dosing group. Following surgery, whole primary specimens were imaged in a closed-field device and the mean fluorescence intensity (MFI) and tumor-to-background ratio (TBR) were assessed. Clinical variables, including dose, time of infusion-to-surgery, age, unlabeled dose, gender, primary tumor site, and tumor size, were analyzed to evaluate the factors affecting the fluorescence intensity in order to identify the optimal dose for intraoperative fluorescence imaging.
A total of 24 primary tumor specimens were imaged and analyzed in this study. Although no correlations between TBR and dose of panitumumab-IRDye800CW were found, there were moderate–strong correlations between the primary tumor MFI and panitumumab-IRDye800CW dose for fixed dose (mg) (R2 = 0.42) and for dose/weight (mg/kg) (R2 = 0.54). Results indicated that the optimal MFI was at approximately 50 mg for fixed dose and 0.75 mg/kg for dose/weight. No significant differences were found for the primary tumor MFI and TBRs between the weight-based dosing and the fixed dosing groups. MFIs significantly increased when the infusion-to-surgery window was reduced to within 2 days (vs. 3 days or more, p < 0.05).
Antibody-based imaging for surgical resection is under investigation in multiple clinical trials. Our data suggests that a fixed dose of 50 mg is an appropriate diagnostic dose for successful surgical fluorescence imaging.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90
Eldeeb H, Macmillan C, Elwell C, Hammod A (2012) The effect of the surgical margins on the outcome of patients with head and neck squamous cell carcinoma: single institution experience. Cancer Biol Med 9:29–33
Ettl T, El-Gindi A, Hautmann M et al (2016) Positive frozen section margins predict local recurrence in R0-resected squamous cell carcinoma of the head and neck. Oral Oncol 55:17–23
McMahon J, O’Brien C, Pathak I et al (2003) Influence of condition of surgical margins on local recurrence and disease-specific survival in oral and oropharyngeal cancer. Br J Oral Maxillofac Surg 41:224–231
Gao RW, Teraphongphom NT, van den Berg NS, Martin BA, Oberhelman NJ, Divi V, Kaplan MJ, Hong SS, Lu G, Ertsey R, Tummers WSFJ, Gomez AJ, Holsinger FC, Kong CS, Colevas AD, Warram JM, Rosenthal EL (2018) Determination of tumor margins with surgical specimen mapping using near-infrared fluorescence. Cancer Res 78:5144–5154
Gao RW, Teraphongphom N, de Boer E, Berg NS, Divi V, Kaplan MJ, Oberhelman NJ, Hong SS, Capes E, Colevas AD, Warram JM, Rosenthal EL (2018) Safety of panitumumab-IRDye800CW and cetuximab-IRDye800CW for fluorescence-guided surgical navigation in head and neck cancers. Theranostic 8:2488–2495
van Keulen S, van den Berg NS, Nishio N, Birkeland A, Zhou Q, Lu G, Wang HW, Middendorf L, Forouzanfar T, Martin BA, Colevas AD, Rosenthal EL (2019) Rapid, non-invasive fluorescence margin assessment: optical specimen mapping in oral squamous cell carcinoma. Oral Oncol 88:58–65
Moore LS, Rosenthal EL, Chung TK, de Boer E, Patel N, Prince AC, Korb ML, Walsh EM, Young ES, Stevens TM, Withrow KP, Morlandt AB, Richman JS, Carroll WR, Zinn KR, Warram JM (2017) Characterizing the utility and limitations of repurposing an open-field optical imaging device for fluorescence-guided surgery in head and neck cancer patients. J Nucl Med 58:246–251
Rosenthal EL, Warram JM, de Boer E, Chung TK, Korb ML, Brandwein-Gensler M, Strong TV, Schmalbach CE, Morlandt AB, Agarwal G, Hartman YE, Carroll WR, Richman JS, Clemons LK, Nabell LM, Zinn KR (2015) Safety and tumor specificity of cetuximab-IRDye800 for surgical navigation in head and neck cancer. Clin Cancer Res 21:3658–3666
Tummers WS, Miller SE, Teraphongphom NT, Gomez A, Steinberg I, Huland DM, Hong S, Kothapalli SR, Hasan A, Ertsey R, Bonsing BA, Vahrmeijer AL, Swijnenburg RJ, Longacre TA, Fisher GA, Gambhir SS, Poultsides GA, Rosenthal EL (2018) Intraoperative pancreatic cancer detection using tumor-specific multimodality molecular imaging. Ann Surg Oncol 25:1880–1888
Miller SE, Tummers WS, Teraphongphom N, van den Berg NS, Hasan A, Ertsey RD, Nagpal S, Recht LD, Plowey ED, Vogel H, Harsh GR, Grant GA, Li GH, Rosenthal EL (2018) First-in-human intraoperative near-infrared fluorescence imaging of glioblastoma using cetuximab-IRDye800. J Neuro-Oncol 139:135–143
Hoogstins CE, Tummers QR, Gaarenstroom KN et al (2016) A novel tumor-specific agent for intraoperative near-infrared fluorescence imaging: a translational study in healthy volunteers and patients with ovarian cancer. Clin Cancer Res 22:2929–2938
Lamberts LE, Koch M, de Jong JS, Adams ALL, Glatz J, Kranendonk MEG, Terwisscha van Scheltinga AGT, Jansen L, de Vries J, Lub-de Hooge MN, Schröder CP, Jorritsma-Smit A, Linssen MD, de Boer E, van der Vegt B, Nagengast WB, Elias SG, Oliveira S, Witkamp AJ, Mali WPTM, van der Wall E, van Diest PJ, de Vries EGE, Ntziachristos V, van Dam GM (2017) Tumor-specific uptake of fluorescent bevacizumab–IRDye800CW microdosing in patients with primary breast cancer: a phase I feasibility study. Clin Cancer Res 23:2730–2741
Nagengast WB, Hartmans E, Garcia-Allende PB, Peters FTM, Linssen MD, Koch M, Koller M, Tjalma JJJ, Karrenbeld A, Jorritsma-Smit A, Kleibeuker JH, van Dam GM, Ntziachristos V (2017) Near-infrared fluorescence molecular endoscopy detects dysplastic oesophageal lesions using topical and systemic tracer of vascular endothelial growth factor A. Gut 68:7–10. https://doi.org/10.1136/gutjnl-2017-314953
van Oosten M, Crane LM, Bart J, van Leeuwen FW, van Dam GM (2011) Selecting potential targetable biomarkers for imaging purposes in colorectal cancer using TArget Selection Criteria (TASC): a novel target identification tool. Transl Oncol 4:71–82
Hoogstins CES, Boogerd LSF, Sibinga Mulder BG, Mieog JSD, Swijnenburg RJ, van de Velde CJH, Farina Sarasqueta A, Bonsing BA, Framery B, Pèlegrin A, Gutowski M, Cailler F, Burggraaf J, Vahrmeijer AL (2018) Image-guided surgery in patients with pancreatic cancer: first results of a clinical trial using SGM-101, a novel carcinoembryonic antigen-targeting, near-infrared fluorescent agent. Ann Surg Oncol 25:3350–3357
Koller M, Qiu SQ, Linssen MD et al (2018) Implementation and benchmarking of a novel analytical framework to clinically evaluate tumor-specific fluorescent tracers. Nat Commun 9:3739
Grandis JR, Tweardy DJ (1993) Elevated levels of transforming growth factor a and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res 53:3579–3584
Hekman MC, Boerman OC, de Weijert M et al (2016) Targeted dual-modality imaging in renal cell carcinoma: an ex vivo kidney perfusion study. Clin Cancer Res 22:4634–4642
Boogerd LSF, Hoogstins CES, Schaap DP, Kusters M, Handgraaf HJM, van der Valk MJM, Hilling DE, Holman FA, Peeters KCMJ, Mieog JSD, van de Velde CJH, Farina-Sarasqueta A, van Lijnschoten I, Framery B, Pèlegrin A, Gutowski M, Nienhuijs SW, de Hingh IHJT, Nieuwenhuijzen GAP, Rutten HJT, Cailler F, Burggraaf J, Vahrmeijer AL (2018) Safety and effectiveness of SGM-101, a fluorescent antibody targeting carcinoembryonic antigen, for intraoperative detection of colorectal cancer: a dose-escalation pilot study. Lancet Gastroenterol Hepatol 3:181–191
Rosenthal EL, Warram JM, de Boer E, Basilion JP, Biel MA, Bogyo M, Bouvet M, Brigman BE, Colson YL, DeMeester SR, Gurtner GC, Ishizawa T, Jacobs PM, Keereweer S, Liao JC, Nguyen QT, Olson JM, Paulsen KD, Rieves D, Sumer BD, Tweedle MF, Vahrmeijer AL, Weichert JP, Wilson BC, Zenn MR, Zinn KR, van Dam GM (2016) Successful translation of fluorescence navigation during oncologic surgery: a consensus report. J Nucl Med 57:144–150
Tummers WS, Warram JM, Tipirneni KE, Fengler J, Jacobs P, Shankar L, Henderson L, Ballard B, Pfefer TJ, Pogue BW, Weichert JP, Bouvet M, Sorger J, Contag CH, Frangioni JV, Tweedle MF, Basilion JP, Gambhir SS, Rosenthal EL (2017) Regulatory aspects of optical methods and exogenous targets for cancer detection. Cancer Res 77:2197–2206
Hendrikx JJMA, Haanen JBAG, Voest EE, Schellens JHM, Huitema ADR, Beijnen JH (2017) Fixed dosing of monoclonal antibodies in oncology. Oncologist 22:1212–1221
Wang DD, Zhang S, Zhao H, Men AY, Parivar K (2009) Fixed dosing versus body size-based dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol 49:1012–1024
Mathijssen RH, de Jong FA, Loos WJ, van der Bol JM, Verweij J, Sparreboom A (2007) Flat-fixed dosing versus body surface area based dosing of anticancer drugs in adults: does it make a difference? Oncologist 12:913–923
Pouliquen AL, Escalup L, Jourdan N, Cottu P, Faure P, Madelaine-Chambrin I (2011) Dose standardisation of anticancer drugs. Int J Clin Pharm 33:221–228
Boogerd LSF, Hoogstins CES, Gaarenstroom KN et al (2017) Folate receptor-α targeted near-infrared fluorescence imaging in high-risk endometrial cancer patients: a tissue microarray and clinical feasibility study. Oncotarget 9:791–801
Harlaar NJ, Koller M, de Jongh SJ, van Leeuwen BL, Hemmer PH, Kruijff S, van Ginkel RJ, Been LB, de Jong JS, Kats-Ugurlu G, Linssen MD, Jorritsma-Smit A, van Oosten M, Nagengast WB, Ntziachristos V, van Dam GM (2016) Molecular fluorescence-guided surgery of peritoneal carcinomatosis of colorectal origin: a single-centre feasibility study. Lancet Gastroenterol Hepatol 1:283–290
Hartmans E, Tjalma JJJ, Linssen MD, Allende PBG, Koller M, Jorritsma-Smit A, Nery MSO, Elias SG, Karrenbeld A, de Vries EGE, Kleibeuker JH, van Dam GM, Robinson DJ, Ntziachristos V, Nagengast WB (2018) Potential red-flag identification of colorectal adenomas with wide-field fluorescence molecular endoscopy. Theranostics 8:1458–1467
Yang BB, Lum P, Chen A, Arends R, Roskos L, Smith B, Pérez Ruixo JJ (2010) Pharmacokinetic and pharmacodynamic perspectives on the clinical drug development of panitumumab. Clin Pharmacokinet 49:729–740
Moore LS, Rosenthal EL, de Boer E, Prince AC, Patel N, Richman JM, Morlandt AB, Carroll WR, Zinn KR, Warram JM (2017) Effects of an unlabeled loading dose on tumor-specific uptake of a fluorescently labeled antibody for optical surgical navigation. Mol Imaging Biol 19:610–616
This work was supported in part by the Stanford Comprehensive Cancer Center, the Stanford University School of Medicine Medical Scholars Program, the Netherlands Organization for Scientific Research (Rubicon; 019.171LW.022), the National Institutes of Health and the National Cancer Institute (R01CA190306), and the Stanford Molecular Imaging Scholars (SMIS) program (NIT T32CA118681). Institutional equipment loans were received from Novadaq, SurgVision, and LI-COR Biosciences.
The study protocol was approved by the Stanford University Institutional Review Board and the FDA (NCT02415881). Informed consent was obtained from all individual participants included in the study. The study was performed in accordance with the Helsinki Declaration of 1975 and its amendments, FDA’s ICH-GCP guidelines, and the laws and regulations of the USA.
Conflict of Interest
Eben Rosenthal is a consultant for LICOR Biosciences that manufactures IRDye800 and has equipment loans from this company.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Nishio, N., van den Berg, N.S., van Keulen, S. et al. Optimal Dosing Strategy for Fluorescence-Guided Surgery with Panitumumab-IRDye800CW in Head and Neck Cancer. Mol Imaging Biol 22, 156–164 (2020). https://doi.org/10.1007/s11307-019-01358-x
- Near-infrared imaging
- Head and neck cancer
- Optimal dosing strategy
- Image-guided surgery