Tumor-Specific Uptake of Fluorescent Bevacizumab–IRDye800CW Microdosing in Patients with Primary Breast Cancer: A Phase I Feasibility Study

Lamberts, Laetitia E.; Koch, Maximilian; Jong, Johannes S. de; Adams, Arthur L.L.; Glatz, Jürgen; Kranendonk, Mariëtte E.G.; Scheltinga, Anton G.T. Terwisscha van; Jansen, Liesbeth; Vries, Jakob de; Hooge, Marjolijn N. Lub-de; Schröder, Carolien P.; Jorritsma-Smit, Annelies; Linssen, Matthijs D.; Boer, Esther de; Vegt, Bert van der; Nagengast, Wouter B.; Elias, Sjoerd G.; Oliveira, Sabrina; Witkamp, Arjen J.; Mali, Willem P.Th.M.; Wall, Elsken van der; Diest, Paul J. van; Vries, Elisabeth G.E. de; Ntziachristos, Vasilis; Dam, Gooitzen M. van

doi:10.1158/1078-0432.ccr-16-0437

Cited by 238 publications

(205 citation statements)

References 41 publications

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“…This method was explored in several clinical trials, including breast, ovarian and head and neck cancer patients. [27–29] For CRLM a clinical trial with SGM-101, which targets CEA is currently ongoing (Netherlands Trial Register number NTR5673). Unfortunately, clinical translation of targeted fluorescent tracers is expensive and time-consuming and requires specific expertise.…”

Section: Discussionmentioning

confidence: 99%

Long-term follow-up after near-infrared fluorescence-guided resection of colorectal liver metastases: A retrospective multicenter analysis

Handgraaf

Boogerd

Höppener

et al. 2017

European Journal of Surgical Oncology (EJSO)

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BACKGROUND Several studies demonstrated that intraoperative near-infrared fluorescence (NIRF) imaging using indocyanine green (ICG) identifies (sub)capsular colorectal liver metastases (CRLM) missed by other techniques. It is unclear if this results in any survival benefit. This study evaluates long-term follow-up after NIRF-guided resection of CRLM using ICG. METHODS First, patients undergoing resection of CRLM with or without NIRF imaging were analyzed retrospectively. Perioperative details, liver-specific recurrence-free interval and overall survival were compared. Second, the prognosis of patients in whom additional metastases were identified solely by NIRF was studied. RESULTS Eighty-six patients underwent resection with NIRF imaging and 87 without. In significantly more patients of the NIRF imaging cohort additional metastases were identified during surgery (25% vs. 13%, p=0.04). Tumors identified solely by NIRF imaging were significantly smaller compared to additional metastases identified also by inspection, palpation or intraoperative ultrasound (3.2 ± 1.8 mm vs. 7.4 ± 2.6 mm, p<0.001). Liver-specific recurrence-free survival at 4 years was 47% with NIRF imaging and 39% without (hazard ratio at multivariate analysis 0.73, 95%CI 0.42–1.28, p=0.28). Overall survival at 4 years was 62% and 59%, respectively (p=0.79). No liver recurrences occurred within 3 years follow-up in 52% of patients in whom additional metastases were resected based on only NIRF imaging. CONCLUSIONS This study suggests that NIRF imaging identifies significantly more and smaller tumors during resection of CRLM, preventing recurrences in a subset of patients. Given its safety profile and low expense, routine use can be considered until tumor targeting fluorescent tracers are clinically available. Keywords: .

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Section: Discussionmentioning

confidence: 99%

Long-term follow-up after near-infrared fluorescence-guided resection of colorectal liver metastases: A retrospective multicenter analysis

Handgraaf

Boogerd

Höppener

et al. 2017

European Journal of Surgical Oncology (EJSO)

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“…Preclinical data has provided evidence that novel tumor-targeting probes can improve detection, margin control, and survival in a variety of cancer types. In addition, recent clinical studies have demonstrated sensitive and specific cancer detection in fluorescence-guided tumor resections using NIR probes conjugated to therapeutic antibodies in several cancer types [9, 10]. Demonstration that approved antibodies can be repurposed for imaging is important and scalable to other cancer types, since the approval process and cost barriers for fluorescent labeling are limited compared to de novo agents that require costly development and toxicology studies.…”

Section: Introductionmentioning

confidence: 99%

First-in-human intraoperative near-infrared fluorescence imaging of glioblastoma using cetuximab-IRDye800

et al. 2018

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Introduction Maximizing extent of surgical resection with the least morbidity remains critical for survival in glioblastoma patients, and we hypothesize that it can be improved by enhancements in intraoperative tumor detection. In a clinical study, we determined if therapeutic antibodies could be repurposed for intraoperative imaging during resection. Methods Fluorescently labeled cetuximab-IRDye800 was systemically administered to three patients 2 days prior to surgery. Near-infrared fluorescence imaging of tumor and histologically negative peri-tumoral tissue was performed intraoperatively and ex vivo. Fluorescence was measured as mean fluorescence intensity (MFI), and tumor-to-background ratios (TBRs) were calculated by comparing MFIs of tumor and histologically uninvolved tissue. Results The mean TBR was significantly higher in tumor tissue of contrast-enhancing (CE) tumors on preoperative imaging (4.0 ± 0.5) compared to non-CE tumors (1.2 ± 0.3; p = 0.02). The TBR was higher at a 100 mg dose than at 50 mg (4.3 vs. 3.6). The smallest detectable tumor volume in a closed-field setting was 70 mg with 50 mg of dye and 10 mg with 100 mg. On sections of paraffin embedded tissues, fluorescence positively correlated with histological evidence of tumor. Sensitivity and specificity of tumor fluorescence for viable tumor detection was calculated and fluorescence was found to be highly sensitive (73.0% for 50 mg dose, 98.2% for 100 mg dose) and specific (66.3% for 50 mg dose, 69.8% for 100 mg dose) for viable tumor tissue in CE tumors while normal peri-tumoral tissue showed minimal fluorescence. Conclusion This first-in-human study demonstrates the feasibility and safety of antibody based imaging for CE glioblastomas.

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“…6 The applicability of intraoperative tumor-specific fluorescence imaging for real-time tumor visualization was successfully demonstrated in a first-inhuman analysis in breast cancer. 1 Studies in mice have demonstrated that residual fluorescence in the tumor margins correlates with local recurrence, whereas image-guided surgery improved outcomes. 7 Recent clinical studies have supported the use of fluorescence molecular imaging (FMI) during surgery to overcome the challenges associated with precise intraoperative detection of tumor margins.…”

mentioning

confidence: 99%

“…8 More recently, the clinical application of bevacizumab-IRDye800CW combined with intraoperative imaging system improved breast tumor resection. 1 Although image-guided surgery has shown promise in both preclinical and clinical studies, surgery itself usually results in a generalized state of immunosuppression in the immediate postoperative period that corresponds to tumor progression. 9 Moreover, resection is often not considered a treatment option for patients with locally advanced tumors or metastases, owing to the high risk of residual outgrowth.…”

mentioning

confidence: 99%

Improved resection and prolonged overall survival with PD-1-IRDye800CW fluorescence probe-guided surgery and PD-1 adjuvant immunotherapy in 4T1 mouse model

Du¹,

Sun²,

Liang³

et al. 2017

IJN

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An intraoperative technique to accurately identify microscopic tumor residuals could decrease the risk of positive surgical margins. Several lines of evidence support the expression and immunotherapeutic effect of PD-1 in breast cancer. Here, we sought to develop a fluorescence-labeled PD-1 probe for in vivo breast tumor imaging and image-guided surgery. The efficacy of PD-1 monoclonal antibody (PD-1 mAb) as adjuvant immunotherapy after surgery was also assessed. PD-1-IRDye800CW was developed and examined for its application in tumor imaging and image-guided tumor resection in an immunocompetent 4T1 mouse tumor model. Fluorescence molecular imaging was performed to monitor probe biodistribution and intraoperative imaging. Bioluminescence imaging was performed to monitor tumor growth and evaluate postsurgical tumor residuals, recurrences, and metastases. The PD-1-IRDye800CW exhibited a specific signal at the tumor region compared with the IgG control. Furthermore, PD-1-IRDye800CW-guided surgery combined with PD-1 adjuvant immunotherapy inhibited tumor regrowth and microtumor metastases and thus improved survival rate. Our study demonstrates the feasibility of using PD-1-IRDye800CW for breast tumor imaging and image-guided tumor resection. Moreover, PD-1 mAb adjuvant immunotherapy reduces cancer recurrences and metastases emanating from tumor residuals.

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Tumor-Specific Uptake of Fluorescent Bevacizumab–IRDye800CW Microdosing in Patients with Primary Breast Cancer: A Phase I Feasibility Study

Cited by 238 publications

References 41 publications

Long-term follow-up after near-infrared fluorescence-guided resection of colorectal liver metastases: A retrospective multicenter analysis

Long-term follow-up after near-infrared fluorescence-guided resection of colorectal liver metastases: A retrospective multicenter analysis

First-in-human intraoperative near-infrared fluorescence imaging of glioblastoma using cetuximab-IRDye800

Improved resection and prolonged overall survival with PD-1-IRDye800CW fluorescence probe-guided surgery and PD-1 adjuvant immunotherapy in 4T1 mouse model

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