What Is the Innovation? During cancer operations, a surgeon only has 2 tools, visual inspection and finger palpation, to decide and execute critical choices that determine the outcome of a tumor resection.1 The hands and eyes can only provide limited data during surgery. Our group and others have hypothesized that fluorescent labeling of tumor cells during surgery will improve intraoperative detection of cancer cells.2,3 If the tumor cells will fluoresce or “glow” during surgery, the surgeons are more likely to identify tumor margins, residual disease, positive lymph nodes, and satellite metastases. This concept of intraoperative molecular imaging requires 2 innovations2: a fluorescent contrast agent that can be injected systemically into the patient that selectively accumulates in the tumor tissues3 and a camera system that can detect and quantify the contrast agent in the tumor tissues.2,4 Several fluorescent contrast agents exist to highlight tumors, including EC17 (folate-fluorescein), indocyanine green, OTL0038 (Pte-Tyr–near-infared [NIR] dye), aminolevulinic acid, bevacizumab–800CW, and hexylaminolevulinate. These agents are given systemically and target tumors by a variety of mechanisms including receptor-mediated binding, enhanced permeability and retention in the tumor microenvironment, and “smart probes” (eg, enzyme activated). In addition, companies such as VisionSense, Quest, Olympus, Novadaq, Karl Storz, Perkin-Elmer, and many others have emerged to offer camera systems for the operating room for visualizing these tracers once they accumulate in tumors. What Are the Key Advantages Over Existing Approaches? Intraoperative molecular imaging provides an important supplement to the standard surgical approaches that use visual review and palpation. This technology is not meant to replace surgeons’ hands, eyes, and intuition in clinical decision making, but rather to augment the data available during an oncologic resection. It is a safe technology because unlike other imaging modalities, it does not require ionizing radiation. The energy to excite fluorescent contrast agents is low (10−1 eV). Furthermore, the technology is visual and does not require special training or experience. Intraoperative molecular imaging does not require advance knowledge of the location of the primary nodule or metastases. Lastly, optical imaging is easy to understand and can image large surfaces in real time without disrupting the natural flow of the operation. How Will This Impact Clinical Care? Surgery remains the single best treatment modality for all solid tumors. To perform a R0 cancer resection and comprehensively stage a patient, a surgeon makes 3 critical decisions: how much to resect, which lymph nodes to remove, and are there detectable satellite lesions? Yet despite the critical role of surgery in the management of patients with cancer, the local recurrence rate in the United States still varies from 8% to 50%, depending on the tumor type. The ability to obtain real-time information during surgery about a cancer using image-guided techniques is likely to decrease local recurrence rates and improve intraoperative staging. Is There Evidence Supporting the Benefits of the Innovation? Several groups are studying the role of intraoperative molecular imaging in improving the outcomes from cancer resection. To our knowledge, Stummer et al5 performed the first randomized phase 3 clinical trial of intraoperative imaging for human use. Patients with malignant gliomas were randomized to aminolevulinic acid (n = 176) or conventional white light (n = 173) neurosurgery. More frequent complete resections and improved progression-free survival were confirmed with imaging, with higher median residual tumor volumes in the white light group. Van der Vorst et al6 subsequently showed that intraoperative optical imaging could improve hepatic metastasectomy with curative intent. In a clinical trial of 40 patients undergoing hepatic resection for colorectal cancer metastases, 71 superficially located colorectal liver metastases were resected using NIR fluorescence imaging. Importantly, in 5 of 40 patients, additional small and superficially located lesions were detected using NIR fluorescence, and they were otherwise undetectable by conventional techniques. Van Dam and colleagues 7 conducted the first successful injection of a human with a targeted molecular probe. In their series, 8 women were infused with a receptor-targeted contrast agent that identified ovarian tumors. The surgeons were able to identify peritoneal implants less than 1.0 mm in size, and they removed on average 21% more disease than seen without optical guidance. Our group has performed 6 intraoperative imaging clinical trials in more than 200 patients. In our first pilot study,8 18 patients with a pulmonary nodule that was suspicious for lung cancer underwent systemic indocyanine green, thoracotomy, and pulmonary resection. Near-infared imaging during surgery identified 5 additional subcentimeter nodules: 3 metastatic adenocarcinomas and 2 metastatic sarcomas. This technology could identify nodules as small as 0.2 cm and as deep as 1.3 cm from the pleural surface (Figure). This approach discovered 3 nodules that were in different lobes than the primary tumor. We subsequently followed up with 2 more clinical trials using the folate–fluorescein isothiocyanate on 80 patients: 50 patients with known pulmonary adenocarcinoma and 30 patients with an undiagnosed lung nodule. In these 2 studies, targeting tumors with a fluorescent molecular agent had greater than 90% sensitivity for locating and identifying lung cancers. Although not specifically studied, there was anecdotal evidence of identifying positive surgical margins, satellite metastases, and lymph nodes with cancer invasion. What Are the Barriers to Implementing This Innovation More Broadly? The greatest bottleneck remains the clinical approval of targeted fluorescent contrast agents that can be used for intraoperative imaging. The other technical issue is our ability to improve the signal-to-noise ratio in tumors that are located deep in solid organs.9 With further refinements to overcome issues such as scatter, the depth of penetration of optical imaging will likely improve. In What Time Frame Will This Innovation Likely Be Applied Routinely? In the next decade, a new era of surgical oncology is likely to emerge where patients will be infused with a cocktail of contrast agents that can selectively bind heterogeneous tumors. This approach will identify tumor cells and critical neurovascular structures while simultaneously providing detailed histological information. In addition, another major area where this technology will be used is “theranostics.”10 Theranostic nanoparticles are small particles that take advantage of the compact packaging of nanoplatforms to carry imaging and therapeutic drugs. The resulting nanosystems have a major opportunity for both imaging and potentially even tumor cell killing. Section Editor: Justin B. Dimick, MD, MPH. Submissions: Authors should contact Justin B. Dimick, MD, MPH, at email@example.com if they wish to submit Surgical Innovation papers. Back to top Article Information Corresponding Author: Sunil Singhal, MD, University of Pennsylvania, 3400 Spruce St, 6 White Bldg, Philadelphia, PA 19104 (firstname.lastname@example.org). Published Online: January 13, 2016. doi:10.1001/jamasurg.2015.3604. Conflict of Interest Disclosures: None reported. References 1. Aliperti LA, Predina JD, Vachani A, Singhal S. Local and systemic recurrence is the Achilles heel of cancer surgery . Ann Surg Oncol. 2011;18(3):603-607.PubMedGoogle ScholarCrossref 2. Singhal S, Nie S, Wang MD. Nanotechnology applications in surgical oncology . Annu Rev Med. 2010;61:359-373.PubMedGoogle ScholarCrossref 3. Vahrmeijer AL, Hutteman M, van der Vorst JR, van de Velde CJ, Frangioni JV. Image-guided cancer surgery using near-infrared fluorescence . Nat Rev Clin Oncol. 2013;10(9):507-518.PubMedGoogle ScholarCrossref 4. Mondal SB, Gao S, Zhu N, Liang R, Gruev V, Achilefu S. Real-time fluorescence image-guided oncologic surgery . Adv Cancer Res. 2014;124:171-211.PubMedGoogle Scholar 5. Stummer W, Tonn JC, Mehdorn HM, et al; ALA-Glioma Study Group. Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. clinical article . J Neurosurg. 2011;114(3):613-623.PubMedGoogle ScholarCrossref 6. van der Vorst JR, Schaafsma BE, Hutteman M, et al. Near-infrared fluorescence-guided resection of colorectal liver metastases . Cancer. 2013;119(18):3411-3418.PubMedGoogle ScholarCrossref 7. van Dam GM, Themelis G, Crane LM, et al. Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results . Nat Med. 2011;17(10):1315-1319.PubMedGoogle ScholarCrossref 8. Okusanya OT, Holt D, Heitjan D, et al. Intraoperative near-infrared imaging can identify pulmonary nodules . Ann Thorac Surg. 2014;98(4):1223-1230.PubMedGoogle ScholarCrossref 9. Keereweer S, Van Driel PB, Snoeks TJ, et al. Optical image-guided cancer surgery: challenges and limitations . Clin Cancer Res. 2013;19(14):3745-3754.PubMedGoogle ScholarCrossref 10. Xie J, Lee S, Chen X. Nanoparticle-based theranostic agents . Adv Drug Deliv Rev. 2010;62(11):1064-1079.PubMedGoogle ScholarCrossref
JAMA Surgery – American Medical Association
Published: Feb 1, 2016
Keywords: contrast media,fluorescence,intraoperative care,nanotechnology,surgical procedures, operative,surgery specialty,tumor cells,cancer surgery,imaging guidance techniques,surgical oncology,molecular imaging,neoplasms
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