Opinion
VIEWPOINT
Eben L. Rosenthal, MD Division of Otolaryngology–Head and Neck Surgery, University of Alabama at Birmingham, Birmingham.
Corresponding Author: Eben L. Rosenthal, MD, Division of Otolaryngology–Head and Neck Surgery, University of Alabama at Birmingham, BDB, 1808 Seventh Ave S, Ste 563, Birmingham, AL 35294-0012 ([email protected]). jamaotolaryngology.com
Optical Imaging of Head and Neck Cancer Opportunities and Challenges There has been expansion in the use and development of optical imaging for cancer detection and surgical navigation over the past decade. New devices have been introduced in the clinic and operating room that are designed to measure native tissue fluorescence or injected fluorescent contrast agents. These technologies allow the surgeon to visualize subclinical foci of cancer and be less dependent on subjective measurements of tissue density and subtle changes in surface topography. For several reasons, head and neck cancer might be the proving ground for optical imaging: positive margins are frequent and associated with worsened outcomes, frozen sections are commonly used, and minimally invasive procedures limit the surgeon’s tactile feedback. As optical imaging technologies become available, it is our responsibility to test their efficacy, be skeptical of their potential benefits over existing techniques, and be aware of both the costs and safety risks.
where there is the least interference from tissue autofluorescence (700-800 nm, or near-infrared range). Cancerspecific imaging agents have 2 primary components: the cancer-targetingcomponentandthefluorophore.Anideal targetingagentwouldberapidlyabsorbedintotumorcells and completely cleared from the circulation at the time of imaging,thuslimitingbackgroundinterference.Cancertargeting leverages the molecular differences between cancer and normal tissues, including the expression of degradative enzymes, the upregulation of growth factor receptors,orthecancercells’increasedmetabolicrate.For example, certain human tumors are folate avid, which can be exploited by binding folate to a fluorescent agent. Clinical trials have demonstrated the feasibility of fluorescently labeled folate capable of detecting micrometastatic ovarian tumors. 5 Other examples include fluorophores covalently linked to growth factors (eg, epidermal growth factor) or antibodies.
Autofluorescence
Fluorescence Angiography
Optical imaging refers to a wide range of technologies that use alterations in light absorption and reflectivity to identify tissue changes that might be associated with cancer. Autofluorescence refers to any technique that shines light at the mucosal surface and measures the differential absorbance by normal as opposed to cancer tissue. For example, in narrow band imaging (NBI), the increased capillary density in cancer and the absorbance of blue light (440-460 nm) by hemoglobin creates areas of darkness within the areas of increased vascularity.1 Although NBI data have shown sensitivity and specificity when compared with white light examination and are available on next-generation endoscopy equipment, adoption in the United States has been limited by the subjective nature of the image interpretation, the fact that a positive result from an examination is associated with absence of fluorescence, and the uncertainty that its use changes clinical outcomes. Similar technology has been introduced for oral cavity cancer screening using handheld devices, but these devices have not undergone randomized clinical trials and are of unclear benefit in the treated population.2 To this point, insurance carriers have been reluctant to reimburse for these services. Autofluorescence has also been applied to identification of intraoperative margins with some success,3,4 although autofluorescence has limited surgical utility since it can only be applied to undisturbed mucosal epithelium of the primary tumor.
Intraoperative angiography uses a systemically injected fluorophore, such as indocyanine green (ICG), to measure tissue perfusion. The agent is excited by nearinfrared laser light (approximately 800 nm). The ICG has a half-life of 2 to 3 minutes and binds to plasma proteins within the intravascular space, thus allowing for repeated assessment of perfusion. This same principle can be applied to cancer detection by using a targeting fluorophore designed to accumulate within the tumor with high specificity. Fluorescence angiography designed to measure ICG has been incorporated into latestgeneration surgical microscopes. Just as fluorescence angiography has been widely adopted in surgical imaging, it is likely that cancer-specific optical contrast agents will soon be incorporated into surgical oncology. Although ICG is US Food and Drug Administration (FDA)-approved and would be ideal for this purpose, it lacks the appropriate moiety, which prevents it from being linked to proteins. Although ICG can be delivered as a targeted nanoparticle, several new optical dyes can be linked to proteins, but none are yet FDA-approved for human use. Fluorescently labeled antibodies are currently being evaluated in the United States (cetuximab) and in Europe (bevacizumab). The safety profile and pharmacokinetics of the therapeutic antibodies are well known, reducing the manufacturing costs and regulatory hurdles. Some optical agents might also have therapeutic properties in a similar manner to photodynamic therapy. Optical imaging might allow the cancer to be visualized prior to surgical treatment and then reimaged after treatment to assess the effect. The best example of a cancer-specific contrast agent that has completed the multi-institutional phase 3 clini-
Fluorescent Contrast Agents Optical imaging also refers to the use of exogenously administered fluorescent contrast agents. Optimal wavelengths for imaging with these agents are in the range
JAMA Otolaryngology–Head & Neck Surgery February 2014 Volume 140, Number 2
Copyright 2014 American Medical Association. All rights reserved.
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93
Opinion Viewpoint
cal trials is the use of aminolevulinic acid for fluorescent-guided removal of gliomas in Europe.6 Many other cancer-specific agents are in the preclinical phase of testing; data for head and neck cancer have shown that microscopic fragments of tumor can be detected by available operating room equipment using fluorescently labeled antibodies.7 Studies in head and neck using fluorescently labeled targeting agents suggest that there may be important opportunities to detect and treat cancer, improve surgical outcomes, limit normal tissue resection, improve surgical survival, and preserve function.
and neck region and esophagus by narrow band imaging: a multicenter randomized controlled trial. J Clin Oncol. 2010;28(9):1566-1572.
ARTICLE INFORMATION Published Online: December 26, 2013. doi:10.1001/jamaoto.2013.6166. Conflict of Interest Disclosures: Work in Dr Rosenthal’s laboratory in optical imaging is supported by support from the National Institutes of Health, an institutional grant from Novadaq (Vancouver, Canada), and equipment loan from LI-COR (Lincoln, Nebraska). He does not have any personal financial relationship with either company. Additional Contributions: Melissa Thibodeaux, BA, University of Alabama, Birmingham, provided administrative assistance. REFERENCES 1. Muto M, Minashi K, Yano T, et al. Early detection of superficial squamous cell carcinoma in the head
94
As techniques for optical surgical navigation become available, it will be important for us to evaluate their potential to improve patient outcomes. There may be parallels to what we have experienced with the introduction of robotic technology, where we have seen potential benefits but also risks associated with the rigorous adoption of technology that is industry driven. Therefore, surgeons must be aware of the potential advantages, disadvantages, and safety of the options that will be available and marketed to them in the very near future.
2. Sweeny L, Dean NR, Magnuson JS, Carroll WR, Clemons L, Rosenthal EL. Assessment of tissue autofluorescence and reflectance for oral cavity cancer screening. Otolaryngol Head Neck Surg. 2011;145(6):956-960. 3. Poh CF, Durham JS, Brasher PM, et al. Canadian Optically-guided approach for Oral Lesions Surgical (COOLS) trial: study protocol for a randomized controlled trial. BMC Cancer. 2011;11:462. 4. Poh CF, Zhang L, Anderson DW, et al. Fluorescence visualization detection of field alterations in tumor margins of oral cancer patients. Clin Cancer Res. 2006;12(22):6716-6722.
5. 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. 6. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ; ALA-Glioma Study Group. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392-401. 7. Heath CH, Deep NL, Sweeny L, Zinn KR, Rosenthal EL. Use of panitumumab-IRDye800 to image microscopic head and neck cancer in an orthotopic surgical model. Ann Surg Oncol. 2012;19(12):3879-3887.
JAMA Otolaryngology–Head & Neck Surgery February 2014 Volume 140, Number 2
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archotol.jamanetwork.com/ by a University of California - San Diego User on 06/08/2015
jamaotolaryngology.com
VIEWPOINT
Eben L. Rosenthal, MD Division of Otolaryngology–Head and Neck Surgery, University of Alabama at Birmingham, Birmingham.
Corresponding Author: Eben L. Rosenthal, MD, Division of Otolaryngology–Head and Neck Surgery, University of Alabama at Birmingham, BDB, 1808 Seventh Ave S, Ste 563, Birmingham, AL 35294-0012 ([email protected]). jamaotolaryngology.com
Optical Imaging of Head and Neck Cancer Opportunities and Challenges There has been expansion in the use and development of optical imaging for cancer detection and surgical navigation over the past decade. New devices have been introduced in the clinic and operating room that are designed to measure native tissue fluorescence or injected fluorescent contrast agents. These technologies allow the surgeon to visualize subclinical foci of cancer and be less dependent on subjective measurements of tissue density and subtle changes in surface topography. For several reasons, head and neck cancer might be the proving ground for optical imaging: positive margins are frequent and associated with worsened outcomes, frozen sections are commonly used, and minimally invasive procedures limit the surgeon’s tactile feedback. As optical imaging technologies become available, it is our responsibility to test their efficacy, be skeptical of their potential benefits over existing techniques, and be aware of both the costs and safety risks.
where there is the least interference from tissue autofluorescence (700-800 nm, or near-infrared range). Cancerspecific imaging agents have 2 primary components: the cancer-targetingcomponentandthefluorophore.Anideal targetingagentwouldberapidlyabsorbedintotumorcells and completely cleared from the circulation at the time of imaging,thuslimitingbackgroundinterference.Cancertargeting leverages the molecular differences between cancer and normal tissues, including the expression of degradative enzymes, the upregulation of growth factor receptors,orthecancercells’increasedmetabolicrate.For example, certain human tumors are folate avid, which can be exploited by binding folate to a fluorescent agent. Clinical trials have demonstrated the feasibility of fluorescently labeled folate capable of detecting micrometastatic ovarian tumors. 5 Other examples include fluorophores covalently linked to growth factors (eg, epidermal growth factor) or antibodies.
Autofluorescence
Fluorescence Angiography
Optical imaging refers to a wide range of technologies that use alterations in light absorption and reflectivity to identify tissue changes that might be associated with cancer. Autofluorescence refers to any technique that shines light at the mucosal surface and measures the differential absorbance by normal as opposed to cancer tissue. For example, in narrow band imaging (NBI), the increased capillary density in cancer and the absorbance of blue light (440-460 nm) by hemoglobin creates areas of darkness within the areas of increased vascularity.1 Although NBI data have shown sensitivity and specificity when compared with white light examination and are available on next-generation endoscopy equipment, adoption in the United States has been limited by the subjective nature of the image interpretation, the fact that a positive result from an examination is associated with absence of fluorescence, and the uncertainty that its use changes clinical outcomes. Similar technology has been introduced for oral cavity cancer screening using handheld devices, but these devices have not undergone randomized clinical trials and are of unclear benefit in the treated population.2 To this point, insurance carriers have been reluctant to reimburse for these services. Autofluorescence has also been applied to identification of intraoperative margins with some success,3,4 although autofluorescence has limited surgical utility since it can only be applied to undisturbed mucosal epithelium of the primary tumor.
Intraoperative angiography uses a systemically injected fluorophore, such as indocyanine green (ICG), to measure tissue perfusion. The agent is excited by nearinfrared laser light (approximately 800 nm). The ICG has a half-life of 2 to 3 minutes and binds to plasma proteins within the intravascular space, thus allowing for repeated assessment of perfusion. This same principle can be applied to cancer detection by using a targeting fluorophore designed to accumulate within the tumor with high specificity. Fluorescence angiography designed to measure ICG has been incorporated into latestgeneration surgical microscopes. Just as fluorescence angiography has been widely adopted in surgical imaging, it is likely that cancer-specific optical contrast agents will soon be incorporated into surgical oncology. Although ICG is US Food and Drug Administration (FDA)-approved and would be ideal for this purpose, it lacks the appropriate moiety, which prevents it from being linked to proteins. Although ICG can be delivered as a targeted nanoparticle, several new optical dyes can be linked to proteins, but none are yet FDA-approved for human use. Fluorescently labeled antibodies are currently being evaluated in the United States (cetuximab) and in Europe (bevacizumab). The safety profile and pharmacokinetics of the therapeutic antibodies are well known, reducing the manufacturing costs and regulatory hurdles. Some optical agents might also have therapeutic properties in a similar manner to photodynamic therapy. Optical imaging might allow the cancer to be visualized prior to surgical treatment and then reimaged after treatment to assess the effect. The best example of a cancer-specific contrast agent that has completed the multi-institutional phase 3 clini-
Fluorescent Contrast Agents Optical imaging also refers to the use of exogenously administered fluorescent contrast agents. Optimal wavelengths for imaging with these agents are in the range
JAMA Otolaryngology–Head & Neck Surgery February 2014 Volume 140, Number 2
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archotol.jamanetwork.com/ by a University of California - San Diego User on 06/08/2015
93
Opinion Viewpoint
cal trials is the use of aminolevulinic acid for fluorescent-guided removal of gliomas in Europe.6 Many other cancer-specific agents are in the preclinical phase of testing; data for head and neck cancer have shown that microscopic fragments of tumor can be detected by available operating room equipment using fluorescently labeled antibodies.7 Studies in head and neck using fluorescently labeled targeting agents suggest that there may be important opportunities to detect and treat cancer, improve surgical outcomes, limit normal tissue resection, improve surgical survival, and preserve function.
and neck region and esophagus by narrow band imaging: a multicenter randomized controlled trial. J Clin Oncol. 2010;28(9):1566-1572.
ARTICLE INFORMATION Published Online: December 26, 2013. doi:10.1001/jamaoto.2013.6166. Conflict of Interest Disclosures: Work in Dr Rosenthal’s laboratory in optical imaging is supported by support from the National Institutes of Health, an institutional grant from Novadaq (Vancouver, Canada), and equipment loan from LI-COR (Lincoln, Nebraska). He does not have any personal financial relationship with either company. Additional Contributions: Melissa Thibodeaux, BA, University of Alabama, Birmingham, provided administrative assistance. REFERENCES 1. Muto M, Minashi K, Yano T, et al. Early detection of superficial squamous cell carcinoma in the head
94
As techniques for optical surgical navigation become available, it will be important for us to evaluate their potential to improve patient outcomes. There may be parallels to what we have experienced with the introduction of robotic technology, where we have seen potential benefits but also risks associated with the rigorous adoption of technology that is industry driven. Therefore, surgeons must be aware of the potential advantages, disadvantages, and safety of the options that will be available and marketed to them in the very near future.
2. Sweeny L, Dean NR, Magnuson JS, Carroll WR, Clemons L, Rosenthal EL. Assessment of tissue autofluorescence and reflectance for oral cavity cancer screening. Otolaryngol Head Neck Surg. 2011;145(6):956-960. 3. Poh CF, Durham JS, Brasher PM, et al. Canadian Optically-guided approach for Oral Lesions Surgical (COOLS) trial: study protocol for a randomized controlled trial. BMC Cancer. 2011;11:462. 4. Poh CF, Zhang L, Anderson DW, et al. Fluorescence visualization detection of field alterations in tumor margins of oral cancer patients. Clin Cancer Res. 2006;12(22):6716-6722.
5. 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. 6. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ; ALA-Glioma Study Group. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392-401. 7. Heath CH, Deep NL, Sweeny L, Zinn KR, Rosenthal EL. Use of panitumumab-IRDye800 to image microscopic head and neck cancer in an orthotopic surgical model. Ann Surg Oncol. 2012;19(12):3879-3887.
JAMA Otolaryngology–Head & Neck Surgery February 2014 Volume 140, Number 2
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archotol.jamanetwork.com/ by a University of California - San Diego User on 06/08/2015
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