- Email: [email protected]
Reply to: Comments on ‘Intraoperative near-infrared fluorescence imaging using indocyanine green in colorectal carcinomatosis surgery: Proof of concept’
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ScienceDirect EJSO 43 (2017) 242e243
www.ejso.com
Correspondence
Reply to: Comments on ‘Intraoperative near-infrared fluorescence imaging using indocyanine green in colorectal carcinomatosis surgery: Proof of concept’
We would like to thank Gabriel Liberale and his group for having initiated a debate on this important topic, which was one of the aims of our paper.1 As described in the title of our paper, the objective of our study was to recreate all the conditions of the operating room in order to validate the use of ICG and near infrared camera for the detection of colorectal peritoneal carcinomatosis by comparing it with a gold standard technique: pathological examination. In order to ensure the accuracy of our technique, we calibrated the FluoStickÔ (the camera that was used in the study) with the help of the Fluoptics society. The sensitivity of the camera was calculated for various signal to noise ratios. According to our analysis, the detection limit corresponding to a signal to noise ratio equal to 2 is 120 nmol/L of ICG.2 In designing our study, we wondered about the integration of a standardized ratio in addition to the calibration of the camera such as the “tumor to background ratio” (TBR) described by Liberale et al. However, even if theoretically the calculation of such a ratio may seem to improve the reproducibility of the technique, we strongly think that this excessive attempt of standardization will eventually lower the accuracy of the technique. First, contrary to what Liberale et al. seem to think, the use of a mathematical ratio will not lower the impact of nonspecific ICG binding. Secondly, too many variables have to be considered for that ratio to be reproducible between different centers or patients (camera type, ICG dose, injection time, tissue type, hepatic clearance .) or even for a same patient (nodule type, nodule depth .). Lastly, we think that imposing a mathematical threshold will eventually cause misinterpretations, especially when non-specific binding of ICG is important as it seemed to be the case in Liberale et al. study.3 Incidentally, the use of a fixed TBR
cut-off >1.3 probably explain why mucinous tumor where not retained as cancerous in their study. This shows that as the interpretation of an x-ray can not simply rely on a mathematical analysis and implies an experimented radiologist, the interpretation of near infrared imaging will also implies an experimented user. Regarding the timing of injection, from the first study of Ishizawa et al. in 20094 until the more recent study of Jiang et al.,5 the timing of ICG injection that is recommended is 24 h before the surgery. This injection time offers many advantages; the most important one is that it allows a good hepatic clearance of ICG lowering fluorescence of non-tumoral tissues while maintaining enough fluorescence in tumoral nodules. With this injection timing, calculation of a TBR turn out to be a less important factor to take into account, thanks to the reduction of the background noise due to the hepatic clearance of ICG. Unfortunately, Liberale et al. used a camera that presents quite a low sensitivity to ICG and needs a higher amount of fluorophore. Regarding the type of adenocarcinoma, we chose not to select patients or nodules according to tumor histology and/ or other parameters such as Liberale et al. did in their paper. Indeed, after a careful reading of their results section, we noticed a selection bias as among the 78 peritoneal nodules that were retrieved, only 63 were analyzed for their fluorescence and only 33 were included in the calculation of the procedure sensitivity and specificity. This actually explains the difference between the sensitivity of our procedure: 72.4% and theirs: 87.5%. In fact, we think Liberate et al. made a dangerous choice in not including mucinous tumor in the calculation of the sensitivity of the technique. Indeed, before surgery, it is impossible to know what the adenocarcinoma type is. Thus, relying on an infrared fluorescence technique that is unable to detect mucinous adenocarcinoma in a situation where the adenocarcinoma is a mucinous one will lead to dramatic outcome for the patient. Nevertheless, as suggested by Liberate et al., we reanalyzed our data looking for patients with a mucinous adenocarcinoma. Among the ten patients of our study, two had a mucinous adenocarcinoma. 22 nodules were removed from these patients. Table 1 shows the repartition of fluorescent nodules compared to pathological examination. This subgroup analysis shows a sensitivity of 72.2% and a
DOI of original article: http://dx.doi.org/10.1016/j.ejso.2016.08.025 http://dx.doi.org/10.1016/j.ejso.2016.10.001 0748-7983/Ó 2016 Elsevier Ltd, BASO w The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.
Correspondence / EJSO 43 (2017) 242e243 Table 1 Repartition of fluorescent nodules of patients with a mucinous adenocarcinoma compared to pathological examination. Fluorescent status
Peritoneal nodules status Malignant
Benign
Total
Positive Negative Total
13 5 18
1 3 4
14 8 22
specificity of 75% which is not different from the values found for our whole population. Finally, regarding the specific histological analysis, we meant practicing a microscopic research of ICG’s depot in tumor tissues. This analysis was neither performed in our study nor in the study of Liberale et al. We feel that research and discussion about ways to optimize near infrared ICG procedures are of great interest and not enough studies are currently published on this topic. We would be very pleased to collaborate with Liberale’s working group in order to combine our data. We strongly think that new and interesting near infrared procedures to support surgery may emerge from such collaboration. Conflicts of interest Dr J-L Coll belongs to the scientific council of Fluoptics society. All authors have disclosed any financial and personal relationships with other people or organizations that could have inappropriately influenced (biased) their work. References 1. Barabino G, Klein JP, Porcheron J, Grichine A, Coll J-L, Cottier M. Intraoperative near-infrared fluorescence imaging using indocyanine green in colorectal carcinomatosis surgery: proof of concept. Eur J Surg Oncol 2016;42:1931–7. http://dx.doi.org/10.1016/j.ejso.2016.06.389. 2. Dorval P, Mangeret N, Guillermet S, et al. A palm-sized high-sensitivity near-infrared fluorescence imager for laparotomy surgery. Phys Med 2016;32(1):218–25. http://dx.doi.org/10.1016/j.ejmp.2015.11.006.
243
3. Liberale G, Vankerckhove S, Caldon MG, et al. Fluorescence imaging after indocyanine green injection for detection of peritoneal metastases in patients undergoing cytoreductive surgery for peritoneal carcinomatosis from colorectal cancer: a pilot study. Ann Surg 2016. http://dx.doi.org/10.1097/SLA.0000000000001618. 4. Ishizawa T, Fukushima N, Shibahara J, et al. Real-time identification of liver cancers by using indocyanine green fluorescent imaging. Cancer 2009;115(11):2491–504. http://dx.doi.org/10.1002/cncr.24291. 5. Jiang JX, Keating JJ, Jesus EMD, et al. Optimization of the enhanced permeability and retention effect for near-infrared imaging of solid tumors with indocyanine green. Am J Nucl Med Mol Imaging 2015; 5(4):390–400.
G. Barabino* Universite Jean Monnet, SAINBIOSE INSERM 1059, 42023 Saint Etienne, France Oncological and Digestive Surgery, Saint Etienne University Hospital, 42000 Saint Etienne, France INSERM-UJF U823, Institut Albert Bonniot, 38706 Grenoble, France J.P. Klein Universite Jean Monnet, SAINBIOSE INSERM 1059, 42023 Saint Etienne, France J. Porcheron Oncological and Digestive Surgery, Saint Etienne University Hospital, 42000 Saint Etienne, France A. Grichine J.-L. Coll INSERM-UJF U823, Institut Albert Bonniot, 38706 Grenoble, France M. Cottier Universite Jean Monnet, SAINBIOSE INSERM 1059, 42023 Saint Etienne, France *Corresponding author. Oncological and Digestive Surgery, Saint Etienne University Hospital, 42000 Saint Etienne, France. E-mail address: [email protected] Accepted 3 October 2016
ScienceDirect EJSO 43 (2017) 242e243
www.ejso.com
Correspondence
Reply to: Comments on ‘Intraoperative near-infrared fluorescence imaging using indocyanine green in colorectal carcinomatosis surgery: Proof of concept’
We would like to thank Gabriel Liberale and his group for having initiated a debate on this important topic, which was one of the aims of our paper.1 As described in the title of our paper, the objective of our study was to recreate all the conditions of the operating room in order to validate the use of ICG and near infrared camera for the detection of colorectal peritoneal carcinomatosis by comparing it with a gold standard technique: pathological examination. In order to ensure the accuracy of our technique, we calibrated the FluoStickÔ (the camera that was used in the study) with the help of the Fluoptics society. The sensitivity of the camera was calculated for various signal to noise ratios. According to our analysis, the detection limit corresponding to a signal to noise ratio equal to 2 is 120 nmol/L of ICG.2 In designing our study, we wondered about the integration of a standardized ratio in addition to the calibration of the camera such as the “tumor to background ratio” (TBR) described by Liberale et al. However, even if theoretically the calculation of such a ratio may seem to improve the reproducibility of the technique, we strongly think that this excessive attempt of standardization will eventually lower the accuracy of the technique. First, contrary to what Liberale et al. seem to think, the use of a mathematical ratio will not lower the impact of nonspecific ICG binding. Secondly, too many variables have to be considered for that ratio to be reproducible between different centers or patients (camera type, ICG dose, injection time, tissue type, hepatic clearance .) or even for a same patient (nodule type, nodule depth .). Lastly, we think that imposing a mathematical threshold will eventually cause misinterpretations, especially when non-specific binding of ICG is important as it seemed to be the case in Liberale et al. study.3 Incidentally, the use of a fixed TBR
cut-off >1.3 probably explain why mucinous tumor where not retained as cancerous in their study. This shows that as the interpretation of an x-ray can not simply rely on a mathematical analysis and implies an experimented radiologist, the interpretation of near infrared imaging will also implies an experimented user. Regarding the timing of injection, from the first study of Ishizawa et al. in 20094 until the more recent study of Jiang et al.,5 the timing of ICG injection that is recommended is 24 h before the surgery. This injection time offers many advantages; the most important one is that it allows a good hepatic clearance of ICG lowering fluorescence of non-tumoral tissues while maintaining enough fluorescence in tumoral nodules. With this injection timing, calculation of a TBR turn out to be a less important factor to take into account, thanks to the reduction of the background noise due to the hepatic clearance of ICG. Unfortunately, Liberale et al. used a camera that presents quite a low sensitivity to ICG and needs a higher amount of fluorophore. Regarding the type of adenocarcinoma, we chose not to select patients or nodules according to tumor histology and/ or other parameters such as Liberale et al. did in their paper. Indeed, after a careful reading of their results section, we noticed a selection bias as among the 78 peritoneal nodules that were retrieved, only 63 were analyzed for their fluorescence and only 33 were included in the calculation of the procedure sensitivity and specificity. This actually explains the difference between the sensitivity of our procedure: 72.4% and theirs: 87.5%. In fact, we think Liberate et al. made a dangerous choice in not including mucinous tumor in the calculation of the sensitivity of the technique. Indeed, before surgery, it is impossible to know what the adenocarcinoma type is. Thus, relying on an infrared fluorescence technique that is unable to detect mucinous adenocarcinoma in a situation where the adenocarcinoma is a mucinous one will lead to dramatic outcome for the patient. Nevertheless, as suggested by Liberate et al., we reanalyzed our data looking for patients with a mucinous adenocarcinoma. Among the ten patients of our study, two had a mucinous adenocarcinoma. 22 nodules were removed from these patients. Table 1 shows the repartition of fluorescent nodules compared to pathological examination. This subgroup analysis shows a sensitivity of 72.2% and a
DOI of original article: http://dx.doi.org/10.1016/j.ejso.2016.08.025 http://dx.doi.org/10.1016/j.ejso.2016.10.001 0748-7983/Ó 2016 Elsevier Ltd, BASO w The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.
Correspondence / EJSO 43 (2017) 242e243 Table 1 Repartition of fluorescent nodules of patients with a mucinous adenocarcinoma compared to pathological examination. Fluorescent status
Peritoneal nodules status Malignant
Benign
Total
Positive Negative Total
13 5 18
1 3 4
14 8 22
specificity of 75% which is not different from the values found for our whole population. Finally, regarding the specific histological analysis, we meant practicing a microscopic research of ICG’s depot in tumor tissues. This analysis was neither performed in our study nor in the study of Liberale et al. We feel that research and discussion about ways to optimize near infrared ICG procedures are of great interest and not enough studies are currently published on this topic. We would be very pleased to collaborate with Liberale’s working group in order to combine our data. We strongly think that new and interesting near infrared procedures to support surgery may emerge from such collaboration. Conflicts of interest Dr J-L Coll belongs to the scientific council of Fluoptics society. All authors have disclosed any financial and personal relationships with other people or organizations that could have inappropriately influenced (biased) their work. References 1. Barabino G, Klein JP, Porcheron J, Grichine A, Coll J-L, Cottier M. Intraoperative near-infrared fluorescence imaging using indocyanine green in colorectal carcinomatosis surgery: proof of concept. Eur J Surg Oncol 2016;42:1931–7. http://dx.doi.org/10.1016/j.ejso.2016.06.389. 2. Dorval P, Mangeret N, Guillermet S, et al. A palm-sized high-sensitivity near-infrared fluorescence imager for laparotomy surgery. Phys Med 2016;32(1):218–25. http://dx.doi.org/10.1016/j.ejmp.2015.11.006.
243
3. Liberale G, Vankerckhove S, Caldon MG, et al. Fluorescence imaging after indocyanine green injection for detection of peritoneal metastases in patients undergoing cytoreductive surgery for peritoneal carcinomatosis from colorectal cancer: a pilot study. Ann Surg 2016. http://dx.doi.org/10.1097/SLA.0000000000001618. 4. Ishizawa T, Fukushima N, Shibahara J, et al. Real-time identification of liver cancers by using indocyanine green fluorescent imaging. Cancer 2009;115(11):2491–504. http://dx.doi.org/10.1002/cncr.24291. 5. Jiang JX, Keating JJ, Jesus EMD, et al. Optimization of the enhanced permeability and retention effect for near-infrared imaging of solid tumors with indocyanine green. Am J Nucl Med Mol Imaging 2015; 5(4):390–400.
G. Barabino* Universite Jean Monnet, SAINBIOSE INSERM 1059, 42023 Saint Etienne, France Oncological and Digestive Surgery, Saint Etienne University Hospital, 42000 Saint Etienne, France INSERM-UJF U823, Institut Albert Bonniot, 38706 Grenoble, France J.P. Klein Universite Jean Monnet, SAINBIOSE INSERM 1059, 42023 Saint Etienne, France J. Porcheron Oncological and Digestive Surgery, Saint Etienne University Hospital, 42000 Saint Etienne, France A. Grichine J.-L. Coll INSERM-UJF U823, Institut Albert Bonniot, 38706 Grenoble, France M. Cottier Universite Jean Monnet, SAINBIOSE INSERM 1059, 42023 Saint Etienne, France *Corresponding author. Oncological and Digestive Surgery, Saint Etienne University Hospital, 42000 Saint Etienne, France. E-mail address: [email protected] Accepted 3 October 2016