A long-awaited novel approach for the treatment of undetectable small-sized lung cancers in thoracoscopic surgery

The combination of lobectomy and lymph node dissection has been performed worldwide as a standard procedure for treating lung cancer since Ginsberg et al. reported a randomized trial concerning surgery for stage 1A lung cancer (1). However, two recent prospective clinical trials (JCOG0802/WJOG4067 and CALGB140503) demonstrated the feasibility of sublobar resection for small-sized lung cancers (2,3). Due to the surgical trend of changing to the sublobar resection approach for treating lung cancer, the outcomes and techniques of this approach will be an increasingly important topic of discussion.

The challenges of sublobar resection for small-sized lung cancers include selection of the appropriate surgical procedure based on the tumor characteristics, as well as the finer technical aspects. These include ensuring precise resection with sufficient surgical margins for the tumors to be undetectable following surgery. These small lung nodules are sometimes undetectable in thoracoscopic surgery. In this case, while lobectomy can definitively and easily eliminate the target tumors, this outcome is not guaranteed by the sublobar resection approach. Among the small-sized lung cancers, tumor characteristics on computed tomography (CT) include solid, semi-solid, and pure ground-glass appearances. In particular, small-sized tumors containing ground-glass components tend to be undetectable during surgery, because they cannot be palpated or visualized when located in deep parenchyma. Some methods for precisely resecting such undetectable tumors have been reported (4-12). Conventionally, tumor marking using hook-wire has been performed worldwide. However, this method has some issues; the puncture of the visceral pleura necessitated by the procedure confers the possibility of serious complications including pneumothorax, pulmonary hemorrhage, and air embolism (13). In light of these risks, various alternative methods have recently been developed. The hook-wire method under cone-beam CT and the microcoil method mitigate the risk of air embolism by puncturing the visceral pleura puncture under breath-controlled conditions (5,6,12). Dye marking methods using methylene blue, indigo-carmine, or indocyanine green (ICG) have also been reported as effective alternatives (7-11). In particular, the method using ICG has been increasingly reported in recent years, because the thoracoscopic scope for ICG has become widespread (11). Other reportedly effective approaches include virtual-assisted lung mapping (VAL-MAP) and radio frequency identification (RFID) (14,15). Although VAL-MAP is well established, RFID has only recently received attention as an alternative innovative method. Both VAL-MAP and RFID methods may have disadvantages, such as the need for certain skills specific to the transbronchial approach as well as the fact that they are both lengthy preoperative procedures and require anesthesia to perform tumor localization. While these technical skills may be overcome by training on these methods, the duration of these procedures and anesthesia would be unavoidable. However, severe complications such as air embolism can be avoided by performing surgery without visceral pleural puncture. On the other hand, anatomic segmentectomies using three-dimensional (3D) CT simulations without any tumor marking have been previously reported (16). Hence, although such an approach could be suitable for patients for whom tumor marking is contraindicated, combining tumor marking with 3D CT simulations during segmentectomy for undetectable tumors in patients where tumor marking can be performed would also aid in the precise resection of those tumors.

Previously published tumor marking methods may be considered indirect approaches, as the markers were administered locally to tissue surrounding the target tumors. In contrast, the method using pafolacianine may be considered more direct because the agent binds the folate receptor, thereby locating the tumor. Furthermore, as many as 85% of pulmonary malignancies have been reported to express the folate receptor (17-19), allowing the target tumors to be precisely resected via this direct molecular system approach.

Pafolacianine is a first-in-class agent that was previously reported to be useful in the intraoperative detection of ovarian cancer (20). On the other hand, the use of pafolacianine has not yet been widely adopted in thoracoscopic surgery. Sarkaria et al. (13) introduced a novel and efficient approach to thoracoscopic surgery for malignant lung tumors by identifying undetectable and synchronous tumors in patients who were intentionally randomized between the white-light group and the intraoperative molecular imaging (IMI) group. One or more clinically significant events that indicated the effect of IMI occurred in 53% of participants, which was significantly greater than the prespecified 10% threshold. Especially, this study utilized pafolacianine as an agent for the marking of clinically undetectable tumors and revealed its potential to aid the precise resection of such tumors. It is essential to ensure a sufficient surgical margin from the cut surface while performing sublobar resections for small-sized lung cancer. Pafolacianine may help secure a sufficient margin, as demonstrated by the way it was used to describe the study’s potential. Furthermore, this method opens up the possibility of detecting the target tumors as well as occult synchronous lesions. Additionally, Sarkaria et al. mention the effectiveness of pafolacianine in cases where the cancer has spread through the airways (13), which leads to a lower prognosis in adenocarcinoma and is recently becoming a topic of interest in the lung cancer field. Thus, the molecular approach using pafolacianine is distinguished from the previously published indirect methods such as the hook-wire approach, dye marking, VAL-MAP, and RFID, and is therefore considered a method with unprecedented potential.

However, although pafolacianine has the advantage of proper tumor marking regardless of the size or the ground-glass component ratio, the depth of the lesion and the close-cut margin have remained the limiting factors of this method. When the target tumor is localized in deep parenchyma, segmentectomy would be a better option than wedge resection for securing sufficient surgical margin (21). Although the sublobar resections performed in this study did not differentiate between wedge resection and anatomic segmentectomy, pafolacianine might have the potential to be involved in the identification of surgical margins as an adjunctive method during segmentectomy. In this study, the indications for this method were not clarified. Although the indications may not be entirely established yet, it is expected that when more patients undergo pafolacianine treatment, the in-depth indications will be examined. Regarding future steps, it will be necessary to also assess the tumor characteristics before surgery because the tumor’s size; its location including distance from the visceral pleura; and the ratio of ground-glass opacity were essential factors in selecting the marking methods during thoracoscopic and robotic surgery. Moreover, despite its novelty and ingenuity, some problems with this method remain, such as its sensitivity and specificity. The possibility that this method could result in false-positive resection for granulomas remains, as it may lead to an increase in needless resections during the resection process. Thoracic surgeons would have to carefully select the cases preoperatively, for which this method would be suitable to avoid unnecessary resections. Additionally, the pafolacianine could not be detected with a usual ICG scope. This is unfortunate, given that the scope has recently become more widely used for the identification of the intersegmental line during segmentectomy. Moreover, pafolacianine is a new agent that has not yet been fully established in the field of thoracic surgery; therefore, it is logically not available in all institutions worldwide. However, it is expected to become widely used shortly. Furthermore, the usual ICG scope could also become available for widespread use of this method in the future.

In conclusion, although the pafolacianine approach still has some barriers to overcome, it is projected to become available at several institutions in the future. Overall, pafolacianine is a very promising drug for sublobar resection of small-sized undetectable lung cancers during thoracoscopic and robotic surgery.

Acknowledgments

The author would like to thank Editage (https://www.editage.jp/) for English language editing.

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-56/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-56/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995;60:615-22; discussion 622-3. [Crossref] [PubMed]
2. Saji H, Okada M, Tsuboi M, et al. Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial. Lancet 2022;399:1607-17. [Crossref] [PubMed]
3. Altorki N, Wang X, Kozono D, et al. Lobar or Sublobar Resection for Peripheral Stage IA Non-Small-Cell Lung Cancer. N Engl J Med 2023;388:489-98. [Crossref] [PubMed]
4. Dendo S, Kanazawa S, Ando A, et al. Preoperative localization of small pulmonary lesions with a short hook wire and suture system: experience with 168 procedures. Radiology 2002;225:511-8. [Crossref] [PubMed]
5. Gill RR, Zheng Y, Barlow JS, et al. Image-guided video assisted thoracoscopic surgery (iVATS) - phase I-II clinical trial. J Surg Oncol 2015;112:18-25. [Crossref] [PubMed]
6. Rouzé S, de Latour B, Flécher E, et al. Small pulmonary nodule localization with cone beam computed tomography during video-assisted thoracic surgery: a feasibility study. Interact Cardiovasc Thorac Surg 2016;22:705-11. [Crossref] [PubMed]
7. Zhang Z, Liao Y, Ai B, et al. Methylene blue staining: a new technique for identifying intersegmental planes in anatomic segmentectomy. Ann Thorac Surg 2015;99:238-42. [Crossref] [PubMed]
8. Thistlethwaite PA, Gower JR, Hernandez M, et al. Needle localization of small pulmonary nodules: Lessons learned. J Thorac Cardiovasc Surg 2018;155:2140-7. [Crossref] [PubMed]
9. Endo M, Kotani Y, Satouchi M, et al. CT fluoroscopy-guided bronchoscopic dye marking for resection of small peripheral pulmonary nodules. Chest 2004;125:1747-52. [Crossref] [PubMed]
10. Kawada M, Okubo T, Poudel S, et al. A new marking technique for peripheral lung nodules avoiding pleural puncture: the intrathoracic stamping method. Interact Cardiovasc Thorac Surg 2013;16:381-3. [Crossref] [PubMed]
11. Ujiie H, Kato T, Hu HP, et al. A novel minimally invasive near-infrared thoracoscopic localization technique of small pulmonary nodules: A phase I feasibility trial. J Thorac Cardiovasc Surg 2017;154:702-11. [Crossref] [PubMed]
12. Hsu PK, Wu YC. The feasibility of electromagnetic navigation-guided percutaneous microcoil localization for thoracoscopic resection of small pulmonary nodules. J Thorac Cardiovasc Surg 2019;157:e211-4. [Crossref] [PubMed]
13. Sarkaria IS, Martin LW, Rice DC, et al. Pafolacianine for intraoperative molecular imaging of cancer in the lung: The ELUCIDATE trial. J Thorac Cardiovasc Surg 2023;166:e468-78. [Crossref] [PubMed]
14. Sato M, Omasa M, Chen F, et al. Use of virtual assisted lung mapping (VAL-MAP), a bronchoscopic multispot dye-marking technique using virtual images, for precise navigation of thoracoscopic sublobar lung resection. J Thorac Cardiovasc Surg 2014;147:1813-9. [Crossref] [PubMed]
15. Sato T, Yutaka Y, Nakamura T, et al. First clinical application of radiofrequency identification (RFID) marking system-Precise localization of a small lung nodule. JTCVS Tech 2020;4:301-4. [Crossref] [PubMed]
16. Kato H, Oizumi H, Suzuki J, et al. Thoracoscopic anatomical lung segmentectomy using 3D computed tomography simulation without tumour markings for non-palpable and non-visualized small lung nodules. Interact Cardiovasc Thorac Surg 2017;25:434-41. [Crossref] [PubMed]
17. Okusanya OT, Deshpande C, Barbosa EM Jr, et al. Molecular imaging to identify tumor recurrence following chemoradiation in a hostile surgical environment. Mol Imaging 2014; [Crossref] [PubMed]
18. Shen J, Putt KS, Visscher DW, et al. Assessment of folate receptor-β expression in human neoplastic tissues. Oncotarget 2015;6:14700-9. [Crossref] [PubMed]
19. Gangadharan S, Sarkaria IN, Rice D, et al. Multiinstitutional Phase 2 Clinical Trial of Intraoperative Molecular Imaging of Lung Cancer. Ann Thorac Surg 2021;112:1150-9. [Crossref] [PubMed]
20. Randall LM, Wenham RM, Low PS, et al. A phase II, multicenter, open-label trial of OTL38 injection for the intra-operative imaging of folate receptor-alpha positive ovarian cancer. Gynecol Oncol 2019;155:63-8. [Crossref] [PubMed]
21. Kato H, Oizumi H, Suzuki J, et al. What is the most appropriate procedure for intraoperative localization of small pulmonary nodules? J Thorac Dis 2018;10:E155-7. [Crossref] [PubMed]