The ELUCIDATE trial: a step closer to complete resection of lung tumors

Lung cancer is the most prevalent and deadliest form of cancer worldwide. Non-small cell lung cancer (NSCLC), the leading cause of cancer-related deaths in the United States, accounts for approximately 85% of all lung cancer patients (1). Despite the surgical removal of malignant lesions, nearly 40% of lung cancer patients experience disease recurrence within 5 years post-surgery (2). Although surgery remains the gold standard for treating early-stage lung cancer, surgeons can face challenges when relying exclusively on visual and tactile guidance (3). Furthermore, advancements in minimally invasive surgery have emphasized the importance of intraoperative imaging techniques. Notably, approximately 10–20% of NSCLC patients develop synchronous disease that often goes undetected during surgery due to limitations in visual and tactile feedback.

Intraoperative molecular imaging (IMI) effectively overcomes this limitation by using specific fluorescing agents, enabling surgeons to identify the cancerous region. Consequently, it allows surgeons to resect the cancer-affected area and assess the margins (4).

ELUCIDATE trial

The ELUCIDATE trial, a phase 3 multicenter study, enrolled 112 patients (4). Patients with suspected or biopsy-confirmed lung cancer scheduled for sublobar lung resection were administered pafolacianine within 24 h before surgery (4). Patients were randomly assigned to either surgery with or without IMI at a ratio of 10:1. We performed 10:1 randomization to reduce the risk of potential bias related to underestimation of the number of lesions initially localized by white light when the investigators knew that near infrared (NIR) would subsequently be utilized.

The primary endpoint was the proportion of patients who experienced a clinically significant event (CSE), indicating a significant change in the surgery. Secondary endpoints included the calculation and estimation of sensitivity and false-positive rates for all patients who underwent IMI.

A CSE was at least one of the following:

• Removal of one or more primary “lung nodule(s)” solely detected via NIR examination (i.e., not under white light and/or palpation) and confirmed by histological examination to not be benign lung parenchymal nodules;
• Removal of one or more synchronous cancerous lesions solely detected via NIR examination (i.e., not under white light and/or palpation) and confirmed by histological examination to be cancerous;
• Identification of a cancer-positive margin ≤10 mm via NIR, as determined in the operating room by the investigator and confirmed via histological examination.

Pafolacianine, a folate analogue indocyanine green-like conjugate, is a novel fluorescent imaging agent. It binds folate receptors (FRs) with approximately 1 nM affinity and eliminates negative tissues with a half-life of <30 min (5). By accumulating preferentially in FR+ tumors, pafolacianine can label cancerous nodules so they are visually highlighted intraoperatively when stimulated using a near-infrared lighting system, with minimal photobleaching. Approximately 85% of pulmonary malignancies that remain unresponsive to chemotherapy express FRs. We hypothesized that IMI using pafolacianine enhances surgical outcomes by reducing positive margins, identifying additional cancers, and localizing hard-to-locate lesions (4).

Each patient received intravenous pafolacianine at 0.025 mg/kg over 60 min within 24 hours before surgery. Each surgery began using white light visualization to identify and localize the target nodules. Upon completion of white light visualization, IMI was incorporated based on randomization (Visionsense VS3 Iridium open imaging camera system; Medtronic, Minneapolis, MN, USA) (4).

In total, 134 samples were obtained from 100 patients who underwent IMI. Of these samples, 108 (81%) acquired from 78 patients exhibited fluorescence under IMI. Regarding the primary endpoint, 53 of 100 patients who underwent IMI experienced ≥1 CSE, surpassing the pre-specified threshold of 10% (95% confidence interval: 42.8–63.1, P<0.0001). Of these, 43 experienced 1 CSE and 10 experienced >1 CSE; overall, 65 CSEs developed in these 53 participants. Nineteen of the CSEs in 19 of 100 participants (19%) were primary nodules that had not been located under white light and/or palpation. NIR imaging identified a total of 10 synchronous cancers in eight participants that had not been detected by preoperative imaging or intraoperative white light inspection. These events included the identification of primary nodules in 19 patients that were not detectable through white light visualization or palpation.

Among the samples sent for pathology analysis, 80/104 were positive for cancer, with the secondary endpoint revealing an estimated sensitivity of 76.9%. Furthermore, 28 of 108 samples (25.9%) yielded false-positive results; 10 and 18 of these results were primary nodules and synchronous lesions, respectively. Histology revealed that the false-positive tissues were principally benign or normal lung parenchymae. When a pathology was identified, it was most often a granulomatous disease; there was one fibrous tumor, one meningothelial-like nodule, one anthracotic nodule, and one lipoid pneumonia.

The median time to localize the primary nodule was 1 min using IMI with white light examination, whereas it was 4 min during white light examination alone (4).

Notably, no drug-related serious adverse events were observed in most patients (94.6%) who received the full pafolacianine dose. However, reactions were observed in 19 patients (17%); nausea was the most common side effect (reported by 10 patients). In total, 524 adverse events were documented across all patients. Although most of these events were unrelated to IMI, they were associated with surgical procedures, such as postoperative pain (79.5%) and respiratory disorders (54.5%).

Limitations of the trial included the short duration of recruitment and follow-up. A longer follow-up duration is required. IMI accessibility can be difficult; however, in this trial, all 12 centers used the same system.

How do we incorporate the ELUCIDATE trial findings into our daily practice?

Incorporating the findings of the ELUCIDATE trial into our daily medical practice can significantly impact early-stage lung cancer management. Although surgery remains the gold standard for treating early-stage lung cancer, complete tumor removal can be difficult (3,6). The ELUCIDATE trial introduced the concept of using IMI to enhance surgical precision and improve patient outcomes. Pafolacianine can enhance surgical outcomes by facilitating the identification of primary tumors and the detection of synchronous lesions (4). The trial findings demonstrated reduced time for primary nodule identification, good sensitivity for detecting lesions, and a low rate of false positives (4). Notably, pafolacianine is well tolerated and exhibits no significant adverse effects; consequently, prescription should be considered, particularly for sublobar resection in early-stage lung cancer surgery. Further studies are needed to assess the application of IMI against cancers with percutaneous or endobronchial localization.

Conclusions

IMI with pafolacianine represents a significant advancement toward complete lung cancer resection. It improves the intraoperative localization of malignant nodules, thereby increasing the possibility of their complete surgical removal. Furthermore, it is a valuable adjunctive tool for surgeons during surgeries, potentially improving patient survival. Further studies are needed to determine the optimal role of pafolacianine during lung tumor resection.

Acknowledgments

We would like to thank Textcheck Inc. for 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-23-20/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-20/coif). M.O. receives speaker fees from Olympus Corporation and AMCO Inc., and serves as an invited guest speaker at academic medical meetings. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are 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

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