Competing Local Therapies - Is Elvis Leaving the Building?

Objective: Close margin distance after wedge resection has been associated with lung cancer recurrence and death. The relationship between pathologic margin and recurrence has not yet been established after anatomic lung resection. We hypothesized that close pathologic margin after anatomic lung resection would not be associated with decreased overall survival.

Methods: Detailed pathology reports were extracted among patients receiving anatomic lung resection at a single institution between 2014-2021. Patients with "distance to closest margin" documented were included. Patients with pathologic metastatic disease were excluded. "Close" pathologic margin was defined as closest pathologic margin <1cm. The outcome of interest was overall survival defined as time from surgery to last follow up or death, which was calculated using state Death Record Indices. Kaplan-Meier survival estimates were performed using log rank test. Multivariable cox proportional hazard analysis was performed, including an interaction analysis, to evaluate close pathologic margin in each "extent of resection": lobectomy, segmentectomy, bilobectomy, pneumonectomy.

Results: Among 246 patients included in the study, 97 (39.4%) had a close pathologic margin. The average margin was 1.87cm (median 1.2cm, IQR 0.5-2.6cm). Close margin status did not vary by extent of resection, or nodal status, but was more likely with higher T-stage tumors (T1 36.8%, T2 28.6%, T3 58.8%, T4 66.7%, p=0.004). Median follow-up was 2.4 years and did not vary by margin status (p=0.399). Overall survival was not decreased among patients with a close margin (Figure 1, p=0.367). In a multivariable cox hazard analysis of overall survival, close margin was not associated with decreased overall survival (HR 0.457, p=0.087), while CHF (HR 4.45, p=0.002), T4 tumors (HR 8.67, p=0.001) and nodal metastasis (HR 4.90, p<0.001) were associated with decreased survival. A multivariable interaction analysis between anatomic margin and extent of resection did not demonstrate decreased survival associated with close pathologic margin among patients receiving segmentectomy (relative to >1cm margin and lobectomy – HR 0.356, p=0.345).

Conclusions: Close pathologic margins are not associated with increased risk of death after anatomic lung resections. In the setting of CALGB 140305, sublobar anatomic lung resection may be increasingly safely performed, and negative pathologic margins after segmentectomy are likely sufficient. 

Objective:

During wedge resections of ground glass opacities, it can be difficult to ascertain negative margins on the parenchymal staple lines by palpation or visualization alone. Frozen section is prone to human error, time consumptive and often difficult to remove staples real-time. We propose a new technology, near-infrared needle-based confocal laser endomicroscopy (NIR-nCLE) to study the presence of cancer cells along the staple line real time during surgery. Our technology utilizes intraoperative molecular imaging with a targeted fluorescent dye and a NIR confocal probe.

Method:
A549 cells (human lung adenocarcinoma cell lines) were co-cultured with a targeted fluorescent probe to cathepsin activity (VGT-309) in an Eppendorf and were compared to a negative and positive control. Fluorescence was measured after 2 hours using Iridium Vision Sense Imaging System (Vision Sense, New York, NY). As a proof of concept, we used normal lung parenchyma from a patient with a negative staple line and injected it with A549-VGT309 cells at two separate locations with 3 x106 and 4.5 x 106 cells. We then translated this data into a murine lung cancer model. Finally, the probe was used over the staple line of a resected tumor from patients who received VGT-309 to assess for any residual disease in real-time. NIR-nCLE probe and ImageJ were used to measure the mean fluorescence intensity (MFI).
Results:

Fluoresce intensity in A549-VGT in an Eppendorf was 71.8a.u, compared to 12.84a.u in our negative control, confirming selective fluorescence in cancer cells. In our proof of concept model, the sites injected with A549-VGT had a MFI of 147.55 arbitrary units (a.u) and 145.37a.u respectively, which was significantly higher than the negative staple line mean of 55.4a.u (p<0.001). Finally, in our pilot clinical model (n=3), tumor MFI was 175.42a.u and 218.78a.u compared to 49.2a.u and 54.6a.u respectively in normal lung parenchyma (p<0.001). We also had an MFI of 55.83a.u on normal parenchyma compared to 50.55a.u on a negative staple line margin (p=0.2) (figure 1).


Conclusion:

NIR-nCLE can detect VGT-targeted cancer cells along a staple line, providing surgeons with a rapid confirmation of their R0 resection. We hypothesize that this technology can be integrated into the OR workflow to expedite surgical decision making and minimize waiting time on pathology with real-time feedback to the surgeon. 

Objective: To evaluate trends in the utilization of stereotactic body radiotherapy (SBRT) and the long-term survival of SBRT versus surgery in healthy patients with early-stage non-small cell lung cancer (NSCLC).

Methods: The National Cancer Database was queried for patients without documented comorbidities, who underwent surgical resection (lobectomy, segmentectomy, or wedge resection) or SBRT for clinical stage I NSCLC between 2012 and 2018. In the SBRT cohort, patients who were coded as not being offered surgery secondary to health or advanced age, were excluded. Perioperative mortality and 5-year survival were compared among propensity matched cohorts of patients who received SBRT vs. surgery, and repeated for the subset of SBRT patients who had documented refusal a recommended surgery.

Results: Overall 30,658 patients were identified, including 24,729 (80.7%) who underwent surgery and 5,929 (19.3%) treated with SBRT. Between 2012 and 2018 the proportion of patients receiving SBRT increased from 15.9% to 26.0% (p<0.001). In logistic regression, increasing age (odds ratio [OR] 1.09; 95% confidence interval [95%-CI] 1.09-1.10; p<0.001) and squamous histology (OR 1.25; 95%-CI 1.17-1.34; p<0.001) were associated with receiving SBRT. The 30-day and 90-day mortality were higher among patients undergoing surgical resection versus SBRT (1.7% vs. 0.3%, p<0.001; 2.8% vs. 1.7%, p<0.001). The unadjusted 5-year survival was greater in surgically managed patients (75.8% vs. 40.5% SBRT; p<0.001). In Kaplan Meier of propensity matched patients, the long-term survival favored SBRT for the first several months, but separated after one year, and by year two, significantly favored surgical management (5-year survival 61.9% for surgery vs 30.3% for SBRT; p<0.001) (Figure 1a). The propensity-matched analysis was repeated to only include SBRT patients who had documented refusal of a recommended surgery, again demonstrating superior survival with surgical management (5-year survival 63.5% with surgery vs 42.8% SBRT; p<0.001) (Figure 1b).

Conclusions
Over the past decade, SBRT has been increasingly used to treat early-stage lung cancer in comorbidity- free patients. Among patients that are eligible for either treatment, the long-term survival appears to favor surgical management over SBRT, particularly for patients with a health-related life expectancy exceeds two years. 

Background
Transbronchial microwave ablation of lung nodules using electromagnetic navigation bronchoscopy (ENB) is an emerging local therapy for lung oligometastases and early lung cancers in unfit patients. In particular, it is useful for the management of multifocal lung cancers as part of lung preserving strategy, as this population has become increasingly prevalent. Concomitant ablation of multiple lung nodules in a single operating session is postulated to provide a one-stop solution for this subgroup of patients.

Methods
Out of 72 patients who underwent ENB microwave ablation in hybrid operating room from April 2020 to October 2022, 18 patients had two or more lung nodules ablated in the same operating session. Nodules were proven or highly suspicious of malignancies or metastases. Feasibility and safety of concomitant ablation were retrospectively reviewed.

Results
A total of 42 nodules in 18 patients (5 males and 13 females) underwent concomitant multi-nodular ablation, with a mean age of 63. Reasons for lung preserving strategy were multifocal lung cancer (83.3%) and lung oligometastases (16.7%). Among those with multifocal disease, 86.7% had previous major lung resection for lung cancer. Majority of patients had ablation to two lung nodules, while 2 had ablation to three nodules and another 2 had ablation to 4 lung nodules. 9 patients had ablation to lesions resided in the same lobe, 7 in different lobes on the same side, and 2 on both sides of lung. Mean nodule size is 9.9mm (range 5-20mm). Mean minimal margin was 5.9mm, while 24 nodules (57.1%) required double ablation to ensure good coverage. Patients undergoing concomitant ablation as opposed to separate sessions benefit from fewer general anesthesia risks, and the approximated time saved for intubation, ENB registration and verification is 30 minutes per patient. The average operating time was 196 minutes for double nodule ablation, while that for single nodule ablation was 126 minutes in our historical cohort. There were no major complications despite overlapping ablation zones and mean hospital stay was 1.19 days. Only 1 patient who had triple nodule ablation developed post-ablation reaction.

Conclusions
Concomitant transbronchial microwave ablation of multiple lung nodules is feasible and safe without increased complication rate. It is an important armamentarium in the contemporary lung preserving strategy for battling multifocal lung cancer or lung oligometastases. 

Objective: Surgical resection is the standard treatment for stage 1 NSCLC, however some patients have comorbidities precluding surgery. The AATS recently published an Expert Consensus Document on the risk assessment and treatment for high-risk patients with Stage I NSCLC, including image-guided-computed-tomography (CT)-guided radiofrequency ablation (RFA) as a treatment option in these patients. The long term oncologic results and the prognostic factors associated with survival after CT-RFA have not been fully evaluated. Our objectives were to evaluate the outcomes of CT-guided RFA for high-risk stage I NSCLC patients, and factors associated with survival.
Methods: We reviewed outcomes of CT-guided RFA in biopsy proven stage I NSCLC in high-risk patients. All procedures were performed by thoracic surgeons under image (CT) guidance. The primary endpoint studied was overall survival (OS). Kaplan-Meier plots were constructed using Greenwood confidence limits. Analysis of individual covariates associated with OS was performed with univariate proportional hazards regression and log rank test.
Results: A total of 111 patients (49 men; 62 women; median age 74 years, range 51-95), underwent CT-guided RFA for NSCLC (stage 1A n=91; stage 1B n=20; median size 2 cm). At a median follow-up of 40 months, the estimated 2-year overall-survival was 69% (CI = 60% - 78%), and 3-year OS was 58% (49% – 69%), with a median survival of 3.5 years (CI = 2.9 – 4.7 years). The survival of Stage 1A was significantly better than stage IB (p = .011). For patients with tumor size less than 2 cm, the 2-year overall-survival was 86% (CI 75% -97%), and 5-year overall-survival was 51% (CI 36% -72%), with an increased median survival of 8.11 years (CI 3.5 – not reached) compared to larger tumors (p = .001;Figure). Covariates that were associated with overall-survival included stage (p = .011), size (p=0.001), histology (squamous vs. adeno; p = .0052), and age (p = .0546).
Conclusions: While surgical resection remains the standard, image-guided RFA provides an alternate treatment option for high-risk patients with Stage 1 NSCLC who are not surgical candidates. Analysis of covariates associated with survival showed that size of the lesion was an important prognostic factor. Further, stage, histology, and age were all associated with survival after RFA. Additional prospective studies with RFA are required to further define patient selection in this high-risk group of patients. 

Objective: To describe multimodality management of lung tumors in a newly established multidisciplinary lung ablation clinic (LAC).
Methods: This retrospective cohort study included consecutive patients with primary lung cancer or pulmonary metastases evaluated in a LAC from its inception in 2/2020 to 10/2022. Thoracic surgeons, radiation oncologists, interventional pulmonologists, and thoracic radiologists experienced in interventional procedures met weekly for 1 hour with input from medical oncologists as needed to discuss imaging and management of patients referred for consideration of percutaneous image-guided thermal ablation (IGTA). Decision-making and treatment recommendation were prospectively recorded. Treatments received within 12 months after the visit were abstracted from the EMR following IRB approval.
Results: 287 patients (male, n=120 [42%]; median age 69 years; 60% ECOG 0 [range 0-3]) with primary lung cancer (n=125 [44%]) or pulmonary metastases (18% sarcoma; 11% colorectal cancer, 5% renal cell carcinoma) were reviewed in 97 LAC sessions. 38 (13%) of patients were reviewed more than once. Pre referral, 137 (48%), 126 (44%), 66 (23%), and 42 (15%) had received systemic therapy or resection, stereotactic ablative radiotherapy (SABR), or IGTA to the lung, respectively. Treatment recommendations considered 1) histology; 2) tumor biology; 3) location, size, and the number of lesions; 4) patient age, co-morbidities, and ECOG status; and 5) lesion-specific risk of complications associated with each modality. Local ablative therapy was recommended for 183 patients (64%), including surgery, SABR, and IGTA, for 24 (8.4%), 43 (15%), and 71 (25%), respectively. Two or more modalities were considered equally appropriate for 45 patients (16%). 170 patients (59%) received local therapy, including surgery for 34 (12%), SABR for 50 (17%), and IGTA for 70 (24%). Multimodal therapy occurred in 14 patients (5%), including 5 treated with SABR, then IGTA; 3 with IGTA then SABR; 3 with surgery then SABR; 2 with surgery then IGTA; 1 with surgery, then SABR, then IGTA. Systemic therapy was recommended for 51 patients (18%), including 26 (9%) who also received local therapy.
Conclusions: Multidisciplinary evaluation of patients with primary and metastatic lung tumors referred for IGTA demonstrated that 17% underwent SABR and 12% underwent resection instead, while 5% required multimodal therapy highlighting the importance of a multidisciplinary LAC.