Node-negative Non-small Cell Lung Cancer Research Articles

Impact of Maximum Point Dose Within the Planning Target Volume on Local Control of Nonsmall Cell Lung Cancer Treated With Stereotactic Body Radiotherapy.

No consensus exists on the maximum dose delivered to the planning target volume (PTV) in the delivery of stereotactic body radiotherapy (SBRT) for primary lung cancer. We investigated whether higher biologically effective doses (BED) within the PTV were associated with improved tumor control. We reviewed patients with early-stage, node-negative nonsmall cell lung cancer who received curative-intent SBRT between 2005 and 2018. We calculated the maximum BED (maxBED) within the PTV for all patients, analyzing outcomes using the cumulative incidence method and Fine-Gray test statistics to assess prognostic impact. We analyzed 171 patients (median age, 70.2; range, 43 to 90y) with 181 lung nodules. Median follow-up was 2.7 years (range, 0.1 to 12y) for all patients and 4.2 years (range, 0.2 to 8.4y) for living patients. Median maximum tumor diameter was 1.9cm (range, 0.7 to 5.6cm). Patients received a prescription of 48 or 50 Gy in 4 or 5 fractions, respectively, except for one who received 60 Gy in 5 fractions. Median maxBED was 120 Gy (range, 101 to 171 Gy). There was no difference in the 3-year local control (LC) rate among patients treated with a maxBED<120 Gy versus ≥120 Gy ( P =0.83). No significant differences in LC were observed between patients with early-stage nonsmall cell lung cancer treated with SBRT in 4 or 5 fractions with a maxBED≥120 Gy. However, a higher maxBED trended toward improved LC rates, suggesting a maxBED threshold greater than 120 Gy may be needed to improve LC rates.

Resectability versus Operability in Early-Stage Non-Small Cell Lung Cancer.

With increased detection of early-stage non-small cell lung cancer (NSCLC) owing to screening, determining optimal management increasingly hinges on assessing resectability and operability. Resectability refers to the feasibility of achieving microscopically negative margins based on tumour size, location and degree of local invasion and achieving an anatomical lobar resection. Operability reflects the patient's tolerance for resection based on comorbidities, cardiopulmonary reserve and frailty. Standardized criteria help guide these assessments, but application variability contributes to practice inconsistencies. This review synthesizes a strategic approach to evaluating resectability and operability in contemporary practice. Standardization promises reduced care variability and optimized patient selection to maximize curative outcomes in this new era of early detection. Recent pivotal trials demonstrate equivalency of sublobar resection to lobectomy for small, peripheral, node-negative NSCLC, expanding options for parenchymal preservation in borderline surgical candidates. Furthermore, recent phase 3 trials have highlighted the benefit of chemoimmunotherapy as a neoadjuvant treatment with an excellent pathological response and a down staging of the tumour, improving the resectability of the early-stage NSCLC. A good assessment of the operability and resectability is paramount in order to offer the best course of treatment for our patients. European and American societies have issued recommendations to help clinicians assess the cardiopulmonary function and predict the extension of pulmonary resection that could afford the patient. This operability assessment is closely linked with the evaluated tumour resectability which will determine the extension of pulmonary resection that is needed for the patient in order to achieve a good oncological outcome. Some major progresses have been done recently to improve the operability and resectability of patients. For instance, prehabilitation program allows better postoperative morbidity. Some studies have shown a potential good oncological outcome with sublobar resection expending access to surgery for patient with reduced lung function. Some others have identified the neoadjuvant immunochemotherapy as a potential solution for downstaging tumours. Work-up of early-stage NSCLC is a key moment and has to be done thoroughly and in full knowledge of the recent findings in order to propose the most appropriate treatment for the patient.

Prognostic Value of Hypoxia Gene Expression Signature in Early-Stage Non-Small Cell Lung Cancer Patients Treated with Stereotactic Body Radiation Therapy

Stereotactic body radiation therapy (SBRT) is an effective alternative to surgery in the treatment of early-stage non-small cell lung cancer (NSCLC). However, disease recurrence occurs in approximately 20-30% of patients. Hypoxia is a well-known factor promoting solid tumor progression, radiation resistance, and immune evasion. In this study, we utilize a previously published hypoxia gene expression signature (Buffa) and measure its association with clinical outcomes in patients with NSCLC treated with SBRT. Our study focused on patients with localized, node-negative NSCLC treated with SBRT, and we identified 92 patients treated at our institution between 2008 and 2018 with available gene expression data. Total RNA from formalin-fixed paraffin-embedded archival biopsy specimens (pre-therapy) was isolated and mRNA expression was analyzed using an assay for human samples. For each gene in the Buffa signature, the top 50% of mRNA abundance values were given a score of +1, and the bottom 50% were given a score of -1 to generate a tumor hypoxia score. High scores suggest a hypoxic tumor and low scores imply normoxia. Kaplan-Meier curves were used to assess overall survival, disease-free survival, local recurrence, regional nodal recurrence, and distant recurrence. Cox proportional hazards were performed to account for confounding due to age, T stage, ECOG performance status, biologically effective dose, patient sex, and histology (squamous vs non-squamous). The patient's gene expression data were dichotomized based on their median hypoxia score (Table 1). Median follow-up was 23.9 months (95% CI 20.6 - 26.6). A high hypoxia score was associated with squamous histology (p = 0.003). On univariate analysis, a high hypoxia score was significantly associated with local recurrence (hazard ratio [HR] = 5.63; 95% CI 1.03 - 30.78; p = 0.046) and distant recurrence (HR = 1.85; 95% CI 1.14 - 3.02; p = 0.013). There was no significant difference in overall survival (HR = 1.93; 95% CI 0.98 - 3.82; p = 0.058), disease-free survival (HR = 2.13; 95% CI 0.93 - 4.89; p = 0.074), or regional nodal recurrence (HR = 1.45; 95% CI 0.41 - 5.14; p = 0.57). On multivariate analysis, a high hypoxia score was associated with worse overall survival (HR = 2.73; 95% CI 1.23 - 6.07; p = 0.014), local recurrence (HR = 12.85; 95% CI 1.08 - 152.49; p = 0.043) and distant recurrence (HR = 1.91; 95% CI 1.13 - 3.22; p = 0.016). Our findings demonstrate that a hypoxia gene signature is significantly associated with worse survival and increased local and distant recurrence after SBRT for localized NSCLC. This hypoxia signature may be useful in prognostication, selecting patients for surgery versus radiation, or selecting patients for treatment intensification with radiation or other systemic agents, and should be prospectively validated.

Stereotactic ablative radiotherapy with or without immunotherapy for early-stage or isolated lung parenchymal recurrent node-negative non-small-cell lung cancer: an open-label, randomised, phase 2 trial

Stereotactic ablative radiotherapy (SABR) is the standard treatment for medically inoperable early-stage non-small-cell lung cancer (NSCLC), but regional or distant relapses, or both, are common. Immunotherapy reduces recurrence and improves survival in people with stage III NSCLC after chemoradiotherapy, but its utility in stage I and II cases is unclear. We therefore conducted a randomised phase 2 trial of SABR alone compared with SABR with immunotherapy (I-SABR) for people with early-stage NSCLC. We did an open-label, randomised, phase 2 trial comparing SABR to I-SABR, conducted at three different hospitals in TX, USA. People aged 18 years or older with histologically proven treatment-naive stage IA-IB (tumour size ≤4 cm, N0M0), stage IIA (tumour size ≤5 cm, N0M0), or stage IIB (tumour size >5 cm and ≤7 cm, N0M0) as per the American Joint Committee on Cancer version 8 staging system or isolated parenchymal recurrences (tumour size ≤7 cm) NSCLC (TanyNanyM0 before definitive surgery or chemoradiotherapy) were included in this trial. Participants were randomly assigned (1:1; using the Pocock & Simon method) to receive SABR with or without four cycles of nivolumab (480 mg, once every 4 weeks, with the first dose on the same day as, or within 36 h after, the first SABR fraction). This trial was unmasked. The primary endpoint was 4-year event-free survival (local, regional, or distant recurrence; second primary lung cancer; or death). Analyses were both intention to treat (ITT) and per protocol. This trial is registered with ClinicalTrials.gov (NCT03110978) and is closed to enrolment. From June 30, 2017, to March 22, 2022, 156 participants were randomly assigned, and 141 participants received assigned therapy. At a median 33 months' follow-up, I-SABR significantly improved 4-year event-free survival from 53% (95% CI 42-67%) with SABR to 77% (66-91%; per-protocol population, hazard ratio [HR] 0·38; 95% CI 0·19-0·75; p=0·0056; ITT population, HR 0·42; 95% CI 0·22-0·80; p=0·0080). There were no grade 3 or higher adverse events associated with SABR. In the I-SABR group, ten participants (15%) had grade 3 immunologial adverse events related to nivolumab; none had grade 3 pneumonitis or grade 4 or higher toxicity. Compared with SABR alone, I-SABR significantly improved event-free survival at 4 years in people with early-stage treatment-naive or lung parenchymal recurrent node-negative NSCLC, with tolerable toxicity. I-SABR could be a treatment option in these participants, but further confirmation from a number of currently accruing phase 3 trials is required. Bristol-Myers Squibb and MD Anderson Cancer Center Alliance, National Cancer Institute at the National Institutes of Health through Cancer Center Core Support Grant and Clinical and Translational Science Award to The University of Texas MD Anderson Cancer Center.

Abstract 734: Comprehensive validation of high-risk clinicopathologic features in early-stage, node-negative non-small cell lung cancer

Abstract Objective: Current guidelines recommend adjuvant therapy for patients with completely resected non-small cell lung cancer (NSCLC) with high-risk clinical or pathologic features. Despite this, the relationship between these features and cancer recurrence is poorly elucidated. Methods: We conducted a retrospective cohort study using a uniquely compiled dataset from the US Veterans Health Administration (VHA) including all Veterans with pathologic early-stage (≤5cm, N0) NSCLC receiving definitive surgical treatment (2010-2016). Based on National Comprehensive Cancer Network guidelines, we evaluated 6 high-risk features: tumor size, tumor grade, visceral-pleural invasion, lymphovascular invasion, non-anatomic wedge resection, and adequacy of nodal sampling. We developed a score reflecting the relationship between these high-risk features and recurrence, using a multivariable competing risk model (death as competing event). The score performance was then tested in an external cohort from the National Cancer Database (NCDB). Results: The study included 3,799 Veterans. The median follow-up was 7.1 years. Recurrence was detected in 800 (21.1%) patients. The association between high-risk features and cancer recurrence were as follows: tumor size (e.g., 31-40mm vs. 0-10mm, multivariable-adjusted hazard ratio, aHR 1.676, 95% CI 1.229-2.285, p=0.001), tumor grade (e.g., III vs. I, aHR 1.884, 95% CI 1.448-2.449, p&amp;lt;0.001), visceral-pleural invasion (aHR 1.096, 95% CI 0.905-1.329, p=0.35), lymphovascular invasion (aHR 1.747, 95% CI 1.441-2.117, p&amp;lt;0.001), non-anatomic wedge resection (aHR 1.335, 95% CI 1.101-1.619, p=0.003), and adequacy of nodal sampling (e.g., 1-4 lymph nodes vs. ≥10 lymph nodes, aHR 1.392, 95% CI 1.149-1.687, p&amp;lt;0.001). Using these parameters, a score was created reflecting the association between high-risk features and recurrence. The score ranged from 0-36, with higher scores reflecting higher cumulative incidence of recurrence. The score was further divided into low- (0-11, n=1,263, 33.3%; 5-yr recurrence risk 13.0%), moderate- (12-15, n=1,134, 29.9%; 5-yr recurrence risk 19.0%), and high-risk (16-36, n=1,402, 36.9%; 5-yr recurrence risk 27.1%) categories. Higher scores were also associated with diminished overall survival (median OS, low-risk: 9.0 yrs; moderate-risk: 7.3 yrs; high-risk: 5.4 yrs). The score was further tested in a cohort of 63,232 patients from the NCDB and higher scores remained associated with worse overall survival (median OS, low-risk: 9.4 yrs; moderate-risk: 8.0 yrs; high-risk: 6.3 yrs). Conclusions: High-risk clinicopathologic features are associated with dramatically higher risk of recurrence and worse overall survival. Multivariable assessment of these features using a comprehensive yet pragmatic score may help to standardize adjuvant treatment eligibility following curative intent resection. Citation Format: Brendan T. Heiden, Daniel B. Eaton, Su-Hsin Chang, Yan Yan, Martin W. Schoen, Bindiya G. Patel, Theodore S. Thomas, Bryan F. Meyers, Benjamin D. Kozower, Varun Puri. Comprehensive validation of high-risk clinicopathologic features in early-stage, node-negative non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 734.

Wedge resection plus adequate lymph nodes resection is comparable to lobectomy for small-sized non-small cell lung cancer.

The study investigated whether wedge resection plus adequate lymph nodes resection conferred comparable survival to lobectomy for node-negative non-small cell lung cancer (NSCLC) ≤2 cm. The Surveillance, Epidemiology, and End Results database was used to identify patients diagnosed with node-negative NSCLC ≤2 cm and underwent wedge resection or lobectomy (2004-2015). Patients were stratified by the procedure (wedge resection, lobectomy) and the size of NSCLC (≤1 cm, 1-2 cm). We assessed survival between patients undergoing wedge resection and lobectomy. The optimal number of lymph nodes resected which made those two procedures comparable was explored by using Kaplan-Meier analysis and Cox regression analysis. Propensity score matching was performed to minimize the effect of confounding factors. 7893 patients with lobectomy and 2536 patients with wedge resection were identified. Wedge resection was associated with worse survival either in the ≤1 cm or 1-2 cm NSCLC before and after matching. For lesions 1-2 cm and receiving lobectomy, more lymph nodes resected conferred statistically significant increase on survival and six nodes were optimal. For lesions ≤1 cm and receiving lobectomy, lymph nodes resection had no impact on survival. Wedge resection and lobectomy were comparable when one or more nodes for lesions ≤1 cm and six or more nodes for lesions 1-2 cm were resected. Wedge resection was inferior to lobectomy for NSCLC ≤1 cm and 1-2 cm. Wedge resection plus adequate lymph nodes resection was comparable to lobectomy.

Outcomes Following SBRT vs. IMRT and 3DCRT for Older Patients with Stage IIA Node-Negative Non-Small Cell Lung Cancer > 5 cm

BackgroundTo describe outcomes and compare the effectiveness of stereotactic body radiotherapy (SBRT) versus 3-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT) in patients with stage IIA lymph node-negative (N0) non-small cell lung cancer (NSCLC) tumors > 5 cm. MethodsWe used the SEER-Medicare database (2005-2015) to identify patients > 65 years with stage IIA (AJCC TNM7) N0 NSCLC > 5 cm tumors who were treated with SBRT, IMRT, and 3DCRT. We used propensity score methods with inverse probability weighting to compare lung cancer-specific survival (LCSS), overall survival (OS), and toxicity. ResultsOf 584 patients, 88 (15%), 140 (24%), and 356 (61%) underwent SBRT, IMRT, and 3DCRT, respectively. The SBRT group was older (P = .004), had more comorbidities (P = .02), smaller tumors (P = .03), and more adenocarcinomas (P < .0001). We found a trend towards higher median unadjusted OS with SBRT compared to IMRT and 3DCRT (19 vs. 13 and 14 months, respectively, P = .37). In our propensity score-adjusted analyses, SBRT was significantly associated with better OS and LCSS compared to IMRT (HROS: 0.78, 95% CI: 0.68-0.89, HRLCSS: 0.70, 95% CI: 0.60-0.81) and 3DCRT (HROS: 0.81, 95% CI: 0.72-0.93, HRLCSS: 0.80, 95% CI: 0.68-0.93). SBRT-treated patients also had lower overall adjusted complication rates compared to IMRT (OR: 0.74, 95% CI: 0.55-0.99) and 3DCRT (OR: 0.53, 95% CI: 0.40-0.71). ConclusionFor patients with NSCLC tumors > 5 cm, SBRT trends towards fewer toxicities and improved survival compared to other forms of radiotherapy. Our findings support SBRT as an appropriate treatment strategy for older patients with larger inoperable NSCLC tumors.

Patterns of Care and Outcomes in Non-Operative, Early-Stage Non-Small Cell Lung Cancer when Stereotactic Body Radiation Therapy is not Feasible

<h3>Purpose/Objective(s)</h3> Stereotactic body radiation therapy (SBRT) is the standard of care treatment for non-operative patients with early-stage non-small cell lung cancer (NSCLC). However, there are cases where safe delivery of SBRT is precluded (e.g., ultracentral tumors or those abutting brachial plexus/stomach) or where SBRT is not available (e.g., centers without SBRT capability). The optimal management with regards to radiation dose/fractionation and whether sensitizing chemotherapy should be considered is unclear. <h3>Materials/Methods</h3> We identified node-negative NSCLC patients with tumors <3 cm (cT1 N0) who received definitive RT in the National Cancer Data Base from 2004-2016. Patients receiving SBRT (defined as 48-60 Gy in £5 fractions or BED₁₀≥100 Gy) were excluded. The use of chemotherapy (none vs. sequential vs. concurrent) and RT type was examined (conventionally fractionated, [CFRT], defined as 59.4-70.2 Gy in 30-39 fractions; and hypofractionated RT [HFRT] defined as 50-72 Gy in >5 fractions using >2 Gy/fraction). Factors associated with receipt of chemotherapy were analyzed via univariable (UV) and multivariable (MV) logistic regression. Overall survival (OS) was evaluated with Kaplan-Meier analyses and log-rank test as well as UV and MV Cox proportional hazards. Propensity score matching was also performed for comparison of OS between groups. P-values less than 0.05 were considered significant. <h3>Results</h3> A total of 2,851 patients were included with 69% receiving CFRT and 31% receiving HFRT. Nearly 26% of patients received chemotherapy, delivered either concurrently (21%) or sequentially (5%). On MV analysis, receipt of chemotherapy was associated with younger age (<70 years, p<0.001), larger tumor size (2+ cm, p<0.001), BED₁₀<80 Gy (p<0.001) and receipt of CFRT (p<0.001). OS was significantly improved for patients receiving concurrent chemotherapy with CFRT compared to patients receiving CFRT alone (p<0.001) and HFRT alone (p=0.003), which remained significant after propensity score matching. On MV analysis, improved OS remained associated with concurrent chemotherapy (p<0.001), as was younger age (<70 years, p=0.024), female gender (p<0.001), fewer comorbidities (Charlson-Deyo score <2, p<0.001), private insurance (p<0.001), treatment at an academic center (p=0.026), smaller tumor size (<2 cm, p<0.001), and non-squamous histology (p=0.004). <h3>Conclusion</h3> Patterns of care for non-operative early-stage NSCLC patients when SBRT is not feasible vary greatly. A surprising proportion of patients (21%) receive concurrent chemotherapy. Interestingly, concurrent chemotherapy with CFRT was associated with improved OS compared to HFRT or CFRT alone, however this finding requires additional validation given the inherent biases of our study.

Lymph node dissections and survival in sublobar resection of non-small cell lung cancer ≤ 20mm.

A randomized trial of lobectomy versus segmentectomy for small-sized (≤ 20mm) non-small cell lung cancer (NSCLC) showed that patients who had undergone segmentectomy had a significantly longer overall survival (OS) than those who had lobectomy. More attention is needed regarding the required extent of thoracic lymphadenectomy in patients with small-sized NSCLC who undergo sublobar resection. The National Cancer Database was queried for patients with clinically node-negative NSCLC ≤ 20mm who had undergone sublobar resection between 2004 and 2017. OS of NSCLC patients by the number of lymph node dissections (LNDs) was analyzed using log-rank tests and Cox proportional hazards model. The cutoff value of the LNDs was set to 10 according to the Commission on Cancer's recommendation. This study included 4379 segmentectomy and 23,138 wedge resection cases. The sequential improvement in the HRs by the number of LNDs was evident, and the HR was the lowest if the number of LNDs exceeded 10. Patients with ≤ 9 LNDs had a significantly shorter OS than those with ≥ 10 LNDs (hazard ratio [HR] 1.50, 95% confidence interval [CI] 1.40-1.61, P < 0.0001). Multivariable analysis revealed that performing ≤ 9 LNDs was an independent factor for predicting OS (HR for death: 1.34, 95% CI 1.24-1.44, P < 0.0001). These results remained significant in subgroup analyses by the type of sublobar resection (segmentectomy, wedge resection). Performing ≥ 10 LNDs has a prognostic role in patients with small-sized NSCLC even if the resection is sublobar.

Characterizing node-negative non-small cell lung cancer patients with similarity networks: A CancerLinQ Discovery analysis.

e20585 Background: Patients with node-negative non-small cell lung cancer (NSCLC) whose tumors are completely resected account for approximately 17% of all patients with lung cancer, and disease recurrence occurs in approximately 1 in 5 of these patients. The lack of consensus on factors associated with risk of disease recurrence among node-negative NSCLC patients is a significant barrier to applying precision medicine strategies in this patient population. Clustering similar patients based on distances between various features of data is an emerging topic in precision medicine. Patient similarity networks represent a new model for clustering patients based on heterogeneous data, whereby any data type is converted into a similarity network by defining a similarity measure. The objective of this study was to examine the utility of patient similarity networks to identify NSCLC patients at higher risk of adverse outcomes. Methods: We conducted a retrospective, observational study of 6,020 node-negative NSCLC patients with an initial diagnosis in 2011-2014 in the CancerLinQ Discovery database. A patient similarity network was assembled based on comorbidities and network communities of patients with similar comorbidities at diagnosis were identified. Using Cox proportional-hazards modeling, we examined the extent to which patient age, sex, race, ethnicity, and network community predicted 2-year disease recurrence and 2-year mortality. Results: In the adjusted analyses, patients in the network community enriched for renal disease and congestive heart failure had an 83% increased risk of mortality (95% CI = 1.39-2.41). Patients in the network community enriched for pulmonary disease had a 37% increased risk of mortality (95% CI = 1.06-1.74) yet a lower risk of recurrence (HR = 0.5, 95% CI = 0.34-0.75). After adjusting for comorbidity network community, male patients had a 14% increased risk of mortality (95%CI = 1.02-1.28) and a 21% increased risk of recurrence (95% CI = 1.05-1.40) and black patients had a lower mortality risk (HR = 0.71, 95% CI = 0.58-0.86). Conclusions: Future studies applying patient similar networks to integrate additional diverse and high dimensional data types may afford more clarity in assigning risk of adverse outcomes.

Lymph node dissections and survival in sublobar resection of non-small cell lung cancer ≤ 20 mm.

e20583 Background: A recent Japanese phase III randomized trial of lobectomy versus segmentectomy for small-sized (≤ 20 mm) peripheral non-small cell lung cancer (NSCLC) (JCOG 0802) showed that patients who had undergone segmentectomy had a significantly longer overall survival (OS) in comparison with those who had lobectomy. More attention is needed regarding the required extent of thoracic lymphadenectomy in patients with small-sized NSCLC who undergo sublobar resection. Methods: The National Cancer Database was queried for patients with clinically node-negative NSCLC ≤ 20 mm who had undergone sublobar resection between 2004 and 2017. OS of NSCLC patients by the number of lymph node dissections (LNDs) was analyzed using Log-rank tests and Cox proportional hazards model. The cut-off value of the LNDs was set to 10 according to the Commission on Cancer’s recommendation. Results: This study included 4,379 segmentectomy and 23,138 wedge resection cases. The sequential improvement in the HRs by the number of LNDs was evident, and the HR was the lowest if the number of LNDs exceeded 10. Patients with ≤ 9 LNDs had a significantly shorter OS than those with ≥ 10 LNDs (hazard ratio [HR]: 1.50, 95% confidence interval [CI]: 1.40–1.61, P &lt; 0.0001). Multivariable analysis revealed that performing ≤ 9 LNDs was an independent factor for predicting OS (HR for death: 1.34, 95% CI: 1.24–1.44, P &lt; 0.0001). These results remained significant in subgroup analyses by the type of sublobar resection (segmentectomy, wedge resection). Conclusions: Performing ≥ 10 LNDs has a prognostic role in patients with small-sized NSCLC even if the resection is sublobar.

Patterns of Failure and Optimal Treatment Paradigm for Large, Inoperable, Node-Negative Non–small Cell Lung Cancer

ObjectivesThe ideal non-operative treatment for patients with large, node-negative non–small cell lung cancer (NSCLC) is poorly defined. To inform optimal treatment paradigms for this cohort, we examined patterns of failure and the impact of radiation therapy (RT) and chemotherapy receipt. Materials and MethodsNode-negative NSCLC patients with 5+ cm primary tumors receiving definitive RT at our institution were identified. Sites of initial progression were analyzed. Local progression, regional/distant progression, progression-free survival, and overall survival were analyzed via cumulative incidence function and Kaplan-Meier. Associations between local vs. regional/distant progression with treatment and clinicopathologic variables were assessed via univariable and multivariable competing risks regression. Results and ConclusionWe identified 88 patients for analysis. Among patients with recurrent disease (N = 36), initial patterns of failure analysis showed that isolated distant (27.8%) and isolated regional progression (22.2%) were most common. Distant or regional failure as a component of initial failure was seen in 88.9% of patients who progressed, while isolated local failure was uncommon (11.1%). Univariable and multivariable competing risks regression showed that receipt of SBRT was associated with reduced risk of local progression (HR 0.23, P = .012), and receipt of chemotherapy was associated with reduced risk of regional/distant progression (HR 0.12, P = .040). In conclusion, patients with large, node-negative NSCLC treated with definitive RT are at high risk of regional and distant progression. SBRT correlates with a reduced risk of local failure while chemotherapy is associated with reduced regional/distant progression in this patient population. Ideal treatment may include SBRT when feasible with appropriate systemic therapy.

Non-small Cell Lung Cancer Surpassing the Elastic Layer Should Remain Classified as pT2a

We aimed to evaluate the prognostic value of visceral pleural invasion on the survival of node-negative non-small cell lung cancer ≤3 cm using a large cohort. The Kaplan-Meier method was used to compare overall survival (OS); competing risk analysis with Fine-Gray's test was used to compare cancer- specific survival between groups. The least absolute shrinkage and selection operator penalized Cox regression model was used to identify prognostic factors. In total, 9725 eligible cases were included in this study, and they were separated into 3 groups: tumor invasion beneath the elastic layer (PL0), 8837 cases; tumor invasion surpassing the elastic layer (PL1), 505 cases; and tumor invasion to the visceral pleural surface (PL2), 383 cases. Visceral pleural invasion was more likely to occur in poorly differentiated and larger-sized tumors. Survival curves displayed that PL0 conferred better survival rates than PL1 and PL2, and PL1 achieved outcomes equivalent to those of PL2. Tumor size and histology subset analyses further corroborated this conclusion. Least absolute shrinkage and selection operator -penalized Cox regression analysis confirmed that PL status was an independent prognostic factor for both OS and cancer- specific survival. This study supported the notion that in node-negative non-small cell lung cancer ≤3 cm, PL1 patients should remain classified as pT2a, which could improve staging accuracy.

Nonoperative Treatment of Large (5–7 cm), Node-Negative Non–Small Cell Lung Cancer Commonly Deviates From NCCN Guidelines

Optimal treatment of nonoperative patients with large, node-negative non-small cell lung cancer (NSCLC) is poorly defined. Current NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) recommend definitive radiotherapy (RT) with or without sequential chemotherapy and do not include concurrent chemoradiotherapy (chemoRT) as a treatment option. In this study, we identified factors that predict nonadherence to NCCN Guidelines. Patients who received definitive RT for nonmetastatic, node-negative NSCLC with tumor size of 5 to 7 cm were identified in the National Cancer Database from 2004 through 2016. Patients were evaluated by RT type (stereotactic body RT [SBRT], hypofractionated RT [HFRT], or conventionally fractionated RT [CFRT]) and chemotherapy use (none, sequential, or concurrent with RT). Patients were classified as receiving NCCN-adherent (RT with or without sequential chemotherapy) or NCCN-nonadherent (concurrent chemoRT) treatment. Demographic and clinical factors were assessed with logistic regression modeling. Overall survival was evaluated with Kaplan-Meier, log-rank, and univariable/multivariable Cox proportional hazards regression analyses. Among 2,020 patients in our cohort, 32% received NCCN-nonadherent concurrent chemoRT, whereas others received NCCN-adherent RT alone (51%) or sequential RT and chemotherapy (17%). CFRT was most widely used (64% CFRT vs 22% SBRT vs 14% HFRT). Multivariable analysis revealed multiple factors to be associated with NCCN-nonadherent chemoRT: age ≤70 versus >70 years (odds ratio [OR] , 2.72; P<.001), treatment at a nonacademic facility (OR, 1.65; P<.001), and tumor size 6 to 7 cm versus 5 to 6 cm (OR, 1.27; P=.026). Survival was similar between the NCCN-nonadherent chemoRT and NCCN-adherent groups (hazard ratio, 1.00; P=.992) in multivariable analysis. A substantial proportion of inoperable patients with large, node-negative NSCLC are not treated according to NCCN Guidelines and receive concurrent chemoRT. Younger patients with larger tumors receiving treatment at nonacademic medical centers were more likely to receive NCCN-nonadherent therapy, but adherence to NCCN Guidelines was not associated with differences in overall survival.

Patterns of Use of Stereotactic Body Radiation Therapy Compared With Surgery for Definitive Treatment of Primary Early-stage Non-small Cell Lung Cancer.

As stereotactic body radiation therapy (SBRT) becomes widely available for early-stage non-small cell lung cancer (NSCLC), there may be concerns in the surgical community that SBRT is being offered for patients with operable tumors, even though surgery is standard of care. We evaluated the trends in SBRT and surgery over time for patients with NSCLC. The National Cancer Database was queried for patients with node-negative NSCLC ≤5 cm from 2004 to 2016. The relationships between definitive local treatment modalities and year were analyzed using a multinomial regression model while controlling for other covariates. Among the 202,367 patients who met the inclusion criteria, there was a steady decrease in mean tumor size in all treatment modalities, from 2.44 cm (SD=1.08) to 2.25 cm (SD=1.00) over the study period. In the multinomial model, the probability of receiving lobectomy demonstrated a slight decline from 58% (2004) to 53% (2016). The use of SBRT increased from 1% to 20%, while patients receiving no therapy declined from 27% to 16%. The likelihood of SBRT increased with year of diagnosis (P<0.0001) and decreasing tumor size (P<0.0001), compared with lobectomy. Age, race, income, facility, and Charlson-Deyo score were also associated with treatment modality. The mean tumor size of early-stage NSCLC decreased over the study period for all treatment modalities. SBRT use has increased, mostly among older patients with smaller tumors and Charlson-Deyo scores ≥3. The increase in SBRT contributed to the significant decline in patients who had no therapy.

Segmentectomy versus wedge resection for radiological solid predominant and low metabolic non-small cell lung cancer.

OBJECTIVESThe prognosis of segmentectomy and wedge resection for solid predominant early-stage non-small cell lung cancer with low metabolic activity is unclear.METHODSThis study aimed to assess patients who underwent segmentectomy or wedge resection with curative intent for clinically node-negative non-small cell lung cancer presenting as a solid predominant tumour (consolidation tumour ratio >50%) with a whole size ≤3 cm and [18F]-fluoro-2-deoxy-D-glucose accumulation weaker than that of the mediastinum tissue (Deauville score, 1 or 2) on positron emission tomography/computed tomography. The cumulative incidence of recurrence (CIR) was compared using the Gray method, and the predictive factor of CIR was analysed using the Fine and Gray method.RESULTSOf 140 patients included in this study, 93 (66.4%) underwent segmentectomy and 47 (33.6%) underwent wedge resection. No significant difference in the clinical stage was found between the 2 groups. The CIR was higher with wedge resection than with segmentectomy (P = 0.004). Recurrence after wedge resection was noted in 4 (8.5%) patients, 2 of whom had a recurrent site containing lung parenchyma of the preserved lobe and hilum lymph node, which would have been resected if segmentectomy had been performed. In the multivariable analysis for CIR using inverse probability of treatment weighting and the procedure, wedge resection was a significantly worse predictive factor (hazard ratio, 12.280; P = 0.025).CONCLUSIONSSegmentectomy rather than wedge resection should be considered for solid predominant, small-size non-small cell lung cancer even if [18F]-fluoro-2-deoxy-D-glucose accumulation is low.

Adjuvant Chemotherapy in Patients with Node-Negative Non-Small Cell Lung Cancer with Satellite Pulmonary Nodules in the Same Lobe.

BackgroundAccording to the eighth TNM (tumor-node-metastasis) staging system, the presence of separate tumor nodules in the same lobe is designated as a T3 descriptor. However, it remains unclear whether adjuvant chemotherapy confers survival advantages in this setting.MethodsWe retrospectively identified 142 pathologic T3N0M0 patients with additional pulmonary nodules in the same lobe from a single-institutional database from 2004 to 2019. The main outcomes were overall survival and recurrence-free survival. Multivariable Cox regression was used to identify the benefit of adjuvant chemotherapy while adjusting for other variables.ResultsSixty-one patients received adjuvant chemotherapy (adjuvant group) and 81 patients did not receive adjuvant therapy after surgery (surgery-only group). There were no demonstrable differences between the 2 groups regarding hospital mortality and postoperative complications, indicating that treatment selection had not significantly occurred. However, the use of adjuvant chemotherapy was associated with improved 5-year overall survival (70% vs. 59%, p=0.006) and disease-free survival (60% vs. 46%, p=0.040). A multivariable Cox model demonstrated that adjuvant chemotherapy was associated with a survival advantage (adjusted hazard ratio, 0.54; p<0.001). In exploratory analyses of subgroups, the effect of adjuvant chemotherapy seemed to be insufficient in those with small main tumors (<4 cm).ConclusionAdjuvant chemotherapy was associated with better survival in T3 cancers with an additional tumor nodule in the same lobe. However, the role of adjuvant chemotherapy in patient subgroups with small tumors or those without risk factors should be determined via large studies.

Quantifying the rate and predictors of occult lymph node involvement in patients with clinically node-negative non-small cell lung cancer

Purpose It is essential to evaluate the risk of occult lymph node (LN) disease in early-stage non-small cell lung cancer (NSCLC), especially because delivering stereotactic ablative radiotherapy (SABR) assumes no occult spread. This study was designed to assist clinicians in roughly quantifying this risk for cN0 NSCLC. Methods The National Cancer Data Base was queried for cN0 cM0 lung squamous cell or adenocarcinoma who underwent surgery and LN dissection without neoadjuvant therapy. Statistics included multivariable logistic regression to evaluate factors associated with pN + disease. Results 109,964 patients were included. For tumors with size ≤1.0, 1.1–2.0, 2.1–3.0, 3.1–4.0, 4.1–5.0, 5.1–6.0, 6.1–7.0, and >7.0 cm, the pN + rate was 4.4, 7.7, 12.9, 18.0, 20.2, 22.5, 24.4, and 26.4%, respectively. When examining patients with more complete LN dissections (defined as removal of at least 10 LNs), the respective values were 6.6, 11.5, 17.6, 25.3, 26.8, 29.7, 30.7, and 31.6%. Moderately-poorly differentiated disease and adenocarcinomas were associated with a higher rate of pN + disease (p < .001 for both). For every cm increase in tumor size, the relative occult nodal risk increased by 10–14% (p < .001). For every elapsed day from initial diagnosis, the relative risk increased by ∼1% (p < .001). Graphs with best-fit lines were created based on tumor size, histology, and differentiation to aid physicians in estimating the pN + risk. Conclusions This nationwide study can allow clinicians to roughly estimate the rate of occult LN disease in cN0 NSCLC. These data can also assist in guiding enrollment on randomized trials of SABR ± immunotherapy, individualizing follow-up imaging surveillance, and patient counseling to avoid post-diagnosis delays.

Narrative review of patterns of lymphatic drainage in early-stage non-small cell lung cancer

: In non-small cell lung cancer (NSCLC), the presence of metastatic nodal disease has been shown to be the most important predictor of long-term disease-specific survival after surgical resection. In patients with early stage, node-negative NSCLC who undergo complete resection, the current standard of care, a significant portion have recurrence of disease within 24 months after surgery. This has raised interest in better understanding the lymphatic drainage of these cancers to determine the exact patterns of loco-regional spread, and whether sentinel lymph node (SLN) identification can be utilized to aid in management of these diseases. Anatomic studies that have attempted to map the lymphatic drainage of tumors from different locations within the lung have revealed patterns of direct mediastinal drainage, which may help explain the prevalence of skip metastases, which is the presence of N2 disease in the absence of N1 disease. This article will provide a narrative review of primary literature concerning the anatomy of the pulmonary lymphatic system, patterns of nodal metastasis in NSCLC as studied through various techniques (including blue dye, radiocolloid tracers, and near-infrared image-guided SLN mapping), and opportunities for improvement in our understanding of how lung tumors interact with the lymphatic system on a structural level.

Detection of second primary lung cancers on surveillance imaging following stereotactic ablative radiotherapy for non-small cell lung cancer

Introduction/BackgroundSecond primary lung cancers (SPLC) are common following non-small cell lung cancer (NSCLC) treatment. Development of SPLC following stereotactic ablative radiation therapy (SABR) may differ as compared to surgical cohorts. We report incidence of and outcomes for SPLC detected by surveillance imaging in a cohort of patients treated with SABR. Materials/MethodsPatients treated with SABR for node-negative NSCLC between February, 2007 to May, 2019 were retrospectively identified. Patient characteristics, frequency of surveillance imaging, development of SPLC, recurrence patterns, and survival were reviewed. Surveillance CT was performed Q3-4 month year 1, Q3-6 month year 2, Q6-12 month year 3-5, and Q12 month thereafter. Actuarial estimates of development of SPLC and overall survival (OS) were generated with competing risk analysis. ResultsWe identified 134 patients treated with SABR with ≥6 months follow up. Eighteen (13.4%) developed a total of 21 SPLC at a median of 28.5 months (range 3.0-84.7 months) following SABR, 19 (90.5%) biopsy-proven. Twenty (95.2%) SPLC were detected by surveillance imaging. Three patients developed 2 metachronous SPLC. Three and 5 year SPLC estimates were 11.7% and 13.1%. Eighteen (85.7%) SPLC were treated with curative intent. Two and 3 year estimate of OS following detection of SPLC was 79.8% and 54.7%. ConclusionSPLC were more common in our cohort than other published studies. Outcomes following surveillance detected SPLC are similar to those of de novo early stage lung cancers. The high frequency of SPLC in our cohort suggests further studies to refine overall surveillance in very high-risk populations are needed.