Management of Stage III Non–Small-Cell Lung Cancer: ASCO Guideline

PURPOSE To provide evidence-based recommendations to practicing clinicians on management of patients with stage III non–small-cell lung cancer (NSCLC). METHODS An Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary oncology, community oncology, research methodology, and advocacy experts was convened to conduct a literature search, which included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2021. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 127 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS Evidence-based recommendations were developed to address evaluation and staging workup of patients with suspected stage III NSCLC, surgical management, neoadjuvant and adjuvant approaches, and management of patients with unresectable stage III NSCLC. Additional information is available at www.asco.org/thoracic-cancer-guidelines .

The Evolving Role of Immunotherapy in Stage III Non-Small Cell Lung Cancer

The management of Stage III non-small cell lung cancer (NSCLC) is complex and requires multidisciplinary input. Since the publication of the PACIFIC trial (consolidative durvalumab post concurrent chemotherapy and radiation in Stage III disease) which showed improved survival for patients in the immunotherapy arm, there has been much interest in the use of immunotherapy in the Stage III setting. In this review, we explore the biologic and clinical rationale for the use of immunotherapy in Stage III NSCLC, present previously published and upcoming data in the neoadjuvant, adjuvant, and concurrent realms of Stage III management, and discuss unanswered questions and challenges moving forward.

Identification of Potential Prognostic and Predictive Immunological Biomarkers in Patients with Stage I and Stage III Non-Small Cell Lung Cancer (NSCLC): A Prospective Exploratory Study

Radiotherapy (RT) and chemotherapy can induce immune responses, but not much is known regarding treatment-induced immune changes in patients. This exploratory study aimed to identify potential prognostic and predictive immune-related proteins associated with progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC). In this prospective study, patients with stage I NSCLC treated with stereotactic body radiation therapy (n = 26) and patients with stage III NSCLC treated with concurrent chemoradiotherapy (n = 18) were included. Blood samples were collected before (v1), during (v2), and after RT (v3). In patients with stage I NSCLC, CD244 (HR: 10.2, 95% CI: 1.8–57.4) was identified as a negative prognostic biomarker. In patients with stage III NSCLC, CR2 and IFNGR2 were identified as positive prognostic biomarkers (CR2, HR: 0.00, 95% CI: 0.00–0.12; IFNGR2, HR: 0.04, 95% CI: 0.00–0.46). In addition, analysis of the treatment-induced changes of circulating protein levels over time (Δv2/v3−v1) also identified CXCL10 and IL-10 as negative predictive biomarkers (CXCL10, HR: 3.86, 95% CI: 1.0–14.7; IL-10, HR: 16.92 (2.74–104.36)), although serum-induced interferon (IFN) response was a positive prognostic. In conclusion, we identified several circulating immunogenic proteins that are correlated with PFS in patients with stage I and stage III NSCLC before and during treatment.

Higher Radiation Dose to the Immune Cells Correlates with Worse Tumor Control and Overall Survival in Patients with Stage III NSCLC: A Secondary Analysis of RTOG0617

Background: We hypothesized that the Effective radiation Dose to the Immune Cells (EDIC) in circulating blood is a significant factor for the treatment outcome in patients with locally advanced non-small-cell lung cancer (NSCLC). Methods: This is a secondary study of a phase III trial, NRG/RTOG 0617, in patients with stage III NSCLC treated with radiation-based treatment. The EDIC was computed as equivalent uniform dose to the entire blood based on radiation doses to all blood-containing organs, with consideration of blood flow and fractionation effect. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS) and local progression-free survival (LPFS). The EDIC–survival relationship was analyzed with consideration of clinical significant factors. Results: A total of 456 patients were eligible. The median EDIC values were 5.6 Gy (range, 2.1–12.2 Gy) and 6.3 Gy (2.1–11.6 Gy) for the low- and high-dose groups, respectively. The EDIC was significantly associated with OS (hazard ratio [HR] = 1.12, p = 0.005) and LPFS (HR = 1.09, p = 0.02) but PFS (HR = 1.05, p = 0.17) after adjustment for tumor dose, gross tumor volume and other factors. OS decreased with an increasing EDIC in a non-linear pattern: the two-year OS decreased first with a slope of 8%/Gy when the EDIC < 6 Gy, remained relatively unchanged when the EDIC was 6–8 Gy, and followed by a further reduction with a slope of 12%/Gy when the EDIC > 8 Gy. Conclusions: The EDIC is a significant independent risk factor for poor OS and LPFS in RTOG 0617 patients with stage III NSCLC, suggesting that radiation dose to circulating immune cells is critical for tumor control. Organ at risk for the immune system should be considered during RT plan.

Outcomes of Image-Guided Moderately Hypofractionated Radiotherapy for Stage III Non-Small-Cell Lung Cancer

Objective. To evaluate the efficacy and toxicity of hypofractionated radiotherapy (hypo-RT) for stage III non-small-cell lung cancer (NSCLC) in the Chinese population. Methods. Eighty-six stage III NSCLC patients who received hypo-RT (60 Gy/20 fractions, BED = 78.00 Gy: 73 patients; 62.5 Gy/25 fractions, BED = 78.13 Gy: 13 patients) were recruited. Fifty-seven patients who received conventional radiotherapy (60 Gy/30 fractions, BED = 72.00 Gy) during the same period were enrolled as the control group. All hypo-RT treatments were conducted using image-guided technology. The efficacy and toxicity of the treatment were compared between the two groups. Results. The median duration of follow-up was 23.0 months (range: 4.0–82.0 months). Univariate and multivariate analyses of all 143 stage III NSCLC patients revealed that hypo-RT was an independent factor for progression-free survival (PFS) and overall survival (OS). The median PFS and OS of hypo-RT were significantly higher than in the conventional RT group (PFS: 14.30, 11.00 months, p = 0.035 ; OS: 43.30, 31.50 months, p = 0.045 ). The incidence rates of symptomatic radiation pneumonitis and radiation esophagitis (≥grade 2) were 17.77% and 27.91%, respectively, in the hypo-RT group. Compared to the conventional radiation therapy group (22.81% and 19.30%, respectively), no significant differences were found between the two common side effects ( p = 0.662 and p = 0.241 , respectively). Conclusion. For Chinese stage III NSCLC patients, image-guided hypo-RT offers favorable prognosis, and the treatment toxicity was totally acceptable. This radiation modality deserves further prospective clinical trials.