Background/aim: mmune checkpoint inhibition (CPI) has an increasing impact in the multimodal treatment of locally advanced non-small cell lung cancer (LA-NSCLC). Increasing evidence suggests treatment outcome depending on tumor cell PD-L1 expression. The purpose of this retrospective study was to investigate the prognostic value of PD-L1 expression on tumor cells in combination with CD8+ tumor stroma-infiltrating lymphocyte (TIL) density in inoperable LA-NSCLC treated with concurrent chemoradiotherapy (CRT). Patients and method: We retrospectively assessed clinical characteristics and initial tumor biopsy samples of 31 inoperable LA-NSCLC patients treated with concurrent CRT. Prognostic impact of tumor cell PD-L1 expression (0% versus ≥1%) and CD8+ TIL density (0–40% vs. 41–100%) for local control, progression-free (PFS) and overall survival (OS) as well as correlations with clinicopathological features were evaluated. Results: Median OS was 14 months (range: 3–167 months). The OS rates at 1- and 2 years were 68 and 20%. Local control of the entire cohort at 1 and 2 years were 74 and 61%. Median PFS, 1-year and 2-year PFS were 13 ± 1.4 months, 58 and 19%. PD-L1 expression < 1% on tumor cells was associated with improved OS, PFS and local control in patients treated with concurrent CRT. Univariate analysis showed a trend towards improved OS and local control in patients with low CD8+ TIL density. Evaluation of Tumor Immunity in the MicroEnvironment (TIME) appears to be an independent prognostic factor for local control, PFS and OS. The longest and shortest OS were achieved in patients with type I (PD-L1^neg/CD8^low) and type IV (PD-L1^pos/CD8^low) tumors (median OS: 57 ± 37 vs. 10 ± 5 months, p = 0.05), respectively. Conclusion: Assessment of PD-L1 expression on tumor cells in combination with CD8+ TIL density can be a predictive biomarker in patients with inoperable LA-NSCLC treated with concurrent CRT.

Background: Loco-regional and distant failure are common in inoperable stage III non small-cell lung cancer (NSCLC) after chemoradiotherapy (CRT). However, there is limited real-world data on failure pattern, patient prognosis and salvage options. Methods: We analysed 99 consecutive patients with inoperable stage III NSCLC treated with CRT between 2011 and 2016. Follow up CT scans from date of the first-site failure were matched with the delivered radiation treatment plans. Intra-thoracic loco-regional relapse was defined as in-field (IFR) vs. out-of-field recurrence (OFR) [in- vs. outside 50Gy isodose line in the involved lung], respectively. Extracranial distant (DMs) and brain metastases (BMs) as first site of recurrence were also evaluated. Using the Kaplan-Meier method, impact of salvage surgery (sS), radiotherapy (sRT), chemotherapy (sCT) and immunotherapy (sIO) on patient survival was assessed. Results: Median follow-up was 60.0 months. Median PFS from the end of CRT for the entire cohort was 7.5 (95% CI: 6.0–9.0 months) months. Twenty-six (26%) and 25 (25%) patients developed IFR and OFR. Median time to diagnosis of IFR and OFR was 7.2 and 6.2 months. In the entire cohort, onset of IFR and OFR did not influence patient outcome. However, in 73 (74%) patients who survived longer than 12 months after initial diagnosis, IFR was a significant negative prognostic factor with a median survival of 19.3 vs 40.0 months (p < 0.001). No patients with IFR underwent sS and/or sRT. 18 (70%) and 5 (19%) patients with IFR underwent sCT and sIO. Three (12%) patients with OFR underwent sS and are still alive with 3-year survival rate of 100%. 5 (20%) patients with OFR underwent sRT with a median survival of 71.2 vs 19.1 months (p = 0.014). Four (16%) patients with OFR received sIO with a numerical survival benefit (64.6 vs. 26.4 months, p = 0.222). DMs and BMs were detected in 27 (27%) and 16 (16%) patients after median time of 5.8 and 5.13 months. Both had no impact on patient outcome in the entire cohort. However, patients with more than three BMs showed significantly poor OS (9.3 vs 26.0 months; p = 0.012). Conclusions: After completion of CRT, IFR was a negative prognostic factor in those patients, who survived longer than 12 months after initial diagnosis. Patients with OFR benefit significantly from salvage local treatment. Patients with more than three BMs as first site of failure had a significantly inferior outcome.

Concurrent chemoradiotherapy (CRT) followed by maintenance treatment with the PD-L1 inhibitor durvalumab is a new standard of care for inoperable stage III NSCLC. The present study compares the oncological outcome of patients treated with CRT to those treated with CRT and durvalumab (CRT-IO) in the real-world setting. The analysis was performed based on the retro- and prospectively collected data of 144 consecutive inoperable stage III NSCLC patients treated between 2011–2020. Local-regional-progression-free-survival (LRPFS—defined as progression in the mediastinum, hilum and/or supraclavicular region at both sites and the involved lung), progression-free survival (PFS), and overall survival (OS) were evaluated from the last day of thoracic radiotherapy (TRT). Median follow-up for the entire cohort was 33.1 months (range: 6.3–111.8) and median overall survival was 27.2 (95% CI: 19.5–34.9) months. In the CRT-IO cohort after a median follow-up of 20.9 (range: 6.3–27.4) months, median PFS was not reached, LRPFS (p = 0.002), PFS (p = 0.018), and OS (p = 0.005) were significantly improved vs. the historical cohort of conventional CRT patients. After propensity-score matching (PSM) analysis with age, gender, histology, tumor volume, and treatment mode, and exact matching for T-and N-stage, 22 CRT-IO patients were matched 1:2 to 44 CRT patients. Twelve-month LRPFS, PFS, and OS rates in the CRT-IO vs. CRT cohort were 78.9 vs. 45.5% (p = 0.002), 60.0 vs. 31.8% (p = 0.007), and 100 vs. 70.5% (p = 0.003), respectively. This real-world analysis demonstrated that durvalumab after CRT led to significant improvement of local-regional control, PFS, and OS in PD-L1 expressing inoperable stage III NSCLC patients compared to a historical cohort.

Background: Stage III non-small cell lung cancer (NSCLC) represents a heterogeneous disease regarding principal patient- and tumor characteristics. A simple score may aid in personalizing multimodal therapy. Methods: The data of 99 consecutive patients with performance status ECOG 0–1 treated until the end of 2016 with multimodal approach for inoperable NSCLC (UICC 7^th edition stage IIIA/B) were evaluated. Patient- and tumor-related factors were examined for their impact on overall survival. Factors showing a negative association with prognosis were then included in the score. Three subgroups with low, intermediate and high-risk score were defined. The results were then validated in the prospective cohort, which includes 45 patients. Results: Most Patients were treated with concurrent (78%) or sequential (11%) chemoradiotherapy. 53% received induction chemotherapy. Median survival for the entire cohort was 20.8 (range: 15.3–26.3) months. Age (P=0.020), gender (P=0.007), pack years (P=0.015), tumor-associated atelectasis (P=0.004) and histology (P=0.004) had a significant impact on overall survival and were scored with one point each. Twelve, 59 and 28 patients were defined to have a low (0–1 points), intermediate (2–3 points) and high-risk (4–5 points) score. Median survival, 1-, 2- and 3-year survival rates were not reached, 100%, 83% and 67% in the low, 22.9 months, 80%, 47% and 24% intermediate and 13.7 months, 57%, 25% and 18% high-risk patients, respectively (P<0.001). Median survival was not reached in prospective cohort; analysis has revealed a trend for the 1-year survival rates with 100% for the low, 93% intermediate and 69% high-risk patients (P=0.100). Conclusions: The score demonstrated remarkable survival differences in inoperable stage III NSCLC patients with good performance status receiving multimodal therapy.

Inoperable stage III non-small cell lung cancer (NSCLC) represents a highly heterogeneous patient cohort. Multimodal treatment approaches including radiotherapy have been the new standard of care, with promising outcomes. The planning target volume (PTV), including the primary tumor, involved lymph node stations and safety margins, can vary widely. In order to evaluate the impact of the PTV for overall survival (OS), progression-free survival (PFS) and loco-regional control, we analyzed retrospective and prospective data of 122 consecutive patients with inoperable stage III NSCLC treated with CRT. The majority of patients (93%) received a total dose ≥ 60 Gy and 92% of all patients were treated with concurrent or sequential chemotherapy. Median follow-up for the entire cohort was 41.2 (range: 3.7–108.4) months; median overall survival (OS) reached 20.9 (95% CI: 14.5–27.3) months. PTVs from 500 to 800 ccm were evaluated for their association with survival in a univariate analysis. In a multivariate analysis including age, gender, total radiation dose and histology, PTV ≥ 700 ccm remained a significant prognosticator of OS (HR: 1.705, 95% CI: 1.071–2.714, p = 0.025). After propensity score matching (PSM) analysis with exact matching for Union internationale contre le cancer (UICC) TNM Classification (7th ed.)T- and N-stage, patients with PTV < 700 ccm reached a median PFS and OS of 11.6 (95% CI: 7.3–15.9) and 34.5 (95% CI: 25.6–43.4) months vs. 6.2 (95% CI: 3.1–9.3) (p = 0.057) and 12.7 (95% CI: 8.5–16.9) (p < 0.001) months in patients with PTV ≥ 700 ccm, respectively. Inoperable stage III NSCLC patients with PTV ≥ 700 ccm had significantly detrimental outcomes after conventionally fractionated CRT. PTV should be considered as a stratification factor in multimodal clinical trials for inoperable stage III NSCLC.

To determine the feasibility of PET/CT-based image-guided moderate hypofractionated thoracic irradiation (Hypo-IGRT) in locally advanced node-positive non-small cell lung cancer patients with highly compromised pulmonary function. Eight highly-selected and closely monitored patients with highly diminished pulmonary function (FEV1 ≤ 1.0 L and/or DLCO-SB ≤ 40% and/or on long-term oxygen therapy) were treated with Hypo-IGRT. Planning was based on 18F-FDG-PET/CT and 4D-CT in the treatment position. Hypo-IGRT was delivered to a total dose of 45 Gy (ICRU) in 15 daily fractions under strict image-guidance. Vital capacity (VC), forced expiratory volume in 1 s (FEV1), and single-breath diffusing capacity of the lung for CO (DLCO-SB) were analyzed prior to, 3 and 6 months after Hypo-IGRT. Eight patients with stage IIIA-C NSCLC (8th TNM Ed.) completed Hypo-IGRT. The median follow-up was 29.4 months. The median age was 64 years. Four, three and one patient(s) presented with COPD GOLD IV, III and II, respectively and 5 patients (63%) were on long-term oxygen therapy. The median PTV was 226.9 cc (range: 100.17–379.80 cc). Median PFS and OS were 19 and 34.3 months. The 6 months and 1-year OS rates were 100, 87.5%, respectively. The 6- and 12- months PFS rates were 87.5 and 52.5%. Three patients developed local failure. Median initial VC, FEV1 and DLCO-SB was 1.69 L/64.8% predicted (range: 1.36–2.66 L/33–80%), 1 L/39.4% predicted (range:0.78–1.26 L/28–60% predicted) and 33.3% (range: 13.3–54%) predicted, respectively. Median values for VC, FEV1, DLCO-SB 3 and 6 months after Hypo-IGRT were 2.05 L/56.35% predicted (range: 1.34–2.33 L/47–81.5%), 1.08 L/47.5% predicted (range: 0.74–1.60 L/30.8–59.59%), 38.55% (range: 24–68%) and 1.64 L/66% predicted (range: 1.41–2.79/35.5–75.5%), 1.0 L/47% predicted (range: 0.65–1.28 L/24.5–54.10%), 31% (range: 27–43%), respectively. Mean lung dose was 9.4 Gy (range: 5.3–11.6 Gy) and V20 for both lungs was 15% (range: 6–19%). Mean esophageal dose was 12.76 Gy (range: 2.1–26.7 Gy). There was no case of grade 2 or higher radiation pneumonitis. Four patients developed grade 2 radiation esophagitis. Hypo-IGRT can be considered for individual and closely monitored patients with locally advanced node-positive NSCLC with highly compromised pulmonary function. No severe pulmonary toxicity and significant decline of pulmonary function parameters was observed in our cohort. Currently, this protocol is being assessed in an ongoing single-centre prospective study.