Planning target volume as a predictor of disease progression in inoperable stage III non-small cell lung cancer patients treated with chemoradiotherapy and concurrent and/or sequential immune checkpoint inhibition.

BACKGROUND: The present study evaluates outcome after chemoradiotherapy (CRT) with concurrent and/or sequential Programmed Cell Death 1 (PD-1) or Ligand 1 (PD-L1) immune checkpoint inhibition (CPI) for inoperable stage III NSCLC patients depending on planning target volume (PTV). METHOD AND PATIENTS: Prospective data of thirty-three consecutive patients with inoperable stage III NSCLC treated with CRT and sequential durvalumab (67%, 22 patients) or concurrent and sequential nivolumab (33%, 11 patients) were analyzed. Different PTV cut offs and PTV as a continuous variable were evaluated for their association with progression-free (PFS), local-regional progression-free (LRPFS), extracranial distant metastasis-free (eMFS) and brain-metastasis free-survival (BMFS). RESULTS: All patients were treated with conventionally fractionated thoracic radiotherapy (TRT); 93% to a total dose of at least 60 Gy, 97% of patients received two cycles of concurrent platinum-based chemotherapy. Median follow-up for the entire cohort was 19.9 (range: 6.0-42.4) months; median overall survival (OS), LRFS, BMFS and eMFS were not reached. Median PFS was 22.8 (95% CI: 10.7-34.8) months. Patients with PTV ≥ 900ccm had a significantly shorter PFS (6.9 vs 22.8 months, p = 0.020) and eMFS (8.1 months vs. not reached, p = 0.003). Furthermore, patients with PTV ≥ 900ccm and stage IIIC disease (UICC-TNM Classification 8th Edition) achieved a very poor outcome with a median PFS and eMFS of 3.6 vs 22.8 months (p < 0.001) and 3.6 months vs. not reached (p = 0.001), respectively. PTV as a continuous variable also had a significant impact on eMFS (p = 0.048). However, no significant association of different PTV cut-offs or PTV as a continuous variable with LRPFS and BMFS could be shown. The multivariate analysis that was performed for PTV ≥ 900ccm and age (≥ 65 years), gender (male), histology (non-ACC) as well as T- and N-stage (T4, N3) as covariates also revealed PTV ≥ 900ccm as the only factor that had a significant correlation with PFS (HR: 5.383 (95% CI:1.263-22.942, p = 0.023)). CONCLUSION: In this prospective analysis of inoperable stage III NSCLC patients treated with definitive CRT combined with concurrent and/or sequential CPI, significantly shorter PFS and eMFS were observed in patients with initial PTV ≥ 900ccm.

Blood Parameters Demonstrating a Significant Survival Impact in Patients With Locally Advanced NSCLC Undergoing Definitive Chemoradiotherapy.

AIM: We investigated blood parameters in patients with inoperable stage III non-small cell lung cancer (NSCLC) to predict individual outcomes after definitive chemoradiotherapy (CRT). PATIENTS AND METHODS: Blood parameters of consecutive patients undergoing definitive CRT between 2010 and 2016 for inoperable stage III NSCLC before multimodal treatment and at first follow-up were measured and analyzed. RESULTS: Blood parameters from 99 patients were evaluated. Histologically, about 50% of patients had an adenocarcinoma. All patients received platinum-based sequential or concurrent CRT. The median total dose to the primary tumor was 60 (range=48-70) Gy. On multivariate analysis after adjustment for all co-founders, median overall survival for pre-treatment cutoffs were: lactate dehydrogenase (LDH) >250 U/l was 17 vs. 27 months [hazard ratio (HR)=2.05, 95% confidence intervaI (CI)=1.15-3.66; p=0.015], thrombocytosis >400×106/l: 11 vs. 23 months (HR=2.75, 95% CI=1.1-6.88; p=0.03), hypoalbuminemia <3.5 g/dl: 12 vs. 24 months (HR=2.42, 95% CI=1.21-4.84; p=0.013) and post-treatment neutrophilia >7×106/l: 12 vs. 27 months (HR=2.5, 95% CI=1.21-5.17; p=0.013). CONCLUSION: Pre-treatment elevated LDH, thrombocytosis, hypoalbuminemia and post-treatment neutrophilia were associated with significantly worse overall survival in patients with inoperable stage III NSCLC treated with CRT. Patients with both pre-therapeutic elevated LDH and hypoalbuminemia demonstrated a dismal prognosis despite completion of multimodal treatment.

Pattern-of-failure and salvage treatment analysis after chemoradiotherapy for inoperable stage III non-small cell lung cancer.

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.

Association of Planning Target Volume with Patient Outcome in Inoperable Stage III NSCLC Treated with Chemoradiotherapy: A Comprehensive Single-Center Analysis.

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.

Prognostic value of PD-L1 expression on tumor cells combined with CD8+ TIL density in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy.

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-L1neg/CD8low) and type IV (PD-L1pos/CD8low) 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.

Survival score to characterize prognosis in inoperable stage III NSCLC after chemoradiotherapy.

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 7th 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.

Performance Status and Its Changes Predict Outcome for Patients With Inoperable Stage III NSCLC Undergoing Multimodal Treatment.

BACKGROUND/AIM: Patient performance scores are used widely in clinical practice to assess a patient's general condition. The aim of this study was to evaluate the prognostic role of Eastern Cooperative Oncology Group performance score (ECOG PS) before, after and its changes during chemoradiotherapy in patients with stage III non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Records of 99 patients with stage III NSCLC were evaluated. ECOG PS before, during and after chemoradiotherapy was analyzed for prognostic impact on overall (OS) and event-free (EFS) survival. RESULTS: Median OS considering the entire cohort was 20.8 months (range=15.3-26.2 months). Median OS, and 1- and 2-year survival rates were 26.4 months, 85% and 53% in patients with ECOG PS 0 versus 18.9 months, 69% and 37% in patients with ECOG PS 1 (p=0.1, log-rank test), respectively. After the first follow-up, 35% of patients presented worsening ECOG PS, while in 65% it was stable or improved. Median EFS according to ECOG PS 0, 1, 2 and 3 was 9.6, 9.0, 7.9 and 3.5 months, respectively, at the first follow-up (p=0.018, log-rank test). Deterioration of ECOG PS after chemoradiotherapy resulted in reduced OS in the subgroups with initial ECOG PS 0 and 1 (p=0.005 and p=0.001, log-rank test). CONCLUSION: ECOG PS and its changes have a strong impact on patient outcome. Deterioration of performance status was a strong negative prognostic factor for EFS and OS.