Efficacy and safety of first-line PD-L1/PD-1 inhibitors in limited-stage small cell lung cancer: a multicenter propensity score matched retrospective study.

Background: The prognosis of small cell lung cancer (SCLC) patients is poor, and the standard first-line treatment for limited-stage small cell lung cancer (LS-SCLC) is still chemotherapy and thoracic radiotherapy. The primary objectives of our study were to confirm the superior efficacy of first-line immune checkpoint inhibitors (ICIs) plus etoposide and platinum (EP) for LS-SCLC and find crucial biomarkers. Methods: We analyzed LS-SCLC patients from three medical centers, employing propensity score matching for group comparability. Survival outcomes were estimated by Kaplan-Meier and Cox regression analyses. Additionally, we conducted univariate and multivariate analyses to investigate potential predictive factors. Results: Among 150 patients in our study, we successfully matched 41 pairs. The median overall survival (OS) was 29.5 months in the EP + ICIs group and 20.0 months in the EP group {hazard ratio (HR) =0.64 [95% confidence interval (CI): 0.41-1.02], P=0.059}. The median progression-free survival (PFS) was significantly extended in the EP + ICIs group (14.6 months), compared to the EP group (8.6 months) [HR =0.42 (95% CI: 0.28-0.63), P<0.001]. After matching, patients receiving chemo-immunotherapy had a median OS of 36.1 months, significantly surpassing those receiving chemotherapy alone (19.0 months) [HR =0.51 (95% CI: 0.28-0.93), P=0.02]. And the patients in the EP + ICIs group also had longer PFS after matching [HR =0.42 (95% CI: 0.25-0.71), P=0.001]. No significant difference in the objective response rate (ORR) and treatment-related adverse events (trAEs) between the two groups was found (ORR: EP: 81.0%, EP + ICIs: 90.0%, P=0.14; trAEs: EP: grade 1-2, 49.3%; grade 3-4, 42.5%; EP + ICIs: grade 1-2, 40.0%; grade 3-4, 49.1%, P=0.62). The multivariate analysis presented that the history of immunotherapy [EP + PD-1 inhibitors: HR =0.33 (95% CI: 0.17-0.62), P=0.001; EP + PD-L1 inhibitors: HR =0.18 (95% CI: 0.06-0.60), P=0.005] and baseline lung immune prognostic index (LIPI) [intermediate: HR =2.22 (95% CI: 1.20-4.13), P=0.01; poor: HR =2.03 (95% CI: 0.71-5.77), P=0.18] were independent prognostic factors for PFS among all LS-SCLC cases. However, no independent prognostic factor was identified for OS. Conclusions: Our real-world data showed promising clinical efficacy and tolerable safety of first-line programmed cell death protein 1 (PD-1) inhibitors or programmed cell death ligand 1 (PD-L1) inhibitors in cases with LS-SCLC. Additionally, LIPI may serve as a valuable prognostic factor.

Prophylactic cranial irradiation-related lymphopenia affects survival in patients with limited-stage small cell lung cancer.

Background: The study aimed to identify the relations of the absolute lymphocyte count (ALC) nadir during prophylactic cranial irradiation (PCI) and patient outcomes in limited-stage small cell lung cancer (LS-SCLC). Methods: We analyzed 268 L S-SCLC patients who underwent PCI from 2012 to 2019. ALC values were collected prior, during, and 3 months post PCI. Kaplan-Meier and Cox regression analyses were performed to assess the relation of ALC to patient prognosis. Two nomograms were developed on the basis of clinical variables for survival prediction. Results: Compared with the ALC before PCI (1.13 × 109 cells/L), the ALC nadir during PCI was significantly reduced by 0.68 × 109 cells/L (P < 0.001) and raised to 1.02 × 109 cells/L 3 months post PCI. Patients with a low ALC nadir during PCI (<0.68 × 109 cells/L) had inferior progression free survival (PFS) (median PFS: 17.2 m vs. 43.7 m, P = 0.019) and overall survival (OS) (median OS: 29.0 m vs 39.1 m, P = 0.012). Multivariate Cox analysis revealed that age, smoking history, clinical stage, and ALC nadir were independent OS (P = 0.006, P = 0.005, P < 0.001 and P = 0.027, respectively), as well as independent PFS predictors (P = 0.032, P = 0.012, P = 0.012 and P = 0.018, respectively). After internal cross-validation, the corrected concordance indices of the predictive nomograms for PFS and OS were 0.637 and 0.663, respectively. Conclusion: LS-SCLC patients with a low ALC nadir during PCI likely have worse survival outcomes. Dynamic evaluation of the ALC during PCI is recommended for LS-SCLC patients.

Prognostic ability of lung immune prognostic index in limited-stage small cell lung cancer.

BACKGROUND: Lung immune prognostic index (LIPI) is a prognostic marker of extensive-stage small cell lung cancer (ES-SCLC) patients received immunotherapy or chemotherapy. However, its ability in limited-stage SCLC (LS-SCLC) should be evaluated extensively. METHODS: We retrospectively enrolled 497 patients diagnosed as LS-SCLC between 2015 and 2018, and clinical data included pretreatment lactate dehydrogenase (LDH), white blood cell count, and absolute neutrophil count levels were collected. According to the LIPI scores, the patients were stratified into low-risk (0 points) and high-risk (1-2 points). The correlations between LIPI and overall survival (OS) or progression-free survival (PFS) were analyzed by the Cox regression. Additionally, the propensity score matching (PSM) and inverse probability of treatment weight (IPTW) methods were used to reduce the selection and confounding bias. A nomogram was constructed using on multivariable Cox model. RESULTS: Two hundred fifty and 247 patients were in the LIPI high-risk group and low-risk group, and their median OS was 14.67 months (95% CI: 12.30-16.85) and 20.53 months (95% CI: 17.67-23.39), respectively. In the statistical analysis, High-risk LIPI was significantly against worse OS (HR = 1.377, 95%CI:1.114-1.702) and poor PFS (HR = 1.338, 95%CI:1.1-1.626), and the result was similar after matching and compensating with the PSM or IPTW method. A novel nomogram based on LIPI has a decent level of predictive power. CONCLUSION: LIPI stratification was a significant factor against OS or PFS of LS-SCLC patients.

Pathologic responses to neoadjuvant chemoimmunotherapy in primary limited-stage small-cell lung cancer.

BACKGROUND: Immunotherapy has been proved to have a large effect on extensive-stage small cell lung cancer, but the role of immunotherapy in limited-stage small-cell lung cancer (LS-SCLC) is still unknown. METHODS: A retrospective study of six patients with LS-SCLC who were treated with neoadjuvant chemoimmunotherapy (durvalumab plus etoposide combined with cisplatin) was performed. Patients were evaluated by the safety, feasibility and pathologic responses of neoadjuvant chemoimmunotherapy. RESULTS: Neoadjuvant durvalumab combined chemotherapy was associated with few immediate adverse events and did not delay planned surgery. All patients achieved partial pathologic response (pPR) instead of major pathologic response, or pathologic complete response. No association was observed between programmed death-ligand 1 expression in tumor specimens and the pathologic response. However, tumors with high expression of immune cells such as CD4+ T cells, CD8+ T cells and FoxP3+ Tregs tended to have better pathologic responses than tumors with low expression of immune cells. CONCLUSIONS: Neoadjuvant durvalumab combined chemotherapy could induce pPR with few side effects in resectable LS-SCLC. The immune cells in the tumor microenvironment might play an important role in neoadjuvant chemoimmunotherapy in resectable LS-SCLC.

Usefulness of pro-gastrin-releasing peptide as a predictor of the incidence of brain metastasis and effect of prophylactic cranial irradiation in patients with limited-stage small-cell lung cancer.

Prophylactic cranial irradiation (PCI) is recommended for patients with limited-stage small-cell lung cancer (LS-SCLC) who respond well to initial treatment. However, PCI is often omitted because of its potential neurotoxicity in the era of modern diagnostic imaging devices. In the present study, we aimed to investigate the risk factors for brain metastasis (BM) in patients eligible for PCI and who may benefit more from it. Patients with LS-SCLC who responded well to definitive thoracic chemoradiotherapy were included in the present study. Competing risk regression was used to identify factors associated with BM, and the Kaplan-Meier method was used to assess overall survival (OS). Between 2004 and 2017, 62 patients were eligible for PCI and were analyzed. Of these, 38 (61.3%) underwent PCI. Overall, 17 patients (27.4%) developed BM, with a 2-year cumulative incidence of 22.8%. Multivariate analysis (MVA) revealed that pretreatment elevated pro-gastrin-releasing peptide (ProGRP) levels were associated with an increased risk for BM (HR, 7.96, P = 0.0091). PCI tended to reduce the risk of BM (HR, 0.33; P = 0.051). The use of PCI was associated with improved OS in patients with ProGRP levels > 410 pg/mL (P = 0.008), but not in those with ProGRP ≤ 410 pg/mL (P = 0.9). Pretreatment ProGRP levels may be useful in predicting the development of BM in patients with LS-SCLC who achieved a good response to initial therapy and to determine which patients should undergo PCI.

Pathological complete response to radical surgery after receiving durvalumab plus neoadjuvant chemotherapy for 1 limited-stage small cell lung cancer patient: a case report.

Background: Small cell lung cancer (SCLC) is clinically the most aggressive subtype of lung cancer, and accounts for about 15% of all newly diagnosed lung cancer cases. Approximately 1/3 of SCLC patients are diagnosed with limited-stage SCLC (LS-SCLC). The standard of treatment for most patients with LS-SCLC is concurrent chemoradiotherapy. LS-SCLC is sensitive to first-line therapy, but has a high recurrence rate and patients show a poor response to second-line treatment. Referring to extensive-stage SCLC (ES-SCLC), durvalumab plus platinum-etoposide chemotherapy has been approved by the Food Drug Administration and National Medical Products Administration. It is hoped that durvalumab will produce good results for LS-SCLC patients. Case Description: In this article, we report the case of a 75-year-old male patient with LS-SCLC of the left lung (tumor, node metastasis stage cT3N0M0 IIB) who received 2 cycles durvalumab plus neoadjuvant chemotherapy. The neoadjuvant therapy was favorable and no adverse events were observed. The assessment of the tumor via Resist1.1 by videography indicated a complete response. Then a thoracoscopic resection of the left lower lobe of the lung was performed under general anesthesia. The operation was successful, and the patient's postoperative recovery was good. Fortunately, the postoperative pathology results showed pathological complete response. After the surgery, the patient received 3 cycles of adjuvant therapy. Now, the patient is still alive and there is no sign of tumor recurrence. Conclusions: This case highlights the benefits of neoadjuvant programmed death-ligand 1 (PD-L1) inhibitor plus chemotherapy and radical surgery for patients with LS-SCLC and identifies a significant treatment option for LS-SCLC patients.

Comprehensive analysis of prognostic predictors for patients with limited-stage small-cell lung cancer who underwent resection followed by adjuvant chemotherapy.

BACKGROUND: The prognosis of patients with limited-stage small-cell lung cancer (LS-SCLC) who undergo resection followed by adjuvant chemotherapy (ACT) is uncertain. Thus, we combined clinicopathological characteristics and next-generation sequencing (NGS) to answer this question. METHODS: In total, the data of 51 LS-SCLC patients who had undergone complete surgical resection and postoperative ACT were retrospectively collected. NGS examinations with a 68-gene panel were performed for each specimen. Patients' genetic status and potentially clinical correlations were statistically evaluated. Progression-free survival (PFS) and overall survival (OS) were plotted using Kaplan-Meier curves. The independent prognostic factors for the primary cohort were investigated using univariable and multivariable cox proportional hazard regression analyses. Subgroup analyses were also conducted based on retinoblastoma protein 1 (RB1) status. RESULTS: Combined SCLC (c-SCLC) had similar clinical and pathological characteristics to that of pure SCLC (p-SCLC). TP53 and RB1 were 2 major genetic mutations present in both p-SCLC and c-SCLC. c-SCLC had a unique genetic profile that was related to the PI3K/AKT/mTOR and WNT/ß-catenin signaling pathways. There was no prognostic difference between c-SCLC and p-SCLC. However, the pathological node (N) stage of lymphovascular invasion (LVI), which was related to PFS and age, corelated with OS. Neither pathological subtypes nor genetic mutations affected the survival outcomes. Notably, RB1 mutated c-SCLC resulted in poorer DFS compared to that of p-SCLC among LS-SCLC patients who underwent resection followed by ACT. CONCLUSIONS: Our examination of LS-SCLC patients who underwent resection followed by ACT showed that c-SCLC and p-SCLC had a clinical and prognostic similarity and a genetic peculiarity. Thus, it is essential that a new classification system be proposed for SCLC. Such a system is especially needed for LS-SCLC.

Re-evaluation of prophylactic cranial irradiation in limited-stage small cell lung cancer: a propensity score matched analysis.

We attempted to re-evaluate the efficacy of prophylactic cranial irradiation (PCI) in limited-stage small cell lung cancer (LS-SCLC) with more recent data. A total of 179 patients with LS-SCLC received radical thoracic radiotherapy and chemotherapy at our institution between 1998 and 2018. One hundred twenty-eight patients who achieved complete response (CR), good partial response (PR), and PR without progression for at least for one year after initial therapy were enrolled in this study. These patients were divided into a PCI group (group A, n = 43), and a non-PCI group (group B, n = 85). Survival outcomes were retrospectively evaluated. Because several background factors differed significantly between groups A and B, propensity score (PS) matching was performed as 1:1 match of the two groups. Finally, we analyzed 64 patients (group A/B = 32/32). Median follow-up periods were 53 and 31 months in groups A and B, respectively. There were no significant differences between the groups' backgrounds. Two-year overall survival (OS) rates were 77% in group A and 62% in group B (p = 0.224). Two-year brain metastasis free survival (BMFS) rates were 85% in group A and 57% in group B (p = 0.008). The number of patients who underwent a brain imaging test for confirmation of no brain metastasis (BM) after radical thoracic radiotherapy and chemotherapy (before PCI) was 84 (group A/B = 32/52). A PS matched analysis for cases of pre-PCI brain imaging group, two-year OS rates for group A/B were 73/59% (p = 0.446). Two-year BMFS rates for group A/B were 91/52% (p = 0.021). Retrospectively, PS matched analysis revealed that adding PCI to LS-SCLC patients who achieved good thoracic control significantly improved BMFS, but OS did not improve.

Preoperative peripheral blood neutrophil-to-lymphocyte ratios (NLR) and platelet-to-lymphocyte ratio (PLR) related nomograms predict the survival of patients with limited-stage small-cell lung cancer.

BACKGROUND: We aim to establish neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) related nomograms based on the clinical data and peripheral blood markers to predict the survivals of patients with limited-stage small-cell lung cancer (LS-SCLC). METHODS: A total of 299 LS-SCLC patients after surgery were enrolled in this study. Univariate and multivariate analyses were conducted to select independent prognostic factors to develop the nomograms and then subjected to bootstrap internal validation. The optimal cutoff value of NLR and PLR before surgery was calculated by X-tile (version 3.6.1) and the overall survival (OS) was analyzed by Kaplan-Meier method and compared by log-rank test. RESULTS: According to the X-tile calculation, the NLR value and PLR cutoff values are 2.6 and 156.7, respectively. The prognosis of patients with elevated NLR or PLR value was significantly worse than patients with lower NLR (HR =1.798, 95% CI: 1.284-2.518, P=0.001) or PLR (HR =1.781, 95% CI: 1.318-2.407, P<0.001) value. Two Nomograms were developed according to the two multivariate cox regression models based on NLR and PLR. Concordance index (C-index) curves and calibration curves show that the two models have a better effect in predicting prognosis. At the same time, compared with the tumor node metastasis (TNM) staging system, our models also show better accuracy and stability. CONCLUSIONS: Elevated NLR and PLR predict poor prognosis in their respective nomograms in patients with LS-SCLC.

Lymphopenia association with accelerated hyperfractionation and its effects on limited-stage small cell lung cancer patients' clinical outcomes.

BACKGROUND: An assessment of trends in lung cancer patient survival is very important to determine the outcomes and to modulate where advancements should be made. This study investigated whether the absolute lymphocyte count just after chemoradiation (after-ALC) and 3 months after chemoradiation initiation (post-ALC) could predict limited-stage small cell lung cancer (LS-SCLC) patients' clinical outcomes. METHODS: We retrospectively reviewed 304 patients who were newly diagnosed with LS-SCLC and received treatment with chemoradiation (CRT). Finally we collected data at the time of pretreatment, after-ALC and post-ALC from 226 patients. Kaplan-Meier survival curves and log-rank statistics were used to assess the prognostic significance of after-ALC and post-ALC for survival rates. Cox proportional hazards models were used to generate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Two hundred and twenty-six patients had a documented ALC pretreatment, just after CRT and 3 months after CRT. Relative lymphopenia of pre-treatment ALC was in 47.8% of patients, whereas the lymphopenia (<655 cells/mm3) proportion was increased to 61.1% just after CRT, and the lymphopenia (<1,430 cells/mm3) proportion continued to rise to 70.4% at the time of 3 months after initiating CRT. After-ALC lymphopenia patients showed inferior median OS (18.1 vs. 36.0 months, P<0.001) and similar PFS (9.7 vs. 26.2 months, P<0.001) compared to patients without lymphopenia. Multivariate analysis demonstrated after-ALC <655 cells/mm3 and post-ALC <1,430 cells/mm3 (HR: 1.339; P=0.038) had a 105% and 33% (HR: 2.056; P<0.001) increase in hazards of death respectively. Similarly, after-ALC <655 cells/mm3 and post-ALC <1,430 cells/mm3 had a 160% (HR: 2.606; P=0.002) and 40% (HR: 1.409; P=0.015) increase in hazards of progression respectively. Furthermore, hyperfractionated RT showed more likely to cause lymphopenia in patients than conventional fractionated RT. CONCLUSIONS: Nearly half of LS-SCLC patients treatment with CRT experienced severe lymphopenia and more than half patients exhibited prolonged lymphopenia. Statistical significance that lymphopenia after treatment was associated with decreased survival was obviously observed. Further study is warranted, given that explanation lymphopenia is a mechanism for shorter survival or just a predictor.