Limited-stage Small-cell Lung Cancer Patients Research Articles

Rational and design of prophylactic cranial irradiation (PCI) and brain MRI surveillance versus brain MRI surveillance alone in patients with limited-stage small cell lung cancer achieving complete remission (CR) of tumor after chemoradiotherapy: a multicenter prospective randomized study

BackgroundProphylactic cranial irradiation (PCI) is part of standard care in limited-stage small cell lung cancer (SCLC) at present. As evidence from retrospective studies increases, the benefits of PCI for limited-stage SCLC are being challenged.MethodsA multicenter, prospective, randomized controlled study was designed. The key inclusion criteria were: histologically or cytologically confirmed small cell carcinoma, age ≥ 18 years, KPS ≥ 80, limited-stage is defined as tumor confined to one side of the chest including ipsilateral hilar, bilateral mediastinum and supraclavicular lymph nodes, patients have received definitive thoracic radiotherapy (regardless of the dose-fractionation of radiotherapy used) and chemotherapy, evaluated as complete remission (CR) of tumor 4–6 weeks after the completion of chemo-radiotherapy. Eligible patients will be randomly assigned to two arms: (1) PCI and brain MRI surveillance arm, receiving PCI (2.5 Gy qd to a total dose of 25 Gy in two weeks) followed by brain MRI surveillance once every three months for two years; (2) brain MRI surveillance alone arm, undergoing brain MRI surveillance once every three months for two years. The primary objective is to compare the 2-year brain metastasis-free survival (BMFS) rates between the two arms. Secondary objectives include 2-year overall survival (OS) rates, intra-cranial failure patterns, 2-year progression-free survival rates and neurotoxicity. In case of brain metastasis (BM) detect during follow-up, stereotactic radiosurgery (SRS) will be recommended if patients meet the eligibility criteria.DiscussionBased on our post-hoc analysis of a prospective study, we hypothesize that in limited-stage SCLC patients with CR after definitive chemoradiotherapy, and ruling out of BM by MRI, it would be feasible to use brain MRI surveillance and omit PCI in these patients. If BM is detected during follow-up, treatment with SRS or whole brain radiotherapy does not appear to have a detrimental effect on OS. Additionally, this approach may reduce potential neurotoxicity associated with PCI.

Six versus four or five cycles of first-line etoposide and platinum-based chemotherapy combined with thoracic radiotherapy in patients with limited-stage small-cell lung cancer: A propensity score-matched analysis of a prospective randomized trial.

The recommended treatment for limited-stage small-cell lung cancer (LS-SCLC) is a combination of thoracic radiotherapy (TRT) and etoposide plus cisplatin (EP) chemotherapy, typically administered over 4-6 cycles. Nonetheless, the optimal duration of chemotherapy is still not determined. This study aimed to compare the outcomes of patients with LS-SCLC who received either 6 cycles or 4-5 cycles of EP chemotherapy combined with TRT. In this retrospective analysis, we utilized data from our prior prospective trial to analyze the outcomes of 265 LS-SCLC patients who received 4-6 courses of EP combined with concurrent accelerated hyperfractionated TRT between 2002 and 2017. Patients were categorized into two groups depending on their number of chemotherapy cycles: 6 or 4-5 cycles. To assess overall survival (OS) and progression-free survival (PFS), we employed the Kaplan-Meier method after conducting propensity score matching (PSM). Among the 265 LS-SCLC patients, 60 (22.6%) received 6 cycles of EP chemotherapy, while 205 (77.4%) underwent 4-5 cycles. Following PSM (53 patients for each group), the patients in the 6 cycles group exhibited a significant improvement in OS and PFS in comparison to those in the 4-5 cycles group [median OS: 29.8 months (95% confidence interval [CI], 23.6-53.1 months) vs. 22.7 months (95% CI, 20.8-29.1 months), respectively, p = 0.019; median PFS: 17.9 months (95% CI, 13.7-30.5 months) vs. 12.0 months (95% CI, 9.8-14.2 months), respectively, p = 0.006]. The two-year and five-year OS rates were 60.38% and 29.87% in the 6 cycles group, whereas 47.17% and 15.72% in the 4-5 cycles group, respectively. Patients diagnosed with LS-SCLC who were treated with EP regimen chemotherapy combined with TRT exhibited notably enhanced survival when administered 6 cycles of chemotherapy, as compared to those who underwent only 4-5 cycles.

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.

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. 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. 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. 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.

Application of postoperative adjuvant radiotherapy in limited-stage small cell lung cancer: A systematic review and meta-analysis

Background and purposeOne of the most important treatments for small cell lung cancer (SCLC) is radiation therapy. Currently, the criteria for administering postoperative adjuvant radiotherapy (PORT) in SCLC remain uncertain. Therefore, we conducted a meta-analysis to investigate the influence of PORT on the prognosis of limited-stage SCLC (LS-SCLC). MethodsWe conducted a comprehensive search across three databases, PubMed, Embase, and the Cochrane Library. Data analysis involved utilizing both random-effects and fixed-effects models for pooling the results. A comparative analysis was performed to assess the prognostic outcomes of patients with LS-SCLC who did and did not undergo PORT. The primary outcome assessed was overall survival (OS), while the secondary outcome was disease-free survival (DFS). ResultsThis analysis included 11 retrospective studies comprising 7694 eligible participants. Among the entire population of LS-SCLC patients, the OS was superior in those receiving PORT than in those not receiving it (hazard ratio [HR]: 0.79, 95 % confidence interval [CI]: 0.71–0.87; P < 0.0001). In pN0 stage LS-SCLC patients, PORT was associated with a detrimental effect on OS (HR: 1.22, 95 % CI: 1.04–1.43; P = 0.01). In pN1 stage LS-SCLC patients, additionally administering PORT did not provide a significant OS advantage as compared to not administering it (HR: 0.82, 95 % CI: 0.60–1.12; P = 0.21). In pN2 stage LS-SCLC patients, those receiving PORT demonstrated a significant improvement in OS (HR: 0.59; 95 % CI: 0.50–0.70; P < 0.0001) as compared to those not receiving it. Regarding DFS in LS-SCLC patients, the difference in the protective effect with and without the administration of PORT was less pronounced (HR: 0.76, 95 % CI: 0.58–1.00; P = 0.053). ConclusionsWith respect to OS, PORT is not advisable in patients with pN0 or pN1 stage LS-SCLC but is highly recommended in pN2 stage LS-SCLC. Further research is warranted to confirm these findings.

Application of a Contralateral Esophageal-Sparing Technique to Reduce Radiation Esophagitis in Limited-Stage Small Cell Lung Cancer Treated with Twice-Daily Radiotherapy and Concurrent Chemotherapy

Acute esophagitis (AE) is a common radiation-related toxicity after concurrent twice-daily hyperfractionated radiotherapy and chemotherapy in limited-stage small cell lung cancer (LS-SCLC) patients, which could limit dose-escalation of the target and make treatment postponed to decrease local tumor control. More esophageal protective techniques should be proposed to reduce radiation severe esophagitis of LS-SCLC patients. We retrospectively applied a contralateral esophagus sparing technique (CEST) in 20 unresectable LS-SCLC patients, who had gross tumor within 1 cm of the esophagus and received a total dose of 45 Gy of concurrent twice-daily radiation and standard chemotherapy regimen. The contralateral esophagus (CE) was contoured as an avoidance structure, and the feasibility of CEST on promoting a steep dose falloff beyond the target volume near esophagus was analyzed. The appropriate dose constraints of CE were also investigated. The AE events were recorded according to the RTOG acute toxicity grading system. We performed CEST in 20 LS-SCLC consecutive patients, among whom three patients experienced severe AE after concurrent chemoradiotherapy. Each treatment plan of eligible patients assured high radiation doses delivering, with the planning and gross tumor volume covered by 95% and 100% of the prescription dose. Among these patients, the median maximum esophagus dose declined from 47.9 Gy (range, 46.6-49.7 Gy) to 41.3 Gy (range, 35.9-48.2 Gy), as well as V30 and V36 of esophagus decreased from 9.22 Gy (range, 0.42-17.71 Gy) and 7.39 Gy (range, 0-16.19 Gy) to 2.40 Gy (range, 0-5.68 Gy) and 0.53 Gy (range, 0 -2.69 Gy) after CEST applying, respectively (all p<0.001). The CE's median maximum dose, V30, and V36 were 41.3 Gy, 2.13 cc, and 0.24 cc, respectively. By using proposed CE dose constraints of Dmax≤42 Gy, V30 ≤3.5 cc and V36 ≤0.5 cc, we confirmed the feasibility and efficacy of CEST to avoid exposing the esophagus cross-section to high prescription doses in LS-SCLC patients receiving twice-daily hyperfractionated IMRT and concurrent chemotherapy. These findings support the clinical practice of CEST in LS-SCLC patients, while more prospective and large-scale studies are warranted.

Effect of Segmental Abutting Esophagus-Sparing Technique to Reduce Severe Esophagitis in Limited-Stage Small-Cell Lung Cancer Patients Treated with Concurrent Hypofractionated Thoracic Radiation and Chemotherapy

To evaluate the effect of segmental abutting esophagus-sparing (SAES) radiotherapy to reduce severe (G3+) acute esophagitis from 20% to 5% in patients with limited-stage small cell lung cancer (LS-SCLC) treated with concurrent chemoradiotherapy. Patients with a clinical target volume (CTV) ≤1 cm close to the esophagus were enrolled in the experimental arm (45 Gy in 3 Gy daily fractions in 3 weeks) of an ongoing phase III randomized clinical trial (NCT02675088), which enrolled patients with histologically confirmed SCLC and clinically staged as LS or I-IIIB (AJCC 7th). This trial was designed to determine whether HYPO TRT (45 Gy in 3 Gy QD, experimental arm) has the same efficacy as CF TRT (60 Gy in 2 Gy QD, controlled arm) in patients with LS-SCLC. The whole esophagus was divided into the involved esophagus and abutting esophagus (AE) to receive different dose limitations according to the distance from the edge of the CTV. The primary endpoint was grade ≥ 3 acute esophagitis. From 1 May 2021 to 30 April 2022, 30 patients were enrolled and completed four cycles of planned chemotherapy and radiotherapy. Our patient population was predominantly male (66.7% men vs. 33.3% women), with a median age of 62 years. A majority of patients presented with Stage N2-3 (90.0%) and T2-4 (76.7%), in which 4 patients had ultracentral-located primary tumors. With the SAES technique, all dosimetric parameters were significantly reduced for the whole esophagus and AE. The maximal and mean dose of the esophagus (47.4±1.9 Gy and 13.5 ± 5.8 Gy, respectively) and AE (42.9±2.3 Gy and 8.6 ± 3.6 Gy, respectively) in the SAES plan were significantly lower than those (esophagus 48.0±1.9 Gy and 14.7± 6.1 Gy, AE 45.1±2.4 Gy and 9.8± 4.2 Gy, respectively) in the non-SAES plan. After the follow-up of more than 7 months (range, 7.0-18.1 months) for all patients, only one patient (3.3%, 95% CI 0.1%-17.2%) experienced grade 3 acute esophagitis and no grade 4-5 acute esophagitis happened (Table 3). For late toxicities, one patient suffered sustained grade 1 late esophagitis and all others had no symptoms of esophagitis. The rate of radiation pneumonitis was very low, with one grade 3 event and no grade 4-5 event. Twelve (40.0%) patients had G3+ hematologic toxic events, including 2 patients with febrile neutropenia. The 1-year OS, LRFS, DMFS and PFS was 96.4%, 88.7%, 78.4% and 64.3%, respectively. No patient developed local recurrence in the abutting esophagus-sparing region. SAES radiotherapy has significant dosimetric advantages compared with standard radiotherapy, which are successfully translated into clinical benefits for patients with LS-SCLC treated with 45 Gy in 3 Gy daily fractions. This may facilitate dose escalation for TRT in LS-SCLC patients.

Could Residual Disease Irradiation be Better than Involved Field Irradiation for Limited-Stage Small Cell Lung Cancer? A Failure Pattern Analysis

For limited-stage small cell lung cancer (LS-SCLC), the thoracic radiotherapy (TRT) plays a vital role. Previous clinical research showed that for the TRT could be limited to the postchemotherapy tumor volume and the positive prechemotherapy lymph node regions. Involved field irradiation (IFI) could be routinely applied. However, the optimum radiation field design remains controversial. In the present study, we retrospectively analyzed the patterns of failure in LS-SCLC patients receiving residual disease irradiation (RDI) in radiotherapy. A total of 47 patients with LS-SCLC treated with RDI with sequent or concurrent chemotherapy were enrolled in this study. The gross tumor volume (GTV) defined as residual volumes of positive node and primary tumor of the post-chemotherapy. The clinical target volume (CTV) included GTV with a margin 0.5 cm. Planning target volume (PTV) involved CTV with a margin 0.5 cm. RFI consisted of 1.5 grays (Gy) twice daily in 30 fractions up to a total dose of 45 Gy or 2.0 Gy daily up to 60 Gy. Treatment failures were divided into local and distant failures, and local recurrences were classified into inside RDI(IN-RDI), between RDI and IFI(RDI-IFI), and outside IFI(OUT-IFI). Among the 46 patients with detailed follow-up data for recurrences, 36 (78.3%) experienced recurrences, with 16 (34.8%) being local recurrence, and 29 (63.0%) being distant failure. For the 16 patients with local recurrences, 10, 5, and 1 were IN-RDI, OUT-IFI, and RDI-IFI recurrences, respectively. Residual disease irradiation (RDI) is feasible for LS-SCLC treated with sequent or concurrent chemotherapy and does not compromise failure inside the involved region.

A Nomogram Based on Radiomics and Genomics Factors for Predicting Radiation Pneumonia in Patients with Limited-Stage Small Cell Lung Cancer after Definitive Chemoradiotherapy

Although definitive chemoradiotherapy (dCRT) is currently the most effective treatment for limited-stage small cell lung cancer (SCLC), some patients may develop severe radiation pneumonia (RP). We aimed to develop a nomogram by combining the clinical, radiomics and genomics factors to predict the RP. Totally 148 limited-stage SCLC patients treated with dCRT were retrospectively enrolled and divided into the training (n = 103) and validation (n = 45) cohorts. All tumor tissue samples were detected by 474 Panel gene sequencing technology. Eight hundred fifty-one radiomics features of lung other than hilum, atelectasis and tumor were extracted from the initial CT images. Least absolute shrinkage and selection operator (LASSO) method was applied to select and build radiomic signature. Combined with genomic, radiomic and clinical features, a nomogram was established by univariate and multivariate analysis. Concordance index (C-index), calibration curve and decision curve were used to evaluate the predictive ability and application value of the nomogram. Six selected radiomic features was used to construct radiomic signature. Multivariate analysis showed that NQO1 gene (OR, 8.354; 95% CI, 1.061-65.765; P = 0.044), radiotherapy technique (OR, 9.586; 95% CI, 1.168-78.70; P = 0.035) and radiomic signature (OR, 5.745; 95% CI, 1.879-17.56; P = 0.002) were independent risk factors for RP. Compared with the single clinical (C-index = 0.621 and 0.533), radiomic (C-index = 0.696 and 0.550) or genetic (C-index = 0.561 and 0.433) factor, the C-index of nomogram was the highest, reaching 0.764 and 0.622 in the training group and validation group, respectively. The calibration curves indicated good agreement between the predictions and actual observations. Moreover, decision curves revealed that the nomogram had high clinical practicability. This study further reveals the potential of radiomics and genomics in predicting the occurrence of RP, and may provide individualized prediction for patients with limited-stage SCLC, as well as theoretical and technical support for physicians to optimize clinical decisions.

Prophylactic cranial irradiation effect on survival in patients with small cell lung cancer: a comprehensive systematic review and meta-analysis.

Prophylactic cranial irradiation (PCI) is a companion treatment option for small cell lung cancer (SCLC) patients. However, its efficacy and associated risk factors have not been clearly defined. In this study, the authors aimed to systematically assess the effectiveness and role of PCI in the treatment plan of SCLC. The PubMed, Scopus, Web of Science, and Cochrane databases were searched using the following key terms and their equivalents: "brain," "radiotherapy," "metastases," "prophylactic," and "small cell lung cancer." Studies comparing overall survival (OS), progression-free survival (PFS), brain metastasis-free survival (BMFS), and incidence of brain metastases between patients receiving PCI and those not receiving it were considered eligible. Risk of bias was assessed using the Risk of Bias in Non-Randomized Studies-of Interventions (ROBINS-I) tool. Meta-analysis was conducted on the mentioned outcomes with subgrouping based on different factors. The authors identified 74 studies published between 1983 and 2022 with 31,551 SCLC patients, of whom 26.7% received PCI. The studies were a mix of prospective randomized and retrospective observational studies. Patients with limited-stage disease receiving PCI had better OS, PFS, and BMFS than those not receiving PCI. Patients receiving PCI also had significantly longer OS times and developed brain metastases significantly later. However, findings regarding extensive-stage SCLC were not as promising. PCI is an effective option for limited-stage SCLC patients. It improves OS and PFS, delays brain metastases, and reduces the incidence of brain metastases. However, it might not benefit patients with extensive-stage SCLC under adequate follow-up with MRI surveillance. Finally, the heterogeneity of the included studies and publication bias were the main limitations of this study.

Analysis of risk factors of radiation-induced toxicity in limited-stage small cell lung cancer treated with hypofractionated intensity-modulated radiotherapy

Objective: To compare the incidence of radiation-related toxicities between conventional and hypofractionated intensity-modulated radiation therapy (IMRT) for limited-stage small cell lung cancer (SCLC), and to explore the risk factors of hypofractionated radiotherapy-induced toxicities. Methods: Data were retrospectively collected from consecutive limited-stage SCLC patients treated with definitive concurrent chemoradiotherapy in Cancer Hospital of Chinese Academy of Medical Sciences from March 2016 to April 2022. The enrolled patients were divided into two groups according to radiation fractionated regimens. Common Terminology Criteria for Adverse Events (CTCAE, version 5.0) was used to evaluate the grade of radiation esophagus injuries and lung injuries. Logistic regression analyses were used to identify factors associated with radiation-related toxicities in the hypofractionated radiotherapy group. Results: Among 211 enrolled patients, 108 cases underwent conventional IMRT and 103 patients received hypofractionated IMRT. The cumulative incidences of acute esophagitis grade ≥2 [38.9% (42/108) vs 35.0% (36/103), P=0.895] and grade ≥ 3 [1.9% (2/108) vs 5.8% (6/103), P=0.132] were similar between conventional and hypofractionated IMRT group. Late esophagus injuries grade ≥2 occurred in one patient in either group. No differences in the cumulative incidence of acute pneumonitis grade ≥2[12.0% (13/108) vs 5.8% (6/103), P=0.172] and late lung injuries grade ≥2[5.6% (6/108) vs 10.7% (11/103), P=0.277] were observed. There was no grade ≥3 lung injuries occurred in either group. Using multiple regression analysis, mean esophageal dose ≥13 Gy (OR=3.33, 95% CI: 1.23-9.01, P=0.018) and the overlapping volume between planning target volume (PTV) and esophageal ≥8 cm(3)(OR=3.99, 95% CI: 1.24-12.79, P=0.020) were identified as the independent risk factors associated with acute esophagitis grade ≥2 in the hypofractionated radiotherapy group. Acute pneumonitis grade ≥2 was correlated with presence of chronic obstructive pulmonary disease (COPD, P=0.025). Late lung injuries grade ≥2 was correlated with tumor location(P=0.036). Conclusions: Hypofractionated IMRT are tolerated with manageable toxicities for limited-stage SCLC patients treated with IMRT. Mean esophageal dose and the overlapping volume between PTV and esophageal are independently predictive factors of acute esophagitis grade ≥2, and COPD and tumor location are valuable factors of lung injuries for limited-stage SCLC patients receiving hyofractionated radiotherapy. Prospective studies are needed to confirm these results.

Impact of the depth of remission by induction chemotherapy on the prognosis of limited stage small cell lung cancer

Objective: To evaluate the effect of depth of remission of induction chemotherapy on the overall prognosis of limited stage small cell lung cancer (L-SCLC). Methods: The study was a retrospective, L-SCLC patients who contained complete imaging data and underwent consecutive standardized treatments at the Department of Thoracic Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University between January 2013 and June 2021 were included. To delineate the volume of tumor before and after induction chemotherapy and to calculate the depth of remission caused by the induced chemotherapy. The time receiver operating characteristic (timeROC) method was used to determine the optimal predictors for prognosis, multi-factor analysis using Cox risk proportional model. Results: A total of 104 patients were included in this study. The median PFS and OS of this cohort were 13.7 months and 20.9 months, respectively. It was observed by timeROC analysis that residual tumor volume after induction chemotherapy had the optimal predictive value of PFS at 1 year (AUC=0.86, 95% CI: 0.78~0.94) and OS at 2 years (AUC=0.76, 95% CI: 0.65~0.87). Multivariate analysis showed residual tumor volume after induction chemotherapy was the independent prognostic factor to PFS (HR=1.006, 95% CI: 1.003~1.009, P<0.01) and OS (HR=1.009, 95% CI: 1.005~1.012, P<0.001). For those whose residual tumor volume remitted to less than 10 cm(3) after induction chemotherapy, the favorable long-term outcomes could be achieved, regardless of their initial tumor load. Conclusion: The depth of remission of induction chemotherapy could be a promising prognostic predictor to the L-SCLC and provide the individualized treatment guidance.

Design and Rationale for a Phase II/III, Randomized, Double-Blind, Placebo-Controlled Study of Sugemalimab as Consolidation Therapy in Patients With Limited-Stage Small-Cell Lung Cancer Who Have Not Progressed Following Concurrent or Sequential Chemoradiotherapy: The SURPASS Study

BackgroundThere is still a substantial need of more treatment options for patients with limited-stage small cell lung cancer (LS-SCLC). The standard therapy for LS-SCLC is platinum-based doublet chemotherapy administered concurrently with thoracic radiotherapy (cCRT). In China, sequential chemoradiotherapy (sCRT) is also a common practice. However, the disease inevitably progresses in most patients despite the curative intent and initial response. Materials and MethodsSugemalimab is an anti-programmed death ligand-1 (PD-L1) antibody that improved clinical outcomes for patients with stage III non-small cell lung cancer after cCRT or sCRT. The SUPPASS study is a phase II/III, randomized, double-blind, placebo-controlled, multicenter study (NCT05623267) that aims to investigate the efficacy and tolerability of sugemalimab as consolidation therapy in patients with LS-SCLC who have no progression following cCRT or sCRT. Approximately 346 patients will be randomized in a 1:1 ratio to receive sugemalimab 1200 mg or placebo every 3 weeks for up to 12 months. The primary endpoint is progression-free survival (PFS). Key secondary endpoints include overall survival (OS), landmark PFS rate, landmark OS rate, objective response rate and safety. Longitudinal molecular residual disease (MRD) testing will be performed as preplanned exploratory analysis. ConclusionStudy results will help demonstrate the efficacy and tolerability of anti-PD-L1 antibody consolidation therapy in LS-SCLC patients who have not progressed following cCRT or sCRT, and help determine the clinical implications of MRD in LS-SCLC.

Application of a contralateral esophageal-sparing technique to reduce radiation esophagitis in limited-stage small cell lung cancer treated with twice-daily radiotherapy and concurrent chemotherapy.

e20644 Background: Acute esophagitis (AE) is a common radiation-related toxicity after concurrent twice-daily hyperfractionated radiotherapy and chemotherapy in limited-stage small cell lung cancer (LS-SCLC) patients, which could limit dose-escalation of the target and make treatment postponed to decrease local tumor control. More esophageal protective techniques should be proposed to reduce radiation severe esophagitis of LS-SCLC patients. Methods: We retrospectively applied a contralateral esophagus sparing technique (CEST) in 20 unresectable LS-SCLC patients, who had gross tumor within 1 cm of the esophagus and received a total dose of 45 Gy of concurrent twice-daily radiation and standard chemotherapy regimen. The contralateral esophagus (CE) was contoured as an avoidance structure, and the feasibility of CEST on promoting a steep dose falloff beyond the target volume near esophagus was analyzed. The appropriate dose constraints of CE were also investigated. The AE events were recorded according to the RTOG acute toxicity grading system. Results: We performed CEST in 20 LS-SCLC consecutive patients, among whom three patients experienced severe AE after concurrent chemoradiotherapy. Each treatment plan of eligible patients assured high radiation doses delivering, with the planning and gross tumor volume covered by 95% and 100% of the prescription dose. Among these patients, the median maximum esophagus dose declined from 47.9 Gy (range, 46.6-49.7 Gy) to 41.3 Gy (range, 35.9-48.2 Gy), as well as V30 and V36 of esophagus decreased from 9.22 Gy (range, 0.42-17.71 Gy) and 7.39 Gy (range, 0-16.19 Gy) to 2.40 Gy (range, 0-5.68 Gy) and 0.53 Gy (range, 0 -2.69 Gy) after CEST applying, respectively (all p &lt; 0.001). The CE’s median maximum dose, V30, and V36 were 41.3 Gy, 2.13 cc, and 0.24 cc, respectively. Conclusions: By using proposed CE dose constraints of Dmax≤42 Gy, V30 ≤3.5 cc and V36 ≤0.5 cc, we confirmed the feasibility and efficacy of CEST to avoid exposing the esophagus cross-section to high prescription doses in LS-SCLC patients receiving twice-daily hyperfractionated IMRT and concurrent chemotherapy. These findings support the clinical practice of CEST in LS-SCLC patients, while more prospective and large-scale studies are warranted.

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as prognostic biomarkers in limited-stage small-cell lung cancer: a meta-analysis.

Background: The role of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic markers in limited-stage small-cell lung cancer (LS-SCLC) remains controversial. Methods: Using pooled hazard ratios (HR) with 95% CIs, we assessed the correlation of pre-treatment NLR and PLR with overall survival (OS) and progression-free survival (PFS) in LS-SCLC. Publication bias was assessed by Begg's and Egger's tests. Results: Ten studies were enrolled in our meta-analysis. Pooled analyses showed that pre-treatment high NLR was significantly associated with poor OS (HR: 1.80) and PFS (HR: 1.69) in LS-SCLC patients. High pre-treatment PLR was also associated with shorter OS (HR: 1.52) and PFS (HR: 1.39) in LS-SCLC patients. Conclusion: Our meta-analysis suggests that high pre-treatment NLR or PLR may be negatively related to OS and PFS in LS-SCLC.

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

BackgroundThe 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). MethodsWe 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. ResultsCompared 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. ConclusionLS-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.

Anomogram to predict the cumulative risk for brain metastases in patients with limited-stage small cell lung cancer without prophylactic cranial irradiation.

Patients with small cell lung cancer (SCLC) have ahigh risk of developing brain metastases (BM). Prophylactic cranial irradiation (PCI) is astandard therapy for limited-stage SCLC (LS-SCLC) patients who achieved complete or partial response after thoracic chemoradiotherapy (Chemo-RT). Recent studies have indicated that asubgroup of patients with alower risk of BM can avoid PCI, and the present study therefore tries to construct anomogram to predict the cumulative risk of development of BM in LS-SCLC patients without PCI. After screening of 2298 SCLC patients who were treated at the Zhejiang Cancer Hospital from December 2009 to April 2016, atotal of 167consecutive patients with LS-SCLC who received thoracic Chemo-RT without PCI were retrospectively analyzed. The paper analyzed clinical and laboratory factors that may be correlated with BM, such as response to treatment, pretreatment serum neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) levels, and TNM stage. Thereafter, anomogram was constructed to predict 3‑ and 5‑year intracranial progression-free survival (IPFS). Of 167patients with LS-SCLC, 50developed subsequent BM. Univariate analysis showed that pretreatment LDH (pre-LDH) ≥ 200 IU/L, an incomplete response to initial chemoradiation, and UICC stageIII were positively correlated to ahigher risk of BM (p < 0.05). Multivariate analysis identified pretreatment LDH level (hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.08-3.34, p = 0.026), response to chemoradiation (HR 1.87, 95% CI 1.04-3.34, p = 0.035), and UICC stage (HR 6.67, 95% CI 1.03-49.15, p = 0.043) as independent predictors for the development of BM. Anomogram model was then established, and areas under the curve of 3‑year and 5‑year IPFS were 0.72 and 0.67, respectively. The present study has developed an innovative tool that is able to predict the individual cumulative risk for development of BM in LS-SCLC patients without PCI, which is beneficial for providing personalized risk estimates and facilitating the decision to perform PCI.

Effect of Segmental Abutting Esophagus-Sparing Technique to Reduce Severe Esophagitis in Limited-Stage Small-Cell Lung Cancer Patients Treated with Concurrent Hypofractionated Thoracic Radiation and Chemotherapy

The aim of the current study is to evaluate the effect of segmental abutting esophagus-sparing (SAES) radiotherapy on reducing severe acute esophagitis in patients with limited-stage small-cell lung cancer treated with concurrent chemoradiotherapy. Thirty patients were enrolled from the experimental arm (45 Gy in 3 Gy daily fractions in 3 weeks) of an ongoing phase III trial (NCT02688036). The whole esophagus was divided into the involved esophagus and the abutting esophagus (AE) according to the distance from the edge of the clinical target volume. All dosimetric parameters were significantly reduced for the whole esophagus and AE. The maximal and mean doses of the esophagus (47.4 ± 1.9 Gy and 13.5 ± 5.8 Gy, respectively) and AE (42.9 ± 2.3 Gy and 8.6 ± 3.6 Gy, respectively) in the SAES plan were significantly lower than those (esophagus 48.0 ± 1.9 Gy and 14.7± 6.1 Gy, AE 45.1 ± 2.4 Gy and 9.8 ± 4.2 Gy, respectively) in the non-SAES plan. With a median follow-up of 12.5 months, only one patient (3.3%) developed grade 3 acute esophagitis, and no grade 4-5 events happened. SAES radiotherapy has significant dosimetric advantages, which are successfully translated into clinical benefits and provide good feasibility for dose escalation to improve local control and prognosis in the future.

Efficacy of Prophylactic Cranial Irradiation According to the Risk of Extracranial Recurrence in Limited-Stage Small Cell Lung Cancer.

We aimed to evaluate the effectiveness of prophylactic cranial irradiation (PCI) for "early brain metastasis", which occurs before extracranial recurrence (ECR), and "late brain metastasis", which occurs after ECR, in limited-stage small cell lung cancer (LS-SCLC). We retrospectively analyzed 271 LS-SCLC patients who underwent definitive chemoradiation. All patients were initially staged with brain magnetic resonance imaging and positron emission tomography. Intracranial recurrence (ICR), ECR, progression-free rate (PFR), and overall survival (OS) were analyzed as clinical endpoints. The competing risk of the first recurrence with ICR (ICRfirst) was evaluated. Significantly associated variables in multivariate analysis of ECR were considered as ECR risk factors. Patients were stratified according to the number of ECR risk factors. The application of PCI was associated with higher PFR (p=0.008) and OS (p=0.045). However, PCI was not associated with any of the clinical endpoints in multivariate analysis. The competing risk of ICRfirst was significantly decreased with the application of PCI (hazard ratio, 0.476; 95% confidence interval, 0.243 to 0.931; p=0.030). Stage III disease, sequential, and stable disease after thoracic radiation were selected as ECR risk factors. For patients without these risk factors, the application of PCI was significantly associated with increased OS (p=0.048) and a decreased risk of ICRfirst (p=0.026). PCI may play a role in preventing early brain metastasis rather than late brain metastasis after ECR, suggesting that only patients with a low risk of ECR may currently benefit from PCI.

Retrospective Clinical Study on Integrated Chinese and Western Medicine in Treatment of Limited-Stage Small Cell Lung Cancer.

To investigate the efficacy of integrated Chinese and Western medicine extending the progression-free survival (PFS) and overall survival (OS) of limited-stage small cell lung cancer (LS-SCLC) patients after the first-line chemoradiotherapy. The data of 67 LS-SCLC patients who received combined treatment of CM and Western medicine (WM) between January 2013 and May 2020 at the outpatient clinic of Guang'anmen Hospital were retrospectively analyzed. Thirty-six LS-SCLC patients who received only WM treatment was used as the WM control group. The medical data of the two groups were statistically analyzed. Survival analysis was performed using the product-limit method (Kaplan-Meier analysis). The median OS and PFS were calculated, and survival curves were compared by the Log rank test. The cumulative survival rates at 1, 2, and 5 years were estimated by the life table analysis. Stratified survival analysis was performed between patients with different CM administration time. The median PFS in the CM and WM combination treatment group and the WM group were 19 months (95% CI: 12.357-25.643) vs. 9 months (95% CI: 5.957-12.043), HR=0.43 (95% CI: 0.27-0.69, P<0.001), respectively. The median OS in the CM and WM combination group and the WM group were 34 months (95% CI could not be calculated) vs. 18.63 months (95% CI: 16.425-20.835), HR=0.40 (95% CI: 0.24-0.66, P<0.001), respectively. Similar results were obtained in the further stratified analysis of whether the duration of CM administration exceeded 18 and 24 months (P<0.001). The combination treatment of CM and WM with continuing oral administration of CM treatment after the first-line chemoradiotherapy for LS-SCLC patients produced better prognosis, lower risks of progression, and longer survival than the WM treatment alone. (Registration No. ChiCTR2200056616).

Benefits and Relevant Risk Factor Assessment of Neoadjuvant Chemotherapy in Combination with Surgery in Limited-Stage Small-Cell Lung Cancer.

To illustrate the benefits of surgery in conjunction with neoadjuvant chemotherapy in patients with limited-stage small cell lung cancer (LS-SCLC), and to evaluate risk factors affecting patient's survival. Forty-six LS-SCLC patients who received surgery in our center from September 2012 to December 2018 were retrospectively analyzed. Twenty-five patients with LS-SCLC diagnosed after surgery who received postoperative adjuvant chemotherapy were classified into control group, and 21 patients with LS-SCLC who received preoperative neoadjuvant chemotherapy were classified into observation group. The observation group were divided into subgroup 1 (negative lymph nodes) and subgroup 2 (positive lymph nodes). Progression-free survival (PFS) and overall survival (OS) of patients were analyzed. Univariate and multivariate Cox regression were utilized to analyze independent risk factors affecting patient's survival. PFS and OS of patients in the control group and observation group had similar outcomes (P > 0.05). Subgroup 1 and subgroup 2 had similar PFS and OS (P > 0.05). PT2, pN2, BM, and two or more positive lymph nodes were significantly associated with poor PFS and OS (P < 0.05). Furthermore, the pT, number of lymph node positive stations and BM were independent risk factors affecting patient's survival (P < 0.05). Surgery combined with neoadjuvant chemotherapy can achieve long-term survival benefit for some patients with LS-SCLC. It is necessary to find a better plan that enables to select patients suitable for surgery after neoadjuvant chemotherapy.