Limited Stage Small Cell Lung Research Articles

Evaluation of Radiation Therapy Treatment Plans in a Randomized Phase 2 Trial Comparing 2 Schedules of Twice-Daily Thoracic Radiation Therapy in Limited Stage Small Cell Lung Cancer

PurposeThere is limited clinical data for recommendations on how to deliver thoracic radiotherapy (TRT) concurrently with chemotherapy in limited stage (LS) small-cell lung cancer (SCLC). We reviewed radiotherapy treatment plans in a randomized phase II trial comparing high-dose with standard-dose twice-daily TRT to assess treatment planning techniques, dose-volume data for target volumes and organs at risk (OARs), evaluate compliance with the protocol, associations with radiation-induced toxicity and whether an imbalance in treatment planning parameters might be a reason for the large survival benefit of the higher dose (median overall survival 43.6 vs. 22.6 months). Methods and Materials170 patients were to receive four courses of platinum/etoposide and randomized to receive twice-daily TRT of 60 Gy/40 fractions (fx) or 45 Gy/30 fx. TRT treatment plans for those who received one or more fx of TRT (n=166) were analyzed. ResultsThe most common treatment planning technique was 3DCRT (67%). The 75th percentile of the reported dose-volume parameters for the OARs were within the protocol-recommended limits for both groups. Mean doses to the esophagus of 25.5 Gy (IQR: 20.2-31.3) [60 Gy/40 fx] and 24.3 Gy (IQR: 20.3-27.5) [45 Gy/30 fx] were associated with 21% and 18% ≥ grade 3 acute esophagitis, respectively. In the 60 Gy/40 fx group, a mean dose to the lungs of 16.5 Gy (IQR: 15.8-16.9), V20Gy of 29.5% (IQR: 28.8-30.4), and V5Gy of 65.6% (IQR: 61.5-68.7) led to ≥ grade 3 pneumonitis in 4% of the patients. There was no ≥ grade 3 pneumonitis in the 45 Gy group. Treatment planning techniques, the percentage change in volumes between original and re-delineated OARs, PTV volumes, relative doses, and laterality were well balanced between the randomly assigned groups. ConclusionConsidering that the incidences of severe radiation-induced toxicities were within the range of other recent trials, the reported doses to the OARs appear to be safe. Treatment planning parameters were well balanced between the randomly assigned groups, supporting that the survival benefit of the twice-daily 60 Gy/ 40 fx TRT schedule was due to the higher dose.

Abstract 1125: TNIK induced chemoradiation resistance in small cell lung cancer

Abstract Chemoradiation (CRT) is the standard first-line therapy for limited stage small cell lung cancer (LS-SCLC), which is characterized by early metastasis, intrinsic-acquired CRT resistance and tumor recurrence. CRT confers a 20-25% 5-year overall survival in patients with LS-SCLC. In this study, we utilized patient-derived xenograft (PDX) models to demonstrate CRT resistance of SCLC and identified CRT resistance candidate genes from various SCLC PDX that represent the majority of molecular subtypes (n=4 that include SCLC-A and SCLC-N subtypes). RNA-seq data identified TNIK (Traf2- and Nck-interacting kinase) as one such gene that is consistently upregulated in SCLC PDXs exposed to CRT compared to single modality treatments. Copy number gains of TNIK were also present in human SCLC samples. Overcoming this CRT resistance is crucial in improving treatment outcomes and patient survival. Genetic depletion or pharmacological inhibition of TNIK reduced the in vitro clonogenic survival of TNIKhigh SCLC cells, NCI-H446 and makes them increasingly sensitive to CRT. In vivo, pharmacological inhibition of TNIK with the inhibitor NCB-0846, enhances the CRT sensitivity of NCI-H446 cell line-derived xenografts (CDX) in NOD SCID immunodeficient mice. Furthermore, pharmacological inhibition of TNIK in vivo demonstrated sensitivity to CRT in LX33 PDX. In conclusion, our results indicate that TNIK plays a role in conferring resistance to CRT in vitro in SCLC cell lines and in vivo in SCLC CDX and PDX models and therefore, can be a potential therapeutic target in limited stage SCLC. Citation Format: Dipanwita Dutta Chowdhury, Eddie Imada, Nick Connis, Triet Nguyen, Jinhee Chang, Danielle Council, Audrey Lafargue, Mohammad Rezaee, Phuoc T. Tran, Luigi Marchionni, Christine L. Hann. TNIK induced chemoradiation resistance in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1125.

Long-Term Outcomes After Concurrent Once- or Twice-Daily Chemoradiation in Limited-Stage Small Cell Lung Cancer: A Brief Report From the CONVERT Trial

CONVERT was a phase 3 international randomized clinical trial comparing once-daily (OD) and twice-daily (BD) radiation therapy (RT). This updated analysis describes the 6.5-year outcomes of these regimens delivered with conformal techniques. CONVERT (NCT00433563) randomized patients 1:1 between OD RT (66 Gy/33 fractions/6.5 weeks) and BD RT (45 Gy/30 fractions/3 weeks), both delivered with concurrent cisplatin/etoposide. Three-dimensional conformal RT was mandatory, intensity-modulated RT was permitted, and elective nodal irradiation was not allowed. Prophylactic cranial irradiation was delivered at the discretion of treating clinicians. RT treatment planning was subject to central quality assurance. Five hundred forty-seven patients were recruited at 73 centers. The median follow-up for the surviving cohort (n = 164) was 81.2 months. The median survival for the OD and BD arms were 25.4 months (95% CI, 21.1-30.9) and 30.0 months (95% CI, 25.3-36.5; hazard ratio, 1.13; 95% CI, 0.92-1.38; P = .247). Performance status and tumor volume were associated with survival on multivariate analysis. No treatment-related deaths occurred subsequent to the initial analysis performed in 2017. Regarding late toxicity, 7 patients in the OD arm developed grade 3 esophagitis, 4 of which went on to develop stricture or fistulation, compared with no patients in the BD arm. Grade 3 pulmonary fibrosis occurred in 2 and 3 patients in the OD and BD arms, respectively. As the CONVERT trial did not demonstrate the superiority of OD RT and this regimen had a slightly worse toxicity profile after 80 months of follow-up, 45 Gy BD should remain the standard of care in limited stage small cell lung cancer.

216TiP A phase II study of consolidation serplulimab following hypofractionated radiotherapy with concurrent chemotherapy for patients with limited stage small cell lung cancer (ASTRUM-LC01)

216TiP A phase II study of consolidation serplulimab following hypofractionated radiotherapy with concurrent chemotherapy for patients with limited stage small cell lung cancer (ASTRUM-LC01)

Construction of brain metastasis prediction model in limited stage small cell lung cancer patients without prophylactic cranial irradiation.

Small cell lung cancer (SCLC) is a highly aggressive lung cancer variant known for its elevated risk of brain metastases (BM). While earlier meta-analyses supported the use of prophylactic cranial irradiation (PCI) to reduce BM incidence and enhance overall survival, modern MRI capabilities raise questions about PCI's universal benefit for limited-stage SCLC (LS-SCLC) patients. As a response, we have created a predictive model for BM, aiming to identify low-risk individuals who may not require PCI. A total of 194 LS-SCLC patients without PCI treated between 2009 and 2021 were included. We conducted both univariate and multivariate analyses to pinpoint the factors associated with the development of BM. A nomogram for predicting the 2- and 3-year probabilities of BM was then constructed. Univariate and multivariate analyses revealed several significant independent risk factors for the development of BM. These factors include TNM stage, the number of chemotherapy (ChT) cycles, Ki-67 expression level, pretreatment serum lactate dehydrogenase (LDH) levels, and haemoglobin (HGB) levels. These findings underscore their respective roles as independent predictors of BM. Based on the results of the final multivariable analysis, a nomogram model was created. In the training cohort, the nomogram yielded an area under the receiver operating characteristic curve (AUC) of 0.870 at 2 years and 0.828 at 3 years. In the validation cohort, the AUC values were 0.897 at 2 years and 0.789 at 3 years. The calibration curve demonstrated good agreement between the predicted and observed probabilities of BM. A novel nomogram has been developed to forecast the likelihood of BM in patients diagnosed with LS-SCLC. This tool holds the potential to assist healthcare professionals in formulating more informed and tailored treatment plans.

Facility-Level Analysis of Twice Daily Radiation Utilization for Limited Stage Small Cell Lung Cancer

Treatment of limited stage SCLC (LS-SCLC) with twice daily (BID) fractionation (fx) to 45 Gy remains the standard of care for many decades. However, many patients receive once daily (QD) treatment as outcomes appear similar. Recent data have suggested that dose escalation to 60 Gy BID may improve outcomes, stressing the importance of BID delivery for SCLC. In this study, we examined the use of BID fractionation across treatment facilities and hypothesized that a substantial number of centers may never utilize BID treatment. The National Cancer Database (NCDB) was used to identify U.S. facilities treating LS-SCLC patients with definitive chemoradiation from 2004 to 2019. Included patients had stage I-III disease, received doublet chemotherapy, and did not undergo surgery. All patients received thoracic radiation therapy (RT), defined as QD (59.4-70.2 Gy in 30-39 fx) or BID (45 Gy in 30 fx). Other RT regimens were excluded. Facilities were classified into two cohorts (BID-treating and QD-only) based on whether or not at least one patient received BID treatment over the study period. Facility-level statistics including facility type, geographic location, and facility volume were analyzed. Predictors of BID-treating facility classification were determined using Chi-squared tests and uni/multivariable logistic regression. From 2004 to 2019, 22,545 LS-SCLC patients were treated by 1,222 facilities. Of the 1,222 facilities, 832 (68%) were BID-treating facilities while 391 (32%) were QD-only facilities. On univariable analysis, facility type (community cancer program, comprehensive community cancer program, integrated network cancer program, or academic program; p = 0.783) and geographic location (Northeast, Midwest, South, West; p = 0.417) were not associated with classification as a BID-treating facility. In contrast, facility volume was significantly associated with classification as a BID-treating facility, with BID use noted in 42.8% of the lowest quartile volume facilities vs. 84.0% of the highest quartile volume facilities (p<0.001). Dichotomized facility type (academic vs. non-academic), geographic location (South vs. other), and facility volume (greater or less than median volume) were included in a multivariable analysis. Facility volume (p<0.001) remained significant while facility type (p = 0.956) and facility location (p = 0.516) remained insignificant. Despite evidence supporting BID fractionation as the standard of care for LS-SCLC, 32% of facilities have never delivered BID treatment over the 15-year study period. Facilities with a low volume of patients are most likely to use QD-only. Barriers to BID treatment adoption will need to be overcome if dose escalated BID fractionation defines a new standard of care for LS-SCLC.

Risk of Esophagitis in Patients with Limited Stage SCLC Treated with QD or BID Chemoradiotherapy Regimens with Contralateral Esophagus Sparing

Recent randomized phase III trials in limited stage (LS) small cell lung carcinoma (SCLC) demonstrate persistent high rates of grade (G) ≥ 3 esophagitis of 16-19% for 45 Gy BID and 66-70 Gy QD radiotherapy (RT). G3 esophagitis dramatically impairs quality of life and is a barrier to treatment intensification. We previously developed a contralateral esophagus sparing technique (CEST) that reduced esophagitis mainly in patients with locally advanced NSCLC treated with chemoRT to 70 Gy/7 weeks. It is not established whether CEST is effective in LS-SCLC patients, especially those receiving BID RT which may limit mucosal esophageal regeneration during treatment. Here, we report our single-institution experience with this approach. We retrospectively analyzed the records of patients with LS-SCLC who received chemoRT between June 2014 and October 2022. Patients were treated with QD or BID schedules at physician discretion though QD has historically been favored at our institution. The esophageal wall contralateral to the tumor was contoured as an avoidance structure. IMRT or VMAT was used to drive steep dose fall-off across the esophagus while maintaining full tumor coverage. Daily cone-beam CT guidance was employed. Toxicity was assessed using CTCAE v5 criteria. Descriptive statistics were used to analyze outcomes. The study was approved by the IRB. We identified 38 consecutive patients with LS-SCLC treated with definitive chemoRT. Median age was 67 years, and 60.5% were female. Twenty-seven were treated with QD RT to a median dose of 63 Gy (range 55.8-70) in 33 fractions (range 31-35). All remaining patients received BID RT 45 Gy in 30 fractions. Median CTV for the QD and BID cohorts was 205 cc and 214 cc, respectively. Almost all patients (n = 37) had tumor located within 1 cm of the esophagus. There were no ≥G3 esophagitis events (95% CI, 0-9.3%). The rate of G2 esophagitis was 21.1% (11.1-36.3%), with no significant difference between QD (26%) and BID (9%) cohorts (p = 0.3). Only two patients required narcotics. For BID patients, CE planning constraints were scaled to reflect the shortened RT course. The median CE maximum dose, V20, and V30 were 44.8 Gy, 7.9 cc, and 6.4 cc, respectively. For the QD cohort, the median CE maximum dose, V45, and V55 were 59.5 Gy, 3.0 cc, and 0.6 cc, respectively. Treatment breaks occurred in nine QD patients due to neutropenia. Median follow-up was 31.0 months. 3-year overall survival was 70.0% (95% CI, 49.8-83.3%). While we are limited by small patient numbers and possible selection bias, our data suggest that CE sparing can be effective in LS-SCLC, with low severe esophagitis risk even for BID RT regimens. CEST is readily adaptable into clinical practice which should facilitate further refinement of empirically derived CE planning constraints.

High Dose Hyperfractionated Thoracic Radiotherapy vs. Standard Dose for Limited Stage Small-Cell Lung Cancer: A Multicenter, Open-Label Randomized, Phase 3 Trial

Limited stage small-cell lung cancer (LS-SCLC) is associated with poor prognosis. We aimed to assess the efficacy and safety of high-dose, hyperfractionated thoracic radiotherapy of 54 Gy in 30 fractions compared with standard dose (45 Gy in 30 fractions) as a first-line treatment for LS-SCLC. The study was an open-label, randomized, phase 3 trial, done at 16 public hospitals in China. Key inclusion criteria were patients aged 18-70 years, with previously histologically or cytologically confirmed LS-SCLC, previously untreated or received 1-2 courses of intravenous cisplatin (75 mg/m²of body-surface area, on day 1 or divided into two days of each cycle) or carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle)and intravenous etoposide (100 mg/m²of body-surface area, on days 1-3 of each cycle), and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.Eligible patients were randomly assigned (1:1) to receive volumetric-modulated arc radiotherapy (VMAT) of 45 Gy in 30 fractions or the simultaneous integrated boost VMAT (SIB-VMAT) of 54 Gy in 30 fractions to the primary lung tumor and lymph node metastases starting 0-42 days after the first chemotherapy course. Both groups of patients received thoracic radiotherapy twice per day and 10 fractions per week. Prophylactic cranial radiation (PCI, 25 Gy in 10 fractions) was implemented to patients with responsive disease. The primary endpoint was overall survival. Safety was analyzed in the as-treated population. Between June 30, 2017, and April 6, 2021, 224 eligible patients were enrolled and randomly assigned to 54 Gy (n = 108) or 45 Gy (n = 116). Median follow-up for the primary analysis was 45 months (IQR 41-48). Median overall survival was significantly improved in the 54 Gy group (62.4 months) compared with the 45 Gy group (43.1 months; p = 0.001). Median progression-free survival was significantly improved in the 54 Gy group (30.5 months) compared with the 45 Gy group (16.7 months; p = 0.044). The most common grade 3-4 adverse events were neutropenia (30 [28%] of 108 patients in the 54 Gy group vs 27 [23%] of 116 patients in the 45 Gy group), neutropenic infections (6 [6%] vs 2 [2%]), thrombocytopenia (13 [12%] vs 12 [10%]), anemia (6 [6%] vs 4 [3%]), and esophagitis (1 [1%] vs 3 [3%]). Treatment-related serious adverse events occurred in 9 [8%] patients in the 54 Gy group and 16 [14%] patients in the 45 Gy group. There were one treatment-related deaths in 54 Gy group (myocardial infarction). Compared with standard thoracic radiotherapy dose of 45 Gy, the high dose of 54 Gy improved overall survival and progression-free survival without increasing toxicities in patients with LS-SCLC, supporting twice-daily hyperfractionated thoracic radiotherapy of 54 Gy with concurrent chemotherapy is an alternative treatment option for LS-SCLC. This study is complete and registered with ClinicalTrials.gov, NCT03214003.

Identification of a visualized web-based nomogram for overall survival prediction in patients with limited stage small cell lung cancer

Small-cell lung cancer (SCLC) is an aggressive lung cancer subtype with an extremely poor prognosis. The 5-year survival rate for limited-stage (LS)-SCLC cancer is 10–13%, while the rate for extensive-stage SCLC cancer is only 1–2%. Given the crucial role of the tumor stage in the disease course, a well-constructed prognostic model is warranted for patients with LS-SCLC. The LS-SCLC patients' clinical data extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2018 were reviewed. A multivariable Cox regression approach was utilized to identify and integrate significant prognostic factors. Bootstrap resampling was used to validate the model internally. The Area Under Curve (AUC) and calibration curve evaluated the model's performance. A total of 5463 LS-SCLC patients' clinical data was collected from the database. Eight clinical parameters were identified as significant prognostic factors for LS-SCLC patients' OS. The predictive model achieved satisfactory discrimination capacity, with 1-, 2-, and 3-year AUC values of 0.91, 0.88, and 0.87 in the training cohort; and 0.87, 0.87, and 0.85 in the validation cohort. The calibration curve showed a good agreement with actual observations in survival rate probability. Further, substantial differences between survival curves of the different risk groups stratified by prognostic scores were observed. The nomogram was then deployed into a website server for ease of access. This study developed a nomogram and a web-based predictor for predicting the overall survival of patients with LS-SCLC, which may help physicians make personalized clinical decisions and treatment strategies.

Revisiting anti-Hu paraneoplastic autoimmunity: phenotypic characterization and cancer diagnosis.

Anti-Hu are the most frequent antibodies in paraneoplastic neurological syndromes, mainly associated with an often limited stage small cell lung cancer. The clinical presentation is pleomorphic, frequently multifocal. Although the predominant phenotypes are well characterized, how different neurological syndromes associate is unclear. Likewise, no specific study assessed the performance of new-generation CT and PET scanners for cancer screening in these patients. Herein, we aimed to describe the clinical pattern and cancer screening in a retrospective cohort of 466 patients with anti-Hu autoimmunity from the French Reference Centre on Paraneoplastic Neurological Syndromes registry. Clinical presentation, cancer screening and diagnosis were analysed. Among the 466 patients, 220 (54%) had multifocal neurological involvement. A hierarchical cluster analysis grouped the patients into (i) mainly limbic encephalitis, (ii) predominantly peripheral neuropathy and (iii) broad involvement of the nervous system (mixed group). Compared with limbic encephalitis and mixed groups, patients in the neuropathy group more frequently had a chronic onset of symptoms (29 versus 13 and 17%), elevated CSF proteins (83 versus 47 and 67%) and died from cancer progression (67 versus 15 and 28%; all P < 0.05). No significant difference in overall survival was observed between groups. Dysautonomia and brainstem signs were associated with a higher risk of death from the neurological cause; cancer diagnosis was the main predictor of all-cause death, especially when diagnosed within 2 years from clinical onset (all P < 0.05). Three hundred and forty-nine (75%) patients had cancer: in 295 (84%) neurological symptoms preceded tumour diagnosis, being lung cancer in 262 (89%), thereof small cell lung cancer in 227 (87%). First CT scan revealed lung cancer in 205/241 (85%), and PET scan shortened the interval to diagnosis when the initial CT scan was negative [7 months (1-66) in 27 patients versus 14 months (2-45) in 6; P < 0.001]. Although cancer diagnosis mostly occurred within 2 years from clinical onset, 13/295 (4%) patients exceeded that threshold. Conversely, 33 patients (7%) were 'cancer-free' after 2 years of follow-up. However, 13/33 (39%) had initial suspicious imaging findings that spontaneously regressed. In conclusion, although anti-Hu autoimmunity clinical presentation is mostly multifocal, we observed patients with a predominant limbic syndrome or isolated sensory neuropathy. Early implementation of PET scan shortens the interval to cancer diagnosis, which was the strongest predictor of death, especially if diagnosed ≤2 years from clinical onset. As cancer was diagnosed >2 years after clinical onset in few patients, screening should be extended up to 5 years. In addition, tumour regression was suspected in a substantial proportion of 'cancer-free' patients.

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.

Associations between patient-reported nutritional status, survival, and toxicity among patients with limited stage small-cell lung cancer (LS SCLC) in a randomized trial of high-dose, twice-daily (BID) thoracic radiotherapy (TRT).

8519 Background: Up to 1/3 of LS SCLC patients are cured by chemoradiotherapy (CRT), but severe toxicity is frequent and population-based studies show that many patients do not receive standard CRT. More knowledge on how to predict who experiences side-effects or achieves long term disease control is needed. Poor nutritional status is strongly associated with inferior survival in many types of cancer including non-small cell lung cancer, but little is known about whether this is the case in LS SCLC. We investigated whether nutritional status reported by patients on the Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF) was associated with toxicity and survival among participants in a trial comparing high dose with standard dose twice-daily TRT in LS-SCLC (NCT02041845, n=170). Methods: Patients received four courses of platinum/etoposide chemotherapy and were randomized to TRT of 60 Gy/40 fractions or 45 Gy/30 fractions. Patients completed PG-SGA SF before treatment commenced and were categorized as having low (PG-SGA SF score 0–3.9), intermediate (4.0–8.9) and high (≥9) risk of malnutrition. Toxicity was graded according to CTCAE 4.0. Median follow-up for survival was 49 months. Results: 113/170 (66.5%) patients completed PG-SGA SF at baseline. Median age was 65 years, 46.0% were men, 88.5% had PS 0-1, 87.6% stage III disease and 22.1% weight loss of &gt;5% the three months before inclusion. Median PG-SGA SF score was 3.0, 52.2% of patients had low, 29.2% intermediate, and 18.6% high risk of malnutrition. Numerically, there were more patients with stage III, PS 1-2 and pleural fluid among those at high risk. There was no difference in mean no. of chemotherapy courses (low: 3.85, intermediate: 3.88, high: 3.90, p=0.95) or TRT completion (low: 96.6%, intermediate: 97.0%, high: 95.2%, p=1.0). There were no statistically significant differences in proportions who experienced grade 3-4 toxicity (low: 88%, intermediate: 91%, high: 86%, p=0.86), median PFS (low: 15.1 months, intermediate: 11.8 months, high: NR, p=0.23), 2-year survival (low: 68%, intermediate: 52%, high: 67%, p=0.28) or median OS (low: 38.1 months, intermediate: 25.8 months, high: NR, p=0.15). Patients with weight loss &gt;5% did not experience more grade 3-4 toxicity (92% vs. 87%, p=0.73), had similar median PFS (24.0 vs. 15.9 months, p=0.69), 2-year survival (64.0% vs. 66.2%, p=0.84) and median OS (30.6 vs. 35.1 months, p=0.93) as those without. Conclusions: Our study suggest that LS SCLC patients tolerate and should receive concurrent chemotherapy and twice-daily TRT regardless of nutritional status and weight loss.

Final survival data from a randomized phase II trial comparing high-dose with standard-dose twice-daily (BID) thoracic radiotherapy (TRT) in limited stage small-cell lung cancer (LS SCLC).

8512 Background: Concurrent chemotherapy and TRT is standard treatment of LS SCLC. BID TRT of 45 Gy/30 fractions is the most recommended schedule. Trials report 5-year survival rates of up to 36%, illustrating that some are cured but also need for better treatment. Many treatment failures are due to relapses within TRT fields, and it has been proposed that higher TRT doses might improve local control and consequently survival. However, high-dose once-daily (QD) TRT of 66-70 Gy do not prolong survival. We investigated whether high-dose BID TRT of 60 Gy/40 fractions was tolerable and improved survival compared with the established 45 Gy schedule (NCT02041845). Primary analyses presented at ASCO 2020 showed that the trial was highly positive for the primary endpoint, 2-year survival (60 Gy: 74.2%, 45 Gy: 48.1%, OR 3.09 [95% CI 1.62-5.89]; p=0.0005). We now present updated and final survival data. Methods: Patients ≥18 years with PS 0-2, confirmed SCLC, LS according to the IASLC definition after PET CT staging received 4 courses of platinum/etoposide and were randomized to receive 60 Gy or 45 Gy to PET CT positive lesions. TRT started concurrently with the 2nd chemotherapy course. Responders were offered QD prophylactic cranial irradiation of 25-30 Gy. All patients were followed for 5 years or until death. Results: 170 eligible patients were randomized at 22 Scandinavian hospitals from 2014-2018 (60 Gy: n=89, 45 Gy: n=81). Median age was 65, 31.2% were ≥70 years, 57.1% women, 89.4% had PS 0-1, 83.5% stage III disease, 7.6% pleural effusion and 20.0% ≥5% weight loss last three months before enrollment. Baseline patient and disease characteristics and TRT planning target volumes were well balanced between treatment arms. Completion rates of chemotherapy (60 Gy: 92.1%, 45 Gy: 87.7%) and TRT (60 Gy: 96.6%, 45 Gy: 91.4%) were similar. Patients on the high-dose arm did not experience more grade 3-4 esophagitis (60 Gy: 21.2%, 45 Gy: 18.2%; p=0.83) or pneumonitis (60 Gy: 3.4%, 45 Gy: 0.0%; p=0.39), other grade 3-4 toxicity or treatment related deaths. The 60 Gy group had numerically longer PFS (median PFS 60 Gy: 18.6 months [95% CI 11.6-25.6], 45 Gy: 10.9 months [95% CI 8.7-13.2], HR 0.76 [95% CI 0.53-1.08]; p=0.13). Results for the primary endpoint remain unchanged. The higher TRT dose significantly prolonged survival (median OS 60 Gy: 43.5 months [95% CI 30.4-56.6], 45 Gy: 22.6 months [95% CI 17.2-28.0], HR 0.69 [0.48-0.99]; p=0.043) and provided higher 4.5 year survival rate (60 Gy: 41.6% [95% CI 30.4-56.6], 45 Gy: 28.4% [95% CI 18.9-39.5], OR: 1.79 [95% CI 0.95-3.41]). 5-year survival rates will be presented at the meeting. Conclusions: Compared with LS SCLC patients who received standard TRT, patients receiving high-dose BID TRT of 60 Gy did not experience more toxicity, had a substantial prolongation of survival and a much higher long term survival rate. Clinical trial information: NCT02041845 .

Efficacy and safety of high dose twice-daily thoracic radiotherapy versus standard dose for limited stage small-cell lung cancer: A multicentre, open-label randomised, phase 3 trial.

8587 Background: We aimed to assess the efficacy and safety of high-dose, hyperfractionated thoracic radiotherapy of 54 Gy in 30 fractions compared with standard dose(45 Gy in 30 fractions) as a first-line treatment for LS-SCLC. Methods: The study was an open-label, randomised, phase 3 trial, done at 16 public hospitals in China.Key inclusion criteria were patients aged 18-70 years, with previously histologically or cytologically confirmed LS-SCLC, previously untreated or received 1-2 courses of intravenous cisplatin (75 mg/m²of body-surface area, on day 1 or divided into two days of each cycle) or carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle)and intravenous etoposide (100 mg/m²of body-surface area, on days 1-3 of each cycle), and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.Eligible patients were randomly assigned (1:1) to receive receive volumetric-modulated arc radiotherapy (VMAT) of 45 Gy in 30 fractions or the simultaneous integrated boost VMAT (SIB-VMAT) of 54 Gy in 30 fractions to the primary lung tumour and lymph node metastases starting 0-42 days after the first chemotherapy course. Both groups of patients received thoracic radiotherapy twice per day and 10 fractions per week.Prophylactic cranial radiation (PCI, 25Gy in 10 fractions) was implemented to patients with responsive disease. The primary endpoint was overall survival. Safety was analysed in the as-treated population. This study is complete and registered with ClinicalTrials.gov,NCT03214003. Results: Between June 30, 2017, and April 6, 2021, 224 eligible patients were enrolled and randomly assigned to 54 Gy (n = 108) or 45 Gy (n = 116).Median follow-up for the primary analysis was 45 months (IQR 41-48). Median overall survival was significantly improved in the 54 Gy group (62.4 months ) compared with the 45 Gy group (43.1 months; p = 0.001). Median progression-free survival was significantly improved in the 54 Gy group (30.5 months) compared with the 45 Gy group (16.7 months; p = 0.044). The most common grade 3-4 adverse events were neutropenia (30 [28%] of 108 patients in the 54 Gy group vs 27 [23%] of 116 patients in the 45 Gy group), neutropenic infections (6 [6%] vs 2 [2%]), thrombocytopenia (13 [12%] vs 12 [10%]), anaemia (6 [6%] vs 4 [3%]), and oesophagitis (1 [1%] vs 3 [3%]). There were one treatment-related deaths in 54 Gy group (myocardial infarction). Conclusions: Compared with standard thoracic radiotherapy dose of 45 Gy, the high dose dose of 54 Gy improved overall survival and progression-free survival without increasing toxicities in patients with LS-SCLC, supporting twice-daily hyperfractionated thoracic radiotherapy of 54 Gy with concurrent chemotherapy is an alternative treatment option for LS-SCLC. Clinical trial information: NCT03214003 .

Prospective Evaluation of Limited-Stage Small Cell Lung Cancer Radiotherapy Fractionation Regimen Usage and Acute Toxicity in a Large Statewide Quality Collaborative

National guidelines on limited stage small cell lung cancer (LS-SCLC) treatment give preference to a hyperfractionated regimen of 45 Gy/30 fractions delivered twice-daily, however use of this regimen is uncommon compared to once-daily regimens. The purpose of this study was to characterize the LS-SCLC fractionation regimens used throughout a statewide collaborative, analyze patient and treatment factors associated with these regimens, and describe real-world acute toxicity profiles of once- and twice-daily RT regimens. Demographic, clinical, and treatment data along with physician toxicity and patient-reported outcomes were prospectively collected by 29 institutions within the [quality consortium] between 2012 and 2021 for patients with LS-SCLC. We modeled the influence of RT fractionation and other patient-level variables clustered by treatment site on the odds of a treatment break specifically due to toxicity with multilevel logistic regression. Common Terminology Criteria for Adverse Events, version 4.0, incident Grade 2 or worse toxicity was longitudinally compared between regimens. There were 78 patients (15.6% overall) treated with twice-daily RT and 421 patients treated with once-daily RT. Patients receiving twice-daily RT were more likely to be married/living with someone (65% vs 51%, p=0.019) and to have no major comorbidities (24% vs 10%, p=0.017). Once-daily RT fractionation toxicity peaked during RT and twice-daily toxicity peaked within 1 month after RT. After stratifying by treatment site and adjusting for patient-level variables, once-daily treated patients had a 4.11 (95% confidence interval 1.31-12.87) higher odds of treatment break specifically due to toxicity than twice-daily treated patients. Hyperfractionation for LS-SCLC remains infrequently prescribed despite the lack of evidence demonstrating superior efficacy or lower toxicity of once-daily RT. With peak acute toxicity after RT and lower likelihood of a treatment break with twice-daily fractionation in real-word practice, providers may start utilizing hyperfractionated RT more frequently.

The Role of Surgery in Stage I Small Cell Lung Cancer: A National VA Database Analysis

BackgroundHistorically, limited stage Small Cell Lung Cancer (SCLC) has been treated with concurrent chemoradiation (CRT). While current NCCN guidelines recommend consideration of lobectomy in node-negative cT1-T2 SCLC, data regarding the role of surgery in very limited SCLC is lacking. MethodsData from the National VA Cancer Cube were compiled. A total of 1,028 patients with pathologically confirmed stage I SCLC were studied. Only 661 patients that either received surgery or CRT were included. Interval-censored Weibull and Cox proportional hazard regression models were used to estimate median overall survival (OS) and hazard ratio (HR), respectively. Two survival curves were compared by a Wald test. Subset analysis was performed based on the location of the tumor in the upper vs. lower lobe as delineated by ICD-10 codes C34.1 and C34.3. ResultsFour-hundred and forty-six patients received concurrent CRT; while 223 underwent treatment that contained surgery (93 surgery only, 87 surgery/chemo, 39 surgery/chemo/radiation and 4 surgery/radiation). The median OS for the surgery-inclusive treatment was 3.87 years (95% CI 3.21-4.48) while median OS for the CRT cohort was 2.45 years (95% CI 2.17-2.74). HR of death for surgery-inclusive treatment when compared to CRT is 0.67 (95% CI 0.55-0.81; P < .001). Subset analysis based on the location of the tumor in both the upper or lower lobes showed improved survival with surgery as compared to CRT regardless of the location. HR for the upper lobe was 0.63 (95% CI 0.50-0.80; P < .001) and lower lobe 0.61 (95% CI 0.42-0.87; P = .006). Multivariable regression analysis accounting for age and ECOG-PS shows a HR 0.60 (95% CI 0.43-0.83; P = .002) favoring surgery. ConclusionsSurgery was used in less than a third of patients with stage I SCLC who received treatment. Surgery-inclusive multimodality treatment was associated with a longer overall survival as compared to chemoradiation, independent of age, performance status or tumor location. Our study suggests a more expansive role for surgery in stage I SCLC.

172 - A feasibility study of high-dose twice-daily thoracic radiotherapy in limited stage small-cell lung cancer (LS-SCLC) at Barking, Havering and Redbridge University Hospitals NHS Trust (BHRUT)

172 - A feasibility study of high-dose twice-daily thoracic radiotherapy in limited stage small-cell lung cancer (LS-SCLC) at Barking, Havering and Redbridge University Hospitals NHS Trust (BHRUT)

Thoracic Radiation in Limited Stage Small Cell Lung Cancer: Trends in Radiation Fractionation

IntroductionThoracic radiotherapy (TRT) is standard of care for limited-stage small cell lung cancer (LS-SCLC). Although initial data supported the use of twice-daily (BID) radiation to a dose of 45 Gy, recent trials have suggested similar efficacy with daily fractionation (QD) to a dose of 60 to 70 Gy. This study evaluates trends in treatment regimen in patients treated with TRT for LS-SCLC. Materials and MethodsThe National Cancer Database (NCDB) was queried for patients with LS-SCLC treated with TRT between 2004 to 2017 grouped by RT fractionation QD vs. BID. Exclusion criteria were unknown stage, and unknown RT dose. Multivariable (MVA) analyses using logistic regression were performed to investigate factors associated with receipt of a specific fractionation schedule. ResultsA total of 17,453 patients met inclusion criteria, with 4,996 receiving BID treatment and 12,457 receiving QD treatment. The most common QD dose was 60 Gy (48.9%). Overall, QD fractionation has increased (1.3%/year). In 2004, 45 Gy BID treatment (41.4%) was the dominant fractionation. By 2017, 60 Gy QD (45.2%) increased (1.9%/y) to be the dominant fractionation, while 45 Gy BID (24.8%) decreased (-1.4%/y) to be the second most common fractionation. On MVA, factors that affect 1 treatment over the other were further stratified. ConclusionSince 2004, QD fractionation has been the preferred TRT regimen for patients with LS-SCLC compared to BID fractionation, with the proportion of patients getting QD treatment continuing to increase. The choice of treatment regimen appears to be influenced by both patient and facility characteristics.

Primary Tumor Recurrence after Chemoradiotherapy in Limited Stage Small Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> Accounting for 13-15% of lung cancer, small cell lung cancer (SCLC) is typically characterized by more extensive local invasion and more frequent metastases compared with other subtypes. Although SCLC is sensitive to chemoradiotherapy, 25% of the patients with limited stage SCLC would meet local regional relapse. Although thoracic radiation had significantly improved local control, primary tumor recurrence is common in clinic. So far, we had little acquaintance of the local relapse details to help us to make progress in the thoracic radiation. To investigate the patterns of patients with local regional recurrence and the prognosis of primary tumor recurrence, we proposed this study. <h3>Materials/Methods</h3> We searched patients with pathological diagnosis of SCLC, with disease of limited stage, received systemic chemotherapy and thoracic intensity modulate radiotherapy at our center with available follow-up records between August 1^st, 2006 and May 31^st,2014. Patients with intrapulmonary recurrence or regional lymph nodes recurrence by the last follow up time, without diffused lung metastasis were selected. All the patients received involved field thoracic radiotherapy with dose of 2Gy per fraction per day. Data regarding patient demographics and treatments. The first local recurrent sites were recorded. Local regional relapse time was calculated from the first day of the treatment delivery to the diagnosis of primary tumor or regional lymph nodes. Overall survival was calculated from the first day of the diagnosis of local relapse to the death using Kaplan Meir Method. <h3>Results</h3> We identified 482 patients with a diagnosis of limited stage SCLC. Among these, 125 patients fulfilled the eligibility criteria. The median dose of radiotherapy is 60Gy. The median local relapse time was 12.97 months. Primary tumor recurrence, ipsilateral hilar and/or mediastinal lymph node recurrence, contralateral hilar and/or lymph node recurrence, and supraclavicular lymph node recurrence, were observed in 92 patients (73.6%), 49 patients (39.2%), 1 patient (0.8%) and 13 patients (10.4%), respectively. There were 26 patients with multisite local recurrence. Out-field relapse was observed in 6 patients (4.8%). The median follows up time was 34.7 months. After second line therapies, the median survival time for these patients diagnosed as recurrent disease was 10.5 months. Of the 92 patients with primary tumor recurrence, 25 patient received re-radiation and 39 patients also met distant metastasis. Median survival time of patients with primary tumor recurrence is slightly shorter than the others (9.9months vs. 12.0months). <h3>Conclusion</h3> For patients with limited stage SCLC who received chemoradiotherapy, primary tumor recurrence is still the leading course in local regional relapses and accompanied by worse survival. Accordingly, simultaneous integrated boost might be taken into consideration to primary tumor. Involved field radiation is reasonable with low out-field local recurrence.

AESOP: Phase 2 Open-Label Trial of Avasopasem Manganese (GC4419) for Reduction of Esophagitis in Patients Receiving Chemoradiotherapy for Nonmetastatic Lung Cancer

<h3>Purpose/Objective(s)</h3> National Cancer Institute (NCI) grade 3+ esophagitis has been reported in up to 20% of advanced lung cancer patients receiving standard fractionation radiotherapy with concurrent chemotherapy (Provencio 2011, Curran 2011). Avasopasem (GC4419) is an investigational selective dismutase mimetic that rapidly and selectively converts superoxide to hydrogen peroxide, interrupting the initiation of radiation-induced mucosal injury (Thompson 2010, Sonis 2021). Avasopasem demonstrated the potential to reduce severe oral mucositis due to chemoradiotherapy for head and neck cancer in a randomized phase 2 clinical trial (Anderson 2019), supporting the hypothesis that avasopasem might reduce severe radiation-induced esophagitis in patients with lung cancer. <h3>Materials/Methods</h3> In a single-arm open-label trial, patients with stage 3 or post-operative stage 2B non-small cell lung cancer (NSCLC) or limited stage small-cell lung cancer (LS-SCLC) received 90 mg avasopasem by 60-minute infusion prior to radiation therapy (1.8–2.0 Gy 5 days/week up to 60 Gy total), in combination with investigator's choice of chemotherapy other than gemcitabine. Primary objective to assess the incidence of acute (NCI ≥gr 2) radiation esophagitis, with observed incidence of grade 3–4 radiation esophagitis as a secondary endpoint. <h3>Results</h3> A total of 39 patients were enrolled and received at least 1 dose of avasopasem: median age 64 (range 38–85); 22 (56.4%) were male; 95% performance status (PS) 0 or 1. Thirty-two (82.1%) had NSCLC and 7 (17.9%) had LS-SCLC. Median duration of exposure to avasopasem was 43.0 days (range 2–54). Preliminary results with data analysis ongoing showed 14 of 29 evaluable patients (48.3%) experienced acute esophagitis at week 6 (95% confidence interval [CI], 29.5–67.5). Of these, 13 (44.8%) were grade 2 and 1 (3.4%) was grade 3; there were no grade 4 events. Adverse events (AEs, all grades) considered possibly related to avasopasem occurring in at least 15% of patients were nausea (36%), paresthesia (26%), dizziness, fatigue (21% each), and hypotension (15%). Three patients had grade 3 AEs (7 events) possible related to avasopasem (nausea, vomiting, dehydration, hypokalemia, dysphagia, muscular weakness, hypoxia). <h3>Conclusion</h3> In this phase 2 open-label study, grade 3 esophagitis was infrequent with avasopasem at an unscheduled interim analysis. The AE profile appeared consistent with expectations for standard therapy and avasopasem appeared well tolerated. Final data will be presented at the conference. This study (NCT04529850) is funded by Galera Therapeutics, Inc.