Real-World Efficacy and Safety of Thoracic Radiotherapy after First-Line Chemo-Immunotherapy in Extensive-Stage Small-Cell Lung Cancer

Xie, Zhaoliang; Liu, Jingru; Wu, Min; Wang, Xiaohan; Lu, Yuhan; Han, Chunyan; Cong, Lei; Li, Jisheng; Meng, Xue

doi:10.3390/jcm12113828

Cited by 5 publications

(4 citation statements)

References 37 publications

(46 reference statements)

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“…However, the impact of bone metastases on the prognosis of small-cell lung cancer patients receiving immune checkpoint inhibitor therapy remains controversial. Studies (Lee et al 2022 ; Xie et al 2023 ) have demonstrated that SCLC patients with pre-existing bone metastases who undergo immune-combination therapy experience significantly reduced average survival rates compared to those without such metastases ( P < 0.05). An increase in bone-related events associated with bone metastases, including pain, hypercalcemia, pathological fractures and spinal cord compression disorders may significantly affect patient quality of life and alter immunotherapy outcomes.…”

Section: Discussionmentioning

confidence: 99%

Construction of a prognostic model for extensive-stage small cell lung cancer patients undergoing immune therapy in northernmost China and prediction of treatment efficacy based on response status at different time points

Dang,

Xu,

Guo

et al. 2024

J Cancer Res Clin Oncol

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Background and purpose Recently, the emergence of immune checkpoint inhibitors has significantly improved the survival of patients with extensive-stage small cell lung cancer. However, not all patients can benefit from immunotherapy; therefore, there is an urgent need for precise predictive markers to screen the population for the benefit of immunotherapy. However, single markers have limited predictive accuracy, so a comprehensive predictive model is needed to better enable precision immunotherapy. The aim of this study was to establish a prognostic model for immunotherapy in ES-SCLC patients using basic clinical characteristics and peripheral hematological indices of the patients, which would provide a strategy for the clinical realization of precision immunotherapy and improve the prognosis of small cell lung cancer patients. Methods This research retrospectively collected data from ES-SCLC patients treated with PD-1/PD-L1 inhibitors between March 1, 2019, and October 31, 2022, at Harbin Medical University Cancer Hospital. The study data was randomly split into training and validation sets in a 7:3 ratio. Variables associated with patients’ overall survival were screened and modeled by univariate and multivariate Cox regression analyses. Models were presented visually via Nomogram plots. Model discrimination was evaluated by Harrell’s C index, tROC, and tAUC. The calibration of the model was assessed by calibration curves. In addition, the clinical utility of the model was assessed using a DCA curve. After calculating the total risk score of patients in the training set, patients were stratified by risk using percentile partitioning. The Kaplan–Meier method was used to plot OS and PFS survival curves for different risk groups and response statuses at different milestone time points. Differences in survival time groups were compared using the chi-square test. Statistical analysis software included R 4.1.2 and SPSS 26. Results This study included a total of 113 ES-SCLC patients who received immunotherapy, including 79 in the training set and 34 in the validation set. Six variables associated with poorer OS in patients were screened by Cox regression analysis: liver metastasis (P = 0.001), bone metastasis (P = 0.013), NLR < 2.14 (P = 0.005), LIPI assessed as poor (P < 0.001), PNI < 51.03 (P = 0.002), and LDH ≥ 146.5 (P = 0.037). A prognostic model for immunotherapy in ES-SCLC patients was constructed based on the above variables. The Harrell’s C-index in the training and validation sets of the model was 0.85 (95% CI 0.76–0.93) and 0.88 (95% CI 0.76–0.99), respectively; the AUC values corresponding to 12, 18, and 24 months in the tROC curves of the training set were 0.745, 0.848, and 0.819 in the training set and 0.858, 0.904 and 0.828 in the validation set; the tAUC curves show that the overall tAUC is > 0.7 and does not fluctuate much over time in both the training and validation sets. The calibration plot demonstrated the good calibration of the model, and the DCA curve indicated that the model had practical clinical applications. Patients in the training set were categorized into low, intermediate, and high risk groups based on their predicted risk scores in the Nomogram graphs. In the training set, 52 patients (66%) died with a median OS of 15.0 months and a median PFS of 7.8 months. Compared with the high-risk group (median OS: 12.3 months), the median OS was significantly longer in the intermediate-risk group (median OS: 24.5 months, HR = 0.47, P = 0.038) and the low-risk group (median OS not reached, HR = 0.14, P = 0.007). And, the median PFS was also significantly prolonged in the intermediate-risk group (median PFS: 12.7 months, HR = 0.45, P = 0.026) and low-risk group (median PFS not reached, HR = 0.12, P = 0.004) compared with the high-risk group (median PFS: 6.2 months). Similar results were obtained in the validation set. In addition, we observed that in real-world ES-SCLC patients, at 6 weeks after immunotherapy, the median OS was significantly longer in responders than in non-responders (median OS: 19.5 months vs. 11.9 months, P = 0.033). Similar results were obtained at 12 weeks (median OS: 20.7 months vs 11.9 months, P = 0.044) and 20 weeks (median OS: 20.7 months vs 11.7 months, P = 0.015). Finally, we found that in the real world, ES-SCLC patients without liver metastasis (P = 0.002), bone metastasis (P = 0.001) and a total number of metastatic organs < 2 (P = 0.002) are more likely to become long-term survivors after receiving immunotherapy. Conclusion This study constructed a new prognostic model based on basic patient clinical characteristics and peripheral blood indices, which can be a good predictor of the prognosis of immunotherapy in ES-SCLC patients; in the real world, the response status at milestone time points (6, 12, and 20 weeks) can be a good indicator of long-term survival in ES-SCLC patients receiving immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Construction of a prognostic model for extensive-stage small cell lung cancer patients undergoing immune therapy in northernmost China and prediction of treatment efficacy based on response status at different time points

Dang,

Xu,

Guo

et al. 2024

J Cancer Res Clin Oncol

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“…However, the impact of bone metastases on the prognosis of small-cell lung cancer patients receiving immune checkpoint inhibitor therapy is still debated. Studies [14,15] show that patients with SCLC who have bone metastases prior to undergoing immune-combination therapy have a signi cantly reduced average survival rate compared to those without these metastases (P < 0.05). An increase in bonerelated events linked to bone metastases, including bone pain, hypercalcemia, pathological fractures, and spinal cord compression disorders, might signi cantly affect the quality of life of patients, thereby altering immunotherapy outcomes.…”

Section: Discussionmentioning

confidence: 99%

Construction of a Prognostic Model for Extensive-Stage Small Cell Lung Cancer Patients Undergoing Immune Therapy in Real-World Settings and Prediction of Treatment Efficacy Based on Response Status at Different Time Points

Dang,

Shang

2024

Preprint

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Background and purpose In recent years, with the clinical application of programmed cell death protein-1 (PD-1) represented by serplumab and programmed cell death ligand-1 (PD-L1) represented by durvalumab, immune checkpoint inhibitors (ICIs) have been used in patients with extensive-stage small cell lung cancer (ES-SCLC). clinical applications, immune checkpoint inhibitors (ICIs) have shown significant efficacy in patients with extensive-stage small cell lung cancer (ES-SCLC), but not all patients are beneficiaries of immunotherapy. Immunomarkers such as PD-L1 expression and tumor mutational burden (TMB), which are good predictors in a variety of malignancies, have been found not to be predictive in small cell lung cancer (SCLC). With the in-depth study of SCLC subtypes, SCLC-Y/SCLC-I molecular subtypes have been recognized as potential immunotherapeutic markers. However, the predictive efficacy of a single marker is limited, so a comprehensive predictive model is needed to achieve precision immunotherapy. National and international studies have found that certain basic clinical characteristics of patients and peripheral blood markers correlate with the prognosis of ES-SCLC immunotherapy. The aim of this study was to establish a model for predicting the prognosis of immunotherapy in ES-SCLC patients using basic clinical characteristics and peripheral hematological indicators of patients, and to explore the potential characteristics of long-term survival of patients, to provide guidance for individualized treatment of patients, and to provide corresponding strategies for clinical immunotherapy. Methods This study utilized a retrospective research method, investigating patients with ES-SCLC who received PD-1/PD-L1 inhibitor treatment at Harbin Medical University Cancer Hospital from March 1, 2019, to October 31, 2022. The research data were randomly divided into a training set and a validation set in a 7:3 ratio. By conducting univariate and multivariate Cox regression analyses, variables related to the overall survival (OS) of patients were identified and used to develop a model. The model was visualized through Kaplan-Meier curves. The discriminative ability of the model was evaluated using Harrell's C-index, time-dependent receiver operating characteristic curve (tROC), and time-dependent area under curve (tAUC). The calibration of the model was assessed using calibration curves. Furthermore, the clinical utility of the model is assessed using Decision Curve Analysis (DCA). Patients are stratified into risk groups using percentile segmentation, and survival curves for Overall Survival (OS) and Progression-Free Survival (PFS) at different risk levels and milestone time points are plotted using the Kaplan-Meier method. The Chi-square test is used to compare differences between groups. Statistical analysis is performed using R 4.1.2 and SPSS 26. Results This study included a total of 113 patients with ES-SCLC who received immunotherapy. Based on the patients' clinical characteristics and hematological indicators, we conducted a series of studies. Firstly, we established a model to predict the prognosis of ES-SCLC patients undergoing immunotherapy, with 79 patients used for model development and 34 patients for model validation. Through univariate and multivariate Cox regression analyses, six variables were identified as being associated with poorer overall survival (OS) in patients: liver metastasis (P=0.001), bone metastasis (P=0.013), neutrophil-to-lymphocyte ratio (NLR) < 2.14 (P=0.005), poor Lung Immune Prognostic Index (LIPI) assessment (P<0.001), Prognostic Nutritional Index (PNI) < 51.03 (P=0.002), and lactate dehydrogenase (LDH) ≥ 146.5 (P=0.037). The model established based on the aforementioned variables demonstrates good discriminability, with Harrell’s C-index of 0.85 (95% CI: 0.76-0.93) for the training set and 0.88 (95% CI: 0.76-0.99) for the validation set. The AUC values corresponding to 12 months, 18 months, and 24 months in the training set's tROC curve are 0.754, 0.848, and 0.819, respectively, while in the validation set, they are 0.858, 0.904, and 0.828, respectively. The tAUC curves indicate that, in both the training and validation sets, the overall tAUC is >0.7 with little fluctuation over time. Calibration plots show the model's good calibration, and the DCA decision curves indicate the model's practical clinical application value. Based on the predicted risk scores in the scatter plot for patients in the training set, patients are categorized into low-risk (0-69 points), medium-risk (70-162 points), and high-risk (≥163 points) groups. In the training set, 52 patients died, with a median OS of 15.0 months and a median PFS of 7.8 months. Compared to the high-risk group, the median Overall Survival (OS) for the medium-risk group was 24.5 months (HR=0.47, P=0.038), and the median OS for the low-risk group was not reached (HR=0.14, P=0.007). Compared to the high-risk group, the median Progression-Free Survival (PFS) for the medium-risk group was 12.7 months (HR=0.45, P=0.026), and the median PFS for the low-risk group was not reached (HR=0.12, P=0.004). In the validation set, 25 patients died, with a median OS of 13.8 months and a median PFS of 6.9 months. Compared to the high-risk group, the median OS for the medium-risk group was 16.8 months (HR=0.47, P=0.047), and the median OS for the low-risk group was not reached (HR=0.40, P=0.001). Compared to the high-risk group, there was no significant improvement in the median PFS for the medium-risk group (HR=0.56, P=0.189), while the median PFS for the low-risk group was significantly extended (HR=0.12, P=0.002). Secondly, we observed that in the real world, patients with ES-SCLC who have undergone immunotherapy demonstrated a median OS (Overall Survival) of 19.5 months for responders, compared to 11.9 months for non-responders at the 6-week mark (P=0.033). At 12 and 20 weeks, the overall survival duration of responders was 20.7 months and 20.7 months, respectively, while for non-responders, it was 11.9 months and 11.7 months (P=0.044 and P=0.015). Additionally, the median PFS (Progression-Free Survival) of responders was significantly prolonged, being 10.6 months at both 6 and 20 weeks, compared to 6.4 months and 6.3 months for non-responders (P=0.036 and P=0.028). At the 12-week time point, the PFS for responders was 9.2 months, while it was 6.3 months for non-responders (P=0.069). Finally, we found that in the real world, ES-SCLC (Extensive-Stage Small Cell Lung Cancer) patients without liver metastasis (P=0.002), bone metastasis (P=0.001), a total number of metastatic organs <2 (P=0.002), and LDH (Lactate Dehydrogenase) ≤ ULN (Upper Limit of Normal) (P=0.09) are more likely to become long-term survivors (LTS) after receiving immunotherapy. Conclusion First, this study constructed a new prognostic model based on basic patient clinical characteristics and peripheral blood indices, which can be a good predictor of the prognosis of immunotherapy in ES-SCLC patients. Second, in the real world, the response status at milestone time points (6, 12, and 20 weeks) can be a good indicator of long-term survival in ES-SCLC patients receiving immunotherapy. Finally, patients with no liver metastases or bone metastases, total metastatic organ count <2 and LDH ≤ULN were more likely to have long-term survival before ES-SCLC patients received immunotherapy.

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“…But a retrospective study including 41 patients with ES-SCLC, 23 patients received 30Gy/10 fractions cTRT after systemic therapy and 18 patients did not receive cTRT, showed that cTRT significantly improved OS compared with systemic therapy only group (1-year OS 78.6% vs. 39.7%, p=0.019 ( 39 ). Furthermore, several single-center retrospective studies have also demonstrated a survival benefit of cTRT after first-line chemoimmunotherapy ( 40 , 41 ). Given that all existing studies are retrospective, the role of cTRT in ES-SCLC in the immunotherapy era should be interpreted with caution, and we look forward to the prospective study results.…”

Section: The Consolidative Thoracic Radiotherapymentioning

confidence: 99%

“…Considering the high incidence of pneumonia associated with immunotherapy and radiotherapy, the safety of combination treatments remains unclear. A real-world study showed that cTRT after first-line chemoimmunotherapy did not increase the incidence of adverse events compared with systemic therapy alone ( 41 ). A retrospective study involving 36 patients with ES-SCLC who received first-line chemoimmunotherapy followed by cTRT at 60Gy/28 fractions in most patients, showed that 8% of patients developed radiation-related pneumonitis, all of which were grade 1-2, and four patients discontinued immunotherapy after immune-related pneumonitis but completed cTRT ( 40 ).…”

Section: The Consolidative Thoracic Radiotherapymentioning

confidence: 99%

Radiotherapy for extensive-stage small-cell lung cancer in the immunotherapy era

Li,

Zhao,

et al. 2023

Front. Immunol.

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Currently, chemoimmunotherapy is the first-line treatment for extensive-stage small-cell lung cancer (ES-SCLC). However, only 0.8%–2.5% of the patients presented complete response after chemoimmunotherapy. Considering that ES-SCLC is highly sensitive to radiotherapy, the addition of radiotherapy after first-line treatment for ES-SCLC could further improve local control, which may be beneficial for patients’ survival. Prior studies have shown that consolidative thoracic radiotherapy (cTRT) can decrease disease progression and improve overall survival in patients with ES-SCLC who respond well to chemotherapy. However, the efficacy and safety of cTRT in the immunotherapy era remain unclear owing to a lack of prospective studies. Prophylactic cranial irradiation (PCI) has been shown to decrease brain metastasis (BM) and prolong survival in patients with limited-stage SCLC in previous reports. However, according to current guidelines, PCI is not commonly recommended for ES-SCLC. Immunotherapy has the potential to reduce the incidence of BM. Whether PCI can be replaced with regular magnetic resonance imaging surveillance for ES-SCLC in the era of immunotherapy remains controversial. Whole brain radiation therapy (WBRT) is the standard treatment for BM in SCLC patients. Stereotactic radiosurgery (SRS) has shown promise in the treatment of limited BM. Considering the potential of immunotherapy to decrease BM, it is controversial whether SRS can replace WBRT for limited BM in the immunotherapy era. Additionally, with the addition of immunotherapy, the role of palliative radiotherapy may be weakened in patients with asymptomatic metastatic lesions. However, it is still indispensable and urgent for patients with obvious symptoms of metastatic disease, such as spinal cord compression, superior vena cava syndrome, lobar obstruction, and weight-bearing metastases, which may critically damage the quality of life and prognosis. To improve the outcome of ES-SCLC, we discuss the feasibility of radiotherapy, including cTRT, PCI, WBRT/SRS, and palliative radiotherapy with immunotherapy based on existing evidence, which may offer specific prospects for further randomized trials and clinical applications.

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Real-World Efficacy and Safety of Thoracic Radiotherapy after First-Line Chemo-Immunotherapy in Extensive-Stage Small-Cell Lung Cancer

Cited by 5 publications

References 37 publications

Construction of a prognostic model for extensive-stage small cell lung cancer patients undergoing immune therapy in northernmost China and prediction of treatment efficacy based on response status at different time points

Construction of a prognostic model for extensive-stage small cell lung cancer patients undergoing immune therapy in northernmost China and prediction of treatment efficacy based on response status at different time points

Construction of a Prognostic Model for Extensive-Stage Small Cell Lung Cancer Patients Undergoing Immune Therapy in Real-World Settings and Prediction of Treatment Efficacy Based on Response Status at Different Time Points

Radiotherapy for extensive-stage small-cell lung cancer in the immunotherapy era

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