Prognostic factors of liver metastases in extensive-stage small cell lung cancer receiving chemo-immunotherapy

Introduction

Small cell lung cancer (SCLC) is a progressive neoplasm with dismal features. The patients with extensive-stage SCLC (ES-SCLC) experience recurrence, regardless even if their initial response to systemic chemotherapy. The combination of platinum-based chemotherapy with an anti-programmed death-ligand 1 (PD-L1) antibody, also called chemoimmunotherapy, has recently been reported to significantly improve prognosis compared to platinum-based chemotherapy alone (1,2). A recent study identified the potential for long-term survival after initiation of chemoimmunotherapy (3). However, the expression level of PD-L1 within tumor tissues remains low in most patients with SCLC and little is known about the detailed mechanism underlying its low expression. Therefore, PD-L1 expression is unavailable for the prediction of immune checkpoint inhibitors (ICIs) in patients with ES-SCLC and has not yet been established as a significant predictor of promising biomarkers including tumor mutation burden or tumor-infiltrative lymphocytes (4).

Several real-world studies have reported potential prognostic biomarkers in patients with ES-SCLC following platinum-etoposide chemotherapy combined with anti-PD-L1 antibodies (5-7). Some retrospective studies using real-world data also confirmed that the combination of an anti-PD-L1 antibody with carboplatin and etoposide is both feasible and effective, with results comparable to those of prospective studies like IMpower 133 and Caspian (5-7). Several researchers have reported that consolidative palliative thoracic radiotherapy, liver metastasis, inflammatory markers, and performance status (PS) are closely associated with valuable prognostic factors (8-10). However, which risk factors can predict the outcome of chemoimmunotherapy for patients with ES-SCLC remains unclear. A previous study described that age ≥65 years old, PS, thoracic radiotherapy, and lactate dehydrogenase are positive prognostic factors for the patients with SCLC receiving platinum-based chemotherapy (11). Moreover, the distant sites of brain, bone, and liver metastases also suggested a shorter survival after platinum-based chemotherapy (11). However, it remains unclear what is most promising for the prognostic factors for ES-SCLC.

Thus, we examined the real-world data of patients with ES-SCLC who received chemo-immunotherapy and explored valuable risk factors, comparing our findings with those from previous studies. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1091/rc).

Methods

Patients

Between December 2019 and December 2023, 110 patients with pathologically confirmed ES-SCLC who received platinum-based chemotherapy, including etoposide and anti-PD-L1 antibodies, at our institution were eligible for the current study. Our study design was a retrospective study. Some of these cases have been reported previously (12,13). Clinical data were extracted from the medical records. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Ethics Committee of the International Medical Center at Saitama Medical University (Nos. 20-125 and 2021-113). The requirement for written informed consent was waived due to the retrospective nature of the study (14).

Treatment and evaluation

All patients received platinum-based regimens (carboplatin or cisplatin) combined with anti-PD-L1 antibodies (atezolizumab or durvalumab). Moreover, IMpower 133 (atezolizumab 1,200 mg, area under the concentration-time curve of 5 mg/mL per min carboplatin, and etoposide 100 mg/m²) and Caspian (durvalumab 1,500 mg, area under the concentration-time curve of 5 mg/mL per min carboplatin or cisplatin 80 mg/m², and etoposide 100 mg/m²) regimens were administered intravenously (1,2). Complete blood counts, biochemical testing, physical examinations, and side effects were assessed based on the chief physician’s judgment. Toxicity was graded based on the Common Terminology Criteria for Adverse Events version 5.0. Additionally, tumor response was examined according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (15).

Assessment of the inflammatory and nutritional indices

Clinical and biological data (e.g., total protein, albumin, and C-reactive protein levels; white blood cell, neutrophil, platelet, and lymphocyte counts; and height and weight) were extracted from medical records and analyzed. Six indices reflecting systemic inflammatory and nutritional status based on a previous study (16) were calculated at baseline within 1 week of the first cycle of each treatment. The inflammatory indices were as follows: (I) neutrophil-to-lymphocyte ratio (NLR) (17); and (II) platelet-to-lymphocyte ratio (PLR) (17). The nutritional indices were as follows: (I) prognostic nutrition index (PNI) = 10 × albumin (g/dL) + 0.005 × lymphocyte count (16); and (II) advanced lung cancer inflammation index (ALI) = body mass index (BMI) (kg/m²) + albumin level (g/dL)/NLR (18).

Statistical analysis

Statistical significance was set at P<0.05. Fisher’s exact test was used to examine the association between two categorical variables. Progression-free survival (PFS) was defined as the time from initial treatment to disease progression or death. Overall survival (OS) was defined as the time from initial treatment to death from any cause. Responders and non-responders were categorized as those with an OS >12 months and those with an OS less than 12 months, respectively. The optimal cutoff values for smoking index, serum pro-gastrin-releasing peptide (ProGRP), NLR, PLR, PNI, and ALI were determined using receiver operating characteristic (ROC) curve analyses. Moreover, sensitivity and specificity were assessed to determine the optimal cutoff value for differentiating responders from non-responders using ROC curves. The Kaplan-Meier analysis was employed to estimate survival as a function of time, with survival differences analyzed using the log-rank test. Univariate and multivariate analyses of variables were performed using Cox regression. As different prognostic factors, age, sex, PS, smoking index, NLR, PLR, PNI, ALI, ProGRP, brain metastases, liver metastases, and bone metastases were analyzed. The median follow-up period was 338 days, ranging from 45 to 1,833 days. Our sample size was identified as 110 patients within the limits of resources. All statistical analyses were performed using GraphPad Prism (v.7.0e; GraphPad Software, San Diego, CA, USA) and JMP Pro 16.0 (SAS Institute Inc., Cary, NC, USA).

Results

Patient demographics

Table 1 displays the characteristics of the 110 patients. The median age of the patients included in the study was 72 years (range, 50–88 years). Eighty-seven (79.1%) patients had a PS of 0 or 1, 91 (82.7%) were male, and 93 (84.5%) presented with stage M1. At diagnosis, metastases were present in the brain (32.7%), liver (25.5%), and bones (39.1%). The platinum-based chemotherapy regimens with atezolizumab and durvalumab were administered to 67.3% and 32.8% of patients, respectively. Among 104 patients with evaluable lesions for response, the objective response rate (ORR) was 63.6%, whereas the disease control rate was 88.2%.

The median values for the NLR, PLR, PNI, ALI, smoking index, and ProGRP before chemo-immunotherapy were 4.2 (range, 0.9–22.3), 205.8 (range, 12.3–1579.2), 42.9 (range, 22.0–57.0), 18.8 (range, 0–120.0), 1,020 (range, 0–2,640), and 600 (range, 31–95,277), respectively. The optimal cutoff values for the NLR, PLR, PNI, ALI, smoking index, and ProGRP as determined by ROC curve analyses were 3.3 (sensitivity: 41.3%, specificity: 75.0%), 197 (sensitivity: 63.0%, specificity: 50.0%), 47 (sensitivity: 47.8%, specificity: 82.8%), 14 (sensitivity: 73.9%, specificity: 43.8%), 1,040 (sensitivity: 77.8%, specificity: 31.3%), and 6,803 (sensitivity: 86.9%, specificity: 23.5%), respectively. The areas under the curve in the ROC analysis were as follows: 0.568 for NLR, 0.507 for PLR, 0.682 for PNI, 0.611 for ALI, 0.488 for smoking index, and 0.479 for ProGRP. High values for the NLR, PLR, PNI, ALI, smoking index, and ProGRP were observed in 68.2%, 55.5%, 26.4%, 59.1%, 55.5%, and 80.0% of patients, respectively.

Survival analysis based on different variables

The median PFS and OS of all the patients were 174 and 372 days, respectively. Ninety-eight patients experienced recurrence, and 82 died due to disease progression. The Kaplan-Meier survival curves for PFS and OS are displayed in Figure 1.

Figure 1 The Kaplan-Meier curves for PFS and OS according to different biomarkers in all patients. The patients with high ALI were significantly better for PFS (A) and OS (B) than those with low ALI. There was statistically significant difference in the PFS (C) and OS (D) between high and low ProGRP. The patients with liver and bone metastasis exhibited significant different PFS (E,G) and OS (F,H) compared to those without liver and bone metastasis. No significant difference for PFS (I,K) was observed between with and without any irAEs, and between high and low ALI, but, significantly different for OS (J,L). ALI, advanced lung cancer inflammation index; irAE, immune-related adverse event; meta, metastases; OS, overall survival; PFS, progression-free survival; ProGRP, pro-gastrin-releasing peptide.

Univariate analysis identified sex, ALI, ProGRP, liver metastasis, and bone metastasis as significant predictors of PFS, while age, sex, PS, NLR, ALI, ProGRP, liver metastasis, and bone metastasis were demonstrated to be significant predictors of OS (Table 2). The application of a univariate log-rank test enabled the screening of variables with a cutoff of P<0.05 for subsequent multivariate analysis. Multivariate analysis demonstrated that liver metastasis was an independent prognostic factor for predicting poor PFS and OS, meanwhile, sex was an independent predictor of OS (Table 2).

Different variables based on efficacy and outcome

Table 3 presents the patients’ characteristics according to OS >12 months, OS >24 months, induction of maintenance therapy, and response to RECIST. Female sex, high PNI, and the absence of liver metastasis were significantly associated with OS >12 months, whereas female sex and low NLR were closely correlated with OS >24 months. However, none of the variables predicted the therapeutic benefit of maintenance therapy or the achievement of complete response or partial response (PR) according to RECIST.

Patient’s characteristics according to the presence of liver metastases

Considering the results of the survival analysis (Table 2), we investigated different variables related to liver metastases (Table 4). High ProGRP levels, bone metastasis, occurrence of immune-related adverse events (irAEs) of any grade, and a PR response were significantly associated with the presence of liver metastasis.

Survival analysis in 28 patients with liver metastasis

Univariate and multivariate analyses of patients with liver metastasis were performed in addition to the survival analysis of all patients (Table 5). The maximum size and number of liver metastases were incorporated into the subsequent analysis. Among the 28 patients with liver metastases, the median maximal diameter of liver metastases was 28 mm, ranging from 9 to 103 mm. Additionally, 18 (64.3%) patients had more than 10 liver metastases. The cutoff values for the maximal size and number of liver metastases were 30 and 10, respectively. Univariate analysis identified ALI, maximal size of liver metastasis, and a combination of a maximal size greater than 30 mm with more than 10 metastases as significant predictors for OS, but not PFS. The application of a univariate log-rank test enabled the screening of variables with a cutoff of P<0.05 for subsequent multivariate analysis. Multivariate analysis identified the combination of maximal size >30 mm and number of metastases >10 as independent predictors of OS in 28 patients with liver metastasis.

Sequential treatment and irAEs in all patients

Of 110 patients, 45 (40.9%) were treated with amurubicin monotherapy as a second-line setting, 9 (8.2%) received a re-challenge of platinum (carboplatin or cisplatin)-based regimens with anti-PD-L1 antibodies (atezolizumab or durvalumab), and four (3.6%) were managed with carboplatin plus etoposide. Among 45 patients receiving amurubicin monotherapy, 16 achieved an ORR of 35.6% (16/45). In subsequent treatments, 10 patients received carboplatin plus paclitaxel, while one patient was treated with irinotecan monotherapy.

Moreover, irAEs were observed in 18 (16.4%) of 110 patients. Grade 1 or 2 hypothyroidism, grade 1 adrenal deficiency, grade 2 renal disorder, grade 1 pneumonitis, grade 1 arthritis, and grade 2 fatigue were observed in five, one, one, one, one, and two patients, respectively. Nine (8.2%) patients experienced grade 3 irAEs: pneumonitis for five patients, encephalitis for one, adrenal deficiency for two, and myocarditis for one. However, no patients experienced treatment-related deaths in this study.

Discussion

We attempted to identify a promising biomarker to predict outcomes following chemoimmunotherapy in patients with ES-SCLC. Although some real-world data is available regarding chemoimmunotherapy for patients with ES-SCLC, little is known about the possible risk factors, aside from consolidative palliative thoracic radiotherapy, liver metastasis, inflammatory markers, and PS (8-10). In the present study, we identified liver metastasis as a significant predictor of outcome after chemotherapy. Furthermore, liver metastasis was significantly associated with high levels of ProGRP, bone metastasis, and resistance to chemoimmunotherapy. Moreover, patients with a maximum tumor size greater than 30 mm and more than 10 liver metastases had an increased risk after chemoimmunotherapy. We believe that the maximal tumor size, in addition to multiple liver metastases, may be resistant to chemoimmunotherapy in patients with ES-SCLC. However, our study could not elucidate why liver metastasis significantly increased the risk of recurrence or death after chemotherapy.

ES-SCLC is biologically characterized by its tendency to rapidly spread to different organs and is highly responsive to chemotherapy and radiotherapy. However, therapeutic prediction of chemotherapy for ES-SCLC is still being developed worldwide. Considering the results of our study, we determined that ALI and liver metastasis are promising predictors for chemoimmunotherapy. Several researchers have reported that a low ALI is significantly associated with poor OS in patients with SCLC (19-21). Although previous reports focused on the heterogeneous population including limited-stage (LS) or ES-SCLC, and chemotherapy or chemoradiotherapy (18-20), Ürün et al. reported that low ALI was identified as an independent predictor for poor OS in 98 patients with ES-SCLC receiving chemotherapy (22). However, little is known about the relationship between ALI and the outcomes after immunotherapy for ES-SCLC. Cai et al. described the efficacy and safety of thoracic radiotherapy combined with chemoimmunotherapy in 78 patients with ES-SCLC, indicating that primary liver metastasis was a predictor of poor outcomes (23). Surveillance, Epidemiology, and End Results data analyzing 27,163 SCLC cases identified age, sex, clinical stage, presence of liver metastasis, and absence of chemotherapy as risk factors for early mortality (24). A recent meta-analysis suggested that lactate dehydrogenase and baseline liver and brain metastases may be helpful risk factors in predicting the efficacy of ICIs in patients with SCLC (25). Although metastasis is generally associated with poor prognosis, the liver microenvironment is particularly conducive to the survival of SCLC cells, and liver metastases promote an immunosuppressive environment (25-30). Therefore, the therapeutic efficacy of immunotherapy can be reduced by inhibiting the immune response to liver metastases. As a possible mechanism, the decreased immune response may be caused by a significant reduction in the CD8⁺ T cells at the margins of liver metastatic tumors in patients with melanoma (31). In addition, our study highlighted the prognostic relevance between poor response and the maximal diameter of liver metastasis. We discovered that patients with SCLC with a maximal tumor diameter of >30 mm and >10 liver metastases were not suitable for chemoimmunotherapy. In these patients, a new targeted therapy may be necessary to improve the efficacy of systemic treatment.

ProGRP is a common tumor marker used for the diagnosis and therapeutic monitoring of patients with SCLC. Li et al. reported that a decrease in ProGRP levels after chemotherapy could be a better predictor of response to chemotherapy in patients with SCLC with high ProGRP levels at baseline (32). However, whether high levels of ProGRP at baseline indicate a poor response to chemoimmunotherapy in ES-SCLC remains unclear. Our study identified ProGRP as a significant predictor of outcome after chemotherapy. Our previous study demonstrated that the metabolic tumor volume as measured by 2-deoxy-2-(fluorine-18)-fluoro-D-glucose (¹⁸F-FDG) uptake within SCLC cells could predict the outcome of chemoimmunotherapy in patients with ES-SCLC (13). The level of ProGRP may also correlate with total tumor volume, similar to the assessment by ¹⁸F-FDG accumulation. In our study, the presence of liver metastasis was significantly correlated with high levels of ProGRP and bone metastasis. Further investigations are required to elucidate the discovery of the close relationship between ProGRP levels and liver metastasis.

Our study had several limitations. First, the sample size was limited to elucidating the optimal conclusion by sub-analysis. The number of patients with liver metastases was 28; thus, further studies are warranted to recruit more patients with liver metastases. Secondly, liver metastasis was identified as a significantly poor outcome following chemotherapy. However, the tumor immune microenvironment in SCLC with liver metastasis, particularly in hepatic tumor specimens, remains unclear. To elucidate the mechanism underlying the poor immune response, a biopsy of hepatic tumor tissues may be required for further analysis. Finally, the follow-up period in our study was limited; thus, we could not examine possible predictors of long-term survival after initial treatment.

Conclusions

Liver metastasis was identified as a significant predictor of outcome after chemoimmunotherapy in patients with ES-SCLC. In particular, the maximal diameter and number of liver metastases may affect the immune response in patients with liver metastasis. ALI is a significant serum biomarker for predicting poor prognosis after chemoimmunotherapy. Further investigations are warranted to elucidate the immunological mechanisms underlying the poor response in patients with ES-SCLC with liver metastasis.

Acknowledgments

The authors thank Ms. Kozue Watanabe, Ms. Saki Toita, and Ms. Koko Kodaira for their assistance in preparing the manuscript. The authors also thank Editage (https://www.editage.jp/) for English language editing.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1091/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1091/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1091/prf

Funding: This work was supported by the JSPS Grant-in-Aid for Scientific Research C (No. 24K10292).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2024-1091/coif). K.K. received a speaker honorarium from Ono Pharmaceutical Company, Chugai Pharmaceutical, and AstraZeneca and research grants from AstraZeneca, and reports that this work was supported by the JSPS Grant-in-Aid for Scientific Research C (No. 24K10292). A.M. and O.Y. received speaker honoraria from Chugai Pharmaceutical and AstraZeneca, respectively. H.K. received research grants and speaker honoraria from Ono Pharmaceutical Company, Bristol-Myers Company, Boehringer Ingelheim, MSD, Chugai Pharmaceutical, and AstraZeneca. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Ethics Committee of the International Medical Center at Saitama Medical University (Nos. 20-125 and 2021-113). The requirement for written informed consent was waived due to the retrospective nature of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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