Factors affecting survival and prognosis in extensive stage small cell lung cancer

Abstract

Although chemotherapy significantly improves the quality of life and prolongs survival in patients with extensive-stage small cell lung cancer (ES-SCLC), relapse is almost inevitable, with only 5% of patients surviving two years after the initial diagnosis. Prophylactic cranial irradiation (PCI) is considered for patients who achieve a complete response, as it has been shown to improve survival rates in this population. Recent studies have also demonstrated that adding PD-L1 inhibitors, such as atezolizumab or durvalumab, to chemotherapy in first-line treatment significantly enhances survival compared to chemotherapy alone. Our study was conducted retrospectively at a single center, including 280 patients with ES-SCLC who began therapy at our institution between July 2009 and February 2023. Patients who underwent thoracic residual radiotherapy (p< 0.001) and PCI (p< 0.001) showed statistically significant improvements in OS. In the first-line treatment group, the median overall survival (OS) for patients receiving cisplatin+etoposide was 12.0 months (10.71 - 13.28), while those treated with carboplatin+etoposide had a median OS of 7.0 months (4.58 - 9.41). For patients receiving carboplatin+etoposide+atezolizumab, the median OS was 35.0 months (21.32 - 48.67), and a statistically significant difference was observed (p< 0.001). In our study, the median OS was 7 months in patients who received ≤ 4 cycles of treatment in the first line and 14 months in patients who received > 4 cycles of treatment. After first-line treatment, the proportion of patients with progression-free survival (PFS) between 0 - 3 months was 21%, and between 3 - 6 months was 24%. PFS was notably worse in those with bone, liver, or brain metastases at diagnosis in the first-line treatment. Multivariate analysis revealed that carboplatin+etoposide+atezolizumab in the first line and cisplatin+etoposide in the second line reduced the risk of both progression and death, while PCI reduced the risk of death. In conclusion, ES-SCLC remains one of the most challenging malignancies, characterized by poor survival rates and short progression-free intervals. Multiple factors influence OS and PFS, some of which are intrinsic to the patient and disease at diagnosis. In contrast, others, such as treatment modalities, the number of treatment cycles, and the application of radiotherapy, can be modified by clinicians.

Introduction

Lung cancer is one of the leading causes of cancer-related deaths worldwide [1]. Although its incidence has decreased in recent years, small cell lung cancer (SCLC) still accounts for approximately 15% of all lung cancers [2]. Compared to other histological types, SCLC progresses rapidly, often presents with distant metastasis at the time of diagnosis, and is highly responsive to chemotherapy and radiotherapy [3]. Unlike other forms of lung cancer, SCLC is classified into two stages: limited stage (LS) and extensive stage (ES). Although chemotherapy significantly improves the quality of life and prolongs survival in patients with ES-SCLC, relapse is almost inevitable, with only 5% of patients surviving two years after the initial diagnosis [4].

The first-line treatment for ES-SCLC typically involves platinum-based chemotherapy, such as cisplatin or carboplatin in combination with etoposide, which aims to palliate symptoms and extend survival. Prophylactic cranial irradiation (PCI) is considered for patients who achieve a complete response, as it has been shown to improve survival rates in this population [5]. Recent studies have also demonstrated that adding PD-L1 inhibitors, such as atezolizumab or durvalumab, to chemotherapy in first-line treatment significantly enhances survival compared to chemotherapy alone [6, 7].

For patients with disease progression or recurrence, treatment options include topotecan, irinotecan, lurbinectedin, temozolomide, the CAV regimen (cyclophosphamide, doxorubicin, and vincristine), paclitaxel, docetaxel, gemcitabine, and immunotherapies like nivolumab or pembrolizumab. In this study, we aimed to evaluate the factors influencing disease recurrence and survival outcomes in patients with ES-SCLC who were followed and treated at our center.

Materials and methods

Our study was conducted retrospectively at a single center, including 280 patients with extensive-stage small cell lung cancer (ES-SCLC) who began treatment at our institution between July 2009 and February 2023. We analyzed various factors, including patients'age at diagnosis, gender, primary tumor location, and size, metastatic sites, treatments received in both the first and second lines, progression-free survival (PFS), overall survival (OS), radiotherapy for thoracic residual lesions after first-line treatment, and the application of PCI.

OS was defined as the time from diagnosis to death, while PFS was defined as the time from the initiation of treatment to disease progression. Treatment responses were assessed using 18 F-fluorodeoxyglucose positron emission tomography-computed tomography (18 F-FDG PET-CT), with imaging performed every 3 months. Radiologic response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) [8]. The best response observed throughout the treatment course was recorded, with response groups classified as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD).

Patients with missing data, those who refused or did not complete their planned treatment, those diagnosed with more than one primary malignancy, and patients under 18 years of age were excluded from the study. Additionally, patients who died from non-malignant causes were not included. The study was approved by the local Ethics Committee and conducted in accordance with the Declaration of Helsinki and ethical principles (Approval date and number: [11/04/2024, 20]).

Statistical analysis

Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 25.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics were presented as frequency (n) and percentage (%) for categorical variables, and as mean ± standard deviation (SD) or median with range (minimum–maximum) for continuous variables. The Kaplan–Meier method was employed to estimate and compare overall survival (OS) and progression-free survival (PFS) across different clinical groups. A multivariate Cox regression analysis was conducted to evaluate the effects of various clinical variables on mortality and progression risk. A p-value of less than 0.05 was considered statistically significant.

Results

The demographic and clinical characteristics of the patients are summarized in Table 1. Among the 280 patients, 79.3% were male, and the mean age at diagnosis was 59.7 years. A total of 116 (45%) patients received second-line treatment. Following first-line therapy, 94 (33.6%) patients received thoracic residual radiotherapy, and 67 (24%) patients were administered PCI. The median follow-up duration was 11 months.

Table 1 Sociodemographic and clinical characteristics data (n= 280)

Table 2 presents the comparisons of OS across different patient groups. The median OS was 11.0 months (9.63–12.36), with a 2-year survival rate of 13.1% and a 5-year survival rate of 3%. The presence of brain (p = 0.001) and liver metastases (p < 0.001) at the time of diagnosis was significantly associated with decreased OS. We found a difference in OS when dividing patients into two groups based on metastasis area: those with a single site of metastasis and those with > 1 site. The median OS for patients with a single site of metastasis was 12.0 months (2–182), while those with > 1 site of metastasis had a median OS of 10.0 months (1–109), with a statistically significant difference (p = 0.001). Patients who underwent thoracic residual radiotherapy (p < 0.001) and PCI (p < 0.001) showed statistically significant improvements in OS. In the first-line treatment group, the median OS for patients receiving cisplatin + etoposide was 12.0 months (10.71–13.28), whereas those treated with carboplatin + etoposide had a median OS of 7.0 months (4.58–9.41). For patients receiving carboplatin + etoposide + atezolizumab, the median OS was 35.0 months (21.32–48.67), with a statistically significant difference observed (p < 0.001). The Kaplan–Meier curve depicting changes in OS based on first-line treatment agents is shown in Fig. 1. Among patients who received cisplatin + etoposide in the second-line treatment, the median OS was 35.0 (20.33–49.66) months, significantly longer than that of patients receiving other second-line treatments (p < 0.001). Second-line treatments included: topotecan (37 patients, 32%), irinotecan (10 patients, 8.7%), cisplatin + irinotecan (15 patients, 13%), carboplatin + irinotecan (8 patients, 6.9%), etoposide (6 patients, 5%), carboplatin + etoposide (7 patients, 6%), CAV (cyclophosphamide, doxorubicin, and vincristine) (10 patients, 8.7%), paclitaxel (3 patients, 2.6%), temozolomide + irinotecan (4 patients, 3.4%), and gemcitabine (2 patients, 1.7%). The Kaplan–Meier curve for changes in OS based on second-line treatments is shown in Fig. 2.

Table 2 OS comparisons of patients

Fig. 1

The Kaplan-Meier curve showing changes in OS based on first-line treatment agents

Fig. 2

The Kaplan-Meier curve showing changes in OS based on second-line treatments

Table 3 includes comparisons of PFS across patients. PFS was notably worse in those with bone, liver, or brain metastases at diagnosis in the first-line treatment. The median PFS for patients receiving cisplatin + etoposide was 7.0 months (6.13–7.86), while those treated with carboplatin + etoposide + atezolizumab in the first-line setting had a median PFS of 20.0 months (17.21–22.78), a significant difference (p < 0.001). The Kaplan–Meier curve illustrating changes in PFS based on first-line treatment agents is shown in Fig. 3. After first-line treatment, the proportion of patients with PFS between 0–3 months was 21%, between 3–6 months was 24%, between 6–9 months was 25%, between 9–12 months was 9%, and those with PFS longer than 12 months made up 21%. Due to the lower number of patients, PFS for second-line treatment agents was calculated only for the respective agents. Median PFS could not be determined for second-line treatments, but PFS was significantly better for patients receiving cisplatin + etoposide (p < 0.001). The Kaplan–Meier curve showing changes in PFS according to second-line treatment agents is shown in Fig. 4.

Table 3 PFS comparisons across patients

Fig. 3

The Kaplan-Meier curve showing changes in PFS based on first-line treatment agents

Fig. 4

The Kaplan-Meier curve showing changes in PFS according to second-line treatment agents

As shown in Table 4, univariate analyses identified several factors as significant: brain, liver, and extrathoracic lymph node metastases, first- and second-line treatments, number of cycles in first-line therapy, thoracic residual radiotherapy, and PCI. These variables were incorporated into a multivariate Cox regression model. The results revealed that liver metastasis increased the risk of death by 2.49 times (HR: 2.49, 95% CI: 1.50–4.14, p < 0.001), carboplatin + etoposide increased the risk by 2.20 times (HR: 2.20, 95% CI: 1.18–4.08, p = 0.012), and oral etoposide increased the risk by 6.46 times (HR: 6.46, 95% CI: 1.29–32.14, p = 0.023) in the first-line treatment. However, carboplatin + etoposide + atezolizumab in the first-line setting (HR: 0.36, 95% CI: 0.16–0.81, p = 0.013), cisplatin + etoposide in the second-line treatment (HR: 0.33, 95% CI: 0.15–0.71, p = 0.004), and PCI (HR: 0.60, 95% CI: 0.36–0.98, p = 0.045) were found to reduce the risk of death.

Table 4 Multivariate Cox regression results of mortality risk on various clinical variables

The multivariate Cox regression analysis of the risk of progression based on various clinical variables is summarized in Table 5. Liver metastasis increased the risk of progression by 1.64 times (HR: 1.64, 95% CI: 1.03–2.61, p = 0.034), while bone metastasis also increased the risk by 1.64 times (HR: 1.64, 95% CI: 1.05–2.56, p = 0.027). Oral etoposide use in the first-line setting was associated with a 5.18 times increased risk of progression (HR: 5.18, 95% CI: 1.17–22.80, p = 0.030). Additionally, CAV in the second-line setting increased the risk of progression by 2.19 times (HR: 2.19, 95% CI: 1.01–4.76, p = 0.047). In contrast, carboplatin + etoposide + atezolizumab in the first-line treatment (HR: 0.26, 95% CI: 0.12–0.57, p = 0.001) and cisplatin + etoposide in the second-line treatment (HR: 0.34, 95% CI: 0.17–0.68, p = 0.002) were associated with a significant reduction in the risk of progression.

Table 5 Multivariate Cox regression results of the risk of progression on various clinical variables

Discussion

ES-SCLC is a rapidly progressing malignancy characterized by a poor prognosis, low likelihood of cure, and notably unfavorable OS and PFS outcomes. A significant proportion of patients succumb to the disease during first-line treatment, often before receiving second-line therapies, due to aggressive disease progression or treatment-related complications. Despite the limited efficacy of current therapies and the lack of significant breakthroughs in treatment development, research on ES-SCLC has remained relatively sparse in recent years compared to other malignancies.

Historically, studies conducted on ES-SCLC patients primarily involved treatment with traditional platinum-based chemotherapy. However, in recent years, studies have emerged demonstrating the survival benefits of combining chemotherapy with new agents, including the tyrosine kinase inhibitor anlotinib and several immunotherapy agents such as atezolizumab, durvalumab, benmelstobart, tislelizumab, adebrelimab, socazolimab, toripalimab, and sintilimab. Although these newer treatment options have shown promise, most of the studies have been conducted on limited patient populations and are still in phase trials. Consequently, it will take time before these agents are incorporated into routine practice and become widely licensed. The inclusion of both patients who received chemotherapy alone and those who received atezolizumab in combination with chemotherapy in our study is significant, as it demonstrates the efficacy and survival benefits of these new treatment strategies [9,10,11,12,13,14,15]. We see that; in the light of the developments in recent years, when the progress of ES-SCLC treatment is examined with all the studies carried out in the historical process, the addition of the mentioned treatment options in line with new strategies to traditional platinum-based chemotherapies and other known classical agents has provided great benefits to these patients.

Previous studies have reported a median OS ranging from 8 to 14 months [16, 17]. Our study observed a median OS of 11 months, which aligns with the existing literature. Notably, liver and brain metastases were found to be statistically significant predictors of OS in our cohort, corroborating findings from prior studies [16, 18].

In addition to metastatic involvement, the treatment modality was a significant factor influencing OS in our study. Patients who received atezolizumab in combination with chemotherapy, particularly in the first-line setting, experienced significantly longer OS. This treatment strategy has recently become a standard practice in managing ES-SCLC [19, 20]. In our cohort, 15 out of 280 patients received chemotherapy plus atezolizumab, with a median OS of 35 months for these individuals. This duration is notably longer than in some prior studies, likely due to the relatively small sample size. However, a remarkable case report has documented an ES-SCLC patient receiving chemotherapy plus atezolizumab, achieving an OS of 60 months [21]. Patients who received cisplatin + etoposide in second-line therapy demonstrated a significantly longer OS compared to those receiving alternative second-line treatments (p < 0.001). This may be attributed to the fact that cisplatin-based regimens were often chosen for patients who responded well to first-line platinum-based chemotherapy and did not exhibit disease progression for at least 3 months.

The number of patients who received atezolizumab treatment in combination with chemotherapy can be considered relatively low in our study. Although this treatment has been in routine use for the past few years, the fact that our study included mostly previous patients may be a reason for this. Another contributing factor is that atezolizumab treatment combined with chemotherapy is not reimbursed by government institutions in our country for ES-SCLC patients. Patients often resort to receiving atezolizumab through personal means or by filing a lawsuit. As our patient population generally has a lower socio-economic status, many seek treatment through legal channels. In our study, all patients who received atezolizumab used this agent for 12 months without any dose reductions.

PCI and thoracic residual radiotherapy were additional factors that positively influenced OS in our patients. Numerous studies have demonstrated the survival benefits of PCI in ES-SCLC patients [22,23,24,25,26]. In our study, PCI was administered to patients who either achieved a complete response following first-line treatment or had a partial response. Similarly, patients who received thoracic residual radiotherapy had either a complete or partial response after first-line treatment. While thoracic radiotherapy has been associated with improved survival outcomes in several studies [27,28,29], its benefit remains debated in some reports [30]. Nonetheless, both thoracic radiotherapy (p < 0.001) and PCI (p < 0.001) were found to enhance OS in our study significantly. The hazard ratio (HR) for mortality in patients who underwent PCI was 0.60 (95% CI: 0.36–0.98), indicating a statistically significant reduction in the risk of death (p = 0.045). A recent meta-analysis, which included 26.467 ES-SCLC patients, reported a similar HR for survival (0.59), further supporting our findings [31]. A controversial issue is that PCI and thoracic residual radiotherapy may seem to contribute to survival because they are applied to patients who already have a complete or partial response to treatment and have a relatively good prognosis.

The impact of first- and second-line treatments on OS was further explored using multivariate Cox regression analysis. Since cisplatin + etoposide and topotecan were the most frequently used first-line treatments in our study, and were used as reference groups. For patients treated with carboplatin + etoposide + atezolizumab in the first line, the HR for OS was 0.36 (95% CI: 0.16–0.81, p = 0.013), and the HR for PFS was 0.26 (95% CI: 0.12–0.57, p = 0.001). In a recent retrospective study with a similar patient cohort and follow-up period, the HR for OS in ES-SCLC patients who received immunotherapy in addition to chemotherapy in the first line was reported as 0.67 (95% CI: 0.26–1.68) [32].

In a larger, more recent study with findings similar to ours, the survival benefits of 4 or more cycles of chemotherapy, cisplatin + etoposide regimens, thoracic radiotherapy, and PCI were highlighted [16]. This study reported a median OS of 15.5 months for patients who received 4 or more cycles of chemotherapy and 6.3 months for those receiving fewer than 4 cycles, which aligns closely with our findings (median OS of 7 months for those who received ≤ 4 cycles and 14 months for those receiving > 4 cycles). Regarding PFS, our study found a median PFS of 7.0 months (95% CI: 6.13–7.86) for patients treated with cisplatin + etoposide in the first-line setting. This result is consistent with a retrospective study published three years ago [33] and aligns with the findings of other studies investigating this treatment regimen [34, 35].

Our study's limitations include its single-center design, the small number of patients receiving immunotherapy, and the relatively short follow-up period. Specifically, the limited number of patients receiving immunotherapy may have caused the median survival of this group to be longer than expected. Therefore, future studies incorporating a larger and more diverse cohort from different centers, with varying ethnic, cultural, and socio-economic characteristics, are needed to make permanent changes in the treatment approach for ES-SCLC. New treatment agents and strategies will likely require time to be licensed and included in guidelines and routine practice. Incorporating patients from different centers with longer follow-up periods and molecular and genomic data to identify predictive biomarkers and develop personalized treatment strategies will accelerate this process.

In conclusion, ES-SCLC remains one of the most challenging malignancies, characterized by poor survival rates and short progression-free intervals. Multiple factors influence OS and PFS, some of which are intrinsic to the patient and disease at diagnosis, while others, such as treatment modalities, the number of treatment cycles, and the application of radiotherapy, can be modified by clinicians. Our study provides real-world data from a single-center cohort, which closely mirrors previous studies in terms of patient demographics, follow-up duration, and treatment regimens. These data enable us to draw conclusions that are consistent with the broader literature regarding factors that influence survival in ES-SCLC.