Introduction
Small cell lung cancer (SCLC) is a highly aggressive lung cancer characte-rized by rapid growth and a poor prognosis. The majority of SCLC patients are smokers, and about two-thirds present with metastatic extensive-stage SCLC (ES-SCLC) [1]. For decades, platinum-based chemotherapy has been the standard of care for ES-SCLC, demonstrating high response rates of 44–78% but with limited median survival of 9–11 months reported in randomized clinical trials [2]. Chemoimmunotherapy, which combines platinum-based chemotherapy with atezolizumab or durvalumab, a type of anti-PD-L1 antibody, has recently led to a significant change in the way ES-SCLC is treated. The difference in the median survival of two months with chemoimmunotherapy is modest compared to chemotherapy alone; however, a subset of patients may experience long-term survival with immunotherapy, achieving a 3-year overall survival (OS) rate from 15% to 17.6% [3–5]. Additionally, those treated with atezolizumab demonstrate long-term survival at a 5-year OS rate of 12% [6]. Currently, there are no reliable biomarkers to predict response to immunotherapy for ES-SCLC [7].
Studies of patients with metastatic prostate cancer receiving docetaxel serve as a good example of the discrepancy between randomized clinical trials and real-world clinical studies [8]. In routine practice, even with the same institution, these patients often experience shorter OS and greater toxicity compared to randomized clinical trial data. Also, using platinum chemotherapy as the first treatment for ES-SCLC is mostly based on data from randomized clinical trials, which may not fully reflect the whole patient population, especially those who are older, have worse overall health, or have multiple health problems [9]. Systematic reviews of real-world effectiveness have suggested that real-world outcomes for patients with ES-SCLC are worse than those reported in clinical trials [10]. A literature search on PubMed using the key terms “SCLC” and “Bosnia and Herzego-vina” identified only four published papers [11–14]. While most were not directly relevant to the topic, one case report describing the use of immunotherapy in ES-SCLC was considered relevant and included in this analysis [11].
In developing countries, such as Bosnia and Herzegovina, the oncology outcomes are usually significantly worse than in well-organized and well-funded medical systems. To improve the existing situation and decrease the number of underserved patients, the first step is to present reliable, real-world results. There has been insufficient research to determine how first-line chemotherapy for ES-SCLC works in real-life medical systems that are imperfectly set up, especially for older patients with poor performance status and significant comorbidities. Therefore, we conducted a retrospective cohort study to ascertain how well first-line platinum-based chemotherapy worked in real-life clinical settings for newly diagnosed patients with ES-SCLC. We also analyzed the response rate, progression-free interval (PFS), and OS in patients with ES-SCLC receiving first-line chemotherapy.
Material and methods
Study design
We conducted a retrospective study of all patients dia-gnosed with ES-SCLC who were evaluated or treated at the Oncology Clinic, University Clinical Hospital Mostar (Bosnia and Herzegovina), between January 2013 and December 2023. The data were analyzed by reviewing both written and electronic medical records through a hospital information system. Ethical approval for the study was obtained from the local institutional review board (University Clinical Hospital Mostar Ethical Committee, approval 1217/22). Informed consent was routinely waived due to the retrospective nature of the study. Before data collection, all patient information was blinded, and the study was conducted following the Declaration of Helsinki.
Patient characteristics
The inclusion criteria for the study were patients ≥ 18 years with a histo- or cytopathologically confirmed diagnosis of SCLC. Based on the Veterans Administration Lung Study Group classification system, all patients included were diagnosed with ES-SCLC [15]. Patients who received first-line chemotherapy based on platinum and etoposide or any other oncological therapy were analyzed. Analysis was also conducted on data from patients with ES-SCLC who were not treated with oncological therapy, primarily due to poor performance status, defined as an Eastern Cooperative Oncology Group (ECOG) score of 3 or 4. Patients with limited-stage SCLC were not included in the study.
The diagnostic work-up included brain computed tomography (CT) or magnetic resonance imaging (MRI), neck ultrasound, chest CT, X-ray, abdominal and/or pelvic CT, bone scintigraphy, or positron emission tomography (PET) CT. Before and during treatment, laboratory tests were performed, including complete blood count with differential and biochemical blood tests. Creatinine clearance was estimated before chemotherapy treatment using either a laboratory measurement or a calculated value based on the equation.
Treatment regimen
For patients undergoing first-line chemotherapy for ES-SCLC, platinum-based chemotherapy combined with etoposide is the standard treatment. The choice and dosage of chemotherapy in the first line depended on the patient’s general condition, age, and comorbidities. If the dose was not initially reduced, cisplatin was admini-stered at a dose of 75 mg/m2 or carboplatin at an area under the curve (AUC) of 5 intravenously on the first day, in combination with etoposide at 100 mg/m2 on the same day, followed by etoposide at 150 mg/m2 orally on the second and third days in 21-day cycles [16]. As part of premedication, patients received an antiemetic, proton pump inhibitor, and dexamethasone intravenously. For those receiving cisplatin, standard premedication included prehydration and posthydration with 1000 ml of 0.9% NaCl intravenously. Chemotherapy was administered for 4–6 cycles, depending on the patient’s response to therapy and tolerance of the chemotherapy. Since immunotherapy with atezolizumab or durvalumab is not included in the Federal Health Insurance Fund of Bosnia and Herzegovina, it was not routinely prescribed. In one patient, a donation was received to fund atezolizumab immunotherapy, which was administered in combination with chemotherapy, followed by maintenance therapy [11].
Response to therapy was evaluated every two to three months following the start of treatment, typically after three or four cycles of chemotherapy. The decision to administer consolidation thoracic radiotherapy was primarily guided by the extent of response to systemic therapy (partial or complete), the patient’s performance status, and the residual intrathoracic disease burden. The choice between prophylactic brain irradiation and MRI surveillance of the brain was based on clinical factors. Prophylactic brain irradiation was most commonly offered to patients with good performance status and response to systemic therapy. Conversely, MRI surveillance was preferred in patients with poorer performance status, advanced age, or comorbidities, where the risks of prophylactic brain irradiation were considered to outweigh potential benefits. Nevertheless, maintaining regular MRI surveillance was occasionally challenging due to limited availability, often driven by prolonged waiting times for MRI imaging. Palliative radiotherapy was administered to patients with brain metastases or painful bone metastases.
Treatment outcomes
Response to therapy, PFS, and OS were analyzed to assess treatment efficacy. Response to therapy was classified according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.1 [17]. A complete response was defined as the complete disappearance of the tumor, while a partial response was defined as a ≥ 30% reduction in tumor size. Disease progression was defined as a ≥ 20% increase in tumor size or the appearance of one or more new tumor lesions, and stable disease was defined as the absence of disease progression or regression.
PFS was defined as the time from diagnosis to disease progression or death from any cause, while OS was defined as the time from diagnosis to death from any cause. Treatment side effects were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, developed by the National Cancer Institute of the United States.
Statistical analysis
Statistical analysis was conducted using SPSS software (version 27.0, IBM Corp., USA). Continuous variables were expressed as medians with interquartile ranges (IQR), while categorical variables were presented as frequencies (n) and percentages (%). The Kolmogorov-Smirnov test was performed to assess the normality of distribution. Following the identification of deviations from normality, the c2 test was used for categorical variables, and the Wilcoxon test was applied for continuous variables. Analysis of PFS and OS was depicted using Kaplan-Meier plots, with statistical significance determined by the log-rank test (Mantel-Cox method). The significance level was set at p ≤ 0.05.
Results
Baseline characteristics of the cohort
Ninety-four patients were diagnosed with SCLC at our institution from January 2013 to December 2023. The baseline data for the patient cohort revealed a significant gender disparity, with 68 men (72.3%) and 26 women (27.7%), having a median age of 64 years (IQR: 58–69) (Table 1). Smoking status indicated that 82 patients (87.2%) were smokers. The ECOG performance status revealed that 21 patients (22.3%) had a score of 0, 45 (47.9%) had a score of 1, 15 (16.0%) had a score of 2, 4 (4.3%) had a score of 3, and 4 (4.3%) had a score of 4. Among the 76 (80.9%) patients who presented with respiratory symptoms, the most commonly reported were cough and shortness of breath, either alone or in combination. Superior vena cava syndrome was present in 13.8% of patients. Pain and weight loss were reported in 29 patients (30.9%), while 11.7% experienced hoarseness. Comorbidities affected 58 patients (61.7%). Five patients reported their COVID-19 history since 2020.
Table 1
Baseline characteristics of the cohort
Brain MRI was performed in 15 patients (16%), while brain CT scans were conducted in 64 (68.1%). Bone scintigraphy was used in 60 patients (63.8%), but PET/CT was rare, with only one patient (1.1%). Initial pulmonary function tests were conducted in 31 patients (33%). Most patients underwent bronchoscopy for biopsy (96.8%), while fewer (2.1%) had transthoracic biopsies or extrathoracic lymph node biopsies (1.1%). Extensive disease was present in all patients according to the Veterans Administration Lung Study Group staging system.
The most common metastatic sites included bone (38.3%), extrathoracic lymph nodes and liver (31.9% each), contralateral lung (23.4%), adrenal gland (21.3%), and brain (20.2%). Pleural effusion was present in 30 patients (31.9%), while 11 patients (11.7%) had pericardial effusion. Rare metastatic sites included the pancreas (3.2%) and soft tissues (2.1%) (Table 2). A significant number of patients (66%) presented with two or more metastatic sites. Moreover, 31.9% of these had a high disease burden characterized by three or more metastases.
Table 2
ES-SCLC-related characteristics
Treatment modalities and response to therapy
Sixty patients (63.8%) received the first-line chemotherapy protocol of cisplatin and etoposide (Table 3). Forty- one patients (43.7%) received six cycles, while eight patients (8.5%) received only one cycle, and five patients (5.3%) received two cycles. Ten patients (10.6%) did not receive any chemotherapy. Of the patients who received first-line chemotherapy, two (2.1%) had a stable disease, 48 (51.1%) showed a partial response, and four patients (4.3%) achieved a complete response. Disease progression was observed in 15 patients (16.0%), while the response was unknown for 12 patients (12.8%). Second-line chemotherapy was administered to 34 patients (36.2%), whereas third-line chemotherapy was administered to five patients (5.3%). The most frequently used second and third-line chemotherapy regimen was CAV (cyclophosphamide, doxorubicin, vincristine), administered in 16.0% and 2.1% of patients, respectively (Table 4).
Table 3
Treatment modalities for patients with ES-SCLC
Table 4
Second- and third-line chemotherapy regimens
Prophylactic cranial irradiation (PCI) was administered to 18 patients (19.1%), while 17 patients (18.1%) received consolidation radiotherapy. Disease recurrence during clinical follow-up was noted in 46 patients (48.9%), while two patients (2.1%) had no recurrence.
Progression-free and overall survival analysis
The median PFS was four months (95% CI: 3.1 to 4.9 months, Figure 1A). Patients who received chemotherapy had a median PFS of five months (95% CI: 4.1 to 5.9 months, Figure 1B). Consolidation radiotherapy improved PFS to eight months (95% CI: 6.8 to 9.2 months) versus four months (95% CI: 2.8 to 5.2 months) for those who did not receive it, as indicated in Figure 1C (p < 0.001). The chemotherapy protocols in Figure 1D showed a similar median PFS of five months for both cisplatin and etoposide and carboplatin and etoposide. In response to primary treatment, complete responders had a median PFS of 10 months (95% CI: 5.2 to 14.8) compared with seven months (95% CI: 6.3 to 7.7) for partial response and four months (95% CI: 2.1 to 5.9) for disease progression, as shown in Figure 1E, underscoring the significant impact of treatment response on PFS (p < 0.001).
Figure 1
A) Progression-free survival (PFS) analysis for the entire cohort. B) PFS for patients who received chemotherapy. C) PFS for patients who received consolidation radiotherapy. D) PFS for different chemotherapy protocols. E) PFS differences based on response to primary treatment
The OS for the entire cohort had a median of six months (95% CI: 4.54 to 7.46) (Figure 2A). Patients receiving chemo-therapy had a median OS of seven months (95% CI: 5.63 to 8.33), significantly longer than those not receiving chemotherapy, who had a median OS of one month (95% CI: 1.0 to 2.0) (p < 0.001) (Figure 2B). The group that did not receive consolidation radiotherapy only lived for five months, while the group that did receive it lived for a median of twelve months (95% CI: 5.27 to 18.72), which is a significant difference (p < 0.001) (Figure 2C). In first-line chemotherapy, both cisplatin and etoposide and carboplatin and etoposide had a median OS of seven months (95% CI: 5.25 to 8.75 and 4.35 to 9.65, respectively). On the other hand, changing from cisplatin and etoposide to carboplatin and etoposide led to a median OS of six months (95% CI: 2.40 to 9.60) (p < 0.001) (Figure 2D). Patients with a partial response had a median OS of eight months (95% CI: 6.49 to 9.51), those with a complete response had 19 months (95% CI: 0.00 to 69.96), patients with disease progression had six months (95% CI: 3.16 to 8.84), and those without oncological treatment had only one month (95% CI: 1.0 to 1.0) (Figure 2E).
Adverse events after first-line chemotherapy
Hematologic toxicities were reported in 90.5% of patients treated with first-line therapy for ES-SCLC (Table 5). Grade 3 or 4 neutropenia was the most common severe adverse event, observed in 21.3% of patients.
Table 5
Adverse events after first-line chemotherapy
Discussion
This study explored response rate, PFS, OS, and toxicity profile in patients with ES-SCLC treated in a real-world setting. The current study represents the first systematic, real-world study on SCLC from Bosnia and Herzegovina. Real-life clinical practice studies in ES-SCLC, especially in medical systems that are having trouble, can tell us a lot about how well treatments work and how they affect patients over time. In real-world clinical practice, a substantial proportion of patients are ineligible for randomized clinical trials due to rigorous inclusion criteria. For example, a study assessing real-world eligibility in ES-SCLC patients found that only 12.1% met the criteria for the IMpower133 trial and 14.7% for the CASPIAN trial [18]. The most common reason for ineligibility was an ECOG performance status of 2 or higher [18]. In our study, 24.6% of patients had a poor performance status with an ECOG score of 2 or higher.
The metastatic pattern in our cohort is similar to the reported studies. The high rate of initial brain metastases (20%) seen in our study is similar to the 15% rate reported in the literature [19]. This confirms the clinical relevance of early brain imaging in the initial evaluation of ES-SCLC. Despite brain MRI being the preferred diagnostic test for detecting brain metastases, only 16% of our patients underwent this imaging modality. This is comparable to a real-world study where MRI was the initial brain imaging modality in 21% of ES-SCLC patients [20]. However, our study included patients with more advanced disease, and if thorough diagnostic imaging, particularly brain MRI, had been systematically performed, we likely would have identified a higher number of patients with brain metastases. It is well known that the number of metastatic sites significantly impacts prognosis in ES-SCLC. Patients with a higher number of metastatic sites have been shown to have poorer survival outcomes [21, 22]. Our study revealed that a significant proportion of patients (66%) presented with two or more metastatic sites. Notably, nearly one-third of these patients (31.9%) had a high disease burden characterized by three or more metastases. This significant disease burden may have contributed to the poorer survival outcomes observed in our study.
Due to its high chemosensitivity, chemotherapy often induces initial responses in most ES-SCLC patients. However, relapse remains a significant challenge, with most patients eventually experiencing disease recurrence. In our study, 58% of patients showed an initial response to first-line chemotherapy. The response rates observed in the chemotherapy-only arms of IMpower 133 and the CASPIAN study were 64% and 58%, respectively [3, 4]. In our study, a complete response was achieved in ~4% of patients, with a median OS of 19 months. First-line immunotherapy with atezolizumab or durvalumab, in combination with platinum and etoposide, is not currently available as a treatment option for patients with ES-SCLC in our country. A single patient in our study who received atezolizumab-based chemotherapy and immunotherapy through a donation program, and then atezolizumab-based maintenance therapy, achieved a full and sustained response [11]. This case underscores the potential impact and importance of access to immunotherapy and other targeted therapies in improving treatment outcomes and survival for patients in low- and middle-income countries. In Bosnia and Herzegovina, access to targeted therapies and molecular profiling remains limited, with long waiting lists for approved and officially available targeted drugs [23].
The efficacy of first-line chemotherapy for ES-SCLC remains limited. A recent review reported a median survival range of ~7–16 months for patients with ES-SCLC treated with first-line chemotherapy [10]. The median OS for patients treated with first-line chemotherapy for ES-SCLC in our study was seven months. The median OS observed in the chemotherapy-only arms of the IMpower 133 and CASPIAN studies was 10.3 months and 10.5 months, respectively [3, 4]. While intravenous platinum-etoposide combination therapy remains the standard of care for ES-SCLC, the use of oral etoposide may provide substantial economic advantages and improved quality of life for patients [16, 24]. In our study, patients received oral etoposide on the second and third days of treatment after receiving intravenous platinum-etoposide on the first day. While oral etoposide offers advantages in terms of patient convenience, reduced treatment costs, and the possibility of outpatient administration, its main flaw is low and variable bioavailability, with an average systemic absorption of only ~50% compared to the intravenous route [16]. This could be one reason why the median OS in our study was so low. However, the median PFS observed in our study for patients treated with first-line chemotherapy for ES-SCLC was five months. This is comparable to the chemotherapy-only arms reported in the IMpower 133 and CASPIAN studies, which showed median PFS of 4.3 months and 5.4 months, respectively [3, 4].
In our study, 36% of patients received second-line chemotherapy, and 5% received third-line chemotherapy. In a real-world clinical practice setting, second and third-line chemotherapy regimens were administered to 43% and 12% of patients with SCLC [25]. The median OS for patients who did not receive chemotherapy in our study was one month, which is lower than the median OS of 3.6 months reported in real-world clinical practice studies, again suggesting the more advanced, late-stage diagnoses of our patients [26].
After completing first-line chemotherapy for ES-SCLC, patients who responded to chemotherapy received consolidation thoracic radiotherapy in our study. Patients who received consolidation radiotherapy in our study demonstrated a statistically significant improvement in median OS of 12 months vs. five months for patients who did not receive consolidation radiotherapy. The role of consolidation thoracic radiotherapy in ES-SCLC has been investigated in two randomized trials [27, 28]. In the Jeremic et al. study [27], consolidation radiotherapy was administered in patients with a complete response of distant metastases, resulting in a median OS of 17 months compared to 11 months for a patient who received chemotherapy alone. In the CREST trial, patients who responded to chemotherapy received consolidation radiotherapy [28]. While there was no statistically significant difference in the primary endpoint of 1-year OS (33% vs. 28%), a significant improvement in 2-year OS (13% vs. 3%) was observed in the radiotherapy group. For patients with ES-SCLC who do not progress after first-line chemotherapy, either MRI brain surveillance or prophylactic brain radiotherapy can be considered [24]. In the EORTC randomized clinical study, it was found that PCI lowers the risk of symptomatic brain metastases and increases OS compared to no PCI [29]. In contrast, a Japanese randomized phase III trial did not show a survival benefit of PCI over active MRI surveillance in patients with ES-SCLC [30]. Furthermore, a cost-effectiveness analysis concluded that PCI was not cost-effective compared to MRI surveillance alone, primarily due to its detrimental effect on neurocognitive function [31]. PCI was administered to 19% of patients in our study, highlighting that a significant proportion of patients were underserved and did not receive guidelines defining optimal therapy.
Hematologic toxicity was the most common adverse event observed in patients treated with first-line chemotherapy for ES-SCLC in our study. In our study, grade 1 and 2 anemia was observed in ~32% of patients, compared to ~21% in the chemotherapy-only group of the IMpower 133 study [3]. Data on grade 1 and 2 anemia were not reported for the CASPIAN study [4]. Additionally, grade 3 and 4 neutropenia was observed in 23% of patients in our study, 24.5% of patients in the IMpower 133 study, and 24% of patients in the CASPIAN study [3, 4].
Considering that our study is a report of experience from one institution, caution is needed in interpreting the data. The limitations of our study include its retrospective design and the small number of patients enrolled from a single institution. Due to the retrospective design of the study, there is a possibility of missing data in the written or electronic medical history.
Our study indicates that the first-line chemotherapy for ES-SCLC may be associated with poorer survival outcomes than those reported in randomized clinical trials. Further clinical studies are necessary to explore optimal therapeutic strategies for ES-SCLC, especially in developing countries like Bosnia and Herzegovina. The study also highlights an unmet need for broader access to targeted drugs and implementation of precision medicine in oncology practice in the country.
