The objective of this study was to determine overall survival (OS) and progression-free survival (PFS) in patients with extensive-stage small cell lung cancer (ES-SCLC) treated with first-line etoposide-platinum (EP) chemotherapy in Hungary from 2013 to 2019, using time to first subsequent treatment (TFST) as a proxy for PFS. TFST was used to infer PFS given that the National Health Insurance Fund (NHIF) database does not record PFS directly. Descriptive statistics were also prepared of patient demographics, regional incidence, and post-progression treatment strategies for the broader cohort diagnosed between 2013 and 2022.

Lung cancer remains the most frequently diagnosed cancer and the cause of cancer-related death worldwide [1–3], although in 2020 female breast cancer surpassed lung cancer in terms of new diagnoses (11.7% vs. 11.4%) but not mortality. While Hungary faced high lung cancer incidence and mortality throughout history [4–7], recent data suggest that the lung cancer burden has started to approach European averages [6, 8–11]. Among lung cancer subtypes, small cell lung cancer (SCLC) accounts for approximately 15%–20% of cases and is characterized by rapid progression and early metastasis, along with a strong association with smoking [12, 13]. Two thirds of all SCLC cases are classified as extensive-stage disease (ES-SCLC), which has a very poor prognosis [12, 13].

For more than two decades, first-line (1L) etoposide-platinum (EP) chemotherapy has been the standard of care in ES-SCLC [14], effectively inducing responses but producing only a limited survival benefit: median overall survival (OS) ranges between 8 and 10 months with this treatment [12, 15, 16]. In ES-SCLC, patients may receive non-curative dosages of thoracic and cranial radiotherapy as adjuvant therapy to complement chemotherapy, and ES-SCLC standard-of-care includes prophylactic cranial irradiation (PCI) too. Recently, phase III trials have introduced immunotherapy combinations (durvalumab-EP in CASPIAN, atezolizumab-EP in IMpower133) that yield improved patient outcomes compared with just EP [16, 17]. In Hungary, access to these therapies was limited to individual requests from 2022, until in 2024 they became nationally reimbursed [7].

Unlike in operable non-small cell lung cancer (NSCLC), where real-world data specific to Hungary are available [18], there is a lack of publications that characterize the Hungarian ES-SCLC population within the breadth of LC data, focusing on the treatment landscape and epidemiology [6]. We used the National Health Insurance Fund (NHIF) database to address this gap, which collects records of diagnoses, medical interventions, and clinical outcomes, covering nearly the entire population of Hungary [7].

In this real-world study, we analyzed patients who received 1L EP for ES-SCLC between 2013 and 2022, with an emphasis on epidemiology, treatment pathways, and survival data. PFS was inferred using TFST, and OS was determined in patient cohorts that were treated within 1 year of C34-coded diagnosis and had a minimum 3-year follow-up period following treatment, hence patients between 2013 and 2019. In sensitivity analyses, we excluded patients who received long-course (5 cycles or more, 25–30 fractions) of radiotherapy to reduce multimodal therapy bias, and kept those who underwent short-course therapy (1-2 cycles, 5–19 fractions maximum). Together these data form a national benchmark for assessing ES-SCLC outcomes in Hungary preceding the widespread implementation of immunotherapy [7].

Epidemiological analysis was performed on 8,104 patients with ES-SCLC, while 5,576 patients who received 1L EP chemotherapy within 1 year of their initial C34 diagnosis were selected for our follow-up efficacy analysis 3 years after undergoing treatment. Of the 5,576 patients within the latter cohort, 5,286 (94.8%) either received first subsequent therapy or died, indicating disease progression, while 290 (5.2%) lived throughout the full study period without the administration of subsequent therapy. Of patients without radiotherapy or with short-course radiotherapy (N = 5,273), 5,009 (95%) either received subsequent therapy or died, while 264 (5%) stayed alive throughout the 3-year period.

It is worth reaffirming that this nationwide, retrospective real-world study followed ES-SCLC cases in Hungary from 2013 to 2022, with the sociodemographic, clinical characteristics, diagnostic, and treatment pattern analysis cohort consisting of 8,104 patients treated with 1L EP chemotherapy during that period. The efficacy analyses were performed on a tighter cohort of 5,576 patients treated between 2013 and 2019 within 1 year of their initial C34 diagnosis to allow for 3-year follow-up. Within this framework, we provide details on progression, and survival outcomes before the implementation of immunotherapy as a treatment option in 2024.

The incidence of ES-SCLC in Hungary cannot be determined directly, as no available national database contains the annual number of lung cancer diagnoses together with reliable histological results and TNM classification data. To address this gap, we developed a methodology to identify the ES-SCLC population using the NHIF claims database.

Although the NHIF database includes a wide range of treatments and interventions, only concurrent chemoradiotherapy has a distinct reimbursement code, whereas sequential chemoradiotherapy is not coded separately. If sequential chemoradiotherapy had been clearly identifiable in the coding system, patients receiving either concurrent or sequential chemoradiotherapy should have been excluded in the first step of cohort selection. Consequently, an important limitation of our study is that, as sequential chemoradiotherapy could not be directly identified, the exclusion criteria included only concurrent chemoradiotherapy, which may have resulted in a slight overestimation of the number of ES-SCLC patients.

To further assess the robustness of our findings, we conducted a sensitivity analysis using a proxy definition for sequential chemoradiotherapy. Specifically, we excluded patients who received long-course radiotherapy after EP chemotherapy, based on the coding practices reported by local oncoradiologists. However, this approach may have led to a slight underestimation of the total number of ES-SCLC patients, as the database does not allow differentiation between patients who received radiotherapy as part of sequential chemoradiotherapy with curative intent for limited-stage SCLC and those who received radiotherapy for palliative purposes after EP chemotherapy in the ES-SCLC setting. As no formal reference defining long-course radiotherapy by a specific dose threshold was identified, the threshold applied in this study was based on routine oncoradiological practice. This is consistent with international clinical practice, in which conventional once-daily thoracic radiotherapy for LS-SCLC commonly consists of 50–66 Gy delivered in 2-Gy fractions. Because radiotherapy is recorded weekly in the NHIF database, this schedule corresponds to 5 or more reported cycles, that is, approximately 25–30 fractions.

Our cohort is at present one of the largest national ES-SCLC datasets in Central Europe. EP chemotherapy patterns captured by the NHIF helped identify patients, and exclusion rules were set based on surgical and concomitant chemoradiotherapy codes characteristic of limited-stage SCLC or curative-intent treatment. The patient population reflects the known demographics of ES-SCLC: men were more frequently affected than women (53.1% vs. 46.9%), and the gender gap slightly narrowed over time, paralleling the reports of shifting smoking trends across Central and Eastern Europe [10, 12, 14], as reported in the Korányi Bulletin and earlier NHIF analyses. Some years saw nearly equal male-to-female ratios (50.3% vs. 49.7% in 2020; 50% vs. 50% in 2022), The Korányi Bulletin recorded a shift in the total lung cancer population within the lung care system over the years: 84% vs. 16% in 1980, 61% vs. 39% in 2013, 53% vs. 47% in 2022.

The majority of cases occurred between ages 60–69 years, slightly shifting toward older ages with time: the proportion of patients aged 70–79 years increased, whereas the proportion of patients below 60 declined. This shift was more pronounced in other studies assessing the entire Hungarian lung cancer population [8]. Furthermore, a large Canadian retrospective RWE study (N = 1,941) of ES-SCLC reported that 81% of their cohort were over 60 [20]. Another study involving five European countries found that the median age of SCLC patients was 66 [21], both reporting similar data to ours.

We observed regional differences as well, with Baranya County reaching the highest age-standardized incidence at 136.4 per 100,000 (95% CI: 124.4–148.4), compared with the national average of 82.7 per 100,000 (95% CI: 80.9–84.5) based on KSH data. This geographic variation may reflect differences in underlying environmental or population-level risk factors. Given Baranya county’s mining history, including operation of a uranium mine between 1957 and 1997, it may be hypothetized that historical environmental exposures could have contributed to the observed pattern. Additionally, several studies have reported association between air pollution and SCLC risk [22–24]. However, these interpretations remain speculative, and no causal relationship can be established from the present data.

EP chemotherapy was the first-line treatment regimen throughout the study period [25, 26], wherein carboplatin use increased, gradually replacing cisplatin administration. Canadian and American studies showed that most patients received carboplatin rather than cisplatin as a platinum agent in 1L ES-SCLC therapy in recent years [20, 27]. In terms of treatment delivery, the course length fell between 2–4 cycles in roughly 46% of cases. Approximately 20% received a single cycle, and this halting of treatment likely reflects chemotherapy intolerance or rapid clinical deterioration in patients.

Long-course radiotherapy generally reflects curative-intent sequential chemoradiotherapy in limited-stage SCLC. In our cohort, more than a third (38.4%) of the patients received radiotherapy, but only small rate of them (4.7%) underwent long-course thoracic radiotherapy.

Among progressing patients, 38.7% received second-line therapy, with EP rechallenge making up almost half of those cases. According to standard European practices, EP rechallenge is preferred in platinum-sensitive relapsed cases. Access to later-line agents such as topotecan and ECO and ECO/B (cyclophosphamide, epirubicin, and vincristine) varied; among patients on subsequent treatment, 17.9% received topotecan and 28.1% received ECO and ECO/B. In international studies, topotecan use ranged from 9% to 40.8% [28, 29] under similar circumstances, and the 2013 ESMO guideline recommended intravenous topotecan and the classical CAV regimen consisting of cyclophosphamide, doxorubicin, and vincristine for platinum-refractory patients [14]. Although the guideline refers to CAV, in Hungarian clinical practice the corresponding regimens used in lung cancer are ECO and ECO/B, which include cyclophosphamide, epirubicin, and vincristine, in accordance with the local chemotherapy protocol [30].

This analysis confirms that ES-SCLC is an aggressive form of cancer that carries poor long-term survival outlooks: Both the directly measured OS and the TFST-proxied PFS paint a similar picture with quick progression emerging frequently despite initial treatment. The median PFS was 6.5 months, where only 52.9% and 19% of patients were progression-free at 6 months and 1 year, respectively, and 5.2% at 3 years. The median OS was 9.3 months, with a 1-year survival rate of 37.5%, and a 3-year survival rate of 9.2%. In the sensitivity analysis, when we excluded patients with long-course radiotherapy, we found similar results, with a median PFS of 6.3 months, a 6-month PFS rate of 51.8% and a 3-year PFS rate of 5.0%. The median OS in the sensitivity analysis was 8.9 months, with a 1-year survival rate of 35.6%, and a 3-year survival rate of 8.7%.

All these efficacy results are consistent with the outcomes reported in other European real-world studies preceding immunotherapy. France reported an OS of 11.8 months and PFS of 6.1 months, while in Spain OS was 8.2 months and PFS was 5 months [15, 16, 31].

In the CASPIAN study, a phase III randomized clinical trial investigating combination therapy with durvalumab and EP in ES-SCLC patients, the control EP arm reportedly had 12- and 24-month PFS rates of 5.3% and 2.9%, with a median PFS of 5.4 months. In IMpower133 study that involved atezolizumab administration in combination with EP, the EP control arm PFS figures were 22.4% at 6 months, 12% at 24 months, and the median PFS was 4.3 months [16, 17, 32].

The slightly longer PFS observed in our study can be attributed to differences in study methods, as progression was proxied using TFST. Given that ES-SCLC is a rapidly progressing disease, even short delays between radiologic progression and the initiation of subsequent therapy may extend TFST in relation to the trial-defined PFS. Furthermore, if supportive care was provided without follow-up therapy, this period was not captured.

Regarding the shorter OS found in our analysis, we propose that it may be due to the criteria of patient selection in clinical trials being much stricter than real-world patients’ data reflect (performance status 0–1, kidney and liver function, life expectancy at least 12 weeks, etc.).

This nationwide real-world analysis characterizes the Hungarian ES-SCLC patient population in the pre-immunotherapy era, and it demonstrates survival outcomes that align with those reported in the EP control arms of the CASPIAN and IMpower133 trials. The slightly longer PFS observed in our study can be explained by PFS being proxied using TFST. However, the shorter OS reflects that real-world patients do not fit the strict eligibility criteria of phase III trials. Together, these findings confirm that the ES-SCLC cohort of Hungary behaves consistently with clinical expectations, and the minor deviations between outcomes are due to well-known differences between routine care and clinical trial frameworks.

Despite the limitations presented by the NHIF database (lacking safety or adverse events data), our study was able to outline the national ES-SCLC population, their treatment pathways and radiotherapy patterns. NHIF data would prove to be more widely applicable if it distinguished between sequential chemoradiotherapy and palliative or prophylactic radiotherapy. The lack of validated biomarkers in ES-SCLC further highlights the need for robust biomarker discovery and prospective validation studies to enable biologically guided patient selection and personalized therapeutic strategies. An ideal cancer registry would operate with standardized coding practices, record structured oncologic variables, and have improved granularity, aiding in determining progression timing and the reason for discontinued treatment.

Given the complexity of ES-SCLC management, multidisciplinary collaboration remains crucial: pulmonary oncologists, radiation oncologists, thoracic surgeons, radiologists, palliative care specialists, and data science analysis teams all elevate patient care and maintain the high quality of real-world evidence.

Immunotherapy is continuously adopted in practice across Hungary; thus it is important to note that the accumulation of real-world follow-up data of chemo-immunotherapy will take time. As of now, long-term data is only available for chemotherapy-based treatment. This renders the current analysis a reliable national baseline, also complementing international evidence as one of the largest ES-SCLC cohorts in Europe, for future comparison of outcomes and assessing the impact of chemo-immunotherapy in practice.