Francisco Aparisi has received honoraria from Boehringer Ingelheim, Mylan, Archimedes, and Takeda, outside the submitted work. Manuel Domine has received honoraria for lectures and advisory boards from AstraZeneca, BMS, Boehringer Ingelheim, MSD, Pfizer, and Roche, outside the submitted work. Joaquim Bosch-Barrera has received grants from Roche-Genentech, Pfizer, and Pierre Fabre; and honoraria from Roche-Genentech, MSD, BMS, AstraZeneca, Novartis, and Boehringer-Ingelheim, outside the submitted work. Mariano Provencio has received grants and non-financial support from BMS, Roche, and AstraZeneca; and honoraria from BMS, Roche, AstraZeneca, MSD, and Takeda, outside the submitted work. Fernando Franco, Enric Carcereny, María Guirado, Ana L. Ortega, Rafael López-Castro, Delvys Rodríguez-Abreu, Rosario García-Campelo, Edel del Barco, Oscar Juan, Jose L. González-Larriba, Jose M. Trigo, Manuel Cobo, Sara Cerezo, Julia Calzas, Bartomeu Massutí, Paula García Coves, and Marta Domènech declare no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Small-cell lung cancer (SCLC) is an aggressive disease with high metastatic potential and poor prognosis. Due to its low prevalence, epidemiological and clinical information of SCLC patients retrieved from lung cancer registries is scarce.
This was an observational multicenter study that enrolled patients with lung cancer and thoracic tumors, recruited from August 2016 to January 2020 at 50 Spanish hospitals. Demographic and clinical data, treatment patterns and survival of SCLC patients included in the Thoracic Tumor Registry (TTR) were analyzed.
With a total of 956 cases, the age of 64.7 ± 9.1 years, 78.6% were men, 60.6% smokers, and ECOG PS 0, 1 or ≥ 2 in 23.1%, 53.0% and 23.8% of cases, respectively. Twenty percent of patients had brain metastases at the diagnosis. First-line chemotherapy (CT), mainly carboplatin or cisplatin plus etoposide was administered to >90% of patients. In total, 36.0% and 13.8% of patients received a second and third line of CT, respectively. Median overall survival was 9.5 months (95% CI 8.8–10.2 months), with an estimated rate of 70.3% (95% CI 67.2–73.4%), 38.9% (95% CI 35.4–42.4%), and 14.8% (95% CI 11.8–17.8%) at 6, 12 and 24 months respectively. Median progression-free survival was 6.3 months. Higher mortality and progression rates were significantly associated with male sex, older age, smoking habit, and ECOG PS 1–2. Long-term survival (> 2 years) was confirmed in 6.6% of patients, showing a positive correlation with better ECOG PS, poor smoking and absence of certain metastases at diagnosis.
This study provides an updated overview of the clinical situation and treatment landscape of ES-SCLC in Spain. Our results might assist oncologists to improve current clinical practice towards a better prognosis for these patients.
Lung cancer remains a major public health issue worldwide, with more than 2 million new cases and 1.8 million deaths estimated in 2018 [
SCLC is characterized by a rapid doubling time, high growth fraction, early development of widespread metastases, and endocrine paraneoplastic syndromes [
Current therapeutic options for SCLC are limited and there is an unmet need for novel effective treatments to improve survival. Given the aggressive nature of the disease, first-line (1L) platinum-based chemotherapy (CT) has been the mainstay for both limited stage (LS) and ES-SCLC; cisplatin and carboplatin are the most recommended platinum agents in combination with etoposide [
The representation of SCLC patients in lung cancer registries is scarce and ranges between 13.5% and 19% [
Observational, prospective, registry-based study that enrolled patients with lung cancer and other thoracic tumors from August 2016 to date. The study was conducted in accordance with the Declaration of Helsinki. Protocol approval was obtained from the institutional review board of Hospital Universitario Puerta de Hierro-Majadahonda (No. PI 148/15). The registry was approved by the Spanish Agency for Medicines and Medical Devices (AEMPS) in 2016, and is registered in the ClinicalTrials.gov database (NCT02941458) [
The TTR-2 study was sponsored by the GECP, an independent, multidisciplinary oncology group that coordinates more than 400 experts and 160 hospitals across the Spanish territory. The registry creation was proposed by the steering committee with the aim of promoting lung cancer research and incorporating treatment advances into clinical practice.
Patients with histologically confirmed lung cancer or other types of thoracic tumors (NSCLC, SCLC, mesothelioma, thymic carcinoma, carcinoid cancer) were eligible for inclusion, without sex or age restrictions. Patients receiving active treatment or palliative care were included. Exclusion criteria were diagnosis of other types of tumors and healthy volunteers. All patients provided signed informed consent before their data were included in the TTR.
Data were collected by research teams from patient medical records using an electronic data capture system (EDC). Sociodemographic, epidemiological, clinical, molecular and treatment outcome variables were recorded in an electronic case report form (eCRF). The information was classified into the following categories: (I) patient personal history, which included performance status (PS), tobacco use, and comorbidities; (II) diagnosis, including histological subtype, TNM classification of the tumor and location of metastases; (III) molecular profiling of the tumor; (IV) treatment patterns (surgery, CT, RT); (V) response and survival, including response rates, overall survival and progression-free survival (PFS); and (VI) prognostic factors.
A descriptive statistical analysis was performed. Quantitative variables are presented as mean, standard deviation (SD), median, interquartile range (IQR), minimum, and maximum. Qualitative variables are described as frequencies in the entire population and percentages. Pearson’s chi-square tests were used to compare patient characteristics according to the drug used in first-line CT (carboplatin vs. cisplatin), using Fisher’s exact tests when possible. The OS curve and PFS curves were estimated using the Kaplan-Meier method, evaluating the effect of different characteristics on diagnosis by adjusting univariate Cox regression models. The SPSS IBM Statistics 22 program was used for analysis, setting a significance level of 5% in all bilateral contrast tests. Comparison of 2-year OS rates was performed using the Fixpoint test (package ComparisonSurv of R, method cloglog), as previously described [
At data cut-off (23rd January 2020), 1,658 (12.9%) SCLC patients were registered in the TTR database, which included a total of 12,867 patients. Of these, 1,037 (62.6%) patients had extensive-stage SCLC, 606 (36.6%) had limited-stage SCLC and 15 (0.9%) had unknown-stage SCLC. Based on data quality and availability, 956 patients with ES-SCLC were finally selected to perform this analysis and their characteristics are shown in
Characteristic | n | % |
---|---|---|
Male | 751 | 78.6 |
Female | 205 | 21.4 |
Mean (SD), years | 64.7 (9.1) | |
Median [min-max], years | 65 [37–88] | |
Distribution | ||
<55 years | 117 | 12.2 |
55–64 years | 355 | 37.1 |
65–74 years | 335 | 35 |
≥75 years | 149 | 15.6 |
Caucasian | 929 | 97.2 |
Other | 27 | 2.8 |
110 | 11.5 | |
Head and neck | 21 | 2.2 |
Bladder/urinary tract | 21 | 2.2 |
Prostate | 14 | 1.5 |
Non-melanoma skin | 10 | 1.0 |
Never smoker | 14 | 1.5 |
Former smoker (> 1-year) | 357 | 37.3 |
Smoker | 579 | 60.6 |
Unknown | 6 | 0.6 |
0 | 221 | 23.1 |
1 | 507 | 53.0 |
≥2 | 228 | 23.8 |
Asymptomatic | 54 | 5.6 |
Symptomatic | 882 | 92.3 |
Unknown | 23 | 2.4 |
924 | 96.7 | |
Liver | 422 | 44.1 |
Bone | 333 | 34.8 |
Thoracic lymphadenopathy | 299 | 31.3 |
Lung | 237 | 24.8 |
Extrathoracic lymphadenopathy | 206 | 21.5 |
Adrenal | 203 | 21.2 |
CNS | 189 | 19.8 |
826 | 86.4 | |
Hypertension | 460 | 48.1 |
Dyslipidemia | 330 | 34.5 |
COPD | 248 | 25.9 |
Diabetes mellitus | 248 | 25.9 |
Heart disease | 180 | 18.8 |
CNS, central nervous system; COPD, chronic obstructive pulmonary disease; ECOG, Eastern Cooperative Oncology Group.
*The most frequent previous tumor locations and current comorbidities are shown.
Most patients (78.6%) were men, 60.6% smokers, with a mean age of 64.7 ± 9.1 years and ECOG PS 0, 1 or ≥ 2 in 23.1%, 53.0% and 23.8% of cases, respectively. According to the TNM classification (
Mean time between diagnosis and first treatment was 0.68 ± 1.63 months. CT alone or in combination with RT was the treatment of choice in 415 (43.4%) and 449 (47.0%) patients, respectively; RT was mainly provided with palliative (30.9%) and cranial prophylactic (9.4%) intent (
Treatment | n | % |
---|---|---|
Radiotherapy (RT) | 18 | 1.9 |
Chemotherapy (CT) | 415 | 43.4 |
Surgery | 1 | 0.1 |
RT + CT | 449 | 47 |
Surgery + RT | 2 | 0.2 |
Surgery + CT | 5 | 0.5 |
Surgery + RT + CT | 10 | 0.1 |
Diagnostic | 7 | 0.7 |
Curative | 6 | 0.6 |
Palliative | 5 | 0.5 |
Radical | 67 | 7 |
Adjuvant | 13 | 1.4 |
Palliative | 295 | 30.9 |
Prophylactic | 90 | 9.4 |
Unknown | 14 | 1.5 |
First line | 879 | 91.9 |
Monotherapy | 19 | 2.2 |
Combination of 2 drugs | 835 | 95 |
Combination of 3 drugs | 25 | 2.8 |
Second line | 344 | 36 |
Third line | 132 | 13.8 |
In contrast, surgery was performed in less than 1% of patients. First-line (1L) CT was used in almost the entire population (91.9%), mostly using a combination of 2 drugs: carboplatin + etoposide (Car + E) (61.8%) or cisplatin + etoposide (Cis + E) (31.7%). In total, 36.0% and 13.8% of patients received a second (2L) and third line (3L) of CT, respectively. Consolidative RT was given to 262/879 (29.8%) patients treated with 1L CT; holocranial (58.8%) and thoracic (29.8%) were the most common irradiated areas.
Of the 879 patients who received 1L CT, 416 (52.7%) received 4 cycles or fewer, while 373 (47.3%) received 5 or more cycles. The mean number of cycles of CT was slightly higher in 1L (4.3) compared to 2L (3.7) and 3L (3.4) (
First line (n = 879) | Second line (n = 344) | Third line (n = 132) | |
---|---|---|---|
Mean (sd) | 4.3 (1.9) | 3.7 (3.3) | 3.4 (2.7) |
Median [min-max] | 4 (1–12) | 3 (1–31) | 3 [1–16] |
Mean (sd) | 2.86 (1.78) | 2.39 (2.67) | 1.96 (2.11) |
Median [min-max] | 3.0 [0–16.1] | 1.8 [0–18.9] | 1.4 [0–15.2] |
CR | 24 (2.7%) | 9 (2.6%) | 1 (0.8%) |
PR | 449 (51.5%) | 64 (18.7%) | 17 (12.9%) |
SD | 72 (8.2%) | 55 (16.0%) | 22 (16.7%) |
PD | 108 (12.3%) | 128 (37.3%) | 49 (37.1%) |
NE | 87 (9.9%) | 48 (14.0%) | 24 (18.2%) |
ND | 50 (5.7%) | 18 (5.2%) | 4 (3.0%) |
CR, complete response; ND, not determined; NE, not estimated; PD, progressive disease; PR, partial response; sd, standard deviation; SD, stable disease.
Likewise, duration of treatment was reduced in subsequent treatment lines from 2.86 months in 1L to 2.39 in 2L and 1.96 in 3L. The best response rates, mainly partial response (PR), were observed after 1L CT (51.5%), while rates of stable disease (SD) showed a 2-fold increase with 2L and 3L compared to 1L. Conversely, progressive disease (PD) was substantially higher in subsequent lines, being observed in more than one-third of patients.
Median OS in the entire population was 9.5 months (95% CI 8.8–10.2 months), with an estimated OS rate of 70.3% (95% CI 67.2–73.4%) at 6 months, 38.9% (95% CI 35.4–42.4%) at 12 months, 26.2% (95% CI 22.8–29.6%) at 18 months, and 14.8% (95% CI 11.8–17.8%) at 24 months after diagnosis (
Overall, 649 (67.9%) patients progressed during follow-up, 105 of whom remained alive at the end of the study. Progressions were mostly distant and/or local, often affecting lung, thoracic lymph nodes, and liver. Median PFS was 6.3 months (95% CI 6.0–6.7 months), with an estimated PFS rate of 53.8% (95% CI 50.4–57.2%) at 6 months, 15.6% (95% CI 13.0–18.3%) at 12 months, 7.9% (95% CI 5.9–9.9%) at 18 months, and 5.8% (95% CI 4.0–7.6%) at 24 months (
In total, 543 patients were treated with Car + E and 279 with Cis + E in 1L.
The number of cycles and duration of treatment did not differ among patients treated with Car + E or Cis + E (
Of the 543 patients with Car + E, 366 (67.4%) died during follow-up, with a median OS of 9.3 months (95% CI 8.7–9.9 months) since diagnosis. A significantly lower rate of mortality was observed among patients treated with Cis + E (162/279, 58.1%), with a higher median OS at 12.5 months (95% CI 10.5–14.6) (p < 0.001) (
In total, 63/956 (6.6%) patients (44 men and 19 women) were alive after a 2-year follow-up. Most (95.2%) were smokers or former smokers and presented ECOG PS 0 (31.7%) or 1 (58.7%) and metastasis at diagnosis, liver (30.2%), bone (23.8%) and lung (22.2%) being the most frequent locations (
2-year OS rate (%) | 95% CI | ||
---|---|---|---|
0.077 | |||
Male | 13.4 | 10.5–17.1 | |
Female | 20.3 | 14.1–29.0 | |
0.117 | |||
<65 years | 17.2 | 12.9–21.9 | |
≥65 years | 12.4 | 8.8–16.6 | |
0.001 | |||
0 | 23 | 15.9–30.9 | |
1 | 14.9 | 11.1–19.2 | |
≥2 | 6.7 | 3.3–11.8 | |
20.7 | 15.6–26.3 | 0.004 | |
Never/former smoker | 11.5 | 8.3–15.2 | |
Smoker | |||
Liver | 9.2 | 5.9–13.3 | 0.001 |
Bone | 9.7 | 6.1–14.4 | 0.012 |
Thoracic adenopathy | 9.6 | 5.5–15.1 | 0.031 |
Lung | 14.3 | 8.8–21.0 | 0.85 |
Extrathoracic adenopathy | 13.3 | 7.9–20.0 | 0.594 |
Adrenal | 10.6 | 6.1–16.5 | 0.117 |
CNS | 11.9 | 6.4–19.3 | 0.367 |
Pleural effusion | 11.8 | 6.2–19.3 | 0.36 |
0.078 | |||
Carboplatin + Etoposide VP16 | 14.3 | 10.8–18.4 | |
Cisplatin + Etoposide VP16 | 21 | 14.8–28.0 |
CI, confidence interval; CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; OS, overall survival.
A significantly greater long-term survival rate was associated with better ECOG PS, poor smoking habit, and the absence of liver, bone, and thoracic lymph node metastasis. Conversely, factors such as sex, age, other metastatic locations, or treatment failed to show statistical differences among this population.
Following the recent publication of the TTR NSCLC population report [
Cis + E has remained the standard of care for ES-SCLC patients for decades, while Car + E is alternatively advised in case of contraindications for Cis (level of evidence I, degree of recommendation A) [
RT for thoracic lesions and metastatic sites, except for brain metastases, has been associated with improved OS and cancer-specific survival in patients with metastatic ES-SCLC [
In line with previous studies, particularly those which included ES-SCLC patients [
Based on the encouraging results from phase III trials, the combination of CT and immunotherapy has been recently established as the first-line treatment of adult patients with ES-SCLC (I, A) [
The main limitations of this study stem from its observational, retrospective design. Despite the potential bias in the recruited population among the participant centers, the sample size was large enough to provide an objective nationwide epidemiological overview of ES-SCLC status. Moreover, all patients had equal opportunities for diagnosis and treatment, as established by the universal coverage of the Spanish National Health System, and they were enrolled in the study over a short time period, thereby enabling a more reliable comparison of therapies and survival.
This study provides an accurate overview of the current clinical situation and treatment landscape of ES-SCLC in Spain. With a high proportion of patients diagnosed with metastatic disease and a very poor prognosis, epidemiological data and survival outcomes of this population are in line with those reported by previous studies across different countries. Since these results support current evidence on the aggressiveness of ES-SCLC and the need for more effective therapies, the development of further studies is warranted. Continuous monitoring of TTR data will help evaluate the impact of current and novel treatments used in clinical practice, with the aim of eventually improving the prognosis and survival of SCLC patients.
(DOCX)
ALK, anaplastic lymphoma kinase; BRAF, B-RAF proto-oncogene, serine/threonine kinase oncogene; EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization; FGFR1, fibroblast growth factor receptor type 1; HER2, human epidermal growth factor receptor type 2; IHC, immunohistochemistry; KRAS, Kirsten rat sarcoma viral oncogene homolog; MET, tyrosine-protein kinase MET/hepatocyte growth factor receptor; PD-L1, programmed death-ligand 1; RET, proto-oncogene tyrosine-protein kinase receptor; RNA, ribonucleic acid; ROS1, ROS proto-oncogene 1 receptor tyrosine kinase; TTF1, thyroid transcription factor 1.
(DOCX)
CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; CI, confidence interval; SD, standard deviation.
(DOCX)
CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; CI, confidence interval; SD, standard deviation.
(DOCX)
CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group.
(DOCX)
CR, complete response; PR, partial response; sd, standard deviation; SD, stable disease; PD, progressive disease; NE, not estimated; ND, not determined.
(DOCX)
CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group.
(DOCX)
The authors received medical writing support in the preparation of this manuscript from Celia Miguel Blanco (Medical Statistics Consulting, S.L., Valencia, Spain).