Background
Lung cancer is a major public health concern in China, accounting for 21.3% of all new cancer cases and 27.1% of all deaths caused by cancer in 2012 [
1]. Approximately 85% of patients presenting with lung cancer have non-small cell lung cancer (NSCLC) [
2], with about 70% of these patients diagnosed with locally advanced or metastatic disease [
3]. Recommended first-line treatments for these patients are platinum-doublet chemotherapy or molecular targeted therapy, if sensitive gene aberrations are detected [
3‐
6]. Platinum-doublet chemotherapy has been shown to prolong survival and improve quality of life in patients with advanced NSCLC [
4], with comparable efficacy among the various regimens [
7]. In NSCLC patients with gene aberrations, molecular targeted therapies have been shown to have greater efficacy and lower toxicity than standard chemotherapy, whereas they have limited efficacy in NSCLC patients without gene aberrations [
8].
Findings from a 2010 survey of physicians [
9] and a retrospective review of hospital outpatient databases from 2004 to 2013 [
10] in China indicated that NSCLC patients were mostly treated with platinum-doublet chemotherapy in the first-line setting. In patients with advanced NSCLC, the most commonly used chemotherapy regimen was gemcitabine/carboplatin-doublet chemotherapy [
9,
10]. Of those patients treated with first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), nearly 50% had an unknown or negative
EGFR mutation status [
10]. Reported rates of
EGFR gene mutation testing in China suggest that only 30% of NSCLC patients with adenocarcinoma are tested for gene aberrations [
11] despite more than 40% having
EGFR mutations [
12,
13].
To determine if these practices have changed in recent times, we investigated first-line anticancer treatment patterns and gene aberration test status of patients with unresectable Stage IIIB/IV nonsquamous NSCLC treated at one of 12 tertiary hospitals throughout China.
Methods
Study design
This was a survey of medical charts from 12 tertiary hospitals located throughout China (Additional file
1: Table S1). Data were extracted from medical charts of patients discharged from hospital between 1 August 2015 and 15 March 2016.
The protocol was approved by the Research Ethics Committee of the Guangdong General Hospital, Guangzhou, Guangdong, China. Each site obtained its own institutional review board or ethics committee approval before the start of the study. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice, and was supported by the Chinese Thoracic Oncology Group (CTONG study number 1506).
Study population
The medical charts of patients meeting the following criteria were included for review: aged ≥18 years; diagnosis of unresectable Stage IIIB or IV (according to the American Joint Committee on Cancer staging system, 7th edition), nonsquamous NSCLC; no previous systemic anticancer treatment for Stage IIIB or IV disease; and most recent hospitalization was for anticancer treatment.
Study protocol
Data from all patients’ medical charts who met the inclusion criteria were extracted and entered into the Medical Record Abstraction Form (MERAF) by designated hospital staff after patient discharge. Data extracted were demographics, NSCLC histological type, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS), gene aberration test status and results (if performed), and first-line anticancer treatment regimen. Data entry was reviewed on-site by an independent data management organization (Shanghai Centennial Scientific Ltd., Shanghai, China), who assessed accuracy of data entry by checking 20% of all MERAFs collected at one hospital selected at random. Completed MERAFs were collected for analysis.
Data from all collected MERAFs were entered into a database for analysis, with data entered and verified twice to ensure accurate data entry. MERAFs were excluded from analysis if data were missing for gene aberration test status or first-line anticancer treatment regimen and if more than 10% of other data were missing.
Statistical analysis
Given that there are no published data in China to describe the proportion of patients receiving different types of chemotherapy, we assumed the proportion of patients receiving first-line TKI treatment was stable and could be estimated using the
EGFR gene mutation rate. The sample size calculation assumed an
EGFR gene mutation rate of 30% for East Asian populations [
11], data from 897 patients to provide 2-sided 95% confidence intervals (CIs) with a precision of 3%, and exclusion of 5 to 10% of MERAFs because of missing data or other errors. Thus, collection of data from 1000 patients was planned.
Data were summarized with descriptive statistics using frequency and percentages for categorical data, and median, minimum, and maximum for continuous data. Analyses were done using SAS® Version 9.3 (SAS Institute, Cary, NC, USA).
Discussion
In this survey, we investigated first-line anticancer treatment patterns and gene aberration test status of patients with unresectable Stage IIIB/IV nonsquamous NSCLC at 12 tertiary hospitals throughout China. More than two thirds of patients had gene aberration testing and 46.5% of those tested had EGFR gene mutations. The predominant first-line treatment regimen for unresectable Stage IIIB/IV nonsquamous NSCLC was pemetrexed/platinum-doublet chemotherapy. Most patients (66.3%) with EGFR gene mutations were treated with first-line EGFR-TKIs. These findings provide an updated and broad overview of the treatment of unresectable Stage IIIB/IV nonsquamous NSCLC in China.
In China, testing for
EGFR gene mutations is recommended before treating advanced NSCLC [
6] and is considered essential for patients with adenocarcinoma given the high rate of
EGFR gene mutations in East Asian patients [
8,
14,
15]. In our survey, 71.4% of patients with unresectable Stage IIIB/IV nonsquamous NSCLC were tested for
EGFR gene mutations, a rate higher than those reported previously [
9,
11]. A 2010 survey of physicians at general hospitals, chest hospitals, and comprehensive cancer centers located in 12 major cities throughout China found only 9.6% of patients with advanced NSCLC (squamous and nonsquamous histology) were tested for
EGFR gene mutations [
9]. Similarly, a 2011 retrospective online survey of patient records found that China had the lowest rate of
EGFR gene mutation testing of the 6 Asian Pacific countries assessed, with 18.3% of all NSCLC patients and 30.3% of NSCLC patients with adenocarcinoma histology tested [
11]. The improved
EGFR gene mutation test rate in our survey suggests changes in clinical practice since 2010–11, possibly due to increased coverage of testing technology, improved tissue sample collection, and reduced cost. In addition, there may have been less reliance on patient characteristics associated with
EGFR positive mutations that prompt testing because similar proportions of never smokers versus previous/current smokers (72.5%, 393/542, vs 69.7%, 272/390, respectively) and females versus males (73.9%, 300/406, vs 69.4%, 365/526) had an
EGFR gene mutation test.
The
EGFR gene mutation rate detected in our study for all patients (46.5%) and for patients with adenocarcinoma histological subtype (47.6%) were similar to those reported previously for Chinese patients with NSCLC of adenocarcinoma histology (40.3–64.5%) [
14]. In a subset analysis of Chinese patients participating in the PIONEER study, a prospective molecular epidemiology study of
EGFR gene mutations in Asian patients newly diagnosed with advanced NSCLC of adenocarcinoma histology, 50.2% (95% CI: 46.6–53.8%) of patients were
EGFR mutation positive [
12]. In addition, characteristics of
EGFR mutation-positive patients in our survey were consistent with those associated with higher
EGFR gene mutation rates (eg, female, never smoker) [
16]. The rate of
ALK gene fusions in our study (11.5%) was slightly higher than those reported previously for Chinese patients with adenocarcinomas (5.1–10%) [
14]. Most patients tested for
ALK gene fusions in our study were
EGFR wild type, which may have influenced the proportion of patients testing positive for an
ALK gene fusion because the occurrence of coexisting
EGFR mutations and ALK gene fusions is rare [
17]. The rate of
ROS1 gene fusions (0.8%) was similar to those reported previously (1–2%) in Chinese patients with NSCLC [
14].
Platinum-doublet chemotherapy is recommended for treatment of unresectable, advanced NSCLC [
6]. Pemetrexed/platinum-doublet chemotherapy was the predominant treatment regimen for unresectable Stage IIIB/IV nonsquamous NSCLC in our survey. In a previous survey of Chinese physicians [
9], gemcitabine/platinum-doublet chemotherapy was the predominant regimen for all advanced NSCLC patients (27.4%) and those with adenocarcinoma histology (32.0%). Although a greater proportion of patients with adenocarcinoma were treated with pemetrexed (16.1% vs non-adenocarcinoma 6%, respectively), the prevalence of gemcitabine was attributed to its favorable benefit/toxicity profile, low cost, reimbursement, and low incidence of alopecia [
9]. The preference for pemetrexed/platinum-doublet chemotherapy in our survey may be result of changes in physician opinion regarding first-line treatment of unresectable Stage IIIB/IV nonsquamous NSCLC due to increasing evidence of improved overall survival, better tolerability, and fewer toxicities with pemetrexed-doublet regimens than other doublet regimens [
18‐
21] and approval of pemetrexed for first-line treatment of nonsquamous NSCLC in combination with cisplatin by the China Food and Drug Administration in 2014.
Molecular targeted therapy drugs are recommended as first-line treatment options for advanced NSCLC if sensitive
EGFR gene mutations or
ALK gene fusions are detected [
3‐
6], because of their higher efficacy and lower toxicity than standard chemotherapy in these patients [
8,
22]. In our survey, a large proportion of
EGFR mutation-positive patients were treated with first-line EGFR-TKIs (66.3%); the remaining
EGFR mutation-positive patients were treated with chemotherapy (30.7%), EGFR-TKIs plus chemotherapy (2.3%), or other TKIs (0.6%). The reason why more than 30% of
EGFR mutation-positive patients received chemotherapy only as first-line treatment requires further analysis. Encouragingly, most (91.9%) patients treated with first-line EGFR-TKIs were
EGFR mutation positive, a proportion higher than that previously reported in a retrospective review of an outpatient oncology database (2004–13) in China (53.5%) [
10].
We acknowledge the following limitations of our survey. Our findings from tertiary hospitals may not reflect the situation for those patients being treated at primary or secondary hospitals throughout China. The standard of lung cancer care in China ranges from practices similar to those in Western countries to basic care because China’s large population, expansive geography, and variable socioeconomic status of patients may affect access to diagnostic tests and quality oncology services and treatment [
10,
23,
24]. In addition, patients refusing treatment and outpatients were excluded from our survey, which may have introduced bias into our findings. In a retrospective review of an outpatient oncology databases in China [
10], 19.1% of patients refused treatment at diagnosis because of poverty, financial insecurity, or lack of medical insurance.
Acknowledgements
The authors would like to thank all study participants.
This study was supported by the Chinese Thoracic Oncology Group (CTONG), a national collaborative clinical research group of 33 member hospitals.
Data collection and analysis was provided by Shanghai Centennial Scientific Ltd., and was funded by Lilly Suzhou Pharmaceutical Co., China. Medical writing assistance was provided by Julie Monk, PhD, CMPP and Mark Snape, MB BS, CMPP of ProScribe – Envision Pharma Group, and was funded by Lilly Suzhou Pharmaceutical Co., China. ProScribe’s services complied with international guidelines for Good Publication Practice (GPP3).