- Email: [email protected]
National survey of the medical treatment status for non-small cell lung cancer (NSCLC) in China
Lung Cancer 77 (2012) 371–375
Contents lists available at SciVerse ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
National survey of the medical treatment status for non-small cell lung cancer (NSCLC) in China Cong Xue a,1 , Zhihuang Hu a,1 , Wei Jiang b , Yuanyuan Zhao a , Fei Xu a , Yan Huang a , Hongyun Zhao a , Jingxun Wu c , Yang Zhang a , Liping Zhao a , Jing Zhang a , Likun Chen a , Li Zhang a,∗ a
State Key Laboratory of Oncology in South China, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China Department of Medical Oncology, Tumor Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China c Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China b
a r t i c l e
i n f o
Article history: Received 22 November 2011 Received in revised form 9 April 2012 Accepted 14 April 2012 Keywords: Chemotherapy Chinese population Epidermal growth factor receptor Non-small cell lung cancer Practice pattern Survey
a b s t r a c t Introduction: Treatment choice for NSCLC in China has not previously been reported. This paper explores the clinical practice and adherence to treatment guidelines for NSCLC. Methods: A specifically designed questionnaire was used. It consisted of personal information of the responders and treatment details (patient identification data was excluded). Questionnaires were delivered to doctors in 12 major cities in China. Doctors were asked to answer the questionnaires based on real cases in their daily practice. Results: 987 cases of NSCLC were included. In first-line chemotherapy, regimens were mostly platinumbased among which gemcitabine plus platinum was predominately used (27.4%), followed by docetaxel plus platinum (16.2%) and paclitaxel plus platinum (13.5%). In second-line therapy some were treated with single agents, such as docetaxel (12.9%), gefitinib (11.1%), pemetrexed (9.3%), and erlotinib (3.5%). 44.5% were with doublet therapy. Detection rate of epidermal growth factor receptor (EGFR) mutation was only 9.6% because of the limited prevalence of testing technology. EGFR mutation rate was 46.8%. EGFR-tyrosine kinase inhibitors (TKIs) were used more frequently as salvage (14.8%) rather than upfront therapy (5.3%). Conclusions: This survey reveals the daily clinical treatment for NSCLC in China. Overall data showed modest adherence to the national guideline (NCCN guideline Chinese version) for first-line chemotherapy. We believe this survey is valuable to provide a reference for further clinical trial design and policy making. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer has been a leading cause of cancer death in the 20th century [1]. The data from the International Agency for Research of Cancer (IARC) show that in 2008 approximately 520,000 people were newly diagnosed with lung cancer and 450,000 died of it in China [2]. NSCLC accounts for 85% of the cases. The growing number of NSCLC was mainly from those increased smokers and exposed people [2–4]. The fiercely debated issue of utilizing limited resources efficiently with expensive anti-lung cancer treatments is awaiting a solution [5].
∗ Corresponding author at: State Key Laboratory of Oncology in South China, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, 651# Dongfeng Road, East, Guangzhou 510060, People’s Republic of China. Tel.: +86 20 87343689; fax: +86 20 8734 3565. E-mail addresses: [email protected], li [email protected] (L. Zhang). 1 These authors contributed equally to this work. 0169-5002/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2012.04.014
Evidence-based guidelines are mandatory in clinical practice, not only guiding doctors to formulate their strategy, but also providing patients with the optimal effective therapies and avoiding waste of medical resource. There are several clinical practice guidelines available, such as guidelines from National Comprehensive Cancer Network (NCCN) (General and Chinese version), American Society of Clinical Oncology, and European Society of Medical Oncology [6–9]. However many objective and subjective reasons might lead to the choice of various regimens. The overall usage of recommended therapies for NSCLC is 52% in the United States [10]. We assume there may be a gap between the clinical practice pattern and the guidelines in China, however the real situation has never been disclosed. In this study, we conducted a survey to explore the current status of medical treatment patterns of NSCLC in China; moreover we aim to assess the adherence to current guidelines and to explore the reasons for the observed findings.
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Table 1 Items included in the survey. Doctor information questionnaire 1. Which hospital do you work? 2. Which level is your hospital in? Which department are you in? 3. What title are you with? 4. How many years have you been a cancer-treating doctor? 5. Have you been a member of any cancer association? 6. 7. How many cancer patients do you manage in a month? 8. How many patients can afford the anti-cancer treatment? (proportion) 9. How many patients can afford the chemotherapy? (proportion) How many patients are able to finish all treatment courses planned? 10. (proportion) Patient information questionnaire 1. Patient characteristics Gender Age Weight Body surface area Current disease status (newly diagnosed, follow-up, recurrent) Performance status (ECOG) Smoking status Current co-morbidities/pre-existing conditions Diagnosis information 2. Date of diagnosis Histology or cytology Current stage Primary site Stage at diagnosis Evidence of metastases (location) EGFR mutation status (if done) EGFR over-expression status (if done) Regimen information 3. Current regimen as (neo-adjuvant/adjuvant/palliative or others) Specific drugs (cytotoxic agents/targeted therapy or others) Route of administration, dosage and days of given Number of cycles given Number of cycles planned Pervious regimens (date/specific drugs) Reason for changing regimen Side effects 4. Anemia, bone pain, mucositis, rash, neuropathy, etc. Use of other drugs 5. Antiemetic use G-CSF and bisphosphonates Antibiotics Analgesics Others Reason of regimen choice 6.
2. Patients and methods This survey was conducted in 12 major cities of China from September to October 2010. The participating cities are Beijing, Shanghai, Guangzhou, Chengdu, Hangzhou, Xi’an, Ji’nan, Wuhan, Tianjin, Nanjing, Chongqing, and Shenyang (Supplementary Fig. 1). 135 general hospitals, chest hospitals, and comprehensive cancer centers were included. We randomly chose departments in these hospitals which treat patients with lung cancer and posted the questionnaires to the doctors. Only one doctor was surveyed in each department and no more than five doctors in one hospital. Each doctor completed up to five consecutive patients’ treatment questionnaires (patient identifiers were exclusive). Patients involved in clinical trials were excluded. We referred to the literature reported by Gridelli et al. [11] when designing the questionnaire. Also some questions we interested in were added. The questionnaire included items with multiple answers (Table 1). The best answer was chosen in the multiple options. Using the raw data, we conducted an analysis and presented the following results.
3. Results 202 doctors participated in this survey and 987 cases of NSCLC were involved. The characteristics of doctors and patients are listed in Supplementary Tables 1 and 2. There were 381 patients with early stage disease who received neo-adjuvant or adjuvant chemotherapy, while 606 patients with stage IIIB–IV disease. Among patients with advanced NSCLC, we further analyzed the 579 patients who received first-line or second-line palliative chemotherapy. Twenty patients with third-line therapy and 7 patients with missing detail were excluded. 77.8% patients (747/960) were treated with platinum therapy including early or advanced stage. Cisplatin accounted for 63.5% of all platinum used (474/747). Others were carboplatin (22.3%, 167/747), nedaplatin (8.6%, 64/747), and oxaliplatin (5.6%, 42/747).
3.1. First-line therapy 525 patients received first-line therapy. Gemcitabine plus platinum was the most commonly used regimen (27.4%, 144/525), followed by docetaxel plus platinum (16.2%, 85/525) and paclitaxel plus platinum (13.5%, 71/525). The top ten regimens are listed in Fig. 1. There was a slight variation as shown in Fig. 2 with the population divided by gender and histology subtype. 16.1% patients with adenocarcinoma were treated with pemetrexed (52/323), while it was used in 6% patients with non-adenocarcinoma (12/199). 26 patients (4.9%) were treated with EGFR-TKIs initially, not all of them were tested for mutation before treatment.
3.2. Second-line therapy 54 patients received second-line therapy. Gemcitabine plus platinum remained the most common choice (18.5%, 10/54). Docetaxel (12.9%, 7/54), gefitinib (11.1%, 6/54), and pemetrexed (9.3%, 5/54) were used with similar frequency (Supplementary Fig. 2). This analysis is for reference only subject to the small sample size.
3.3. Neo-adjuvant and adjuvant therapy There were 381 patients with stage I-IIIA NSCLC treated with chemotherapy. 54 and 327 patients received neo-adjuvant and adjuvant chemotherapy respectively. The majority of chemotherapy regimens were platinum based (341/381, 89.5%) with cisplatin used most frequently (72.4%, 247/341). The proportion with carboplatin was 15.8% (54/341) while 10.3% and 1.5% of early stage patients received nedaplatin and oxaliplatin (35/341 and 5/341 respectively). Gemcitabine plus platinum was used more than any other regimens in early stage (29.1%, 111/381), followed by docetaxel plus platinum (17.3%, 66/381) and paclitaxel plus platinum (14.7%, 56/381) as shown in Fig. 3. The distribution by gender and histology subtype is shown in Fig. 4. The top three regimens in neo-adjuvant chemotherapy were gemcitabine/platinum (43.7%), vinorelbine/platinum and docetaxel/platinum (both 10.9%). In adjuvant chemotherapy the regimens mostly chosen were gemcitabine/platinum (26.6%), docetaxel/platinum (18.4%) and paclitaxel/platinum (15.9%). 81 patients with early stage disease also received concurrent chemotherapy with radiation (Supplementary Fig. 3). Due to the limited information available regarding the details of chemoradiation (such as sequence or dosage), a further analysis of this subgroup was not performed.
C. Xue et al. / Lung Cancer 77 (2012) 371–375
373
Fig. 1. Regimens in first-line therapy (n = 525).
Fig. 2. First-line regimens in different gender and histology type (n = 522). (Three patients with unknown gender were excluded; platinum excluded.)
3.4. EGFR mutation testing 9.6% patients with stage IIIB or IV disease had EGFR-related testing performed (58/606). 21 patients had EGFR mutation testing while 11 patients had EGFR over-expression testing and the remaining 26 patients had both. Methodology was not addressed in the survey. EGFR mutation rate was 46.8% (22/47). EGFR overexpression rate was 81.1% (30/37). 4. Discussion To our knowledge, this survey is the first national survey describing the status of medical treatment of NSCLC in China. Similar surveys have been conducted in other countries [10–13] however they reflect management practices in western countries
and no studies have previously focused on the Asian NSCLC perspective. Our study emphasizes real clinical practice in the Chinese population for the first time. It provides a comprehensive understanding of treatment status of NSCLC in China and, furthermore serves as a reference for further clinical trial and policy making. When compared with the treatments listed in NCCN guidelines (Chinese version) [6], we found the majority of chemotherapy managements did follow the guidelines. Interestingly, in the firstline treatment gemcitabine/platinum was most often used which reflected as the typical European clinical practice [11,13], while in U.S. taxanes/platinum was predominately used [12]. Gridelli et al. showed that 80% patients with pulmonary squamous cell carcinoma in Italy received gemcitabine/platinum initially, as did 54% with non-squamous cell carcinoma. Even in the elderly or poor performance status patients, single-agent therapy gemcitabine was
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Fig. 3. Regimens in adjuvant and neo-adjuvant therapy (n = 381).
Fig. 4. Adjuvant and neo-adjuvant regimens in different gender and histology type (n = 380). (One patient with unknown gender was excluded; platinum excluded.)
chosen much more than other agents (52% in elder and 56% in poor PS). They attributed the choice of gemcitabine to its benefit/toxicity balance, less expensive cost and reimbursement [11]. These reasons may be similar in our country. Furthermore we attributed it to the imperfect mode of patient-referral practice in China. Aside from medical oncologists, surgeons and respiratory clinicians can also prescribe chemotherapy for NSCLC. However, appropriate prevention and management of chemotherapy toxicity does require oncology-specific training and experience. For instance, paclitaxelrelated anaphylactic shock and vinorelbine-related severe phlebitis may be difficult for doctors in other specialties to manage. They may rather prefer to prescribe a drug with similar efficacy but relatively easier to manage. Moreover gemcitabine caused less alopecia, which is an aspect that the Chinese population is sensitive about. This might explain why gemcitabine is the dominant choice in China. Although doctors approved platinum-based therapy, 14.2% of them (106/747) preferred nedaplatin or oxaliplatin which lacks qualified evidence in NSCLC in other countries. The domestic data showed that with similar efficacy, nedaplain and oxaliplatin
seemed to cause less nausea and vomiting compared with cisplatin [14,15]. In addition some patients with squamous cell carcinoma were treated with pemetrexed (4.5%, 17/378). Pemetrexed is a histology-specific agent. The misuse implies the off-label usage in China. The prevalence of indication and contraindication of novel drugs still needs improvement. Previously doctors preferred using docetaxel in the second-line more than other agents [11]. Nevertheless in China docetaxel, gefitinib or pemetrexed were chosen with similar frequency. This may be due to the relatively milder side effect of pemetrexed, and the specifically higher EGFR mutation rate in Chinese population. But we found nearly half of our patients (26/54) received two-drug chemotherapy in their second-line treatment. We traced back the first-line therapy and found that the majority (21/26) were treated with doublet chemotherapy already. This may suggest excessive pursuit of efficacy of some doctors which bring them to overtreat their patients with doublet therapy for the second time. Although EGFR mutation test is recommended in China for all histologic subtypes, subject to NCCN guideline (Chinese version) [6], it was not routinely done unless the patients, the family, or
C. Xue et al. / Lung Cancer 77 (2012) 371–375
the oncologists required mainly because of the limited coverage of technology. In addition we attributed it to the inadequate sample for detection, expensive testing fee, and other reasons. The EGFR detection rate was only 9.6% in our survey. Moreover, we assume it may be offered to the selected population (female, non-smoker, and adenocarcinoma), which may explain why the percentage of EGFR mutation and overexpression was a somewhat higher (46.8% and 81.1% respectively). Several limitations of our study need to be mentioned. Firstly, the investigation was held only in the general hospitals or comprehensive cancer centers of major cities in China, which may not be representative of the situation in the whole country. Especially, one may question the low detection rate of EGFR mutation. However we deem that the majority of patients in our country are actually treated in these major cities. Even in the big cities, there exist a large group of hospitals unqualified for EGFR mutation status testing which is why most patients did not have the EGFR detection done through their disease process. So, we assert that these results are reliable and valuable. Secondly, as this was not a longitudinal study, the proportion of patients receiving treatments might not represent the practical situation. Particularly, the percentage of patients receiving second line chemotherapy or beyond was not accurately evaluated. Thirdly, the aspect of traditional medicine was not included in our survey. So we are unable to comment on the practice of patients treated with Chinese medicine concurrently with chemotherapy or EGFR-TKIs, which might be commonly seen in China. Finally, we only described the treatment status and did not correlate to survival or response rate outcomes, which should be further explored in future. In summary, this survey is the first study revealing the actuality of NSCLC treatment practices in China. We consider it of great value for the government, academic and industry perspective to comprehend the overall pattern. Moreover, it is also serves as a reference for setting policy or conducting clinical trials in the future. Conflict of interest statement Li Zhang has received research grants for his institution from Sanofi aventis. All other authors declare that they have no conflict of interest. Acknowledgments We thank all the doctors who participated in the study. We thank Professor Sharlene Gill from BC Cancer Agency (now as a
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Visiting Professor in Sun Yat-Sen University Cancer Center) for her helpful advice in manuscript editing. This study was supported by Science and Technology Commission of Guangzhou (2010J-E151) and Wu Jieping Medical Foundation (08-JC-003). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.lungcan. 2012.04.014. References [1] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300. [2] Globocan. International agency for research of cancer.. [10] Potosky AL, Saxman S, Wallace RB, Lynch CF. Population variations in the initial treatment of non-small-cell lung cancer. J Clin Oncol 2004;22:3261–8. [11] Gridelli C, Rossi A, de Marinis F. Pattern of care for advanced non-small cell lung cancer in the era of histology-based treatment: a survey of the Italian Association of Thoracic Oncology (AIOT). Lung Cancer 2010;67: 339–42. [12] Ramsey SD, Howlader N, Etienne RD, Donator B. Chemotherapy use, outcomes, and costs for older persons with advanced non-small-cell lung cancer: evidence from surveillance, epidemiology and end results—Medicare. J Clin Oncol 2004;22:4971–8. [13] Gridelli C, Arizona A, Barn S, Chino L, Capriole A, Piazza E, et al. Medical treatment choices for patients affected by advanced NSCLC in routine clinical practice: results from the Italian observational “SUN” (Survey on the lUng cancer maNagement) study. Lung Cancer 2011;74: 462–8. [14] Chen LK, Xu GC, Guan ZZ, Hang Y, Yang QY. Nadaplatin or cisplatin combined with paclitaxol in treatment for non-small cell lung cancer: a randomized controlled study. Zhonghua Zhong Liu Za Zhi 2007;29:437–40. [15] Li M, Huang H, Tan J, Lin D. A randomized clinical trial on taxol plus oxaliplatin versus taxol plus cisplatin as first-line treatment in advanced non-small cell lung cancer. Zhongguo Fei Ai Za Zhi 2006;9:452–4.
Contents lists available at SciVerse ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
National survey of the medical treatment status for non-small cell lung cancer (NSCLC) in China Cong Xue a,1 , Zhihuang Hu a,1 , Wei Jiang b , Yuanyuan Zhao a , Fei Xu a , Yan Huang a , Hongyun Zhao a , Jingxun Wu c , Yang Zhang a , Liping Zhao a , Jing Zhang a , Likun Chen a , Li Zhang a,∗ a
State Key Laboratory of Oncology in South China, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China Department of Medical Oncology, Tumor Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China c Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China b
a r t i c l e
i n f o
Article history: Received 22 November 2011 Received in revised form 9 April 2012 Accepted 14 April 2012 Keywords: Chemotherapy Chinese population Epidermal growth factor receptor Non-small cell lung cancer Practice pattern Survey
a b s t r a c t Introduction: Treatment choice for NSCLC in China has not previously been reported. This paper explores the clinical practice and adherence to treatment guidelines for NSCLC. Methods: A specifically designed questionnaire was used. It consisted of personal information of the responders and treatment details (patient identification data was excluded). Questionnaires were delivered to doctors in 12 major cities in China. Doctors were asked to answer the questionnaires based on real cases in their daily practice. Results: 987 cases of NSCLC were included. In first-line chemotherapy, regimens were mostly platinumbased among which gemcitabine plus platinum was predominately used (27.4%), followed by docetaxel plus platinum (16.2%) and paclitaxel plus platinum (13.5%). In second-line therapy some were treated with single agents, such as docetaxel (12.9%), gefitinib (11.1%), pemetrexed (9.3%), and erlotinib (3.5%). 44.5% were with doublet therapy. Detection rate of epidermal growth factor receptor (EGFR) mutation was only 9.6% because of the limited prevalence of testing technology. EGFR mutation rate was 46.8%. EGFR-tyrosine kinase inhibitors (TKIs) were used more frequently as salvage (14.8%) rather than upfront therapy (5.3%). Conclusions: This survey reveals the daily clinical treatment for NSCLC in China. Overall data showed modest adherence to the national guideline (NCCN guideline Chinese version) for first-line chemotherapy. We believe this survey is valuable to provide a reference for further clinical trial design and policy making. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer has been a leading cause of cancer death in the 20th century [1]. The data from the International Agency for Research of Cancer (IARC) show that in 2008 approximately 520,000 people were newly diagnosed with lung cancer and 450,000 died of it in China [2]. NSCLC accounts for 85% of the cases. The growing number of NSCLC was mainly from those increased smokers and exposed people [2–4]. The fiercely debated issue of utilizing limited resources efficiently with expensive anti-lung cancer treatments is awaiting a solution [5].
∗ Corresponding author at: State Key Laboratory of Oncology in South China, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, 651# Dongfeng Road, East, Guangzhou 510060, People’s Republic of China. Tel.: +86 20 87343689; fax: +86 20 8734 3565. E-mail addresses: [email protected], li [email protected] (L. Zhang). 1 These authors contributed equally to this work. 0169-5002/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2012.04.014
Evidence-based guidelines are mandatory in clinical practice, not only guiding doctors to formulate their strategy, but also providing patients with the optimal effective therapies and avoiding waste of medical resource. There are several clinical practice guidelines available, such as guidelines from National Comprehensive Cancer Network (NCCN) (General and Chinese version), American Society of Clinical Oncology, and European Society of Medical Oncology [6–9]. However many objective and subjective reasons might lead to the choice of various regimens. The overall usage of recommended therapies for NSCLC is 52% in the United States [10]. We assume there may be a gap between the clinical practice pattern and the guidelines in China, however the real situation has never been disclosed. In this study, we conducted a survey to explore the current status of medical treatment patterns of NSCLC in China; moreover we aim to assess the adherence to current guidelines and to explore the reasons for the observed findings.
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C. Xue et al. / Lung Cancer 77 (2012) 371–375
Table 1 Items included in the survey. Doctor information questionnaire 1. Which hospital do you work? 2. Which level is your hospital in? Which department are you in? 3. What title are you with? 4. How many years have you been a cancer-treating doctor? 5. Have you been a member of any cancer association? 6. 7. How many cancer patients do you manage in a month? 8. How many patients can afford the anti-cancer treatment? (proportion) 9. How many patients can afford the chemotherapy? (proportion) How many patients are able to finish all treatment courses planned? 10. (proportion) Patient information questionnaire 1. Patient characteristics Gender Age Weight Body surface area Current disease status (newly diagnosed, follow-up, recurrent) Performance status (ECOG) Smoking status Current co-morbidities/pre-existing conditions Diagnosis information 2. Date of diagnosis Histology or cytology Current stage Primary site Stage at diagnosis Evidence of metastases (location) EGFR mutation status (if done) EGFR over-expression status (if done) Regimen information 3. Current regimen as (neo-adjuvant/adjuvant/palliative or others) Specific drugs (cytotoxic agents/targeted therapy or others) Route of administration, dosage and days of given Number of cycles given Number of cycles planned Pervious regimens (date/specific drugs) Reason for changing regimen Side effects 4. Anemia, bone pain, mucositis, rash, neuropathy, etc. Use of other drugs 5. Antiemetic use G-CSF and bisphosphonates Antibiotics Analgesics Others Reason of regimen choice 6.
2. Patients and methods This survey was conducted in 12 major cities of China from September to October 2010. The participating cities are Beijing, Shanghai, Guangzhou, Chengdu, Hangzhou, Xi’an, Ji’nan, Wuhan, Tianjin, Nanjing, Chongqing, and Shenyang (Supplementary Fig. 1). 135 general hospitals, chest hospitals, and comprehensive cancer centers were included. We randomly chose departments in these hospitals which treat patients with lung cancer and posted the questionnaires to the doctors. Only one doctor was surveyed in each department and no more than five doctors in one hospital. Each doctor completed up to five consecutive patients’ treatment questionnaires (patient identifiers were exclusive). Patients involved in clinical trials were excluded. We referred to the literature reported by Gridelli et al. [11] when designing the questionnaire. Also some questions we interested in were added. The questionnaire included items with multiple answers (Table 1). The best answer was chosen in the multiple options. Using the raw data, we conducted an analysis and presented the following results.
3. Results 202 doctors participated in this survey and 987 cases of NSCLC were involved. The characteristics of doctors and patients are listed in Supplementary Tables 1 and 2. There were 381 patients with early stage disease who received neo-adjuvant or adjuvant chemotherapy, while 606 patients with stage IIIB–IV disease. Among patients with advanced NSCLC, we further analyzed the 579 patients who received first-line or second-line palliative chemotherapy. Twenty patients with third-line therapy and 7 patients with missing detail were excluded. 77.8% patients (747/960) were treated with platinum therapy including early or advanced stage. Cisplatin accounted for 63.5% of all platinum used (474/747). Others were carboplatin (22.3%, 167/747), nedaplatin (8.6%, 64/747), and oxaliplatin (5.6%, 42/747).
3.1. First-line therapy 525 patients received first-line therapy. Gemcitabine plus platinum was the most commonly used regimen (27.4%, 144/525), followed by docetaxel plus platinum (16.2%, 85/525) and paclitaxel plus platinum (13.5%, 71/525). The top ten regimens are listed in Fig. 1. There was a slight variation as shown in Fig. 2 with the population divided by gender and histology subtype. 16.1% patients with adenocarcinoma were treated with pemetrexed (52/323), while it was used in 6% patients with non-adenocarcinoma (12/199). 26 patients (4.9%) were treated with EGFR-TKIs initially, not all of them were tested for mutation before treatment.
3.2. Second-line therapy 54 patients received second-line therapy. Gemcitabine plus platinum remained the most common choice (18.5%, 10/54). Docetaxel (12.9%, 7/54), gefitinib (11.1%, 6/54), and pemetrexed (9.3%, 5/54) were used with similar frequency (Supplementary Fig. 2). This analysis is for reference only subject to the small sample size.
3.3. Neo-adjuvant and adjuvant therapy There were 381 patients with stage I-IIIA NSCLC treated with chemotherapy. 54 and 327 patients received neo-adjuvant and adjuvant chemotherapy respectively. The majority of chemotherapy regimens were platinum based (341/381, 89.5%) with cisplatin used most frequently (72.4%, 247/341). The proportion with carboplatin was 15.8% (54/341) while 10.3% and 1.5% of early stage patients received nedaplatin and oxaliplatin (35/341 and 5/341 respectively). Gemcitabine plus platinum was used more than any other regimens in early stage (29.1%, 111/381), followed by docetaxel plus platinum (17.3%, 66/381) and paclitaxel plus platinum (14.7%, 56/381) as shown in Fig. 3. The distribution by gender and histology subtype is shown in Fig. 4. The top three regimens in neo-adjuvant chemotherapy were gemcitabine/platinum (43.7%), vinorelbine/platinum and docetaxel/platinum (both 10.9%). In adjuvant chemotherapy the regimens mostly chosen were gemcitabine/platinum (26.6%), docetaxel/platinum (18.4%) and paclitaxel/platinum (15.9%). 81 patients with early stage disease also received concurrent chemotherapy with radiation (Supplementary Fig. 3). Due to the limited information available regarding the details of chemoradiation (such as sequence or dosage), a further analysis of this subgroup was not performed.
C. Xue et al. / Lung Cancer 77 (2012) 371–375
373
Fig. 1. Regimens in first-line therapy (n = 525).
Fig. 2. First-line regimens in different gender and histology type (n = 522). (Three patients with unknown gender were excluded; platinum excluded.)
3.4. EGFR mutation testing 9.6% patients with stage IIIB or IV disease had EGFR-related testing performed (58/606). 21 patients had EGFR mutation testing while 11 patients had EGFR over-expression testing and the remaining 26 patients had both. Methodology was not addressed in the survey. EGFR mutation rate was 46.8% (22/47). EGFR overexpression rate was 81.1% (30/37). 4. Discussion To our knowledge, this survey is the first national survey describing the status of medical treatment of NSCLC in China. Similar surveys have been conducted in other countries [10–13] however they reflect management practices in western countries
and no studies have previously focused on the Asian NSCLC perspective. Our study emphasizes real clinical practice in the Chinese population for the first time. It provides a comprehensive understanding of treatment status of NSCLC in China and, furthermore serves as a reference for further clinical trial and policy making. When compared with the treatments listed in NCCN guidelines (Chinese version) [6], we found the majority of chemotherapy managements did follow the guidelines. Interestingly, in the firstline treatment gemcitabine/platinum was most often used which reflected as the typical European clinical practice [11,13], while in U.S. taxanes/platinum was predominately used [12]. Gridelli et al. showed that 80% patients with pulmonary squamous cell carcinoma in Italy received gemcitabine/platinum initially, as did 54% with non-squamous cell carcinoma. Even in the elderly or poor performance status patients, single-agent therapy gemcitabine was
374
C. Xue et al. / Lung Cancer 77 (2012) 371–375
Fig. 3. Regimens in adjuvant and neo-adjuvant therapy (n = 381).
Fig. 4. Adjuvant and neo-adjuvant regimens in different gender and histology type (n = 380). (One patient with unknown gender was excluded; platinum excluded.)
chosen much more than other agents (52% in elder and 56% in poor PS). They attributed the choice of gemcitabine to its benefit/toxicity balance, less expensive cost and reimbursement [11]. These reasons may be similar in our country. Furthermore we attributed it to the imperfect mode of patient-referral practice in China. Aside from medical oncologists, surgeons and respiratory clinicians can also prescribe chemotherapy for NSCLC. However, appropriate prevention and management of chemotherapy toxicity does require oncology-specific training and experience. For instance, paclitaxelrelated anaphylactic shock and vinorelbine-related severe phlebitis may be difficult for doctors in other specialties to manage. They may rather prefer to prescribe a drug with similar efficacy but relatively easier to manage. Moreover gemcitabine caused less alopecia, which is an aspect that the Chinese population is sensitive about. This might explain why gemcitabine is the dominant choice in China. Although doctors approved platinum-based therapy, 14.2% of them (106/747) preferred nedaplatin or oxaliplatin which lacks qualified evidence in NSCLC in other countries. The domestic data showed that with similar efficacy, nedaplain and oxaliplatin
seemed to cause less nausea and vomiting compared with cisplatin [14,15]. In addition some patients with squamous cell carcinoma were treated with pemetrexed (4.5%, 17/378). Pemetrexed is a histology-specific agent. The misuse implies the off-label usage in China. The prevalence of indication and contraindication of novel drugs still needs improvement. Previously doctors preferred using docetaxel in the second-line more than other agents [11]. Nevertheless in China docetaxel, gefitinib or pemetrexed were chosen with similar frequency. This may be due to the relatively milder side effect of pemetrexed, and the specifically higher EGFR mutation rate in Chinese population. But we found nearly half of our patients (26/54) received two-drug chemotherapy in their second-line treatment. We traced back the first-line therapy and found that the majority (21/26) were treated with doublet chemotherapy already. This may suggest excessive pursuit of efficacy of some doctors which bring them to overtreat their patients with doublet therapy for the second time. Although EGFR mutation test is recommended in China for all histologic subtypes, subject to NCCN guideline (Chinese version) [6], it was not routinely done unless the patients, the family, or
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the oncologists required mainly because of the limited coverage of technology. In addition we attributed it to the inadequate sample for detection, expensive testing fee, and other reasons. The EGFR detection rate was only 9.6% in our survey. Moreover, we assume it may be offered to the selected population (female, non-smoker, and adenocarcinoma), which may explain why the percentage of EGFR mutation and overexpression was a somewhat higher (46.8% and 81.1% respectively). Several limitations of our study need to be mentioned. Firstly, the investigation was held only in the general hospitals or comprehensive cancer centers of major cities in China, which may not be representative of the situation in the whole country. Especially, one may question the low detection rate of EGFR mutation. However we deem that the majority of patients in our country are actually treated in these major cities. Even in the big cities, there exist a large group of hospitals unqualified for EGFR mutation status testing which is why most patients did not have the EGFR detection done through their disease process. So, we assert that these results are reliable and valuable. Secondly, as this was not a longitudinal study, the proportion of patients receiving treatments might not represent the practical situation. Particularly, the percentage of patients receiving second line chemotherapy or beyond was not accurately evaluated. Thirdly, the aspect of traditional medicine was not included in our survey. So we are unable to comment on the practice of patients treated with Chinese medicine concurrently with chemotherapy or EGFR-TKIs, which might be commonly seen in China. Finally, we only described the treatment status and did not correlate to survival or response rate outcomes, which should be further explored in future. In summary, this survey is the first study revealing the actuality of NSCLC treatment practices in China. We consider it of great value for the government, academic and industry perspective to comprehend the overall pattern. Moreover, it is also serves as a reference for setting policy or conducting clinical trials in the future. Conflict of interest statement Li Zhang has received research grants for his institution from Sanofi aventis. All other authors declare that they have no conflict of interest. Acknowledgments We thank all the doctors who participated in the study. We thank Professor Sharlene Gill from BC Cancer Agency (now as a
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Visiting Professor in Sun Yat-Sen University Cancer Center) for her helpful advice in manuscript editing. This study was supported by Science and Technology Commission of Guangzhou (2010J-E151) and Wu Jieping Medical Foundation (08-JC-003). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.lungcan. 2012.04.014. References [1] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300. [2] Globocan. International agency for research of cancer.