Cq

YQa

Db

c

d

a

ARRAA

KNMCTdQP

1

wp

cFp

h00

CORE e.ac.uk

Provided by Els

Complementary Therapies in Medicine 24 (2016) 81–89

Contents lists available at ScienceDirect

Complementary Therapies in Medicine

jo ur nal homep age: www.elsev ierhea l th .com/ journa ls /c t im

hinese herbal medicine as maintenance therapy for improving theuality of life for advanced non-small cell lung cancer patients

an Hana, Huan Wanga, Weiru Xua, Bangwei Caob, Lei Hanc, Liqun Jiad, Yongmei Xua,ing Zhanga, Xiaoming Wanga, Ganlin Zhanga, Mingwei Yua, Guowang Yanga,∗

Department of Oncology, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, No.23 Meishuguanhou Street,ongcheng District, Beijing 100010, ChinaDepartment of Oncology, Beijing Friendship Hospital Affiliated to Capital Medical University, No.95 Yongan Road, Xicheng District, Beijing 100050, ChinaDepartment of Oncology, Daxing Hospital Affiliated to Capital Medical University, No.26 Huangcun West Street, Daxing District, Beijing 12600, ChinaDepartment of Integrative Medicine in Oncology, China-Japan Friendship Hospital, No.2 Yinghuayuan East Street, Chaoyang District, Beijing 100029, China

r t i c l e i n f o

rticle history:eceived 13 January 2015eceived in revised form 9 June 2015ccepted 20 December 2015vailable online 28 December 2015

eywords:on-small cell lung canceraintenance therapy

hinese herbal medicinereatment according to syndromeifferentiationuality of liferogression-free survival

a b s t r a c t

Objective: The purpose of the study was to assess the efficacy and safety of using Chinese herbal medicine(CHM) as maintenance therapy considering the survival of advanced non-small-cell lung cancer (NSCLC)patients after first-line conventional platinum-based chemotherapy.Design: An open-label, randomized, controlled trial.Setting: Four hospitals in China.Interventions and main outcome measures: A total of 106 patients were eligible and randomly divided intotwo groups from four hospitals in China. Both groups received the best supporting care (BSC). Additionally,patients in the trial group were given CHM every day until the disease became aggravated or the patientsresigned. The study took both progression-free survival (PFS) and quality of life (QOL) as the primaryoutcomes to comprehensively evaluate the effect of the treatment. QOL was measured by the FunctionalAssessment of Cancer Therapy-Lung (FACT-L) 4.0 questionnaire. Side effects and safety were evaluatedat the same time.Results: Of the 106 patients, 99 completed the study. After treatment and follow-up for PFS, there wereno significant differences in the median PFS time and the 6-month PFS probability between the twogroups. However, the 3-month PFS probability in the trial group was significantly higher than that in thecontrol group (FAS, PPS: P < 0.01). For QOL, there were significant differences between the two groups in

Metadata, citation and similar papers at cor

evier - Publisher Connector

the following: physical well-being, emotional well-being, functional well-being, lung cancer symptomdomain and total score of the FACT-L4.0 (FAS, PPS: P < 0.05). There was no significant difference in thesocial well-being domain. No serious adverse side effects to the treatment were observed.Conclusions: CHM is well tolerated and may improve the QOL of advanced NSCLC patients. CHM is worthstudying in future investigations.

© 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND

. Introduction

Lung cancer is the first leading cause of cancer-related deathorldwide.1,2 It is estimated that more than one hundred millioneople die from lung cancer each year.3 Moreover, the morbidity

Abbreviations: CHM, Chinese herbal medicine; NSCLC, non-small-cell lung can-er; BSC, best supporting care; PFS, progression-free survival; QOL, quality of life;ACT-L, Functional Assessment of Cancer Therapy-Lung; FAS, full analysis set; PPS,er-protocol analysis set.∗ Corresponding author.

E-mail address: guowang yang@163.com (G. Yang).

ttp://dx.doi.org/10.1016/j.ctim.2015.12.008965-2299/© 2015 The Authors. Published by Elsevier Ltd. This is an open access article /).

license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

and mortality of lung cancer are increasing annually in China,4,5

indicating a major threat to health in this country. Non-small celllung cancer (NSCLC) accounts for over 80% of newly diagnosed lungcancers.6 The only way to cure patients with NSCLC is to completelyremove the tumor in a surgical procedure. As typical symptomsare imperceptible during the early stages, approximately two-thirds of patients are unresectable because of metastatic or locallyadvanced disease at their initial diagnosis.7 If untreated, the mediansurvival time for NSCLC is only 4–5 months.8 Currently, the stan-

dard first-line treatment for advanced NSCLC is platinum-basedcombination regimen chemotherapy, which ranges in efficiencyfrom 20% to 40%,9 adding approximately 3 months to the medianprogression-free survival (PFS) time10 and 8–10 months to the

under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.

https://core.ac.uk/display/82268077?utm_source=pdf&utm_medium=banner&utm_campaign=pdf-decoration-v1dx.doi.org/10.1016/j.ctim.2015.12.008http://www.sciencedirect.com/science/journal/09652299http://www.elsevierhealth.com/journals/ctimhttp://crossmark.crossref.org/dialog/?doi=10.1016/j.ctim.2015.12.008&domain=pdfhttp://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/mailto:guowang_yang@163.comdx.doi.org/10.1016/j.ctim.2015.12.008http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/

8 erapi

mpsNkspss2c

tcctbcfswcirnp(tclthaftithctfma

rusteiputimtatmttctwv

2 Y. Han et al. / Complementary Th

edian overall survival (OS) time.11,12 In accordance with therevious standard treatment modalities, first-line chemotherapyhould be administered for no more than six cycles in advancedSCLC patients, and after documented disease control,9 patients areept waiting and under observation13 to restore their performancetatus (PS) and immune system. If there is disease progression,atients are recommended a second-line treatment. However, theecond-line chemotherapy has lower efficiency, short-term remis-ion, and quicker disease progression.14 In addition, approximately0–80% of patients have no opportunity to receive second-linehemotherapy.15

Maintenance therapy has emerged in recent years as a novelherapeutic paradigm for advanced NSCLC that aims to sustain alinically favorable state after first-line chemotherapy. It refers toontinued use of the drug treatment until disease progression orhe occurrence of intolerable adverse events (AEs) if there is a sta-le disease (SD) or better response after completion of the first-linehemotherapy. The theoretical foundation of the therapy originatesrom the Goldie–Coldman theory,16 which states that resistant andlowly growing cancer cells remain after first-line chemotherapy,hich has primarily killed the sensitive and rapidly proliferating

ells. Use of different non-cross-resistant chemotherapy regimenss effective in eradicating the remaining resistant cancer cells. Inecent years, there are a number of clinical studies on mainte-ance therapy, which has been shown to have a potential benefit inrolonging PFS.17–21 The National Comprehensive Cancer NetworkNCCN) version 2.2013 recommends several cytotoxic agents andarget agents for use in maintenance therapy.15 However, carefulonsideration of maintenance therapy is still required, and the fol-owing should be noted: one of the major goals of maintenanceherapy is increasing the quality of life (QOL), but most studiesave not evaluated the QOL; the selection of maintenance ther-py depends on histologic type, PS, genetic alternations and otheractors, indicating that only some patients can benefit from it; con-inuing cytotoxic agents will result in cumulative toxicity, damagemmune function, lower QOL and increase the risk of drug resis-ance; and the prices of chemotherapy and targeted drugs are veryigh such that a proportion of patients cannot afford them, espe-ially in a developing country. Therefore, the current maintenanceherapy in advanced NSCLC still excites debates and requires forurther research, which presents opportunities for Chinese herbal

edicine (CHM) to treat the disease and act as maintenance therapyt the same time.

CHM, which has a long history in China and has accumulatedich experience in the treatment of malignant tumors, is widelysed in the treatment of advanced NSCLC. Some studies havehown that CHM combined with chemotherapy, radiotherapy andargeted therapy can alleviate side effects of cancer treatment,nhance short-term therapeutic effects, stabilize the disease andmprove the long-term efficacy of treatment.22–24 In regards toatients who cannot accept conventional therapy, CHM can besed alone to ameliorate symptoms, improve QOL, and prolonghe survival time with a tumor.25 CHM shows an irreplaceable rolen the comprehensive treatment of advanced NSCLC.26 In fact, a

ajority of advanced NSCLC patients receive CHM as consolida-ion therapy after completion of first-line chemotherapy, whichctually includes maintenance therapy. CHM has a definite advan-age, including stabilizing tumor growth, relieving symptoms and

ild adverse events, which can help patients to “survive with aumor”.27,28 It also meets a criterion that the optimal maintenanceherapy agent should be associated with an improvement in out-ome, have good patient tolerance, and be devoid of cumulative

oxicities. Furthermore, CHM is not limited to treating patientsith histologic type, PS, or genetic alternations and is subsequently

ery suitable for maintenance therapy. In China, some studies have

es in Medicine 24 (2016) 81–89

reported that CHM serving as maintenance therapy can prolong PFSand improve the QOL.29,30 However, studies about CHM as mainte-nance therapy are limited, and almost all of the studies were smallsample, non-randomized controlled trials (RCT), which lack strongevidence to prove that CHM can have an effective role as mainte-nance therapy. According to our previous pilot study, 28 cases ofadvanced NSCLC patients accepted CHM and best supported care(BSC) as maintenance therapy; the median PFS was 5.0 months,which showed a significant benefit compared with the literaturereporting placebo and BSC as maintenance therapy (median PFSwas 2.6 months).31 Therefore, a multicenter randomized controlledstudy was carried out to evaluate the efficacy and safety of usingCHM as maintenance therapy.

2. Patients and methods

2.1. Study design

This was a multicenter, randomized, open-label, controlled trial.The study was approved by the medical Ethics Committees of Bei-jing Hospital of Traditional Chinese Medicine affiliated to CapitalMedical University, and written informed consent to participatein the study was received by all of the participating patients. Thestudy was conducted following the principles of the Declaration ofHelsinki, good clinical practices and local regulations.

2.2. Patients

2.2.1. Eligibility criteria included the followingNo more than one week from completion of 4–6 cycles of

platinum-based first-line induction therapy32 with radiographicevidence of a complete response (CR) or partial response (PR) orSD; a histologic or cytological diagnosis of stage IIIB or stage IVNSCLC (using the seventh edition TNM staging system available atthe time the study was conducted)33; between the ages of 18 and75 years old; an estimated life expectancy of at least 3 months; anEastern Cooperative Oncology Group (ECOG) PS of 0–2; at least onemeasurable lesion according to the Response Evaluation Criteria inSolid Tumors (RECIST version 1.1)34; and adequate liver and kidneyfunction.

2.2.2. Exclusion criteria included the followingKnown brain metastasis (except for stable metastases being

treated with stereotactic radiation or surgery); any serious con-comitant systemic disorder, such as unstable angina pectoris,myocardial infarction, significant cardiac arrhythmia, stroke, orsevere hypertension; pregnancy or breast-feeding; mental disease;allergies to any components of the study drug; unable to consent orcomply with the protocol; concurrent or planned chemotherapy ortargeted maintenance treatment or any other clinical and biochem-ical test; and unwilling or unable to complete QOL questionnairesand give written consent.

2.3. Treatment

Patients in the control group were treated with BSC rec-ommended by the NCCN Cancer Palliative Care Guide (Version1.2010)35 at any time during the study if it was felt to be in thepatient’s best interest. This included, but was not restricted to, anal-gesics, paracentesis, psychosocial care, nutritional support, or bloodtransfusions. Localized radiotherapy to alleviate pain was allowed,

provided that the radiation dose was in the palliative range. How-ever, no other anticancer therapies were permitted during thestudy. Strict quality control measures for BSC were implementedand monitored.

erapi

tvowsadstettoaCbpPoo

2

2

tut1sco

2

Lcrpdtqctrabetw(

2

ema(

2

stot

Y. Han et al. / Complementary Th

Patients in the trial group were treated with BSC and CHM. CHMreatment was applied with a decoction composed of 10–20 herbarieties. The CHM was made based on a series process. First, basedn our extensive experience in clinical practice and in combinationith previous studies36 and modern pharmacological studies, we

ummarized the characteristics of Chinese Medicine syndrome indvanced NSCLC. For each syndrome, we developed an appropriateiagnostic criterion and corresponding fixed prescription compo-ition of 3–5 herbs (Appendix A). Then, based on the theory ofreatment according to syndrome differentiation combined withach patient’s symptoms, the Chinese Medicine expert determinedhe syndromes and chose the corresponding prescriptions to formhe CHM treatment prescription (decoction). Due to the changef syndrome over time, experts would re-determine syndromesnd adjust the CHM treatment prescription every two weeks. TheHM was given orally, 200 ml each time, twice daily. The treatmentegan the day of random assignment and continued until diseaserogression, patient-physician decision, or unacceptable toxicity.atient follow-ups were done by regular monthly telephone callsr during their monthly visit to the hospital until progression wasbserved.

.4. Outcomes

.4.1. PFSPFS was defined as the time from the date of randomization to

he time of disease progression or death. It was based on the day as anit. Tumor assessments were performed by the radiologist blindedo group allocation at each investigative site, per RECIST (version.1) requirements,34 at baseline and every two month during thetudy period until documented disease progression, death or studylosure. We compared Median PFS time and the PFS probabilitiesf 3 months and 6 months between the two groups.

.4.2. QOLThe Functional Assessment of Cancer Treatment-Lung (FACT-

) Chinese version 4.0 questionnaire was adopted. It has beenonfirmed that the instrument has good reliability, validity andesponsiveness and can be used to measure QOL for Chineseatients with lung cancer.37 There are 36 questions loaded on 5omains of FACT-L, which include physical well-being (7 ques-ions), social well-being (7 questions), emotional well-being (6uestions), functional well-being (7 questions) and the lung can-er symptom (9 questions) domain. The questionnaire was in theypical format of a 5-point Likert scale, in which each questionanged from 0 to 4, positive questions scored forward, and neg-tive questions scored in reverse. The domain score was calculatedy summing each question’s score. The total score was the sum ofach domain score. For each domain and the total score, the higherhe score was, the better the QOL of the patients. The date of QOLas observed and recorded at baseline (week 0) and at the 4th week

week 4) and the 8th week (week 8) during the treatment period.

.4.3. SafetyRoutine urine was collected and liver and kidney function and

lectrocardiograms (ECG) were assessed before and after treat-ent, as were AEs recorded during treatment. The AEs were graded

ccording to the Common Terminology Criteria for Adverse EventsCTCAE), version 3.0.38

.4.4. Calculation of sample sizeThe primary end point of this study was PFS. To determine

ample size, the following fixed design parameters were used39: awo-sided 0.05 significance level, 90% power, randomization ratiof 1:1, and all patients enrolled had an expected time of no morehan 26 months and a total accrual duration of no more than 33

es in Medicine 24 (2016) 81–89 83

months. Interim analysis was not planned. Considering that therewas no previous RCT in this setting, to our knowledge, median PFSin the BSC arm was assumed to be 2.6 months based on our retro-spective study and a literature review.40 Our previous single-armplot trial showed that the median PFS in CHM/BSC was 5 months.Thus, 106 patients in both arms were expected, with 53 patients ineach group.

2.4.5. RandomizationPatients were chronologically randomized into two groups, and

the distribution ratio was 1:1. A random number from 001 to 106was generated by SPSS 19.0 and saved in a sealed envelope. Treat-ment allocation occurred when the participant met the inclusioncriteria and signed the informed consent. The result of random-ization was opened to patients and investigators along with theperformance of the study. To strengthen the quality control forthis open-label trial, an investigator separate from all of the clinicalresearchers was assigned in each center as the contact person whopreserved and recorded the randomization information.

2.4.6. Statistical analysisAll clinical data were analysed using SPSS 19.0 by an indepen-

dent clinical statistician uninvolved in providing the interventionor management. The outcomes were analysed by the intention-to-treat (ITT) model and supplemented by per-protocol (PP) analysis.Student’s t-test or the Chi-square test was used to compare the twogroups’ baseline characteristics. PFS assessments for patients with-out disease progression at the end of the study were considered ascensored data. For each treatment arm, the Kaplan–Meier methodwas used to estimate PFS curves and calculate the median PFS andassociated 95% Confidence Interval (CI) and survival probabilitiesof 3 months and 6 months. The PFS curves were compared usingthe log rank test. For the QOL assessment, the independent-samplet-test or the Mann–Whitney U-test, based on the distribution, wasused to compare differences between the two groups at specifictime points (baseline, 4 week treatment and 8 week treatment).Repeated measures were used to compare differences over timefor continuous observation. All P values were two-tailed, and an �level less than 0.05 was considered statistically significance.

3. Results

3.1. Patient enrollment and comparison of general information

All patients were recruited (September 2011–March 2014) from4 hospitals. Seven patients did not fully complete the study due toviolations of the protocol during the study. At the end, 99 patientscompleted the study treatment. No patient was lost to follow-up.Therefore, the per-protocol analysis set (PPS) population was 99,and the full analysis set (FAS) population was 106. Patient enroll-ment and completion values for the study are shown in Fig. 1.

There was no significant difference in age, gender, staging,pathological type, chemotherapy cycle, response after standardchemotherapy, or ECOG performance status between the twogroups (FAS, PPS: P > 0.05). The comparison of general informationat baseline between the two groups is shown in Table 1.

3.2. Comparison of PFS

The cut-off date for analysis was July 2014, resulting in a medianfollow-up time at day 146 (censoring those who were progres-sion free at the end of the study); at the cut-off date, 95 patients

had disease progression (89.6%). The number of patients who wereprogression free in the trial group and control group were 7 and4, respectively. There was no significant difference in the aspectsof the median PFS time and the 6-month PFS probability between

84 Y. Han et al. / Complementary Therapies in Medicine 24 (2016) 81–89

ents a

tgP6Pi

3

d

TC

NP

Fig. 1. Enrolment of the pati

he two groups. However, the 3-month PFS probability in the trialroup was significantly higher than that in the control group (FAS,PS: P < 0.01). The median PFS time, 3-month PFS probability and-month PFS probability of both groups are shown in Table 2. TheFS curves in a per-protocol and full analysis population are shownn Fig. 2A and B, respectively.

.3. Comparison of QOL

Before treatment, there was no significant difference in eachomain score and its total score between the two groups (P > 0.05).

able 1omparison of general information between the two groups.

Variable Per-protocol analysis set

CHM + BSC group(n = 52) BSC group(n = 47) P

Mean age, year ±SD 59.19 ± 9.44 59.63 ± 10.06 0Range 27–75 31–75

Sex 0Male 33 24 Female 19 23

Stagingb 0IIIB 9 5 IV 43 42

Pathological type 0Adenocarcinoma 35 29

Squamous carcinoma 13 12 Other type 4 6

Chemotherapy cycle 04 24 16 5 7 6 6 21 25

Responsec 0CR+PR 9 11 SD 43 36

ECOG PS 00 6 10 1 26 19 2 20 18

otes: CHM—Chinese herbal medicine; BSC—best support care; n—number of patients S—performance status; ECOG—Eastern Cooperative Oncology Group.a T-test or Chi-square test.b Based on TNM Classification, 7th edition.c Response after standard first-line chemotherapy determined by RECIST criteria.

nd completion of the study.

The QOL scores of the trial group continued to increase over timeand were significantly higher than those of the control groupfor physical well-being (Fig. 3A, P ≤ 0 .04), functional well-being(Fig. 3B, P ≤ 0.012), lung cancer symptom (Fig. 3C, P ≤ 0.020) andtotal score (Fig. 3D, P ≤ 0.026). There was also an increase over timein the score for the emotional well-being domain in the trial groupbut a decrease in the control group, and the difference between

the two groups was significant (Fig. 3E, P ≤ 0.025). However, thescore for the social well-being domain barely changed over timeand showed no difference between the groups (Fig. 3F, P ≥ 0.628). Atthe 4th and 8th weeks, the trial group had higher QOL scores com-

Full analysis set

a CHM + BSC group(n = 53) BSC group(n = 53) Pa

.826 59.42 ± 9.49 59.46 ± 9.93 0.98127–75 31–75

.213 0.32334 2919 24

.342 0.4039 644 47

.687 0.79636 34

13 134 6

.411 0.20124 167 622 31

.451 0.63210 1243 41

.378 0.3256 1127 2120 21

in each group; CR—complete response; PR—partial response; SD—stable disease;

Y. Han et al. / Complementary Therapies in Medicine 24 (2016) 81–89 85

Table 2Median PFS time and 3-month/6-month PFS rates of the two groups.

Full analysis set Per-protocol analysis setCHM + BSC group N = 53 BSC group N = 53 HR (95%CI) P CHM + BSC group N = 52 BSC group N = 47 HR (95%CI) P

Median PFS time 165 119 0.791 0.260 163 140 0.848 0.440(95%CI), day (137–192) (79–158) (0.527–1.189) (136–190) (100–180) (0.556–1.294)

3-Month PFS 0.005 0.005Rate/% 84.9 67.9 84.6 68.1

6-Month PFS 0.141 0.377Rate/% 40.6 31.2 39.3 33.1

Notes: CHM—Chinese herbal medicine; BSC—best support care; PFS—progression free survival; HR—hazard risk; CI—confidence interval.

Fig. 2. Unadjusted, unstratified PFS for the maintenance therapy (from randomization) for the per-protocol survival population (A) and the full analysis population (B).

86 Y. Han et al. / Complementary Therapies in Medicine 24 (2016) 81–89

Fig. 3. Change in quality of life and comparison of FACT-L4.0 questionnaire in physical well-being, social well-being, emotional well-being, functional well-being, the lungc etwee

pel

3

aaotgrCmca

ancer symptom domain and total score at baseline and at the 4th and 8th weeks b

ared with the control group for physical well-being (P ≤ 0.022),motional well-being (P ≤ 0 .013), functional well-being (P ≤ 0.005),ung cancer symptoms (P ≤ 0.037), and total scores (P ≤ 0.015).

.4. Evaluation of safety

There were no significant differences in routine blood, urinend stool tests, liver and kidney function tests and ECG beforend after treatment in each group. AEs were recorded when theyccurred. However, there was no significant difference betweenhe two groups in terms of AEs (P > 0.05). Ten cases in the trialroup experienced dry mouth, nausea, loss of appetite, and diar-hea, which appeared after taking CHM and may be associated with

HM treatment. Five cases in the control group experienced dryonth, nausea, constipation, and loss of appetite, which may be

aused by the BSC treatment. The grade of these AEs was 1, andfter temporary CHM withdrawal or symptomatic treatment, these

n the two groups.

symptoms disappeared in a week. No patients quit the trial becauseof the AEs.

4. Discussions

In recent years, maintenance therapy of advanced NSCLC hasbecome a hot spot for research. The U.S. National Cancer Institute’smedical dictionary defines maintenance therapy as “any treatmentthat is given to help keep cancer from progressing after it has beensuccessfully controlled by the appropriate initial front-line therapy;it may include treatment with drugs, vaccines, or antibodies, and itshould be given for a long time”.13 CHM is based on a unique theoryformed from long-term practical experience. For the last thousand

years, CHM has been widely practiced in China and has recentlybeen widely used internationally as a complementary and alter-native therapy. More than 90% of modern Chinese cancer patientshave received CHM treatment.41 Recently, CHM has also been used

erapi

atrta

tgsaCawotuhbacfa

dmmtOiaraslcistfiafimojstctdvcsin

Y. Han et al. / Complementary Th

broad and is well accepted in many countries, particularly forhe treatment of oncology.42 Nevertheless, more rigorous trials areequired to further verify CHM efficacy. Therefore, we conductedhe study to evaluate CHM as maintenance therapy consideringdvanced NSCLC patients’ tumor control and QOL.

Our results showed that PFS was not significantly different inhe two groups, despite an extended period of PFS time in the trialroup. Furthermore, the 3-month rate of disease progression wasignificantly reduced in the trial group, but the 6-month PFS prob-bilities of the two groups were similar, which reflected that theHM may have a short-term benefit for maintenance therapy ofdvanced NSCLC. However, it appeared that the advantages of CHMere not sustained, which may be related to the rapid deterioration

ver time of advanced NSCLC. In addition, it should be noted thathe study did not chose overall survive (OS) as an endpoint to eval-ate survival. The purpose of our study was to explore if CHM couldave an effective role as maintenance therapy, and it is not possi-le to control for post-study events in the clinical trial that wouldllow for fair assessment of a new therapy. Given this real worldhallenge, the PFS endpoint becomes even more important, not justor trials evaluating maintenance treatment strategies but also forll future definitive therapeutic trials in this patient population.

QOL is an important prognostic factor43 and a significant pre-ictor of survival44 in advanced NSCLC. The change of the medicalodel from the bio-medical model to a bio-psycho-social medicalodel makes us pay more attention to QOL and not just focus on

ime of survival in the treatment of advanced cancer patients. Thencologic Drugs Advisory Committee (U.S. Food and Drug Admin-

stration) has also recommended that the QOL should be observeds an important endpoint in cancer clinical trials.45 Silvestri G46

eported that a majority of patients were more willing to choose method of treatment that can alleviate symptoms, although thistudy could not bring about prolonged survival. Because advancedung cancer patients are usually accompanied by a persistent cough,hest tightness, wheezing, pain and other symptoms that can resultn a limitation of daily activities, they cannot take care of them-elves and must rely on family members. In addition, because ofhe difficulty of cancer therapy, rapid progression of disease, andnancial burden, patients experience low self-esteem, depression,nxiety and other damages to their mental well-being. There-ore, for advanced NSCLC, it is important to treat these patients tomprove their QOL. However, there is a lack of data about QOL with

aintenance therapy. We chose QOL as one of the main end pointsf our study to build knowledge in this area. Because QOL is sub-ective, a questionnaire is an important tool for its assessment. Ourtudy adopted the FACT-L questionnaire, which was developed byhe Chicago Rush-Presbyterian-St. Luke’s Medical Center for can-er research and is widely used in the world. Our result showedhat after treatment, the improvement of the physical well-beingomain (16.7% vs 3.48%), functional well-being domain (12.23%s 2.93%), emotional well-being domain (11.36% vs 4.53%), lung

ancer symptoms well-being domain (13.28% vs 9.41%), and totalcore (11.11% vs 2.59%) in the trial group were better than thosen the control group. However, the social well-being domain wasot improved. The items of this domain are all focused on social

es in Medicine 24 (2016) 81–89 87

support and emotional intimacy between family and friends. Thus,we think the score of this domain may mainly depend on family,friends, neighbors or others to provide various forms of support andhelp.

However, there are some limitations to this study. First, thisstudy was performed as an open-label study, but some measureswere taken to strengthen quality control. The development of theCHM treatment followed strict procedures aiming to confirm thesyndrome diagnostic criteria and treatment standards to avoidsubjective arbitrary treatment. Moreover, CHM took into accountthe requirements of individual care combined with standard ther-apy. It was possible to form CHM standards in treating advancedNSCLC, which is worth applying in clinics and beneficial to dis-covering effective compounds and monomers. To ensure accuratePFS measurement, a strict schedule of efficacy assessment andpatient follow-up was implemented, and a radiological evaluationor diagnosis was performed every 2 months; to further increasethe confidence in PFS assessment, an independent review of radio-graphic images was frequently performed. For QOL, all patientswere required to complete the questionnaire by themselves andthe researchers could not give the suggestion, so we are confi-dent about the accuracy of our PFS and QOL data. In addition,the randomization, allocation, and data management were han-dled by independent individuals. Second, a placebo for CHM wasnot adopted in the study; the reason for this is that a placebo of aCHM decoction is difficult to make, and it is difficult to obtain ethi-cal patient consent. Third, due to the stringent inclusion criteria ofpatients, it became hard to collect qualified patients, and we spentalmost three years working to complete the study.

5. Conclusions

Overall, our findings suggest a limited role for CHM as main-tenance therapy to prolong patients’ PFS time, but it may bebeneficial in improving the QOL. The U.S. Food and Drug Adminis-tration has recommended that the beneficial effects on QOL and/orsurvival be the basis for approval of new anticancer drugs. There-fore, from a regulatory standpoint, drugs that have an impact onsurvival or demonstrate a favorable effect on QOL are more impor-tant than most other traditional measures used to assess efficacy,such as objective tumor response.45 Thus, CHM may be consideredas maintenance treatment, and further research is required andworthwhile.

Conflict of interest

None.

Acknowledgements

The study was supported by the Capital Citizen Health Cul-

tivation Project of Beijing Scientific and Technological Program(No.Z111107067311044), National Natural Science Foundation ofChina (No.81473643), and Capital Characteristic Clinical Applica-tion Research (No.Z131107002213037).

8 erapi

Aa

cond

ontanind, sngue,

bdomr teethulse

iritleeafnes

issioale tonulse

equenwer er, deee nav

astelesema,

lump

idal feeek, fd ton

maciary coungue ready

iritleumbnngue,

arkishry skin

norexhlegm

retennsatio

r yello

epressatus, dink orr, stri

ar of rine, tpid ps The

R

8 Y. Han et al. / Complementary Th

ppendix A. Syndrome types, syndrome diagnostic criteriand corresponding prescription in advanced NSCLC

Syndrome types Syndrome diagnostic criteria

Main symptoms Se

Lung Dyspnoea, shortness of breath, lowcough sound, easier to catch cold

SpwtoQi deficiency

Spleen Anorexia, poor appetite, abdominaldistention after eating, fatigue, loose stool

AopQi deficiency

Kidney Soreness and weakness of waist and knees,frequent micturition, dribble of urine, frequenturination at night, incontinence of urine

SpdemppQi deficiency

Kidney Soreness and weakness of waist andknees, loss of hair, fear of cold

FrlofuthYang deficiency

Spleen Loose stool, diarrhea with undigestedfood

TedpYang deficiency

Lung Dry and withered lips, dry throat, drycough

TchreYin deficiency

Kidney Soreness of loins, tinnitus, dysphoriawith feverish sensation in chest, palmsand soles

EdtothYin deficiency

Blood Pale complexion and lips, dizziness,palpitation

SpntoDeficiency

Blood Stabbing and fixed pain increasingwith pressure, dark purple tongue orspotted, hesitant pulse

Dd

Stasis

Phlegm Cough, coughing of phlegm, oppressionin chest, suffocation

AptoseoCoagulation

Qi Cough with shortness of breath,oppression in chest, suffocation,distending pain in abdomen

DflpfuStagnation

Heat-toxicity Fever, red complexion, much yellow phlegm,cough with bad breath

Feura

Toxin retention Rapid tumor progression, increasing radicular symptomwas seriously damaged, increase of tumor markers

eferences

1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin.2014;64:9–29.

2. Ferlay J, Shin H-R, Bray F, Forman D, Mathers C, Parkin DM. Estimates ofworldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer.2010;127:2893–2917.

3. Parkin DM, Bray F, Ferlay J, Pisani P. Global Cancer statistics, 2002. CA Cancer JClin. 2005;55:74–108.

4. Guo P, Huang ZL, Yu P, Li K. Trends in cancer mortality in China: an update.Ann Oncol. 2012;23:2755–2762.

5. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancerstatistics. CA Cancer J Clin. 2011;61:69–90.

6. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of

small-cell lung cancer in the United States over the last 30 years: analysis ofthe surveillance, epidemiologic, and end results database. J Clin Oncol.2006;24:4539–4544.

7. Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl JMed. 2004;350:379–392.

es in Medicine 24 (2016) 81–89

Optional herbal treatment

ary symptoms

eous sweating, aversion topiritlessness, weakness, pale

weak pulse

Radix astragali, dry radix ginseng,Adenophora tetraphylla, Dioscoreaopposita Thunb

inal pain, tastelessness, plump tongue-printed tongue, thready and weak

Radix astragali, Tuckahoe, Atractylodesmacrocephala, Codonopsis pilosula

ssness and weakness, tinnitus,s, nocturnal emission, nightn, impotence, thin leukorrhea,gue, white fur, deep and weak

Semen cuscutae, Schisandra chinensis,Fructus ligustri lucidi

t urination at night, edema ofxtremity, pale tongue, whitep and slow pulse, pain aroundel, diarrhea

Fructus Psoraleae, Radix aconiticarmichaeli, Herba Epimedii,Cinnamomum cassia

sness without desire to drink, thin leukorrhea, pale andtongue, deep and weak pulse

Rhizoma zingiberis, Myristica fragrans,Rhizoma Atractylodis Macrocephalae

ver, night sweating, hecticeverishness in palms and soles,gue, thready and rapid pulse

Radix Glehniae, Ophiopogon japonicus,Dendrobium, Radix trichosanthis

tion, tidal fever, night sweating,gh, hectic cheek, red and drywithout fur, luxated teeth,

and rapid pulse

Rehmannia glutinosa, Fructus Corni,Scrophularia ningpoensis, Carapaxtrionycis

ssness, weakness, insomnia,ess in palms and soles, pale

thin white fur, thready pulse

Donkey-hide glue, Angelica sinensis,Placenta Hominis, Lycium barbarum

complexion, squamous and, purple macula

Rhizoma Curcumae, Spatholobussuberectus, Ligusticum chuanxiongHort, Leech

ia, loose stool, vomiting of-drool, dizziness, wheezing duetion of phlegm in throat, heavyn of body, pink tongue, white

w greasy fur, slippery pulse

Pinellia ternata, Fructus trichosanthis,Fritillaria thunbergii Miq

ed, irritable, bloating, frequentistending or scurrying pain,

dark tongue, white or greasyngy and thready pulse

Fructus toosendan, Magnoliaofficinalis, Radix curcumae, Rhizomacyperi, Pericarpium Arecae

wind, constipation, yellowhirst, red tongue, yellow fur,ulse

Paris polyphylla Sm., Fagopyrumcymosum, Herba Houttuyniae,Scutellaria

body function Momordica cochinchinensis, Solanumnigrum, Scutellaria barbata D.Don

8. Rapp E, Pater JL, Willan A, et al. Chemotherapy can prolong survival inpatients with advanced non-small-cell lung cancer report of a Canadianmulticenter randomized trial. J Clin Oncol. 1988;6:633–641.

9. Pfister DG, Johnson DH, Azzoli CG, et al. America Society of Clinical Oncologytreatment of unresectable non-small-cell lung cancer guideline. J Clin Oncol.2004;22:330–353.

10. Requart N, Cardona AF, Rosell R. Role of erlotinib in first-line andmaintenance treatment of advanced non-small-cell lung cancer. CancerManag Res. 2010;38:143–156.

11. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapyregimens for advanced non-small-cell lung cancer. N Engl J Med.2002;36:92–98.

12. Kelly K, Crowley J, Bunn PA, et al. Randomized phase III trial of paclitaxel pluscarboplatin versus vinorelbine plus cisplatin in the treatment of patients withadvanced non-small-cell lung cancer: a Southwest Oncology Group trial. J ClinOncol. 2001;19:3210–3218.

13. Owonikoko TK, Ramalingam SS, Belani CP. Maintenance therapy for advancednon-small cell lung cancer: current status, controversies, and emergingconsensus. Clin Cancer Res. 2010;16:2496–2504.

http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0005http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0005http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0005http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0005http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0005http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0005http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0005http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0005http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0005http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0005http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0005http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0005http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0005http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0005http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0005http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0005http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0005http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0005http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0005http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0010http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0015http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0020http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0025http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0030http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0035http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0035http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0035http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0035http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0035http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0035http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0035http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0035http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0035http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0035http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0035http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0035http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0035http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0035http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0035http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0035http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0035http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0040http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0045http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0050http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0055http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0060http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0065

erapi

the U. S. Food and Drug Administration perspective. J Natl Cancer Inst Monogr.1996;20:7–9.

46. Silvestri G, Pritchard R, Welch HG. Preferences for chemotherapy in patientswith advanced non-small cell lung cancer: descriptive study based on

Y. Han et al. / Complementary Th

14. Zheng LH, Lin JR, Xie B, et al. Therapeutic effect between Pemetrexeddisodium and Docetaxel as second line chemotherapy on advanced non-smallcell lung cancer. Chin J Cancer Prev Treat. 2012;20:368–370.

15. Jeong EL, Chae-Uk C. Update on the evidence regarding maintenance therapy.Tuberc Respir Dis. 2014;76:1–7.

16. Goldie JH, Coldman AJ. A mathematic model for relating the drug sensitivityof tumours to their spontaneous mutation rate. Cancer Treat Rep.1979;63:1727–1733.

17. Paz-Ares L, de Marinis F, Dediu M, et al. Maintenance therapy withpemetrexed plus best supportive care versus placebo plus best supportivecare after induction therapy with pemetrexed plus cisplatin for advancednon-squamous non-small-cell lung cancer (PARAMOUNT): a double blind,phase 3, randomized control trial. Lancet Oncol. 2012;13:247–255.

18. Brodowicz T, Krzakowski M, Zwitter M, et al. Cisplatin and gemcitabinefirst-line chemotherapy followed by maintenance gemcitabine or bestsupportive care in advanced non small cell lung cancer: a phase III trial. LungCancer. 2006;52:155–163.

19. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or withbevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–2550.

20. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. SATURN: a double-blind,randomized, phase III study of maintenance erlotinib versus placebofollowing non-progression with first-line platinum-based chemotherapy inpatients with advanced NSCLC. 13th World Conference on Lung Cancer (WCLC):Abstract A2.1. 2009.

21. Zhang L, Ma S, Song X, et al. Gefitinib versus placebo as maintenance therapyin patients with locally advanced or metastatic non-small-cell lung cancer(INFORM; C-TONG0804): a multicenter, double-blind randomized phase 3trial. Lancet Oncol. 2012;13:466–475.

22. Lin HS, Zhang Y. Evidence-based medical study of traditional Chinesemedicine on non small cell lung cancer. Mod Tradit Chin Med MaterMed—World Sci Technol. 2008;10:121–125.

23. Ren SR, Liao DB, Zhou XQ, Wang J. Shen Qi Fu Zheng Injection combined withradiotherapy on treating 34 senile advanced non-small cell lung cancerpatients. Chin J Integr Tradit West Med. 2006;26:876.

24. Cai HB, Dai FG, Min QF, Shi M, Liao JX, Luo RC. Clinical study of the effects ofradiotherapy in combination with traditional Chinese medicine on non-smallcell lung cancer. J First Mil Med Univ. 2001;22:1112–1114.

25. Lin HS, Zhang Y. The review and the prospect of traditional Chinese medicineoncology. Global Tradit Chin Med. 2009;2:321–326.

26. Xue N, Lin HS. Initial exploration of traditional Chinese medicine asmaintenance therapy for advanced non-small cell lung cancer. Chin Clin Oncol.2012;17:1–5.

27. Lin HS, Li DR. Quality of life and evaluation of Chinese medicine treatment ofcancer. Oncol Prog. 2007;5:249–251.

28. Jiang Y, Liu LS. Maintenance therapy in advanced non-small cell lung cancer.Chin J Integr Tradit West Med. 2010;30:324–328.

29. Liu ZZ, Se ZY, OuYang XN, et al. Effect of maintenance therapy with Fei Tai

capsules in patients with advanced non-small lung cancer. Chin Clin Oncol.2009;14:344–346.

30. Li JH. A clinical comparative study on traditional Chinese medicine serving asconsolidation treatment in patients with advanced non-small cell lungcancer. Chin J Lung Cancer. 2007;10:520–522.

es in Medicine 24 (2016) 81–89 89

31. Stinchcombe TE, Socinski MA. Treatment paradigms for advanced stagenon-small cell lung cancer in the era of multiple lines of therapy. J ThoracOncol. 2009;4:243–250.

32. The Chinese edition (Version.1) of NCCN Clinical Practice Guidelines inOncology Non-Small Cell Lung Cancer Guideline 2010. Originates Englishedition (Version.2). Available from:http://www.nccn.org.

33. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7thedition of the AJCC cancer staging manual and the future of TNM. Ann SurgOncol. 2010;17:1471–1474.

34. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteriain solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer.2009;45:228–247.

35. NCCN Clinical Practice Guideline in Oncology Palliative Care (Version.1) 2010.Available from: http://www.nccn.org/professionals/physician gls/fguidelines.asp.

36. Yang GW, Wang XM, Han D, et al. Study on traditional Chinese medicinecomprehensive therapy in the treatment of advanced non-small cell lungcancer. Chin J Infor Tradit Chin Med. 2005;12:11–13.

37. Pan Y, Xu YH, Wang WM, Ye H. Measurement on quality of life inchemotherapeutical patients with lung cancer by FACT-L Chinese Version 4. 0.Chin Health Resour. 2010;13:265–267.

38. Cancer therapy Evaluation Program. Common Terminology Criteria forAdverse Events, Version 3.0. DCTD, NCI, NIH, DHHS; 2006: pp 1–70.

39. Chow Shein-Chung, Shao Jun, Wang Hansheng, eds. Sample Size Calculations inClinical Research. 2nd edition New York, PA: Chapman& Hall/CRC;2008:1–354.

40. Paz-Ares LG, Altug S, Vaury AT, et al. Treatment rationale and study design fora phase III, double-blind, placebo-controlled study of maintenancepemetrexed plus best supportive care versus best supportive careimmediately following induction treatment with pemetrexed plus cisplatinfor advanced nonsquamous non-small cell lung cancer. BMC Cancer.2010;10:85.

41. Chen Z, Gu K, Zheng Y, Zheng W, Lu W, Shu XO. The use of complementaryand alternative medicine among Chinese women with breast cancer. J AlternComplement Med. 2008;14:1049–1055.

42. Chang KH, Brodie R, Choong MA, Sweeney KJ, Kerin MJ. Complementary andalternative medicine use in oncology: a questionnaire survey of patients andhealth care professionals. BMC Cancer. 2011;11:196.

43. Montazeri A, Milroy R, Hole D, et al. Quality of life in lung cancer patients: asan important prognostic factor. Lung Cancer. 2001;31(2–3):233–240.

44. Nishiyama O, Taniguchi H, Kondoh Y, et al. Quality of life as an independentprognostic factor in advanced non-small-cell lung cancer in general practice.Nihon Kokyuki Gakkai Zasshi. 2006;44(5):368–373.

45. Beitz J, Gnecco C, Justice R. Quality-of-life end points in cancer clinical trials

scripted interviews. BMJ. 1988;317(7161):771–775.

http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0070http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0075http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0075http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0075http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0075http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0075http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0075http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0075http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0075http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0075http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0075http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0075http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0075http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0075http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0075http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0075http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0075http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0075http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0075http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0080http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0085http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0090http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0095http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0100http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0105http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0110http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0115http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)30029-7/sbref0120http://refhub.elsevier.com/S0965-2299(15)3