REVIEWARTICLE

Effect of chemotherapy on quality of life in patientswith non-small cell lung cancer

Eileen Mannion & J. J. Gilmartin & Paul Donnellan &

Maccon Keane & Dympna Waldron

Received: 13 November 2013 /Accepted: 28 January 2014# Springer-Verlag Berlin Heidelberg 2014

AbstractPurpose This study was conducted to evaluate the extent towhich quality of life (QoL) assessment has been incorporatedinto clinical trials of patients with advanced non-small celllung cancer (NSCLC) receiving palliative chemotherapy.Patients and methods Phase III trials for patients withNSCLC treated with palliative chemotherapy were identifiedby a literature search of PubMed. All abstracts and relevantarticles from August 1986 to October 2011 were reviewed.The primary focus was on (a) whether these articles hadincorporated QoL as an endpoint, (c) what instruments wereused to measure QoL and (c) impact of chemotherapy onQoL.Results There were 3,780 items indexed under ‘quality of lifeand lung cancer’. One hundred three studies were identifiedwhich measured QoL using validated QoL instruments. Fifty-five of these trials assessed the effects of palliative chemother-apy on QoL in patients with advanced NSCLC. The EuropeanOrganisation for Research and Treatment of Cancer-Qualityof Life Questionnaire was the most widely used questionnaire;other commonly used measurement scales used were theFunctional Assessment of Cancer Therapy-Lung and theLung Cancer Symptom Scale. The majority of studies showedthat chemotherapy had a positive impact on QoL and disease-specific symptoms.

Conclusion It is now widely accepted that QoL should beconsidered as a primary endpoint of treatment in patients withadvanced lung cancer both in clinical practice and clinicaltrials to further define meaningful response. As the traditionaloutcome measures of survival and tumour response are poorin this population, QoL assessment may offer a more compre-hensive approach to evaluating the relative risks and benefitsassociated with treatments.

Keywords Palliative chemotherapy . Quality of life .

Non-small cell lung cancer

Introduction

Lung cancer is one of the most common malignancies andremains the leading cause of cancer-related deaths in Europeand the USA [40,76]. Many individuals present initially at anadvanced stage of illness, and despite advances in treatments,the prognosis remains poor and survival from time of diagno-sis is often short [13,19]. The impact of chemotherapy onsurvival and quality of life (QoL) in advanced non-small celllung cancer (NSCLC) has long been the subject of debate andled to the publication of five meta-analyses of randomisedtrials between 1993 and 1999 testing the addition of chemo-therapy to best supportive care alone [44,64,69,102]. Thesemeta-analyses concluded that chemotherapy, mainly cisplatin-based regimens, had a modest beneficial impact on survival,with a 10 % improvement in 1-year survival and an estimatedgain in median survival of 1.5 months [69].

In recent years, a number of new agents have becomeavailable for the treatment of metastatic NSCLC, includingtaxanes, gemcitabine, vinorelbine, and pemetrexed. In the late1990s, many phase II, single institution trials of these newagents alone or in combination with cisplatin found highresponse rates (40–50 %) and substantial numbers of patients

E. Mannion (*) :D. WaldronDepartment of Palliative Medicine, Galway University Hospital,Newcastle Road, Galway, Irelande-mail: dreileenmannion@yahoo.co.uk

J. J. GilmartinDepartment of Respiratory Medicine, Galway University Hospital,Newcastle Road, Galway, Ireland

P. Donnellan :M. KeaneDepartment of Medical Oncology, Galway University Hospital,Newcastle Road, Galway, Ireland

Support Care CancerDOI 10.1007/s00520-014-2148-9

survived for 1 or 2 years [2,3,57,59,88]. However, in subse-quent studies by Schiller et al. [90] and Kelly et al. [52], theresponse rates were lower than expected ( 16.6 to 27 %) andthe 1-year rate of survival approached 31 to 39 %. It istherefore not surprising that there remains a high degree ofpessimism about the gains made in clinical care of patientswith advanced lung cancer especially when one considers theside effects of treatment and the cost involved [13,19].

As the traditional outcome measures of survival and tu-mour response are so poor in this group, a patient-based QoLassessment may offer a more comprehensive approach toevaluating the relative risks and benefits associated with treat-ment. Few early studies evaluating the effects of chemother-apy in patients with advanced NSCLC included QoL analy-ses, the main outcome measures being response rate andsurvival. However, research has demonstrated that QoLchanges may be among the most important factors in a pa-tient’s decision whether to receive palliative chemotherapy. Ina study of 81 patients previously treated with cisplatin-basedchemotherapy for advanced NSCLC, when given the choicebetween best supportive care and chemotherapy, only 22 % ofpatients chose chemotherapy for a survival benefit of3 months; 68 % chose chemotherapy if it substantially re-duced symptoms without prolonging life [97]. These findingsdemonstrate the need to estimate the effects on QoL of anynew therapy for advanced NSCLC.

Quality of life measurement

The past decade has seen a burgeoning interest in QoL re-search within oncology and palliative medicine. It is nowwidely accepted that some consideration of patient QoL mustbe an integral part of optimal medical care. The term has abroad meaning which includes not only health-related factorssuch as physical, functional and mental well being, but alsonon-health-related elements such as social, work or relation-ship issues [11,12]. In addition, modern approaches to patienttreatment increasingly recognise the importance of subjectivepatient ratings [39,60,81,98] and the need to incorporate theviews of patients in treatment planning [74]. The dynamic andindividual nature of QoL is difficult to capture when usingquestionnaires based on grouped data, in which the questionsasked, the response format provided and the relative weightsapplied to the answers have all been predetermined. Althoughsuch measures, which are generally referred to as health-related QoL measures [77], provide important informationregarding health status, their promulgation as measures ofQoL is more questionable. Calman [17] defined QoL in cancerpatients as the difference, or the gap, that exists at a particularpoint in time between the hopes and expectations of theindividual and that individual’s present experiences. The in-dividual’s own view of his or her present reality, hopes and

expectations can only be described by the individual [51,70].It has been proposed that a valid QoL measure for patientswith advanced cancer should permit assessment of QoL fromthe unique perspective of the individual without imposing apredetermined external value system [71,114,115].

There are a number of instruments specifically developedfor the evaluation of QoL in patients with lung cancer [49].The European Organisation for Research and Treatment ofCancer lung cancer questionnaire (LC-13) is usually adminis-tered with the quality of life questionnaire (EORTC-QLQ).The lung cancer questionnaire module comprises 13 multiple-item and single-item measures of lung cancer-associatedsymptoms and treatment-related side effects.

This has been shown to be a clinically valid and useful toolfor assessing disease and treatment-specific symptoms in pa-tients with lung cancer [7,68]. The Lung Cancer SymptomScale (LCSS) is a 15-item site-specific scale. It focuses on thephysical and functional dimensions of QoL, measuring majorlung cancer symptoms and their effect on activity status [50].The Functional Assessment of Cancer Therapy-Lung (FACT-L) is a 44-item self-reported instrument and consists of twoparts: a 34-item measure of general health-related quality oflife and a 10-item measure with emphasis on lung cancersymptoms [20]. Other measures that have been used includethe Functional Living Index—Cancer Scale (FLIC) [91], theRotterdam Symptom Checklist (RSCL) [25] and the MedicalResearch Council Daily Diary Card (MRC DDC) [28]. Thepurpose of this literature review was to evaluate the extent towhich quality of life assessment has been incorporated intoclinical oncology trials of patients with advanced lung cancer.

Specific problems with QoL evaluation in lung cancer

Traditionally, QoL has been viewed as a difficult endpoint toincorporate into clinical trials as analysis is complex andrequires careful interpretation [27]. Although extensive re-search on how to measure QoL has led to the developmentof validated instruments, there are some specific problemsrelated to QoL measurement in lung cancer patients [37,71].Patient compliance and data collection are serious problems.These losses will reduce the statistical power of the analysisbut can be reduced by following published guidelines [1]. Theshort-term survival of advanced lung cancer patients and therapid deterioration of performance status produce problems incollecting QoL questionnaires. It has been shown that patientsdeteriorating are likely to be less compliant for further evalu-ations [48] and baseline QoL estimates are worse for thosepatients who fill in a few questionnaires as compared to thosewho are fully compliant with QoL assessment until the end oftreatment [108]. In those situations, the drop-out process isinformative but most of the used statistical methods for dataanalysis assume that missing data occur at random. Thus, bias

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can be introduced in the comparisons [72]. As lung cancerpredominantly affects patients in their sixth and seventh de-cades of life, many will have co-morbidities, all of whichimpact and potentially bias QoL evaluation and lead to prob-lems in the interpretation of results [72].

Methods

A PubMed search was carried out using the key words ‘qual-ity of life’ and ‘lung cancer’. This provided the initial databasefor the review. The search was completed in October 2011.There were 3,780 items indexed dating from August 1986 toOctober 2011. All abstracts were reviewed and relevant arti-cles obtained. The primary focus was on (a) whether theseclinical trials had incorporated quality of life as an endpoint,(b) what instruments were used to measure quality of life and(c) what were the findings.

Results

A total of 132 of the 3,780 citations purported to measurequality of life (QoL) in patients with lung cancer. Whenreviewed, 103 studies were identified which measured QoLusing validated QoL instruments; the other 29 studies hadassessed performance status or symptom scores rather thanQoL and had not used recognised QoL measurement scales.Fifty-five of these trials measured QoL as an endpoint inpatients with advanced NSCLC receiving chemotherapy.Forty-six of these studies were published since 2000 reflectingthe growing interest in QoL as an endpoint in clinical trials.The EORTC-QLQ supplemented with the Lung Cancer mod-ule (LC-13) was the most commonly used measure (29 stud-ies), followed by the LCSS in 14 studies and the FACT-L in 8studies. Other instruments used included the Daily Diary Card(DDC), RSCL and the FLIC. Some studies used more thanone instrument, e.g. EORTC-QLQ combined with SpitzerQuality of Life Index [105], Sickness Impact Profile (SIP)[8] or Hospital Anxiety and Depression Scale (HADS) [116].The EORTC-QLQ was most commonly used in Europeantrials, while the LCSS and the FACT-L were most commonlyused in North American trials.

Chemotherapy versus best supportive care

Few early studies in advanced NSCLC included QoL analy-ses; however, the completed randomised trials that did evalu-ate QoL showed that platin-based combinations improvedQoL compared to best supportive care. In a controlledmulticentre Swedish study, Helsing et al. compared supportivecare only to supportive care plus carboplatin/etoposide

chemotherapy [47]. Patients in the chemotherapy group re-ported better overall physical functioning and symptom con-trol compared with the supportive care group. In a large UK-based study, Cullen et al. conducted two randomised paralleltrials to determine whether the addition of chemotherapyinfluenced duration and quality of life in localizedunresectable and extensive disease [23]. There was an im-provement in QoL in both groups receiving chemotherapy anddeterioration with standard treatment.

The Big Lung Trial (BLT) was established to evaluate theaddition of chemotherapy to primary treatment in NSCLC[104]. In the supportive care group, there was a small butsignificant survival benefit in patients treated with chemother-apy compared with supportive care alone. A total of 725patients were recruited to the supportive care setting, and asubset of these (273 patients) were entered into the QoL study[14]. Baseline QoL scores across all scales were better for thechemotherapy group compared with the no chemotherapygroup.

A number of newer chemotherapeutic agents haveshown quality of life benefits when compared to best sup-portive care. The first new drug to be studied and approvedby the FDA for NSCLC was vinorelbine. The Elderly LungCancer Vinorelbine Italian Study compared best supportivecare to best supportive care plus chemotherapy in patientsolder than 70 years [108]. QoL analysis showed that pa-tients treated in the vinorelbine arm scored better thancontrols on many subsets including global health status/QoL, several functioning scales and a number of symptomscales.

In a UK-based study, Anderson et al. [4] comparedgemcitabine plus BSC with BSC alone in 300 patients withinoperable NSCLC. The percentage change in mean symptomscores on the EORTC-QLQ from baseline to 2 months was a10 % improvement for gemcitabine plus BSC and a 1 %deterioration for BSC alone. These improvements in patient-assessed QoL were significant in magnitude and weresustained greater than 4 weeks.

A number of studies have evaluated the effects of doce-taxel and paclitaxel compared to best supportive care.Shepherd et al. assessed response to single-agent docetaxelversus best supportive care in patients with NSCLC previ-ously treated with platinum-based chemotherapy [94]. Inaddition to response and survival benefits, treatment withdocetaxel had a favourable impact on QoL parameters.Roszkowski et al. had similar findings in their randomisedstudy of 207 patients with unresectable or metastaticNSCLC who were treated with docetaxel plus BSC orBSC alone [85]. There was an improvement in dyspnoeaand pain scores in the docetaxel group compared to BSC.Ranson et al. evaluated the addition of paclitaxel to BSC toBSC alone [82]. QoL was similar for both treatment arms;however, survival was significantly better in the paclitaxel

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arm than in the supportive care alone arm (median surviv-al=6.8 versus 4.8 months) (Tables 1, 2, 3 and 4).

Effect of platinum-based combinations on QoL

In the past few years, a number of new chemotherapy agentshave been shown to improve survival and relieve symptoms instage IIIB and IV NSCLC patients; these include taxanes,vinorelbine, gemcitabine and the topoisomerase inhibitors[16]. In most instances, the combination of one of these newagents with cisplatin or carboplatin led to higher responserates than those reported for either agent alone, but there weresome concerns that these combination regimes might result inincreased treatment-related toxicities. The inclusion of QoL asan endpoint in clinical trials has gone some way towardsaddressing these concerns. Giaccone et al. from the EORTCLung Cancer Cooperative Group compared paclitaxel/cisplatin versus cisplatin/teniposide in a randomised study of332 patients with advancedNSCLC [38]. Response rates weresuperior in the paclitaxel arm (41 %) versus (28 %) in theteniposide arm (p=0.018). In addition, the paclitaxel groupobtained better palliation with patients achieving a better scoreat week 6 for emotional, cognitive and social functioning,global health status, fatigue and appetite loss.

The Eastern Cooperative Oncology Group compared sur-vival and QoL in 599 patients with advanced NSCLC treatedwith two dose levels of paclitaxel combined with cisplatinversus etoposide with cisplatin [9]. Superior survival wasobserved with the combined paclitaxel regimens comparedwith etoposide plus cisplatin. All three regimens demonstratedsignificant decreases in QoL scores over 6 months, but there

were no significant differences between the regimens.Gatzemeier et al. compared high-dose cisplatin (100 mg/m2)with a combination of paclitaxel (175 mg/m2) and cisplatin(80 mg/m2) every 21 days [34]. The paclitaxel/cisplatin armproduced a better clinical response resulting in an increasedtime to disease progression (4.1 versus 2.7 months in cisplatinonly arm; p=.026); however, there was no significant differ-ence in survival or QOL scores between the two groups.

Kelly et al. compared paclitaxel plus carboplatin versusvinorelbine plus cisplatin in 408 patients with advancedNSCLC [52]. The two drug combinations produced equiva-lent response rates (25 versus 28 %) and survival rates of 38and 36 %, respectively. However, vinorelbine and cisplatinwere associated with increased treatment-related toxicities andtwice as many patients in this group refused therapy becauseof toxicity as compared with those in the paclitaxel/carboplatin arm (28 versus 14 %; p=0.001).

As a single agent, gemcitabine has response rates of 20 to26 % in advanced NSCLC with favourable toxicity [87]. Inthree randomised studies, gemcitabine compared with oldercisplatin doublets showed similar efficacy, with improvedtolerance and functioning [63,80,110]. As carboplatin has amore favourable toxicity profile compared to its analoguecisplatin, it has been substituted for cisplatin in a number ofregimens in a palliative treatment setting. Sederholm et al.compared single-agent gemcitabine versus gemcitabine/carboplatin in patients with locally advanced or metastaticNSCLC [93]. An intent-to-treat analysis showed significantlybetter overall survival and 2-year survival favouring thegemcitabine/carboplatin arm (15 versus 5 %; p=0.009).Rudd et al. from the London Lung Cancer Group comparedgemcitabine plus carboplatin (GCa) with mitomycin/

Table 1 Summary of selected quality of life studies in patients with non-small cell lung cancer receiving chemotherapy

Study Treatment Sample QoLmeasure

Result

Giaccone et al. [38] Paclitaxel/cisplatin versuscisplatin/teniposide

332 EORTC Paclitaxel group achieved better QoL score at week 6which was lost at week 12, no difference insurvival

Helsing et al. [47] Carboplatin/eroposide versus BSC 150 EORTC CT group reported better physical and Sx control

Thongprasert et al. [109] BSC versus BSC + CT (I/Epi/Cis)versus (M/V/Cis)

287 FLIC Improvement in QoL score in CT arm

Cullen et al. [23] Mitomycin/ifosfamide/cisplatin 798 QoL assessedin 134

EORTC Improvement in QoL in patients on CT. Deteriorationwith standard treatment

Crino et al. [22] Gemcitabine/cisplatin versusetoposide/cisplatin

135 EORTC No clinically significant difference in QoL betweentreatments

Cardenal et al. [18] Gemcitabine/cisplatin versusetoposide/cisplatin

135 EORTC No clinically significant difference between treatmentarms in functional domains or QoL

Roszkowski et al. [85] Docetaxel versus BSC 207 EORTC Overall survival significantly longer in the docetaxelgroup. QoL scores in favour of docetaxel

BSC best supportive care, CT chemotherapy, QoL quality of life, FLIC Functional Living Index—Cancer, EORTC European Organisation for Researchand Treatment of Cancer, I isofamide, Epi epirubicin, Cis cisplatin,M mitomycin, V vinblastine, Sx symptoms

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ifosfamide/cisplatin (MIC) in chemotherapy naive patientswith advanced NSCLC [86]. In addition to a significant sur-vival advantage for GCa compared with MIC, QoL parame-ters also favoured the GCa arm.

Effect of new agent combinations on QoL

Comparisons of chemotherapy doublets incorporating newerdrugs have demonstrated no difference in terms of overall

Table 2 Summary of selected quality of life studies in patients with non-small cell lung cancer receiving chemotherapy

Study Treatment Sample QoL measure Result

Bonomi et al. [9] Paclitaxel/cisplatin versusetoposide/cisplatin

559 FACT-L Longer median survival inP/Cis arm. Significantdecline in QoL in bothgroups over 6 months

Gatzemeier et al. [34] High-dose cisplatinversus paclitaxel/cisplatin

414 EORTC P/Cis produced betterclinical response. QoLsimilar in both groups

Anderson et al. [4] Gemcitabine + BSCversus BSC

300 EORTC QoL scores showed greaterimprovement ingemcitabine arm

Frasci et al. [31] Gemcitabine/vinorelbineversus vinorelbine

120>70 years

LCSS Significantly better survivalin G/V arm. Delay in Sx+ QoL deterioration

Ranson et al. [82] Paclitaxel/BSC versusBSC

157 Rotterdam Sx checklist Significantly improvedsurvival + time to diseaseprogression in paclitaxelarm. QoL similar in botharms

Shepherd et al. [94] Docetaxel versus BSC2nd line

103 LCSS in the USAEORTC in Europe

All QoL parameters favourdocetaxel

The Elderly Lung CancerVinorelbine ItalianStudy Group [108]

Vinorelbine versus BSCin elderly patients

191 EORTC Median survival greater invinorelbine arm

BSC best supportive care, Sx symptoms, QoL quality of life, FACT-L Functional Assessment of Cancer Therapy-Lung, EORTC European Organisationfor Research and Treatment of Cancer, LCSS Lung Cancer Symptom Scale, Cis cisplatin, P paclitaxel, V vinorelbine, G gemcitabine

Table 3 Summary of selected quality of life studies in patients with non-small cell lung cancer receiving chemotherapy

Study Treatment Sample QoL measure Result

Kelly et al. [52] Paclitaxel/carboplatin versus vinorelbine/cisplatin

202 FACT-L Median survival 8 months in botharms. Gtr toxicity in V/Cis arm

Moinpour et al. [66] (SWOG) Cisplatin/vinorelbine versus carboplatin/paclitaxel

222 FACT-L No statistical difference on QoLbetween arms

Socinski et al. [101] 4 cycles carboplatin/paclitaxel versuscontinuous therapy

230 FACT-L No overall benefit in survival or QoLto continuing Rx beyond 4 cycles

Langer et al. [58] Cisplatin/eroposide versus paclitaxel 57486>70 years

FACT-L Older females had higher baselineQoL + less change over time thanyounger females

Rosell et al. [84] Paclitaxel/carboplatin versus paclitaxel/cisplatin

618 EORTC Overall QoL similar and low rate ofsevere toxicities in both groups

Gridelli et al. [41] Gemcitabine/vinorelbine versus cisplatin/vinorelbine versus cisplatin/gemcitabine

501 EORTC No significant difference in QoLscores or function scales betweenstudy arms

Smit et al. [99] Paclitaxel/cisplatin versus gemcitabine/cisplatin versus paclitaxel/gemcitabine

480 EORTC Global QoL scores improvedtemporarily in all arms. Nosurvival advantage in the non-platinum arm

QoL quality of life, Rx treatment, EORTC European Organisation for Research and Treatment of Cancer, FACT-L Functional Assessment of CancerTherapy, SWOG South West Oncology Group, Cis cisplatin, V vinorelbine

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survival between the platinum and non-platinum-based regi-mens; however, the non-platinum combinations have a morefavourable toxicity profile [16,36,54]. Georgoulias et al. com-pared the activity and tolerability of docetaxel/gemcitabineand vinorelbine/cisplatin in chemotherapy naive NSCLC pa-tients [37]. Although the two regimens produced comparableoverall survival the docetaxel/gemcitabine arm had a bettertoxicity profile.

Gridelli et al. performed a multicentre randomised phase IIItrial to compare gemcitabine plus vinorelbine with cisplatinplus vinorelbine or cisplatin plus gemcitabine in patientsyounger than 70 years with advanced NSCLC [41]. Therewas no significant difference in general QoL or functionalscales between the different arms after 2 months of treatment.Cisplatin-based chemotherapy improved disease-relatedsymptoms but worsened appetite, vomiting and alopecia.Patients who were treated with a cisplatin-based regimenhad significantly more grade 3/4 neutropenia, vomiting, alo-pecia and ototoxicity. Smit et al. conducted a randomisedstudy of two cisplatin-based regimens and paclitaxel plusgemcitabine in 480 patients with advanced NSCLC [99].There was a trend towards lower progression-free survivaland shorter duration of response for the non-platinum arm.Global QoL score improved temporarily in all three arms andthen returned to baseline values.

Comparison of treatment schedules

Given the non-curative nature of chemotherapy in advancedNSCLC, the duration of chemotherapy administrationmust bebalanced against the toxicity, costs and inconvenience ofchemotherapy. A number of trials have been designed to

ascertain the optimal duration of therapy that maximises thesurvival and palliative effects of chemotherapy [15,100].Socinski et al. compared 4 cycles of paclitaxel/carboplatintherapy (arm A) versus continuous treatment with paclitaxel/carboplatin until disease progression (arm B) in 230 patientswith stage IIIB/IV NSCLC [101]. At progression, all patientsin both arms were to receive second-line weekly paclitaxel. Inarm A, 57 % of patients completed four courses of therapy. Inarm B, the median number of cycles administered was 4(range 0 to 19 cycles); median survival time and 1-yearsurvival rates were 6.6 months and 28 % for arm A and8.5 months and 34 % for arm B, respectively. There were nostatistical differences in QoL between treatment groups.

A number of studies have compared a weekly docetaxelschedule with the 3-weekly docetaxel schedule as second-linechemotherapy for advanced NSCLC. Schuette et al. conduct-ed a multicentre phase III study to ascertain whether a weeklyschedule of docetaxel improved survival, toxicity profile andQoL when compared with the classic 3-weekly schedule [92].Overall response rates were 12.6 versus 10.5% with 3-weeklyversus weekly docetaxel. Significantly fewer patients reportedgrade 3 to 4 toxicities with weekly docetaxel versus 3-weeklydocetaxel (p<0.05). In a similar study (n=220), Gridelli et al.found that both schedules were of equal efficacy; reducedtoxicity was observed for weekly docetaxel versus 3-weeklydocetaxel, including a significant reduction in the incidence ofhaematologic grade 3 to 4 events (p=0.0003) [42]. Fidias et al.compared immediate versus delayed docetaxel in patientspreviously treated with first-line gemcitabine/carboplatin[30]. There was a significant improvement in progression-free survival in patients treated with immediate docetaxel.Hanna et al. compared pemetrexed versus docetaxel in pa-tients with advanced NSCLC previously treated with

Table 4 Summary of selected quality of life studies in patients with non-small cell lung cancer receiving chemotherapy

Study Treatment Sample QoL measure Result

Dancey et al. [24] 2nd line docetaxel versus BSC 49 LCSS Improved survival and QoL in docetaxel arm

Laack et al. [56] Gemcitabine/vinorelbine versusgemcitabine/vinorelbine/cisplatin

300 EORTC G/V was better tolerated. No difference in QoLbetween groups

Paccagnella et al. [75] Mitomycin/vinorelbine/cisplatinversus mitomycin/vinorelbine/carboplatin

153 EORTC Similar RR. Better toxicity profile in carboplatinarm

Kubota et al. [55] Docetaxel/cisplatin versus vindesine/cisplatin

302 Anti-cancer drugs QOLQ Greater RR and better QoL in docetaxel arm

Gridelli et al. [42] Weekly versus 3-weekly docetaxel 220 EORTCDDC

RR and QoL similar in both arms

Baka et al. [5] Comparison of 2 gemcitabineschedules

174 LCSS No significant differences in QoL between arms

Rudd et al. [86] Gemcitabine/carboplatin versusmitomycin/ifosfamide/cisplatin

422 EORTC Better QoL + survival in G/C group

Brown et al. [14] Addition of CT to primary treatment 273 EORTC No important adverse effects of CT on QoL

CT chemotherapy, QoL qualty of life, RR response rate, EORTC European Organisation for Research and Treatment of Cancer, LCSS Lung CancerSymptom Scale, DDC Daily Diary Card, Cis cisplatin, V vinorelbine, G gemcitabine, C carboplatin

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chemotherapy [46]. Both groups had similar response rates,but fewer side effects were reported in the pemetrexed group(Table 5).

Role of molecular-targeted agents

In the past few years, efforts to improve the outcomes in themanagement of NSCLC have focused on the addition of amolecular-targeted agent to standard platinum-based combi-nation regimens. The epidermal growth factor receptor(EGFR) inhibitors have been the most extensively studied incombination with chemotherapy. High levels of EGFR ex-pression have been associated with a poor prognosis in lungcancer patients in several studies [32,79,112]. Erlotinib andgefitinib are orally active, selective EGFR tyrosine kinaseinhibitors that block signal transduction pathways implicatedin the proliferation and survival of cancer cells. In 2003,Fukuoka et al. evaluated the efficacy and tolerability of gefi-tinib in patients with advanced NSCLC previously treatedwith one or two chemotherapy regimens [33]. Efficacy wassimilar for the 250- and 500-mg per day groups. Objectivetumour response rates were 18.4 and 19.05 %; symptom

improvement rates were 40.3 and 37.0 % and median overallsurvival times were 7.6 and 8.0 months, respectively.However, in another study, in which Thatcher et al. comparedgefitinib with placebo plus best supportive care in patientswho were refractory or intolerant of their latest chemotherapyregimen, there was no significant improvement in survival inthe gefitinib group [107]. The National Cancer Institute ofCanada Clinical Trials Group compared erlotinib with placeboin 731 patients with stage IIIB/VI disease after failure of first-line or second-line chemotherapy [96]. The response rate was8.9 % in the erlotinib group and less than 1 % in the placebogroup (p<0.001); the median duration of response was 7.9and 3.7 months, respectively. Overall survival was 6.7 and4.7 months, respectively, in favour of erlotinib (p<0.001). Inthe IPASS (Iressa Pan-Asia Study), gefitinib was comparedwith carboplatin plus paclitaxel as first-line treatment in clin-ically selected patients in East Asia who had advancedNSCLC [67]. The objective response rate in the overall pop-ulation was significantly higher with gefitinib than withcarboplatin/paclitaxel (43 versus 32.2 %); the objective re-sponse rate was 71.2 % with gefitinib versus 47.3 % withcarboplatin/paclitaxel in the positive subgroup (p<0.001) and1.1 versus 23.5 %, respectively, in the mutation negative

Table 5 Summary of selected quality of life studies in patients with non-small cell lung cancer receiving chemotherapy

Study Treatment Sample QoL measure Result

Georgoulias et al. [37] Vinorelbine/cisplatin versus docetaxel/gemcitabine

413 LCSS Similar overall survival between studyarms. D/G had better toxicity profile

Lillenbaum et al. [61] Vinorelbine/gemcitabine versuscarboplatin/paclitaxel

165 LCSS Lower toxicity in V/G arm. QoLsimilar in both groups

Sederholm et al. [93] Gemcitabine/carboplatin versusgemcitabine

334 EORTC Significant survival benefit in G/C arm.No difference in QoL between arms

Schuette et al. [92] Weekly versus 3-weekly docetaxel 215 EORTC Weekly docetaxel had similar efficacy+ better tolerability

von Plessen et al. [113] 3 versus 6 courses of carboplatin/vinorelbine

297 EORTC No survival benefit or significantdifferences in QoL between arms

Belani et al. [6] 2 Docetaxel/platinum regimens versusvinorelbine/cisplatin

926 LCSSEuro QoL

Better QoL scores in docetaxel arms

Hanna et al. [46] Pemetrexed versus docetaxel inpatients previously treated withchemotherapy

571 LCSS RR similar in 2 groups but fewer S.E.with pemetrexed. Similarimprovement/stabilisation in ASBI

Fidias et al. [30] Immediate versus delayed docetaxelafter 1st line G/C

566 LCSS Significant improvement in PFS withimmediate docetaxel. Majority ofpatients in both arms had stableASBI

Gronberg et al. [45] Pemetrexed/C versus G/C 436 EORTC No difference in QoL or OS betweenboth arms. Increased haematologictoxicity in the G arm

Gebbia et al. [35] Cis/docetaxel versus Cis/V 76 EORTC QOL data improved in both arms. Nosignificant difference between arms.Increased haematologic toxicity in Varm

QoL quality of life, EORTC European Organisation for Research and Treatment of Cancer, LCSS Lung Cancer Symptom Scale, V vinorelbine, Ggemcitabine, C carboplatin, ASBI Average Symptom Burden Index, PFS progression-free survival, Cis cisplatin, RR response rate, OS overall survival

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subgroup (p=0.001). Significantly more patients in the gefi-tinib group had a clinically relevant improvement in quality oflife (Table 6).

Bevacizumab, a monoclonal antibody against vascular en-dothelial growth factor (VEGF), has been shown to benefitpatients with a variety of cancers [10,29,53]. In a pivotal phaseIII study (ECOG 4599), Sandler et al. randomised patientswith advanced NSCLC to treatment with carboplatin withpaclitaxel alone or in combination with bevacizumab [89].Following 6 cycles of therapy, patients in the experimentalarm with a response or stable disease were given maintenancemonotherapy with bevacizumab until disease progression orunacceptable toxicity. There were higher incidences of neu-tropenia, hypertension, haemorrhage, proteinuria andtreatment-related deaths with the three drug regime. Despitethis, there was a longer overall survival time (12.3 versus10.3 months) and a higher response rate (35 versus 15 %)with the addition of bevacizumab to carboplatin pluspaclitaxel.

Conclusions

The last decade has seen significant improvement in first- andsecond-line treatment of NSCLC. Chemotherapy prolongssurvival, alleviates disease-related symptoms and can improveQoL in this patient population compared to best supportivecare [14,23,47,104]. Superiority in efficacy, toxicity and QoLhas been demonstrated for new platinum-containing regimenscompared with older regimens [9,34,38,52,63,80,87,93,110].Non-platinum-containing regimens have also demonstratedequivalence in efficacy with differing toxicit ies

[36,37,41,54,99]. Another important consideration is the op-timal duration of palliative chemotherapy. Studies suggest thatthe efficacy benefits of chemotherapy are reached after 3–4 cycles, and further treatment beyond this may only increasetoxicity and reduce QoL [15,100,101].

Significant advances have been achieved in molecularbiology, including the identification of critical genes relatedto the pathogenesis of NSCLC, which have formed the basisfor new targeted therapeutic approaches. Two oral EGFRtyrosine kinase inhibitors, gefitinib and erlotinib, and theVEGF monoclonal antibody bevacizumab have shown prom-ising activity in both first- and second-line settings in patientswith advanced NSCLC. These agents have been shown to beeffective for relieving symptoms, maintaining stable diseaseand improving QoL without the adverse events associatedwith cytotoxic therapies [33,96,107]. The novel multitargetedantimetabolite pemetrexed has shown significant activity anda favourable toxicity profile in the first- and second-linetreatment of NSCLC, both as a single agent and in combina-tion with a platin or gemcitabine [43,62,95].

Recently, the positive role of palliative care in this patientpopulation was highlighted in a study by Temel et al. [106].The goal of this study was to examine the effect of earlypalliative care integrated with standard oncologic care onpatient-reported outcomes, the use of health services and thequality of end-of-life care among patients with metastaticNSCLC.

QoL and mood were assessed at baseline and 12 weeks.Patients assigned to early palliative care had a better QoL thandid patients assigned to standard care. Despite the fact thatfewer patients in the early palliative care group than in thestandard care group received aggressive end-of-life care,

Table 6 Summary of selected quality of life studies in patients with NSCLC receiving chemotherapy +/− EGFR-TKI

Study Treatment Sample QoLmeasure

Result

Fukuoka et al. [33] (IDEAL-1 Trial) Gefitinib 250 or 500 mg for previouslytreated advanced NSCLC

210 FACT-L RR and symptom improvement similar in bothgroups

Shepherd et al. [96] Erlotinib versus placebo in patientswho had received priorchemotherapy

731 EORTC Erlotinib prolonged survival. Improvement inSx in the erlotinib group

Thatcher et al. [107] Gefitinib versus placebo in previouslytreated NSCLC

1,692 FACT-L No significant improvement in survival in thegefitinib group. Gefitinib group hadsignificant improvement in Sx scores

Cella et al. [21] Gefitinib 250 or 500 mg in patientswho had prior chemotherapy

216 FACT-L Sx improved rapidly and correlated with tumourresponse at 250 mg dose

Maruyama et al. [65] Gefitinib versus docetaxel after failed1st/2nd line chemotherapy

490 FACT-L Gefitinib significantly improved RR and QoLversus docetaxel

Mok et al. [67] 1st line gefitinib versus carboplatin/paclitaxel

1,217 FACT-L Superior 1 year progression-free survival andimprovement in QoL in gefitinib group

QoL quality of life, Sx symptoms, EORTC European Organisation for Research and Treatment of Cancer, FACT-L Functional Assessment of CancerTherapy-Lung, NSCLC non-small cell lung cancer, EGFR-TKI epidermal growth factor receptor tyrosine kinase inhibitor, RR response rate

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median survival was longer among patients receiving earlypalliative care (11.6 versus 8.9 months; p=0.02).

Improving patient QoL is an important goal in health care[78,103] and oncology clinical trials [73,111]. While it isimportant to measure performance status over the course ofa clinical trial, it is not adequate by itself as a measurement ofoverall QoL [51,70,71,114,115]. The increasing recognitionof patient autonomy [26,83] means that subjective measureswill become more important and such measures must be validand reliable. As the efficacy benefits of chemotherapy forNSCLC plateau, QoL becomes a more important outcomemeasure in determining the best standard of care for patients.In this patient population, QoL should be considered morefrequently as a primary endpoint of treatment both in clinicalpractice and in clinical trials to further define meaningfulresponse.

Conflict of interest The authors have no conflict of interest to declarein relation to sponsorship or authorship of this research. They havecontrol of the content of this review and the journal can review the dataif requested.

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