Systematic literature review of health-related quality of life in locally-advanced non-small cell lung cancer: Has it yet become state-of-the-art?

Critical Reviews in Oncology / Hematology 119 (2017) 40–49

Contents lists available at ScienceDirect

Critical Reviews in Oncology / Hematology journal homepage: www.elsevier.com/locate/critrevonc

Oncology reviews

Systematic literature review of health-related quality of life in locallyadvanced non-small cell lung cancer: Has it yet become state-of-the-art?

MARK

⁎

Lotte van der Weijsta, , Veerle Surmontb, Wim Schrauwenc, Yolande Lievensa a b c

Department of Radiation Oncology, Ghent University Hospital and Ghent University, Ghent, Belgium Department of Respiratory Medicine, Ghent University Hospital and Ghent University, Ghent, Belgium Department of Medical Psychology, Ghent University Hospital, Ghent, Belgium

A R T I C L E I N F O

A B S T R A C T

Keywords: Health-related quality of life Non-small cell lung cancer Systematic literature review

Lung cancer and its treatment have an important impact on the patients’ health-related quality-of-life (HRQoL). A systematic literature review of prospective clinical studies published since 2005 and measuring HRQoL in patients with locally-advanced non-small cell lung cancer (LA- NSCLC) was performed. Besides reviewing the HRQoL impact of LA-NSCLC treatment, it critically examined the frequency, methodology and quality of HRQoL data collection and analysis in LA-NSCLC clinical studies. Out of 814 potentially eligible publications, only 27 (representing 19 individual studies) met the inclusion criteria. Eight studies documented an impact on HRQoL. Large variability in use of HRQoL instruments, statistical analysis and methodological quality was observed. Reporting of HRQoL data lacks standardization, but recent initiatives establishing recommendations to standardize the analysis and reporting of HRQoL in cancer trials are expected to address these issues. Overall, more research is needed to evaluate the treatment impact on HRQoL in both clinical trials and daily care.

1. Introduction Lung cancer is the most common cause of cancer death globally (Ferlay et al., 2015). Currently, non-small cell lung cancer accounts for more than 80% of all lung cancers, of which the vast majority presents with advanced disease stages and 30–35% has locally-advanced disease (LA-NSCLC) at diagnosis. Choosing the optimal treatment for these patients is difficult because of the large heterogeneity in disease extend and pathology, as well as in co-morbidity and general condition of each individual patient (Stinchcombe and Socinski, 2009). To date no single therapeutic approach can be recommended for all patients, hence the need for personalized care. The prognosis of LA-NSCLC is poor (Aupérin et al., 2010). Regardless of the unceasing efforts made to improve outcome by optimizing multimodality treatment – often consisting of novel combinations of radiotherapy and systemic therapy – the impact on survival remains typically limited to the order of magnitude of months (Stinchcombe and Socinski, 2009; Tanvetyanon et al., 2007). In this context, measuring health-related quality-of-life (HRQoL), in addition to traditional outcome measurements, is considered to be of added value (Damm et al., 2013; Osoba, 2011). In randomized controlled trials (RCT), HRQoL may offer an additional tool to forecast and assess the relative risks and benefits of a new treatment. Moreover, being identified as a prognostic

⁎

factor for survival (Efficace et al., 2006; Langendijk et al., 2000; Lemonnier et al., 2014; Movsas et al., 2009), pretreatment HRQoL measurement has the potential to aid daily clinical decision-making and choosing the optimal treatment for the individual patient (Damm et al., 2013). Whereas quality-of-life (QoL) tools measure all facets of life, including non-health related aspects, HRQoL measurement instruments quantify only the degree to which a disease and the therapy chosen impacts the patient’s life. Yet, the terms QoL and HRQoL are frequently used interchangeably. Although the definition of HRQoL may differ from study to study, it generally refers to a multidimensional concept covering physical, role, emotional, social, cognitive, sexual and spiritual functioning (Fayers and Machin, 2000; McKenna, 2011). We define HRQoL measurements in lung cancer as measurements evaluating the relation between lung cancer and its treatment and the various aspects of functioning and of lung cancer-related symptoms, such as pain, appetite-loss and nausea. If these measurements are performed directly by the patient, they are referred to as patient-reported outcomes, PRO (Frost et al., 2007). The aim of this systematic literature review is to provide an overview of prospective clinical studies in LA-NSCLC published over the last decade using HRQoL as an endpoint. In particular, this review wants to shed light on how often and how HRQoL is included in LA-NSCLC

Corresponding author at: Department of Radiation Oncology, Ghent University Hospital, De Pintelaan 185, Ghent 9000, Belgium. E-mail address: [email protected] (L. van der Weijst).

http://dx.doi.org/10.1016/j.critrevonc.2017.09.014 Received 22 June 2016; Received in revised form 4 August 2017; Accepted 26 September 2017 1040-8428/ © 2017 Elsevier B.V. All rights reserved.

Critical Reviews in Oncology / Hematology 119 (2017) 40–49

L. van der Weijst et al.

3.1. General characteristics

studies and whether HRQoL has an additional value to determine outcome in this critical patient population. Moreover, the statistical approach and methodological quality of HRQoL assessment and reporting in these studies is reviewed.

Of the 19 studies in this review, 11 were RCTs, (6 phase II; 5 phase III), 7 were single arm studies (1 phase I, 2 phase II, and 4 phase I–II) and one was a pilot study. The impact of a variety of therapeutic options was evaluated. Of interest is that all studies included radiotherapy, either in combination with systemic cancer therapy, surgery or with medication aiming to reduce adverse effects. Different radiotherapy approaches were studied including external beam radiotherapy and brachytherapy, curative and palliative radiotherapy schedules, loco-regional radiotherapy and prophylactic cranial irradiation, various fractionation schedules. One study lacked specification on the radiotherapy treatment (Whitney et al., 2010, 2008).

2. Materials and methods 2.1. Literature search A literature search, conducted according to the PRISMA principles (Moher et al., 2009) was performed in Medline, Web of Science, Embase and Cochrane database with both systematic and free text terms concerning HRQoL, locally advanced and NSCLC. The last search was performed on March 31st, 2017. In addition, hand-searching the references of the eligible publications was undertaken to identify more potentially relevant papers.

3.2. HRQoL measurement The way in which HRQoL parameters were evaluated differed amongst the studies. In only two studies, HRQoL was a co-primary endpoint (Goldberg et al., 2015; Van der Meij et al., 2012a, 2012b, 2010). In the remaining 17 studies, HRQoL was a secondary endpoint. One study looked into confounders possibly influencing the relation between cognitive functioning and chemotherapy (Whitney et al., 2010, 2008). Overall, four different HRQoL measurement instruments were identified within the included studies: the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30) questionnaire along with its brain (QLQ-BN20) and lung cancer supplement (QLQLC13/LC14) (Koller et al., 2015), Lung Cancer Symptom Scale (LCSS), the 36-Item Short Form Survey (SF-36) and Functional Assessment of Cancer Therapy Lung (FACT-L) version II, of which one study used a validated component (FACT-TOI) (Movsas et al., 2016). Compliance rate to follow-up varied greatly among the studies and typically decreased over time, from almost 100% at baseline in most studies to as low as 20% at 30 months follow-up in one trial (Li et al., 2015). Seven studies did not report compliance rates, one of these did not provide details on follow-up time points (De Ruysscher et al., 2007).

2.2. Study selection All prospective clinical studies, both clinical trials and observational studies, published in English between January 2005 and December 2016, focusing on the treatment of LA-NSCLC and reporting repeated assessments of HRQoL, were included. In case the HRQoL concept was briefly mentioned without comprehensive details, an attempt was made to search for companion papers that addressed HRQoL data in more detail. Studies measuring symptom scores assessed by HRQoL measurements were also included. Review articles, conference presentations, short reports, study protocols, editorials and letters were excluded, as well as publications without full-text availability. HRQoL analyses published independently from the clinical studies, identified by screening the bibliography of the selected papers, were reviewed along with the original publication. In case a study was presented in more than one publication, all relevant publications were included in this review, but were counted as one study. 2.3. Data extraction Abstract screening was performed by three investigators (LVDW, VS, YL). For each included study, general characteristics and data on HRQoL parameters were abstracted. Data extraction of articles was performed by one investigator (LVDW) in close collaboration with two others (VS, YL). Reviewers met early in the reviewing process to ascertain consensus and avoid discrepancies.

3.3. HRQoL outcome Only four of the 11 RCTs reported a significant difference in HRQoL between treatment arms. Two showed an improvement in HRQoL. One following the addition of oral nutritional supplements with fatty acids (Van der Meij et al., 2012a, 2012b, 2010); another after concurrent chemo-radiotherapy over chemotherapy alone (Strøm et al., 2014a, 2014b, 2013). Another study evaluating accelerated hypofractionated radiotherapy delivered concurrently with chemotherapy showed a mixed response with better emotional, social and cognitive functioning and less chest pain while worsening alopecia in this arm compared with neoadjuvant chemotherapy followed by standard radiotherapy (Roy et al., 2016). The RTOG 0617 study reversely reported a clinically meaningful decline in HRQoL after 74 Gy compared to 60 Gy at 3 months (Movsas et al., 2016). Additionally, two RCTs reported no significant difference between therapy arms, but reported an overall HRQoL decline in both arms (Shehata et al., 2013; Stephens et al., 2005). In 7 single arm studies HRQoL was monitored over time. In only three of these, a significant difference in HRQoL was reported. A radiotherapy dose-escalation study found decreased global health status and worsened functional parameters and symptoms at the end of treatment compared to baseline (Bral et al., 2010). In another study, HRQoL remained stable during induction therapy, but decreased significantly after surgery and concurrent chemo-radiotherapy. During adjuvant therapy and follow-up HRQoL recovered to baseline (Kocher et al., 2014). At last, one showed patients receiving brachytherapy experienced improved HRQoL at one month after therapy (Mallick

2.4. Evaluating the methodological quality of HRQoL assessment The methodological quality of each primary study was assessed by the 2013 CONSORT (Consolidated Standards of Reporting Trials) PRO (patient-reported outcome) extension checklist. This checklist provides guidance on reporting PROs in RCTs with PROs as primary or secondary endpoints. The CONSORT-PRO extension checklist added 5 items to the CONSORT 2010 checklist to aid optimal reporting of PRO data (Calvert et al., 2013). As certain items in the checklist are not applicable for some of the included studies, such as those concerning blinding and randomization, analysis in these studies was restricted to the applicable items. 3. Results Eight hundred fourteen articles were extracted, in addition, 12 publications were found through hand search the references. After abstract review, 68 articles were submitted to full text analysis. As a result, 27 publications (representing 19 studies) were submitted to qualitative synthesis. The stages of the review process are summarized in Fig. 1. Details of the general characteristics of the included studies and of the HRQoL evaluation are presented in Table 1, respectively 2. 41

Critical Reviews in Oncology / Hematology 119 (2017) 40–49

L. van der Weijst et al.

Fig. 1. Flow chart describing the review of the manuscripts and the data extraction process.

over the last decade. Although a total of 814 references was retrieved, only 19 clinical studies for LA-NSCLC included HRQoL as an endpoint. This scarcity underscores the need for further research in this topic of interest in a disease entity with limited outcome in terms of survival. This also shows that the importance of HRQoL in LA-NSCLC patients is still underestimated. Traditionally, clinical trials have focused on biomedical endpoints, particularly survival and disease free survival or local control in radiotherapy trials, to define response to therapeutic interventions (Fiteni et al., 2014). However, it is increasingly recognized that HRQoL parameters are important to ascertain overall treatment effectiveness in clinical trials testing new interventions in cancer care. As a result, the proportion of cancer clinical trials that include HRQoL as an endpoint has been rising during the last decades (Fiteni et al., 2014; Goodwin et al., 2003; Osoba, 2011). In these cases, HRQoL outcomes are generally used as non-primary endpoints to provide additional support for biomedical outcomes. As shown by our data, relatively little research has been conducted on HRQoL in clinical studies for LA-NSCLC patients, maybe because the major emphasis lies on treatment with curative intent. On the contrary, a substantial number of clinical trials studied HRQoL outcomes in patients presenting with metastatic disease, where cure is no longer achievable. It seems evident that weighting disease- and therapy-related HRQoL outcomes is more frequently undertaken in decisionmaking for treatment in the non-curative setting, where the primary aim is prevention and alleviation of suffering more than prolonging life (Simone and Jones, 2013). This is exemplified in the work undertaken by Saad and colleagues, in which a systematic literature review on HRQoL in advanced NSCLC, referring to stages IIIB ‘wet’ and IV was conducted. They observed that HRQoL was assessed in almost 60% of phase III studies, accounting for 72 out of 122 extracted studies in advanced NSCLC published between January 1998 and December 2009 (Saad et al., 2012). A growing interest for HRQoL can also be observed in adjuvant therapeutic settings, such as chemotherapy in breast cancer or hormone therapy in prostate cancer (Adamowicz et al., 2012; Penson et al., 2003). The role of adjuvant treatment in preventing or delaying recurrence after primary therapy and its potential early and delayed impact on HRQoL plays an important role in therapeutic decisionmaking. Clinical benefits and preservation of HRQoL clearly need to be balanced, hence evaluated. Yet, in early-stage lung cancer trials, limited

et al., 2007). Defining the treatment impact on HRQoL is not straightforward: two single-arm studies did not report any conclusions; one due to premature closure of the study (Dilling et al., 2014; Gore et al., 2011a); two RCTs stated that the conclusions drawn should not be considered conclusive due to small sample sizes (De Ruysscher et al., 2007; Whitney et al., 2010, 2008). In addition to, purely measuring HRQoL, it is also important to know how they align with clinical outcomes. In the two studies mentioned previously, concurrent chemo-radiotherapy did not only have a positive impact on survival and local control, but also on HRQoL (CONRAD; Roy). The inverse is seen in the RTOG 0617 study, where dose escalation not only negatively impacted on HRQoL, but also surprisingly on survival and local control (Movsas). In four studies, no difference in outcome and HRQoL was reported. One study reported a decline in HRQoL, regardless of better clinical outcome, using surgical multimodality treatment compared to radical radiotherapy. In most cases, however, such conclusions are difficult to draw, as clinical outcome or HRQoL impact is insufficiently reported. 3.4. Statistical analysis Different statistical analytic techniques have been applied to interpret the HRQoL data over time. Eight studies did not specify the statistical approach used to evaluate the HRQoL parameters. Eight studies used the repeated t-test, ANOVA technique to calculate differences in mean HRQoL scores and 3 studies calculated the difference in HRQoL for each participant between baseline and follow-up with a decrease of 10 points considered to be a clinically relevant decrease in HRQoL. 3.5. Methodological quality The methodological quality and completeness of HRQoL data reporting differed substantially. Fig. 2 provides an overview of adherence with the CONSORT-PRO extension checklist. Particularly, details on PRO are missing. 4. Discussion Our data provides a comprehensive and in-depth review of the existing evidence on HRQoL in clinical studies of LA-NSCLC treatments 42

n = 151

n = 40

RCT/II

RCT

Nyman et al.(2009) − RAKET Van der Meij et al. (2010, 2012a, 2012b)

43 RT + cetuximab followed by CT + cetuximab

n = 27

Singlearm/ II

Singlearm/II

Dilling et al. (2014)

Kocher et al. (2014) − TAX-AT 1.203 Trial

n = 78

CRT versus CT

n = 191

RCT/III

Induction therapy + surgery or CRT+ adjuvant therapy

EBRT (hypo) + EC versus EC versus EBRT (hypo)

Strøm et al. (2013, 2014a, 2014b, Conrad

Shehata et al.(2013)

n = 40

CT followed by EBRT + cetuximab

n = 71

Singlearm/ I-II

Singlearm/ II RCT

RT + celecoxib

n = 18

RCT/III

Gore et al. (2011a) and Sun et al. (2011) RTOG 0214 Gore et al. (2011b) − RTOG 0213

Hallqvist et al. (2011) Satellite

PCI versus observation

n = 180

Singlearm/I

dose-escalation CRT

CRT + nutritional supplement ± fatty acids

EBRT (hyper) versus CRT (daily/weekly CT)

CRT

EBRT ± celecoxib

Bral et al. (2010)

n = 34

n = 14

n = 41

Pilot study

De Ruysscher et al. (2007)

Whitney et al. (2008, 2010)

BT ± EBRT (hypo)

n = 45

Singlearm/ I-II RCT/II

Mallick et al. (2007)

CT + S versus RT

n = 48

RCT

CT + CRT (hyper) ± AM

n = 242

RCT/III

Movsas et al. (2005, 2009) and Sarna et al. (2008) RTOG 9801 Stephens et al. (2005)

Treatment outline

Patient numbers

Study/ Phase

Author (Year) − STUDY

Table 1 Study characteristics.

unresectable stage III endobronchial NSCLC, WHO PS 0–2, therapy-naïve unresectable stage III NSCLC, no pleural effusion, tumor size ≥8 cm, PS ≥ 2 or weight loss > 10% over the last 6 months and no candidates for radical EBRT, CTnaïve inoperable/unresectable stage IIA − ‘dry’ IIIB NSCLC, ECOG PS 2 or weight loss ≥ 5% over the last 3 months or R aged ≥ 70 years stage II-III

unresectable/inoperable IIB – IIIB NSCLC, Zubrod PS 2 and/or weight loss > 5% over the last 3 months or usual of CT or comorbidity precluding CRT unresectable/inoperable stage III NSCLC, WHO PS 0–1, therapy-naïve

inoperable stage III NSCLC, life expectancy ≥ 12 weeks, KPS ≥ 80, weight loss ≤ 10% over the last 3 months stage III NSCLC after definitive therapy without disease progression

IIIA-N2/IIIB NSCLC eligible for multimodality therapy

inoperable stage III NSCLC, WHO PS 0–1

stage III NSCLC without pre-existing neurologic impairment

stage II/III NSCLC

inoperable T3, N1, M0 or T1-3, N2, M0 NSCLC with the potential to become resectable following CT, WHO PS 0–2 LA-NSCLC with endobronchial disease with ≥ 1 symptoms, d KPS 60–80

stage II/III inoperable NSCLC

Study population

(continued on next page)

ORR to neoadjuvant induction

PFS

PFS

To define the feasibility and efficacy of neoadjuvant induction therapy with cisplatin/docetaxel in LA-NSCLC, as part of a treatment plan including radical resection, if possible, or CRT as alternative

OS

Symptom response

Clinical benefit at 12 months, defined as CR, PR and SD

Phase I: Safety of concurrent EBRT and celecoxib Phase II: OS

OS

Toxicity

QoL and functional status

TTP

Response 3 months post-treatment, local PFS 9 months post-treatment, radiopneumonitis, maximal acute oesophagitis and OS Neuro-cognitive functioning

To compare a palliative CRT regimen to palliative CT alone, with respect to survival, HRQoL and toxicity

To explore how potentially confounding variables might affect the relationship between cognitive function and CT To compare loco-regional control in patients treated with EBRT or CRT To investigate the effects of an oral nutritional supplement containing (n-3) PUFA on nutritional status and inflammatory markers in patients undergoing multimodality therapy To determine the maximum tolerated dose of helical tomotherapy EBRT administered concurrently with docetaxel and cisplatin To test whether OS rate at 1 year improved by 20% in the PCI arm compared with observation To investigate celecoxib in combination with EBRT, either 60–66 Gy/30-33 fractions or 45 Gy/15 fractions, in patients with relatively poor prognostic factors To assess the clinical benefit of conventionally fractionationated RT combined with cetuximab To evaluate the outcome of EC and/or EBRT

Survival

To assess whether neo-adjuvant CT followed by S results in better outcomes than radical RT in inoperable patients To test the hypothesis of reduced endobronchial symptoms and improved QoL of BT with or without EBRT To investigate whether celecoxib could improve tumor response to radiation.

Symptom response and duration of symptom control

Rate of esophagitis

Primary endpoint

To test the ability of AM to reduce the rate of esophagitis in patients receiving concurrent hyperfractionated CRT

Primary objective

L. van der Weijst et al.

Critical Reviews in Oncology / Hematology 119 (2017) 40–49

Critical Reviews in Oncology / Hematology 119 (2017) 40–49

stage III, age < 70, squamous cell cancer, ECOG PS 0–1, no prior oncology treatment, no significant comorbidity, no synchronous or prior malignancy CT followed by external RT versus accelerated hypo CRT n = 35 RCT/II Roy et al. (2016)

Abbreviations: AM, amifostine; BT, brachytherapy; CR, complete response; CT, chemotherapy; CRT, concurrent chemo-radiotherapy; CT-RT, sequential chemo-radiotherapy; DFS, disease-free survival; EBRT, external-beam radiotherapy; EC, endobronchial electrocauter; ECOG, Eastern Cooperative Oncology Group; hypo, hypofractionated; hyper, hyperfractionated; KPS, Karnofsky Performance Status; LC, local control; NSCLC, non-small cell lung cancer; ORR, overall response rate PCI, prophylactic cranial irradiation; PFS, progression-free disease; PR, partial response; PS, performance status; PUFA, polyunsaturated fatty acids; QoL, quality of life; RT, radiotherapy; RCT, randomized controlled trial; RTOG, Radiation Therapy Oncology Group; SD, stable disease; TTP, time to progression; WHO, World Health Organization

ORR and PFS

OS Standard-dose RT versus high-dose RT + CT + /− Cetuximab RCT/III Movsas et al. (2016) − RTOG 0617

n = 424

RCT/III Li et al. (2015)

n = 156

PCI versus observation

completely resected stage IIIA–N2 NSCLC with high risk of cerebral metastases after adjuvant CT, age 18–75, ECOG PS 0–2 unresectable stage III NSCLC, ECOG PS-0-1

To compare OS after standard-dose versus high-dose conformal CRT and cetuximab to concurrent RCT To evaluate the feasibility and efficacy of accelerated hypo CRT

DFS

Survival and QoL

To analyze high-dose-rate endobronchial BT in the palliation of obstructive symptoms in lung cancer patients To compare the effect PCI versus observation on DFS stage III with endobronchial disease and obstructive symptoms BT Singlearm Goldberg et al. (2015)

n = 98

Study/ Phase Author (Year) − STUDY

Table 1 (continued)

Patient numbers

Treatment outline

Study population

Primary objective

Primary endpoint

L. van der Weijst et al.

attention has been so far been paid to HRQoL in adjuvant setting (Burdett et al., 2006). In this review, only 9 out of the 19 included clinical studies reported a significant difference in HRQoL outcomes within and between treatment arms, of which only three studies reported a deterioration of HRQoL at the end of therapy or three months after completion of therapy (Bral et al., 2010; Movsas et al., 2016; Stephens et al., 2005). Additionally, Kocher et al. initially reported a HRQoL deterioration, but recovery nearly to pre-therapy levels thereafter (Kocher et al., 2014). This seems to suggest that the potential negative effects of treatment on HRQoL in LA-NSCLC are temporary with HRQoL returning to baseline shortly after treatment termination or that the negative impact on HRQoL was compensated by the therapeutic effect. But there may be another reason why changes in HRQoL stay under the radar. Hallqvist, Bergman and Nyman performed an additional exploratory HRQoL analysis using the data from their respective studies (Hallqvist et al., 2012, 2011; Nyman et al., 2009). The aim was to compare HRQoL in patients receiving concurrent cetuximab and thoracic irradiation to those undergoing more standard treatments using accelerated hyperfractionated radiotherapy only or concurrent daily or weekly chemo-radiotherapy. In contrast to the original studies, they observed significant differences in global QoL: patients receiving cetuximab and thoracic irradiation faired significantly better over time than those receiving the other treatment approaches (p = 038). That the effect only becomes evident when pooling the two studies, which on their own did not reach statistical significance for HRQoL parameters, suggests that a higher statistical power was needed to make HRQoL effects evident. Statistical power analyses are typically based on the primary endpoint (Neill, 1997). Therefore, the potential effect of therapy on HRQoL may possibly be underestimated. Measuring HRQoL in LA-NSCLC is challenging, in line with the patient- and tumor-specific characteristics of the disease. The majority of patients diagnosed with LA-NSCLC is elderly, which increases the risk of co-morbidities (De Ruysscher et al., 2009), and in turn may bias HRQoL assessments. Baseline HRQoL data are generally lower in patients that experience quick disease evolution. While LA-NSCLC is associated with low overall survival, when relapse occurs a rapid deterioration of physical health is frequently observed (Gridelli et al., 2001). Deterioration of performance status again is associated with lower compliance to HRQoL measurements, and incomplete outcome data with high risk of bias (Gridelli et al., 2001). That missing data over time in HRQoL measurement of LA-NSCLC may lead to problems in data analysis and to misinterpretation of the results is illustrated by the experience of Sun et al., evaluating the addition of PCI in stage III NSCLC after definitive therapy without disease progression. They reported that the accrual goal of the study was not reached as compliance rate dropped to 37% at 12 months (Gore et al., 2011b; Sun et al., 2011). Due to missing data, they were unable to identify subgroups of patients with the highest risk of developing toxicities impacting on HRQoL. The amount of missing data clearly depends on baseline characteristics and follow-up period. In order to be able to interpret HRQoL data adequately, it is essential to report missing data by arm and over time (Claassens et al., 2011). In addition, upfront power calculations determining the number of participants that are required should ensure internal validity of the study (Walters, 2004). As mentioned previously, in the majority of the studies included in this review, detailed reporting on missing data is lacking, as well as power calculation for the secondary HRQoL endpoints. A further methodological problem is that HRQoL outcomes are analyzed inconsistently, yielding data that are hardly comparable statistically due to lack of standardization (Damm et al., 2013; Efficace et al., 2007). In our review, the majority of studies measured changes in HRQoL scores over time by calculating mean group differences at different time points. However, these techniques have a few drawbacks. These methods 44

Critical Reviews in Oncology / Hematology 119 (2017) 40–49

L. van der Weijst et al.

Fig. 2. Overview of adherence with CONSORT-PRO extension checklist.

population are not truly representing the target population. In contrast to above-mentioned standard statistical tests that rely greatly on the assumption of independence of observation and therefore have too small standard errors, mixed models allow analyzing data from repeated measures in the same subjects. They have the ability to consider variances in time between measures. Furthermore, mixed models accept missing data on subjects as long as they meet the missing at random definition. (Hox, 2004). Furthermore, interpretation of individual HRQoL trends in which each patient serves as his or her own control, as was performed in three of the evaluated studies (Gore et al., 2011a; Movsas et al., 2016, 2009,

ignore the sampling hierarchy; the assumption is made that the variances of the sample population is equal to the target population; and they lacks the ability to accommodate missing data points (Quené and Van Den Bergh, 2004). Sampling hierarchy refers to multiple stages sampling. This means that sampling is carried out in multiple stages using smaller sampling unites for each stage. Patient populations recruited for clinical studies have a hierarchical structure, because they are recruited from certain health care facilities in certain geographical locations. Because of all these reasons, mixed models to analyze longitudinal HRQoL data is recommended. Mixed models (also known as multi-level models) take into account that the variances of the sample

45

46

Secondary

Secondary

Secondary

Co-primary

Secondary

Secondary

Strøm

Dilling

Kocher

Goldberg

Li

Movsas

Secondary

Bral

Secondary

Co-primary

Van der Meij

Shehata

Secondary

Nyman

Secondary

Secondary

Whitney

Hallqvist

Secondary

De Ruysscher

Secondary

Secondary

Mallick

Gore

Secondary

Stephens

Secondary

Secondary

Movsas; Sarna

Gore; Sun

HRQoL endpoint

Author

Table 2 HRQoL evaluation.

FACT-TOI

EORTC QLQC30 + QLQ-LC13 FACT-L

EORTC QLQ-C30

FACT-L

EORTC QLQC30 + QLQ-LC13

EORTC QLQ-C30

EORTC QLQC30 + LC14

LCSS

EORTC QLQC30 + QLQ-BN20

EORTC QLQC30 + FACT-L

EORTC QLQ-C30

EORTC QLQC30 + LC14

FACT-L

EORTC QLQC30 + QLQ-LC13

EORTC QLQ-C30

SF-36

EORTC QLQC30 + QLQ-L13

HRQoL instrument

Baseline and every 3 months for at least 1 year Baseline, 6, 12, 18, 24 and 30 months after PCI

Before treatment, at 1 week and 1 month following treatment At randomization, at every CT course and every 8th week after the end of treatment until 1 year after randomization Baseline, 9–11 and 18 weeks after start of therapy Baseline, at induction therapy, surgery, CRT, adjuvant therapy, end of treatment and follow up

Baseline, before EBRT, 6 weeks and 4 months after EBRT

Baseline, 3, 6 and 12 months

Baseline, 6 and 12 months after start study

Beginning and end of therapy

Baseline, after 3 and 5 weeks of start CT

Baseline, before EBRT, 1 and 4 months after end therapy

Baseline, 1 and 7 months post-CT

Not specified

Baseline, 12 weeks and 6 months after randomisation Before and 1 month after treatment

Baseline, before start of CRT, week 6 of CRT and 6 weeks after end CRT

Follow-up HRQoL

During induction therapy, HRQoL parameters remained mainly stable. HRQoL decreased significantly after S or CRT. During adjuvant therapy and follow-up, HRQoL improved, mostly to pre-therapy levels BT dose was not found to affect survival or HRQoL No significant differences in deterioration rate for QoL between treatment arms More patients had clinically meaningful decline in HRQoL in high-dose RT than

Not specified

PCI: 95 − 61 − 62 − 47 − 51 − 32; Observation: 97 − 58 − 55 − 41 − 34 − 21 72 (at baseline) − 57 (1 year)

Not specified

No conclusion on HRQoL

Not specified

99 (at randomization) − 84 − 85.5 (after 6 months; CT vs CRT) − 67 − 75 (during last 6 months; CT vs CRT)

Not specified

97 − 96 − 94 − 93a

Approximately 60 − 40 − 30

PCI: 90 − 47 − − 34 Observation: 92 − 71 − 50

Not specified

100 − 87.5 − 75

99 − 96 − 92 − 92a

100 − 93 − 64

Not specified

Not specified

CRT is superior to CT alone in terms of HRQoL

No significant differences between and within treatment arms over time, except for pain, favoring AM arm No significant difference between arms, but HRQoL decline was seen in both arms Symptom scores, functional scales and overall QoL were improved in patient receiving EBRT; other HRQoL parameters were maintained No significant difference in HRQoL between treatment arms; no definitive conclusions due to the limited number of patients No significant correlations between HRQoL variables and cognitive test scores; no definitive conclusions due to the limited number of patients No significant differences between treatment arms according to the parameters: dyspnoea, dysphagia, global QoL scores and expected toxicity Significant difference between supplements with/without fatty acids, favoring supplements with fatty acids Decrease in several functional parameters and increase in most symptom scores after treatment; global health status decreased at the end of treatment No significant differences between treatment arms at 6 or 12 months amongst any HRQoL parameter No conclusion on HRQoL due to premature study closure No substantial decrease in functional scales, but some temporarily worsening in therapyrelated symptoms HRQoL improved significantly

AM: 91 − 66 − 5 − 55 Observation: 93 − 62 − 43 − 40 90 − 65 − 69

HRQoL outcome

Compliance rate (%)

9/25 (36%)

Not specified

Individual HRQoL differences

Not specified

(continued on next page)

23/24 (96%)

13/24 (54%)

7/21 (33%)

10/22 (45%)

Not specified

Not specified

6/21 (29%)

17/25 (68%)

8/24 (33%)

7/22 (32%)

7/21 (33%)

Not specified

ANOVA

Not specified

ANOVA

Not specified

15/25 (60%)

7/21 (33%)

ANOVA and Student ttests

Individual HRQoL differences

16/22 (73%)

12/25 (48%)

Not specified

ANOVA

6/22 (27%)

12/21 (57%)

Paired T-test

Not specified

10/24 (42%)

17/26 (65%)

Adherence with checklist n (%)

Mann–Whitney test

Individual HRQoL differences

Statistical analysis

L. van der Weijst et al.

Critical Reviews in Oncology / Hematology 119 (2017) 40–49

Critical Reviews in Oncology / Hematology 119 (2017) 40–49 Abbreviations: CT, chemotherapy; CRT, chemo-radiotherapy; EBRT, external-beam radiotherapy; EC, endobronchial electrocauter; EORTC QLQ-C30, Quality of life questionnaire of the European Organization for Research and Treatment of Cancer; FACT-L, Functional Assessment of Cancer Therapy-Lung; FLIC, Functional Living-Index Cancer; HRQoL, health-related quality of life; PCI, prophylactic cranial irradiation; QoL, quality of life; RT, radiotherapy; RTOG, Radiation Therapy Oncology Group. a Corrected for drop-outs due to death during treatment or follow-up.

Improvement of emotional, social, cognitive function and chest pain and worsening of alopecia was observed in neoadjuvant therapy with accelerated hypo CRT 100 − 78 Secondary Roy

EORTC QLQC30 + QLQ-LC13

Baseline, during the last week of CRT, and 3 and 12 months after onset therapy Pre- and post therapy

standard-dose RT (45% versus 30%) at 3 months

Compliance rate (%) HRQoL endpoint Author

Table 2 (continued)

HRQoL instrument

Follow-up HRQoL

HRQoL outcome

Statistical analysis

Two-sample Wilcoxon rank-sum test

16/24 (67%)

Adherence with checklist n (%)

L. van der Weijst et al.

2005; Sarna et al., 2008; Sun et al., 2011) is recommended (Osoba et al., 2005). Mean scores in long-term trends in multiple therapy groups ignore the fact that patients with considerably low pre-therapeutic HRQoL may either benefit more or less from therapy in terms of HRQoL than those with a high self-reported baseline HRQoL. Statistical significance does not guarantee clinical relevance. The same holds for HRQoL. Clinically significant effects refer to the smallest meaningful differences in HRQoL perceived by the patients. Even if some studies reported significant improvements or worsening of HRQoL scores, their clinical relevance for the patient was not addressed (Norman et al., 2003). Yet, as a rule, patient-perceived meaningful differences should drive HRQoL data reporting and analysis. Here again, using the above-mentioned statistical approach where each patient acts as his/her own control, with analysis driven by predefined clinically relevant changes, may be most optimal. The establishment of clinically meaningful differences for different HRQoL assessment tools needs further standardization. Along with the variability in – or almost lack of – valid statistical approach, the quality of HRQoL evaluation in our reviewed studies was also found highly variable (see Table 2). Although no formal international consensus has yet been reached for the analysis of HRQoL and other PRO data in clinical trials, the “Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data (SISAQOL)” initiative has been launched to address this issue. The consortium aims to establish recommendations to analytically approach HRQoL endpoints and interpret HRQoL data in randomized cancer trials (Bottomley et al., 2016). Adherence to such basic quality reporting of HRQoL or PRO would avoid bias in the interpretation of HRQoL/PRO of different therapeutic options and is necessary to support evidence-based decision-making (Calvert et al., 2013). In our review the absence of detailed information concerning PRO was frequently missing, such as PRO hypothesis (37%), PRO-specific limitations and implications for generalizability and clinical practice (11%) and statistical methods to deal with missing data (5%). In addition, other basic aspects of quality reporting are often overlooked, including details on accessibility of protocol (11%), registration number (32%) and blinding details (33%). The 2013 CONSORT PRO-extension is a useful tool to help researches describing HRQoL and other PRO data (Calvert et al., 2013). This systematic literature review has some limitations. First, publications were limited to the English language and published between January 2005 and December 2016. The publication time frame covering the last decade was chosen to capture data from recently conducted clinical studies, expected to be most representative for HRQoL of patients undergoing nowadays LA-NSCLC treatments. Secondly, due to the limited number of eligible studies, the variability in evaluated therapies and heterogeneity in methodology used for HRQoL analysis, it remains hazardous to draw any firm conclusions on the HRQoL effect of therapeutic interventions in LA-NSCLC evaluated in the context of clinical studies. Lastly, having restricted the analysis to clinical studies may be considered a limitation as well. As is customary, the studies included in this systematic review have highly selective eligibility criteria, such as for age or performance status, which may limit external validity of the results. The infrequent inclusion of elderly patients in lung cancer trials, for example, is a well-known drawback, as they represent the vast majority of the population in daily clinical care (De Ruysscher et al., 2009). Moreover, once considered eligible for a trial, the treatment allocation is performed according to study algorithms, typically disregarding patients’ specificities and preferences, which may not guarantee the most patient-centered approach in this heterogeneous patient population. In conclusion, HRQoL research is not well developed in clinical studies exploring new therapeutic interventions for LA-NSCLC. Yet unfortunately, survival remains poor in this patient population underscoring the importance to focus on quality of the remaining life. Due to the large range in treatments investigated, along with the variability in 47

Critical Reviews in Oncology / Hematology 119 (2017) 40–49

L. van der Weijst et al.

Hochstenbag, M., Dingemans, A.M.C., Bootsma, G., Geraedts, W., Simons, J., Pitz, C., Lambin, P., 2009. Eligibility for concurrent chemotherapy and radiotherapy of locally advanced lung cancer patients: a prospective, population-based study. Ann. Oncol. 20, 98–102. http://dx.doi.org/10.1093/annonc/mdn559. Dilling, T.J., Extermann, M., Kim, J., Thompson, L.M., Yue, B., Stevens, C.W., Antonia, S., Gray, J., Williams, C., Haura, E., Pinder-Schenck, M., Tanvetyanon, T., Kim, S., Chiappori, A., 2014. Phase 2 study of concurrent cetuximab plus definitive thoracic radiation therapy followed by consolidation docetaxel plus cetuximab in poor prognosis or elderly patients with locally advanced non-small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 90, 1–6. http://dx.doi.org/10.1016/j.ijrobp.2014.07.023. Efficace, F., Bottomley, A., Smit, E.F., Lianes, P., Legrand, C., Debruyne, C., Schramel, F., Smit, H.J., Gaafar, R., Biesma, B., Manegold, C., Coens, C., Giaccone, G., Van Meerbeeck, J., 2006. Is a patient’s self-reported health-related quality of life a prognostic factor for survival in non-small-cell lung cancer patients? A multivariate analysis of prognostic factors of EORTC study 08975. Ann. Oncol. 17, 1698–1704. http://dx.doi.org/10.1093/annonc/mdl183. Efficace, F., Osoba, D., Gotay, C., Sprangers, M., Coens, C., Bottomley, a., 2007. Has the quality of health-related quality of life reporting in cancer clinical trials improved over time? Towards bridging the gap with clinical decision making. Ann. Oncol. 18, 775–781. http://dx.doi.org/10.1093/annonc/mdl494. Fayers, P.M., Machin, D., 2000. Quality of Life. John Wiley & Sons Ltd.http://dx.doi.org/ 10.1002/0470846283. Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.M., Forman, D., Bray, F., 2015. Cancer incidence and mortality worldwide: sources, methods and major patterns in Globocan 2012. Int. J. Cancer 136, E359–E386. http://dx.doi.org/10.1002/ijc.29210. Fiteni, F., Westeel, V., Pivot, X., Borg, C., Vernerey, D., Bonnetain, F., 2014. Endpoints in cancer clinical trials. J. Visc. Surg. 151, 17–22. http://dx.doi.org/10.1016/j. jviscsurg.2013.10.001. Frost, M.H., Reeve, B.B., Liepa, A.M., Stauffer, J.W., Hays, R.D., 2007. What is sufficient evidence for the reliability and validity of patient-reported outcome measures? Value Heal 10, S94–S105 Frost–Wiley Online Library. Goldberg, M., Timotin, E., Farrell, T., Puksa, S., Donde, B., Sur, R., 2015. A prospective analysis of high-dose-rate endobronchial brachytherapy in the palliation of obstructive symptoms in lung cancer patients: a single-institution experience. Brachytherapy 14, 655–661. http://dx.doi.org/10.1016/j.brachy.2015.04.005. Goodwin, P.J., Black, J.T., Bordeleau, L.J., Ganz, P.A., 2003. Health-related quality-of-life measurement in randomized clinical trials in breast cancer-taking stock. J. Natl. Cancer Inst. 95, 263–281. http://dx.doi.org/10.1093/jnci/95.4.263. Gore, E., Bae, K., Langer, C., Extermann, M., Movsas, B., Okunieff, P., Videtic, G., Choy, H., 2011a. Phase I/II trial of a COX-2 inhibitor with limited field radiation for intermediate prognosis patients who have locally advanced non-small-cell lung cancer: radiation therapy oncology group 0213. Clin. Lung Cancer 12, 125–130. http://dx. doi.org/10.1016/j.cllc.2011.03.007. Gore, E.M., Bae, K., Wong, S.J., Sun, A., Bonner, J.A., Schild, S.E., Gaspar, L.E., Bogart, J.A., Werner-Wasik, M., Choy, H., 2011b. Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small-cell lung cancer: primary analysis of radiation therapy oncology group study RTOG 0214. J. Clin. Oncol. 29, 272–278. http://dx.doi.org/10.1200/JCO.2010.29.1609. Gridelli, C., Perrone, F., Nelli, F., Ramponi, S., de Marinis, F., 2001. Quality of life in lung cancer patients. Ann. Oncol. 12, S21–S25. Hallqvist, A., Wagenius, G., Rylander, H., Brodin, O., Holmberg, E., Lödén, B., Ewers, S.B., Bergström, S., Wichardt-Johansson, G., Nilsson, K., Ekberg, L., Sederholm, C., Nyman, J., 2011. Concurrent cetuximab and radiotherapy after docetaxel-cisplatin induction chemotherapy in stage III NSCLC: satellite–a phase II study from the Swedish Lung Cancer Study Group. Lung Cancer 71, 166–172. http://dx.doi.org/10. 1016/j.lungcan.2010.05.011. Hallqvist, A., Bergman, B., Nyman, J., 2012. Health related quality of life in locally advanced NSCLC treated with high dose radiotherapy and concurrent chemotherapy or cetuximab − Pooled results from two prospective clinical trials. Radiother. Oncol. 104, 39–44. http://dx.doi.org/10.1016/j.radonc.2012.05.006. Hox, J.J., 2004. Robustness issues in multilevel regression analysis. Statistica Neerlandica. http://dx.doi.org/10.1046/j.0039-0402.2003.00252.x. Kocher, F., Pircher, A., Mohn-Staudner, A., Romeder, F., Duller, W., Steinmauer, M., Eckmayr, J., Schmid, T., Hilbe, W., Feigl, M., Greil, R., 2014. Multicenter phase II study evaluating docetaxel and cisplatin as neoadjuvant induction regimen prior to surgery or. Lung Cancer. http://dx.doi.org/10.1016/j.lungcan.2014.06.019. Koller, M., Warncke, S., Hjermstad, M.J., Arraras, J., Pompili, C., Harle, A., Johnson, C.D., Chie, W.C., Schulz, C., Zeman, F., Van Meerbeeck, J.P., Kulis̈, D., Bottomley, A., 2015. Use of the lung cancer-specific Quality of Life Questionnaire EORTC QLQ-LC13 in clinical trials: a systematic review of the literature 20 years after its development. Cancer 121, 4300–4323. http://dx.doi.org/10.1002/cncr.29682. Langendijk, H., Aaronson, N.K., de Jong, J.M.A., ten Velde, G.P.M., Muller, M.J., Wouters, M., 2000. The prognostic impact of quality of life assessed with the EORTC QLQ-C30 in inoperable non-small cell lung carcinoma treated with radiotherapy. Radiother. Oncol. 55, 19–25. http://dx.doi.org/10.1016/s0167-8140(00)00158-4. Lemonnier, I., Guillemin, F., Arveux, P., Clément-Duchêne, C., Velten, M., WoronoffLemsi, M.C., Jolly, D., Baumann, C., 2014. Quality of life after the initial treatments of non-small cell lung cancer: a persistent predictor for patients’ survival. Health Qual. Life Outcomes 12. http://dx.doi.org/10.1186/1477-7525-12-73. Li, N., Zeng, Z.F., Wang, S.Y., Ou, W., Ye, X., Li, J., He, X.H., Zhang, B.B., Yang, H., Sun, H.B., Fang, Q., Wang, B.X., 2015. Randomized phase III trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA-N2 nonsmallcell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy. Ann. Oncol. 26, 504–509. http://dx.doi.org/10.1093/annonc/mdu567. Mallick, I., Sharma, S.C., Behera, D., 2007. Endobronchial brachytherapy for symptom

statistical methods used and in the overall quality of the HRQoL analyses, valid conclusions are hard to draw. Further studies in this area should focus on establishing long-term data collection and on defining a more standardized approach to analyzing and reporting HRQoL data that are clinically meaningful, in order to improve comparability of trial results and to assist clinical decision-making. A number of promising initiatives have recently been launched, such as SISAQOL and the CONSORT-PRO extension checklist to guide researchers in HRQoL data reporting and analysis. Their wider update can be expected to substantially change the landscape of HRQoL in clinical trials over the coming years. Moreover, the growing interest for big data will hopefully also expand this field of research to real-life settings, as this is equally crucial to provide better guidance in the daily clinical care of this highly heterogeneous patient population. Funding Agency for Innovation by Science and Technology (IWT), Brussels, Belgium. Contract number: IWT TBM 130262 Conflicts of interest statement We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. References Adamowicz, K., Jassem, J., Katz, A., Saad, E.D., 2012. Assessment of quality of life in advanced breast cancer. An overview of randomized phase III trials. Cancer Treat. Rev. 38, 554–558. http://dx.doi.org/10.1016/j.ctrv.2011.07.002. Aupérin, A., Le Péchoux, C., Rolland, E., Curran, W.J., Furuse, K., Fournel, P., Belderbos, J., Clamon, G., Ulutin, H.C., Paulus, R., Yamanaka, T., Bozonnat, M.C., Uitterhoeve, A., Wang, X., Stewart, L., Arriagada, R., Burdett, S., Pignon, J.P., 2010. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-smallcell lung cancer. J. Clin. Oncol. 28, 2181–2190. http://dx.doi.org/10.1200/JCO. 2009.26.2543. Bottomley, A., Pe, M., Sloan, J., Basch, E., Bonnetain, F., Calvert, M., Campbell, A., Cleeland, C., Cocks, K., Collette, L., Dueck, A.C., Devlin, N., Flechtner, H.H., Gotay, C., Greimel, E., Griebsch, I., Groenvold, M., Hamel, J.F., King, M., Kluetz, P.G., Koller, M., Malone, D.C., Martinelli, F., Mitchell, S.A., Moinpour, C.M., Musoro, J., O’Connor, D., Oliver, K., Piault-Louis, E., Piccart, M., Pimentel, F.L., Quinten, C., Reijneveld, J.C., Schrmann, C., Smith, A.W., Soltys, K.M., Taphoorn, M.J.B., Velikova, G., Coens, C., 2016. Analysing data from patient-reported outcome and quality of life endpoints for cancer clinical trials: a start in setting international standards. Lancet Oncol. 17, e510–e514. http://dx.doi.org/10.1016/S1470-2045(16) 30510-1. Bral, S., Duchateau, M., Versmessen, H., Verdries, D., Engels, B., De Ridder, M., Tournel, K., Collen, C., Everaert, H., Schallier, D., De Greve, J., Storme, G., 2010. Toxicity report of a phase 1/2 dose-escalation study in patients with inoperable, locally advanced nonsmall cell lung cancer with helical tomotherapy and concurrent chemotherapy. Cancer 116, 241–250. http://dx.doi.org/10.1002/cncr.24732. Burdett, S., Pignon, J.P., Tierney, J., Tribodet, H., Stewart, L., Le Pechoux, C., Aupérin, A., Le Chevalier, T., Stephens, R.J., Arriagada, R., Higgins, J.P.T., Johnson, D.H., van Meerbeeck, J., Parmar, M.K.B., Souhami, R.L., Bergman, B., Douillard, J.Y., Dunant, A., Endo, C., Girling, D., Kato, H., Keller, S.M., Kimura, H., Knuuttila, A., Kodama, K., Komaki, R., Kris, M.G., Lad, T., Mineo, T., Piantadosi, S., Rosell, R., Scagliotti, G., Seymour, L.K., Shepherd, F.A., Sylvester, R., Tada, H., Tanaka, F., Torri, V., Waller, D., Liang, Y., 2006. Adjuvant chemotherapy for resected non-small cell lung cancer. Oncology 1, 180–187. http://dx.doi.org/10.1002/14651858. CD011430. www. cochranelibrary.com. Calvert, M., Blazeby, J., Altman, D.G., Revicki, D.A., Moher, D., Brundage, M.D., 2013. Reporting of patient-reported outcomes in randomized trials. J. Am. Med. Assoc. 309, 814–822. Claassens, L., van Meerbeeck, J.P., Coens, C., Quinten, C., Ghislain, I., Sloan, E., Wang, X.S., Velikova, G., Bottomley, A., 2011. Health-related quality of life in non-small-cell lung cancer: an update of a systematic review on methodologic issues in randomized controlled trials. J. Clin. Oncol. 29, 2104–2120. http://dx.doi.org/10.1200/JCO. 2010.32.3683. Damm, K., Roeske, N., Jacob, C., 2013. Health-related quality of life questionnaires in lung cancer trials: a systematic literature review. Health Econ. Rev. 3. http://dx.doi. org/10.1186/2191-1991-3-15. De Ruysscher, D., Bussink, J., Rodrigus, P., Kessels, A., Dirx, M., Houben, R., Wanders, R., 2007. Concurrent celecoxib versus placebo in patients with stage II-III non-small cell lung cancer: a randomised phase II trial. Radiother. Oncol. 84, 23–25. http://dx.doi. org/10.1016/j.radonc.2007.05.008. De Ruysscher, D., Botterweck, A., Dirx, M., Pijls-Johannesma, M., Wanders, R.,

48

Critical Reviews in Oncology / Hematology 119 (2017) 40–49

L. van der Weijst et al.

doi.org/10.1038/bjc.2013.466. Strøm, H.H., Bremnes, R.M., Sundstrøm, S.H., Helbekkmo, N., Aasebø, U., 2014a. Poor prognosis patients with inoperable locally advanced NSCLC and large tumors benefit from palliative. J. Thorac. Oncol. 9, 825–833. Strøm, H.H., Bremnes, R.M., Sundstrøm, S.H., Helbekkmo, N., Aasebø, U., 2014b. How do elderly poor prognosis patients tolerate palliative concurrent chemoradiotherapy for locally advanced non-Small cell lung cancer stage III? A subset analysis from a clinical phase III trial. Clin. Lung Cancer 16, 183–192. http://dx.doi.org/10.1016/j. cllc.2014.08.005. Sun, A., Bae, K., Gore, E.M., Movsas, B., Wong, S.J., Meyers, C.A., Bonner, J.A., Schild, S.E., Gaspar, L.E., Bogart, J.A., Werner-Wasik, M., Choy, H., 2011. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: neurocognitive and quality-of-life analysis. J. Clin. Oncol. 29, 279–286. http://dx.doi.org/10.1200/JCO.2010.29.6053. Tanvetyanon, T., Soares, H.P., Djulbegovic, B., Jacobsen, P.B., Bepler, G., 2007. A systematic review of quality of life associated with standard chemotherapy regimens for advanced non-small cell lung cancer. J. Thorac. Oncol. 2, 1091–1097. Van Der Meij, B.S., Langius, J.A.E., Smit, E.F., Spreeuwenberg, M.D., von Blomberg, B.M.E., Heijboer, A.C., Paul, M.A., van Leeuwen, P.A.M., 2010. Oral nutritional supplements containing (n-3) polyunsaturated fatty acids affect the nutritional status of patients with stage III non-small cell lung cancer during multimodality treatment. J. Nutr. 140, 1774–1780. http://dx.doi.org/10.3945/jn.110.121202. Van der Meij, B.S., Langius, J.A.E., Spreeuwenberg, M.D., Slootmaker, S.M., Paul, M.A., Smit, E.F., van Leeuwen, P.A.M., 2012a. Oral nutritional supplements containing n-3 polyunsaturated fatty acids affect quality of life and functional status in lung cancer patients during multimodality treatment: an RCT. Eur. J. Clin. Nutr. 66, 399–404. http://dx.doi.org/10.1038/ejcn.2011.214. Van der Meij, B.S., Schoonbeek, C.P., Smit, E.F., Muscaritoli, M., van Leeuwen, P.A.M., Langius, J.A.E., 2012b. Pre-cachexia and cachexia at diagnosis of stage III non-smallcell lung carcinoma: an exploratory study comparing two consensus-based frameworks. Br. J. Nutr. 1–9. http://dx.doi.org/10.1017/s0007114512004527. Walters, S.J., 2004. Sample size and power estimation for studies with health related quality of life outcomes: a comparison of four methods using the SF-36. Health Qual. Life Outcomes 2. http://dx.doi.org/10.1186/1477-7525-2-26. Whitney, K.A., Lysaker, P.H., Steiner, A.R., Hook, J.N., Estes, D.D., Hanna, N.H., 2008. Ischemobrain a transient state? a prospective pilot study among persons with nonsmall cell lung cancer. J. Support. Oncol. 6, 313–321. Whitney, K.A., Steiner, A.R., Lysaker, P.H., Estes, D.D., Hanna, N.H., 2010. Dimensional versus categorical use of the PHQ-9 depression scale among persons with non-smallcell lung cancer: a pilot study including quality-of-life comparisons. J. Support. Oncol. 8, 219–226. http://dx.doi.org/10.1016/j.suponc.2010.09.025.

palliation in non-small cell lung cancer-analysis of symptom response, endoscopic improvement and quality of life. Lung Cancer 55, 313–318. http://dx.doi.org/10. 1016/j.lungcan.2006.10.018. McKenna, S.P., 2011. Measuring patient-reported outcomes: moving beyond misplaced common sense to hard science. BMC Med. 9. http://dx.doi.org/10.1186/1741-70159-86. Moher, D., Liberati, A., Tetzlaff, J., Altman, D.G., 2009. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 89, 873–880. http://dx.doi.org/10.1371/journal.pmed.1000097. Movsas, B., Scott, C., Langer, C., Werner-Wasik, M., Nicolaou, N., Komaki, R., Machtay, M., Smith, C., Axelrod, R., Sarna, L., Wasserman, T., Byhardt, R., 2005. Randomized trial of amifostine in locally advanced non-small-cell lung cancer patients receiving chemotherapy and hyperfractionated radiation: radiation therapy oncology group trial 98-01. J. Clin. Oncol. 23, 2145–2154. http://dx.doi.org/10.1200/JCO.2005.07. 167. Movsas, B., Moughan, J., Sarna, L., Langer, C., Werner-Wasik, M., Nicolaou, N., Komaki, R., Machtay, M., Wasserman, T., Watkins-Bruner, D., 2009. Quality of life supersedes the classic prognosticators for long-term survival in locally advanced non-small-cell lung cancer: an analysis of RTOG 9801. J. Clin. Oncol. 27, 5816–5822. http://dx.doi. org/10.1200/JCO.2009.23.7420. Movsas, B., Hu, C., Sloan, J., Bradley, J., Komaki, R., Masters, G., Kavadi, V., Narayan, S., Michalski, J., Johnson, D.W., Koprowski, C., Curran, W.J.J., Garces, Y.I., Gaur, R., Wynn, R.B., Schallenkamp, J., Gelblum, D.Y., MacRae, R.M., Paulus, R., Choy, H., 2016. Quality of life analysis of a radiation dose-escalation study of patients with non-small-cell lung cancer: a secondary analysis of the radiation therapy oncology group 0617 randomized clinical trial. JAMA Oncol. 2, 359–367. http://dx.doi.org/ 10.1001/jamaoncol.2015.3969. Neill, R.T.O., 1997. Secondary endpoints cannot be validly analyzed if the primary endpoint does not demonstrate clear statistical significance. Control. Clin. Trials 18, 550–556. Norman, G.R., Sloan, J.A., Wyrwich, K.W., 2003. Interpretation of changes in healthrelated quality of life: the remarkable universality of half a standard deviation. Med. Care 41, 582–592. http://dx.doi.org/10.1097/01.MLR.0000062554.74615.4C. Nyman, J., Friesland, S., Hallqvist, A., Seke, M., Bergström, S., Thaning, L., Lödén, B., Sederholm, C., Wagenius, G., 2009. How to improve loco-regional control in stages IIIa-b NSCLC? Results of a three-armed randomized trial from the Swedish Lung Cancer Study Group. Lung Cancer 65, 62–67. http://dx.doi.org/10.1016/j.lungcan. 2008.10.021. Osoba, D., Bezjak, A., Brundage, M., Zee, B., Tu, D., Pater, J., 2005. Analysis and interpretation of health-related quality-of-life data from clinical trials: basic approach of the National Cancer Institute of Canada Clinical Trials Group. Eur. J. Cancer 41, 280–287. http://dx.doi.org/10.1016/j.ejca.2004.10.017. Osoba, D., 2011. Health-related quality of life and cancer clinical trials. Ther. Adv. Med. Oncol. 3, 57–71. http://dx.doi.org/10.1177/1758834010395342. Penson, D.F., Litwin, M.S., Aaronson, N.K., 2003. Health related quality of life in men with prostate cancer. J. Urol. 169, 1653–1661. http://dx.doi.org/10.1097/01.ju. 0000061964 49961.55. Quené, H., Van Den Bergh, H., 2004. On multi-level modeling of data from repeated measures designs: a tutorial. Speech Commun. 43, 103–121. http://dx.doi.org/10. 1016/j.specom.2004.02.004. Roy, S., Pathy, S., Mohanti, B.K., Raina, V., Jaiswal, A., Kumar, R., Mani, K., 2016. Accelerated hypofractionated radiotherapy with concomitant chemotherapy in locally advanced squamous cell carcinoma of lung: evaluation of response, survival, toxicity and quality of life from a phase II randomised study. Br. J. Radiol. 89. Saad, E.D., Adamowicz, K., Katz, A., Jassem, J., 2012. Assessment of quality of life in advanced non-small-cell lung cancer: an overview of recent randomized trials. Cancer Treat. Rev. 38, 807–814. http://dx.doi.org/10.1016/j.ctrv.2012.02.012. Sarna, L., Swann, S., Langer, C., Werner-Wasik, M., Nicolaou, N., Komaki, R., Machtay, M., Byhardt, R., Wasserman, T., Movsas, B., 2008. Clinically meaningful differences in patient-reported outcomes with amifostine in combination with chemoradiation for locally advanced non-small-cell lung cancer: an analysis of RTOG 9801. Int. J. Radiat. Oncol. Biol. Phys. 72, 1378–1384. http://dx.doi.org/10.1016/j.ijrobp.2008. 03.003. Shehata, S.M., El-Shora, A.E., Mazroaa, M.A., Ragab, M.I., 2013. Outcome of endobronchial electrocautery versus external beam radiotherapy or both together in the palliative management of non-small cell lung cancer. Egypt. J. Chest Dis. Tuberc. 62, 173–181. http://dx.doi.org/10.1016/j.ejcdt.2013.03.010. Simone, C.B., Jones, J.A., 2013. Palliative care for patients with locally advanced and metastatic non-small cell lung cancer. Ann. Palliat. Med. 02, 178–188. Stephens, R.J., Girling, D.J., Hopwood, P., Hospital, C., Trust, N.H.S., Road, W., Manchester, M., 2005. A randomised controlled trial of pre-operative chemotherapy followed, if feasible, by resection lung cancer. Lung Cancer 395–400. http://dx.doi. org/10.1016/j.lungcan.2005.04.001. Stinchcombe, T.E., Socinski, M.A., 2009. Current treatments for advanced stage non-small cell lung cancer. Proc. Am. Thorac. Soc. 6, 233–241. http://dx.doi.org/10.1513/pats. 200809-110LC. Strøm, H.H., Bremnes, R.M., Sundstrøm, S.H., Helbekkmo, N., Fløtten, Ø., Aasebø, U., 2013. Concurrent palliative chemoradiation leads to survival and quality of life benefits in poor prognosis stage III non-small-cell lung cancer: a randomised trial by the Norwegian Lung Cancer Study Group. Br. J. Cancer 109, 1467–1475. http://dx.

Lotte van der Weijst is a PhD candidate at the department of Radiation Oncology and Experimental Cancer Research at the University of Ghent under the supervision of Prof. Dr. Lievens, Prof. Dr. Surmont and Mr. Schrauwen. Lotte obtained her Bachelor of Science in European Public Health at the University of Maastricht and her Master of Science in Health Sciences from Free University Amsterdam. The focus of her PhD research is the effect of first-line chemo- and/or radiotherapy on health-related quality of life, acute and late toxicity and neuro-cognitive functioning and its correlations in locally advanced and metastatic non-small cell lung cancer patients. Prof. dr. Veerle Surmont is professor of Thoracic Oncology at the University Hospital Ghent, head of the department of Thoracic Oncology and coordinator of LONG (Lung Oncological Network Gent). She is also active member of IASLC (International Association for the Study of Lung Cancer) and ETOP (European Thoracic Oncology Platform). She is currently chairman of the Belgian Society of Pulmonology, Workgroup Thoracic Oncology. Prof. Dr. Surmont is principal investigator and study coordinator of several local, regional, national and international phase 1-3 clinical trials in diagnosis and treatment of lung cancer and mesothelioma (> 10 years experience). She has organized different scientific and educational international meetings on thoracic oncology and she has been an invited speaker to numerous international congresses. Mr. Wim Schrauwen is a clinical psychologist and head of department of Medical Psychology at the University Hospital Ghent, Belgium. He obtained his Master of Science in Psychology from the University of Ghent. He received post-academic training in neuropsychology. He is a PhD candidate in health sciences where he works on cognitive performance and emotion regulation in breast cancer patients during and after therapy. Prof. Dr. Yolande Lievens is associate professor in Radiation Oncology, with a focus on Thoracic Oncology, at the Ghent University. She has participated in a series of investigator- as well as industry-initiated trials in the context of lung cancer. She also has a vested interest in health care management and health services research in radiation oncology, and more broadly in the field of global oncology. She is co-author of > 70 international peer reviewed publications and of 7 book chapters. She has appointed expert by the Belgian Health Care Knowledge Centre (KCE) in various projects focusing on thoracic oncology and radiation oncology related topics. She is the current president of the Belgian College for Radiation Oncology and of the European Society for Radiation Oncology (ESTRO).

49