Clinical effectiveness of first-line chemoradiation for adult patients with locally advanced non-small cell lung cancer: a systematic review

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Chapter 1 Background

Diagnosis

As noted earlier, lung cancer at an early stage is usually asymptomatic and thus diagnosis is often at a late stage. Unfortunately, two-thirds of patients are diagnosed when the cancer has metastasised. Across England and Wales a significant proportion of each age group presents with late-stage metastatic disease. 4 According to recently updated National Institute for Health and Clinical Excellence (NICE) guidelines,5 urgent referral for chest radiography should be offered when a patient presents with haemoptysis or any of the following unexplained or persistent (i.e. lasting > 3 weeks) symptoms or signs:

• cough

• chest/shoulder pain

• dyspnoea

• weight loss

• chest signs

• hoarseness

• finger clubbing

• features suggestive of metastasis from a lung cancer (e.g. in brain, bone, liver or skin)

• cervical/supraclavicular lymphadenopathy.

The updated NICE guidelines5 for the diagnosis and treatment of lung cancer recommend that, if a chest radiograph or chest computerised tomography (CT) scan suggests lung cancer, patients should be offered an urgent referral, usually to a chest physician, who should choose further investigations that give the most information about diagnosis and staging with the least risk to the patient. There are various diagnostic and staging techniques for non-small cell lung cancer (NSCLC) in the UK. Within this diagnostic process there are a number of key issues that need to be considered, including disease staging, performance status (PS), histology and the presence of comorbid disease.

Disease staging

The stage of lung cancer at diagnosis reflects the degree of spread of cancer and is crucially important to determine which patients have potentially curative disease and which do not; this helps to estimate a patient's prognosis. The TNM classification provides a system for staging the extent of cancer. T refers to the size and extent of the primary tumour, N refers to the involvement of the lymph nodes and M refers to the presence of metastases or distant spread of the disease. Recently, changes have been made to the predominantly used Union Internationale Contre le Cancer (UICC) TNM system for classification of NSCLC disease stage5 (previous UICC versions are available from the American Joint Committee on Cancer). There are several differences in staging between UICC versions 6 and 7 that are specifically relevant to patients with advanced lung cancer. For example, pleural effusion is classed as stage IIIB in version 6 and has been reclassed as stage IV in version 7. Table 2 shows how the stages from the sixth edition that have been modified compare with the new stages in the seventh edition. Table 3 shows the stage groupings in the seventh edition of the TNM classification.

TABLE 2 - TNM staging of NSCLC in the sixth edition compared with the seventh edition of the UICC classification system

Sixth edition (2002)	Seventh edition (2009)
TNM stage	TNM stage	Descriptor
T1	T1a	Maximum dimension ≤ 2 cm
	T1b	Maximum dimension 2–3 cm
T2	T2a	Maximum dimension 3–5 cm
	T2b	Maximum dimension 5–7 cm
	T3	Maximum dimension > 7 cm
T4	T3	Additional nodule in same lobe
M1	T4	Additional nodule in ipsilateral different lobe
M1	M1a	Additional nodules in contralateral lung
M1	M1a	Ipsilateral pleural effusion

TABLE 3 - Surgical stage groupings in the seventh edition of the TNM classification

Stage	T	N	M
Stage 0	Tis	N0	M0
Stage IA	T1a, b	N0	M0
Stage IB	T2a	N0	M0
Stage IIA	T1a, b	N1	M0
	T2a	N1	M0
	T2b	N0	M0
Stage IIB	T2b	N1	M0
	T3	N0	M0
Stage IIIA	T1, T2	N2	M0
	T3	N1, N2	M0
	T4	N0, N1	M0
Stage IIIB	T4	N2	M0
	Any T	N3	M0
Stage IV	Any T	Any N	M1a, b

Performance status

Performance status is a measure used to quantify cancer patients' general well-being and is used to determine whether or not a patient is fit enough to receive treatment and to assess how much supportive care a patient needs. There are three main scales used to measure PS: the World Health Organization (WHO) PS scale,6 the Karnofsky PS scale (KPS)6 and the Eastern Cooperative Oncology Group (ECOG) PS scale. 7 A summary of the WHO PS scale is shown in Table 4 as this is the most commonly used scale in clinical practice in the UK. 6 A score of 0 on the WHO scale indicates that a patient is completely able to look after him- or herself and a score of 4 shows that a patient requires a lot of support.

TABLE 4 - World Health Organization PS criteria8

Scale	WHO criteria
0	Patient is fully active and more or less the same as before illness
1	Patient is unable to carry out heavy physical work but can do anything else
2	Patient is up and about more than half the day; able to look after him/herself but not well enough to work
3	Patient is in bed or sitting in a chair for more than half the day; needs some help in looking after him/herself
4	Patient is in bed or a chair all the time and needs a lot of looking after

Histology

Histological confirmation (i.e. a diagnosis made by taking a sample of tissue or cells) is an important element of diagnosis because it helps to determine a patient's treatment pathway. However, a proportion of diagnoses are based on clinical examination and radiological investigations alone, without histological evidence. The LUCADA data show that, for England and Wales, histological confirmation of the cancer diagnosis is made in 72% of cases, with wide (regional) variation from 25% to > 85%. 4 Recent NICE guidance for the first-line treatment of NSCLC recommends histological testing and therefore histological testing rates are expected to increase. 4

There are two main types of lung cancer: NSCLC accounts for approximately 84% of all lung cancers diagnosed and the remaining 15% are small cell lung cancer. The main subtypes of NSCLC are squamous cell carcinoma (33%) and non-squamous cell carcinoma (29%); the latter includes adenocarcinoma (25%) and large cell carcinoma (4%). Approximately 36% of patients are listed as being NSCLC ‘not otherwise specified’, 1% are carcinoma in situ and 1% are bronchioloalveolar. 9

Squamous cell carcinoma commonly begins in the bronchi, centrally in the lungs. Adenocarcinoma starts in the periphery of the lungs and can be present for a long time before detection. It is usually the type of lung cancer found in non-smokers and is the most common type seen in women. Large cell carcinomas often occur in the outer regions of the lungs and tend to grow rapidly and spread more quickly than some other forms of NSCLC. 10

Treatment options for non-small cell lung carcinoma

Figure 1 shows a treatment pathway for patients with NSCLC and estimates of the proportions and numbers of patients with NSCLC along the treatment pathway in England and Wales based on histology and staging data, NICE guidelines5 and NICE guidance. 10–14 A proportion of patients have small cell disease and recommendations for this group are not discussed in this report.

FIGURE 1.

Treatment pathway for patients with NSCLC. PLAT, platinum (cisplatin or carboplatin); S, stage. a, M Peak, data from the National Lung Cancer Audit, audit period 2009, personal communication, 2011; b, M Peak, data from the National Lung Cancer Audit, audit period 2008, personal communication, 2011.

In total, 30% of patients with NSCLC are diagnosed with stage I–IIIA disease. These patients may be suitable for potentially curative surgery or radical radiotherapy (RT). Surgery for NSCLC consists of lobectomy, pneumonectomy and wedge resection. Approximately 50% of patients undergoing these procedures will relapse and will then be eligible for further treatment. Patients with stage IIIA–IIIB disease who are not amenable to surgery can be treated with potentially curative chemoradiation (CTX-RT). CTX-RT can be delivered in different ways: as induction, sequential, concurrent and/or consolidation CTX-RT. For example, gemcitabine (GEM)-, vinorelbine (VNB)-, docetaxel (DOC)- and paclitaxel (PAX)-based CTX can be used alongside RT.

The majority (70%) of patients with NSCLC have stage IIIB or IV disease and a PS of 0 or 1 at the time of diagnosis. These patients are assessed for their suitability for first-line chemotherapy (CTX); less than half (48%) of patients who are assessed are considered suitable and actually receive treatment. Among those who receive CTX, almost half will respond to treatment and have either a complete or a partial response. Of these patients, a relatively small proportion can go on to have maintenance treatment and only 28% are suitable for second-line CTX.

The majority of patients with NSCLC are diagnosed late and have metastatic or locally advanced disease. Therefore, up to 50% of patients are treated with best supportive care (BSC) alone. During all stages of treatment, patients receive BSC or ‘active supportive care’ in addition to any anticancer treatment. In the recently published lung cancer guidelines,5 NICE defines ‘supportive care’ as ‘the multidisciplinary holistic care offered to all patients and their carers throughout the pathway to help them cope with cancer and treatment of it. BSC packages include options for information giving, symptom control and psychological, social and spiritual support. Palliative care provides a similar holistic approach, but is specific to those patients with advanced progressive illness’ (p. 98).

Combined chemotherapy and radiotherapy treatment

Radiotherapy is the treatment of cancer with high-energy radiation. RT can be either radical (potentially curative) or palliative. For patients of good PS in whom the disease can be encompassed within a radical RT treatment volume (mainly stage IIIA and selected stage IIIB), high doses of RT at conventional fractionation were the standard treatment with potential curative intent until the 1990s. Developments in RT regimens, including improved techniques and fractionation schedules,5 coupled with the addition of CTX have improved local control, systemic relapse and overall survival (OS). 19 Radical RT now commonly means potentially curative external beam RT and includes several fractionation schedules, including conventional fractionated RT, split-course RT, hyperfractionated RT, continuous hyperfractionated accelerated RT (CHART) and hyperfractionated accelerated RT (HART). In addition, there have been considerable recent technological advances in RT equipment [e.g. four-dimensional planning to account for tumour movement over the breathing cycle and On-Board Imager^® treatment verification (Varian Medical Systems, Palo Alto, CA, USA)] that allow RT to be more accurately delivered to the tumour with less damage to normal tissues. 5 Also, recent innovation has enabled new approaches to be developed, for example stereotactic body RT. 5

The aim of adding CTX to RT is to improve the cure rate obtained with RT alone; CTX is used as a systemic treatment to control micrometastases and the risk of systemic relapse. In addition, many CTX agents have a radiation-sensitising effect and offer potential benefits in locoregional control. 5 RT is aimed at improving local control of the tumour. CTX-RT is described in different ways depending on the timing of the CTX relative to the RT (Table 5).

TABLE 5 - Definitions of CTX-RT

Terms	Description
Radical RT	All RT that is not palliative in intent. Minimum dose of 50 Gy in 25 daily fractions or its radiobiological equivalent
Combined CTX-RT	Treatment given to patients eligible for potential curative RT at presentation; the treatments are given either sequentially or concurrently
Concurrent CTX-RT	CTX given on the same days as RT treatment
Sequential CTX-RT	CTX given before a course of RT but not during RT
Consolidation CTX-RT	CTX given subsequent to RT
Induction CTX	CTX given before CTX-RT

Compared with RT alone, both sequential and concurrent CTX-RT have shown a 4% improvement in 2-year survival rates. 20,21 A Cochrane meta-analysis22 of 13 trials (2214 patients) confirmed a statistically significant reduction in risk of death at 2 years with concurrent CTX-RT compared with RT alone, although there was significant heterogeneity across the trials. An update of the Cochrane review19 compared sequential with concurrent CTX-RT. The authors of the review demonstrated a statistically significant benefit in median survival for concurrent CTX-RT (16–17 months) over sequential CTX-RT (13–15 months). However, the treatment-related mortality was almost twice as high in the concurrent arm and the incidence of acute oesophagitis was 19% in the concurrent arm compared with 3% in the sequential arm. The authors of the Cochrane review19 recognise that there was considerable heterogeneity related to the frequency of administration and doses of CTX.

Outcome measures

Survival is considered to be the most reliable cancer end point within a randomised controlled trial (RCT) and, when trials can be conducted to adequately assess survival, it is usually the preferred end point. OS is a measure of the time from randomisation to death from any cause; median OS is the point in time at which 50% of people with a condition will have died and 50% are still alive. Year 1 and year 2 survival risk is defined as the probability of survival in intervals of time elapsed from randomisation to year 1 and year 2 respectively.

Many trials also report progression-free survival (PFS) as an intermediate surrogate measure of survival. PFS measures the amount of time between randomisation until tumour progression or death from any cause. In most trials tumour progression is defined using RECIST criteria (Response Evaluation Criteria in Solid Tumors) as at least a 20% growth in the size of the tumour or spread of the tumour since the beginning of treatment with a 5-mm absolute increase in size. 23 Time to progression (TTP) is defined as the time from randomisation until tumour progression (and does not include death). The majority of RCTs measure overall response rate (ORR), which is the proportion of patients who have a response (the tumour shrinks), which can be complete or partial. Stable disease is recorded when there is no response and the tumour does not change in size. Stable disease also means that no new tumours have developed and that the cancer has not spread to any new regions of the body. 24

Adverse event (AE) rates and health-related quality-of-life (HRQoL) data are also measures of important clinical benefit and provide information on how well patients are able to tolerate CTX treatments. AEs within trials are graded for severity (1–4), and usually the more severe events at grades 3 and 4 are of interest to clinicians. These are discussed in more detail in Chapter 3 (see Adverse events).

In advanced NSCLC, CTX-RT treatment is also given in an effort to improve HRQoL. Commonly used HRQoL tools within NSCLC trials include the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C3025 and the lung cancer-specific module QLQ-LC13,26 the Lung Cancer Symptom Scale (LCSS)27 and the Functional Assessment of Chronic Illness Therapy – Lung (FACT-L) questionnaire. 28 The European Quality of Life-5 Dimensions (EQ-5D)29 is a standardised generic instrument for measuring HRQoL that may be used in lung cancer trials. It provides a utility score for health and a self-rating of HRQoL. AEs, both from the disease itself and from CTX, have a considerable impact on HRQoL. 30

Despite HRQoL being both a vitally important measure of a patient's general emotional, physical and mental well-being and a very relevant measure of the ‘success’ of CTX treatment, because advanced-stage NSCLC is not curable, only a minority of trials address HRQoL issues.

Current UK guidelines and guidance

The National Institute for Health and Clinical Excellence produces clinical guidance and guidelines recommending appropriate treatments and care for people with NSCLC; NICE issues recommendations based on the best available clinical effectiveness and cost-effectiveness evidence. Comprehensive guidelines31 on the management of patients with lung cancer published by NICE in 2005 concluded that sequential CTX-RT is more beneficial than RT alone for patients with locally advanced NSCLC. The clinical evidence available appeared to support the use of concurrent CTX-RT, but the results of further clinical efficacy studies were required to ensure that informed decision-making could take place.

NICE guidelines5 on the diagnosis and treatment of lung cancer were updated in 2011. The updated guidelines state that CTX-RT is now an established approach to treatment, with curative intent of patients with NSCLC when surgery is not suitable, and the potential benefit in survival needs to be balanced with the risk of additional toxicities. Current NICE guidelines5 recommend that CTX-RT is the treatment of first choice for patients with stage II and stage III cancer who are not suitable for surgery; however, how currently available CTX and RT regimens should be optimally combined within concurrent CTX-RT remains unclear.

Rationale for this review

Given the advances in first-line treatment of NSCLC it was felt that an updated review was required. The Assessment Group conducted this review as part of a larger systematic review32 of all first-line CTX and CTX-RT treatments for patients with locally advanced or metastatic NSCLC. It was the opinion of the members of the clinical panel for the project that patients with potentially curable disease (e.g. stage IIIA) are different from those who are considered only for palliative treatment of more advanced disease and therefore that the results relating to these former patients should be reported separately.

Chapter 2 Definition of the decision problem

Chapter 3 Assessment of clinical effectiveness

Results of the review of clinical effectiveness

Quantity of research available

As shown in Figure 2, the electronic searches identified 5378 citations (Table 7 describes in detail the results of the database searching). Initial screening identified 330 potentially relevant references; these were obtained as full-text copies and the 240 references that were published post 2000 were assessed for eligibility for inclusion. Overall, 19 trials were included that compared different regimens of CTX-RT. The initial search identified a relatively large number of ‘hits’ because this review was part of a more extensive systematic review32 that examined CTX compared with CTX as well as CTX-RT compared with CTX-RT.

FIGURE 2.

Flow diagram of inclusion of CTX-RT trials.

TABLE 7 - Results of database searches

Database	Dates	Number	Deduplicated	First screen	Second screen	2000–10	CTX-RT vs CTX-RT
MEDLINE	1990–March Week 3 2009	2594	3848	329	265	175	11
EMBASE	1990–Week 13 2009	3034
MEDLINE	2009–August Week 3 2010	316	455	35	34	34	5
EMBASE	2009–Week 34 2010	370
Cochrane Central Register of Controlled Trials	2000–Issue 3 of 4, July 2010	1034	1034	174	31	31	3
Cochrane Database of Systematic Reviews	2000–Issue 3 of 4, July 2010	4	4	0	0	0	0
Database of Abstracts of Reviews of Effects	2000–Issue 3 of 4, July 2010	22	22	0	0	0	0
Health Technology Assessment	2000–Issue 3 of 4, July 2010	15	15	0	0	0	0
Total number of references		7389	5378	538	330	240	19
Total number of RCTs							19

Assessment of effectiveness

In total, 19 RCTs met the inclusion criteria of the systematic review and compared CTX-RT with CTX-RT. 45–63

Quality

The results of the methodological quality assessment of trials are presented in Table 8. Overall methodological quality of included trials was poor, with nearly all trials failing to report relevant methodology; in particular, methods of randomisation, allocation concealment and blinding were inadequately described.

TABLE 8 - Quality assessment

✓, item adequately addressed; ✗, item not adequately addressed; ✓✗, item partially addressed; NA, not applicable; NS, not stated.

When no p-values are reported the trial was assessed as NS.

This is second-line CTX and/or palliative RT.

Although trial intended to exclude non-completers from analysis all patients completed treatment.

Reference ID	Randomisation			Baseline comparability		Eligibility criteria specified	Co-interventions identifiedb	Blinding				Withdrawals		ITT	Other outcomes
	Truly random	Allocation concealment	Number stated	Presented	Achieveda			Assessors	Administration	Participants	Procedure assessed	> 80% in final analysis	Reasons stated
Jeremic 200163	NS	NS	✓	✓✗	NS	✓	NS	NS	NS	NS	NS	✓	✓	✗	✗
Komaki 200250	NS	✓	✓	✓	NS	✓	NS	NS	NS	NS	NS	✓	✓	✗	✗
Schild 200262	NS	NS	✓	✓	✓	✓	NS	NS	NS	NS	NS	✓	✓	✗	✗
Vokes 200247	NS	✓	✓	✓	NS	✓	NS	NS	NS	NS	NS	✓	✓	✗	✗
Zatlouka 200451	NS	✗	✓	✓	✓	✓	NS	✗	✗	✗	NA	✓	✓	✓	✗
Belan 200552	NS	NS	✓	✓	✓✗	✓	NS	NS	NS	NS	NS	✓	✓	✗	✗
Fournel 200549	NS	✓	✓	✓✗	✓✗	✓	NS	✗	✗	✗	NA	✓	✓	✗	✗
Reinfuss 200556	✓	NS	✓	✓	NS	✓	NS	NS	NS	NS	NS	✓	✓	✗	✗
Dasgupta 200656	NS	NS	✓	✓	NS	✓	✓✗	NS	NS	NS	NS	✓	NA	✗c	✗
Gouda 200659	NS	NS	✓	✓	✓	✓	NS	NS	NS	NS	NS	✓	NA	✓	✗
Belderbos 200754	NS	NS	✓	✓	✓✗	✓	NS	NS	NS	NS	NS	✓	✓	✓	✓
Vokes 200748	NS	✓	✓	✓✗	✓✗	✓	NS	NS	NS	NS	NS	✓	✓	✓	✗
Liu 200853	NS	NS	✓	✓	✓✗	✓	NS	NS	NS	NS	NS	✓	✓	✗	✗
Socinski 200855	NS	NS	✓	✓	✓✗	✓	NS	NS	NS	NS	NS	✓	✓	✗	✗
Berghmans 200945	✓	✓	✓	✓	NS	✓	NS	NS	NS	NS	NS	✓	✓	✗	✗
Crvenkova 200957	NS	NS	✓	✓✗	✓	✓	NS	NS	NS	NS	NS	✓	✗	NS	✗
Nyman 200958	NS	NS	✓	✓	NS	✓	NS	NS	NS	NS	NS	✓	✗	✗	✓
Zhu 200960	NS	NS	NS	✓✗	NS	✓	NS	NS	NS	NS	NS	NS	NA	NS	✗
Movsas 201061	NS	NS	✓	✓	NS	✓	NS	NS	NS	NS	NS	✓	✓	✓	✗

Only two RCTs45,46 provided sufficient information regarding randomisation methods. Random assignment was performed centrally in five trials45,47–50 and so allocation concealment was assessed as adequate in these trials. Another trial used randomisation by envelope to conceal allocation. 51 Eighteen trials clearly reported the number of participants randomised. 45–59,61–63 All trials reported details of participant comparability at baseline.

Six trials48,49,52–55 reported imbalance between trial groups at baseline; these were assessed as achieving partial comparability. Two trials54,55 reported significant imbalance between treatment groups for baseline disease. In one trial55 62% of patients had stage IIIB disease in the concurrent GEM plus carboplatin (CARB)-RT arm compared with 32% of patients in the concurrent PAX plus CARB-RT arm. In the trial by Belderbos et al. ,54 47.4% of the patients in the sequential CTX-RT arm had stage IIIB disease compared with 63.8% in the concurrent CTX-RT arm.

All trials reported eligibility criteria. One trial56 reported details of co-interventions; however, it was unclear how many patients in each treatment arm had received any of the co-interventions. Two trials49,51 were reported as ‘open’ and it was assumed that assessors, administrators and participants were not blinded to treatment; blinding was not stated in the remaining 17 trials. Over 80% of patients were assessed in 18 trials. 45–59,61–63 Fourteen trials45–55,61–63 reported reasons for withdrawals, two trials57,58 failed to report this and in three trials56,59,60 there were no withdrawals. Six trials46,48,51,54,59,61 used an ITT approach and assessed all participants according to the groups to which they were randomised. The trial by Dasgupta et al. 56 intended to exclude non-completers from analyses; however, there were no non-completers and so all patients were assessed.

Two trials54,58 intended to measure HRQoL. In the trial by Belderbos et al. 54 it is not clear whether or not HRQoL was measured as it was not reported, and in the trial by Nyman et al. 58 HRQoL outcomes were measured and are to be reported in a future publication.

Five of the 19 trials were closed prematurely for the following reasons: confirmation of the benefit of concurrent CTX-RT,52 poor accrual,54 poor accrual due to administrative problems,45 high rate of serious AEs in the induction/concurrent CTX-RT arm55 and slow accrual coupled with interim analysis results that demonstrated a statistically significant difference in survival in favour of the concurrent CTX-RT arm. 51 One trial experienced slow accrual that led to a reduction in the target number of participants recruited. 62

Trial characteristics

Trial characteristics are presented in Appendix 6. The 19 trials were published between 2001 and 2010. Of the 13 multicentre trials, three have international centres. 45,54,61 There were seven Phase II47,50,52,54,55,58,61 and six Phase III trials45,48,49,56,62,63 and six trials in which the phase is unclear. 46,51,53,57,59,60 Eight trials47,48,50,51,54,55,62,63 were funded by research grants, four trials49,52,58,61 were funded by pharmaceutical companies and the funding source was not stated in seven trials. 45,46,53,56,57,59,60 Five trials47,48,58,62,63 were sufficiently powered to evaluate the primary outcome of each trial, which included TTP, median OS, response rate and 2-year survival rate. Five trials45,49,51,54,61 were inadequately powered and the power of nine trials46,50,52,53,55–57,59,60 was unclear. Median follow-up of patients ranged from 16.5 to 60 months.

Details of trial interventions are presented in Appendix 7. Concurrent CTX is defined as CTX given on RT treatment days (whether before or after each fraction of RT). Sequential CTX-RT is defined as CTX given before or after a course of RT but not during. Consolidation CTX-RT is defined as CTX given subsequent to RT, and induction CTX-RT is defined as CTX given prior to RT.

Four trials46,51,54,60 compared sequential with concurrent CTX-RT, four trials49,52,56,57 compared sequential with concurrent/consolidation CTX-RT, three trials48,50,59 compared induction/concurrent CTX-RT with concurrent CTX-RT and two trials45,52 compared induction/consolidation CTX-RT with concurrent/ consolidation CTX-RT. The remaining six trials47,55,57,58,61,62 could not be grouped for comparison as they compared a variety of different CTX-RT regimens.

Different CTX agents were used both across and within trials. It is worth noting that GEM, PAX and VNB were used by a similar number of trials, whereas DOC was used by relatively few trials. Etoposide (ETOP) plus platinum (cisplatin or carboplatin) (PLAT) was used in seven trials. 49,50,56,57,61–63

Radiation doses, number of fractions, schedule, relative dose intensity (RDI) and overall treatment time also varied between and within trials. Details of RDI are presented in Appendix 8. Twelve trials45,46,49–56,60,61 reported details of actual treatment received including median time to complete treatment, percentage of patients who completed treatment as per protocol and details of reductions and delays in CTX and RT. A sample of the within-trial differences that are demonstrated to be statistically significantly different are discussed here.

In the trial by Fournel et al. ,49 88% of patients in the concurrent CTX-RT arm received at least 60 Gy RT, compared with 59.4% in the sequential CTX-RT arm (p < 0.001); 54% received two planned cycles of consolidation CTX, 7% received only one course and 39% received no consolidation CTX. In the Zatloukal et al. trial,51 only 58% of patients in the sequential CTX-RT group completed four courses of CTX, compared with 83% in the CTX-RT concurrent group (p < 0.0007), and only 64% of the sequential CTX-RT group received RT, compared with 94% of concurrent CTX-RT group (p = 0.0002). The required time for completing treatments was statistically significantly different between the two groups in the trial by Zhuan and Wu;60 the concurrent CTX-RT group took, on average, 31 days less than the sequential CTX-RT group to complete treatment (p = 0.05).

In the trial by Reinfuss et al.,46 treatment was administered to 75% of patients in the concurrent CTX-RT arm on average, compared with 96.7% of participants in the sequential CTX-RT arm; the difference is statistically significant (log-rank test, p < 0.01). The only difference in treatment between the trial groups was the sequence of CTX and RT. Reported toxicity was significantly higher in the concurrent CTX-RT group than in the sequential CTX-RT group. Because of this toxicity, treatment was not completed in 21.4% of participants in the concurrent CTX-RT arm compared with 2.2% in the sequential CTX-RT arm.

It appears that the percentage of patients who completed treatment, and a higher dose intensity, was higher for all three CTX drugs regimens in the concurrent/consolidation CTX-RT arm than in the induction/concurrent CTX-RT arm of the trial by Berghmans et al. 45 Significantly fewer patients completed 7 weeks of CTX in the induction/concurrent CTX-RT arm than in the concurrent/consolidation CTX-RT arms of the trial by Belani et al. 52

In the trial by Movsas et al. ,61 in which patients received consolidation with either GEM or GEM/DOC after identical CTX-RT, 90.6% received all three planned cycles of GEM, compared with 68.8% who received all three cycles of GEM/DOC.

In the trial by Socinski et al. ,55 87.2% completed therapy to at least 74 Gy in the PAX plus CARB-RT arm, compared with 78.3% in the GEM plus CARB-RT arm. Rates of compliance with induction CTX, initiation and completion of concurrent CTX-RT and average dose and completion of thoracic RT were all higher in the PAX plus CARB-RT arm than in the GEM plus CARB-RT arm (this arm was closed prematurely because of the high rate of grade 4/5 pulmonary toxicity).

Patient characteristics

Details of patient characteristics are given in Appendix 9. The inclusion/exclusion criteria adopted by each of the trials are presented in Appendix 10. The number of patients randomised to trial arms ranged from 2059 to 184. 48 More than 50% of patients within the trials were male, with a median age of 40–64 years. With the exception of three trials,45,50,54 all trials included patients with disease stage IIIA or IIIB only. All but seven trials49,51,53,54,56,60,61 specifically excluded pleural effusions (see Appendix 10). The majority of patients within each trial had either adenocarcinoma or squamous cell carcinoma, and three trials46,48,63 failed to report details describing patient histology. In the majority of trials PS ranged from 0 to 1 [using a variety of PS criteria: ECOG, the Cancer and Leukemia Group B (CALGB)48, WHO] or from 60 to 100 (KPS). One trial51 included a small percentage of patients with ECOG PS 2 and one trial63 included a small percentage of patients with KPS 50.

Outcomes

Trial outcomes are presented in Table 9. Across the trials, median OS ranged from 12 to 29.5 months (16 trials), survival rate ranged from 37% to 80% at 1 year (14 trials) and from 14.3% to 66.6% at 2 years (16 trials). Across the trials, median PFS ranged from 5.4 to 14.9 months (11 trials) and median TTP ranged from 7.3 to 13.3 months (two trials). Across the trials, tumour ORR ranged from 33% to 88% (14 trials).

TABLE 9 - Trial outcomes

CIS, cisplatin; HFX, hyperfractionated; NR, not reported.

TTP not PFS.

Reference ID	Treatment	Median OS			Median PFS			Survival 1 year		Survival 2 years		Tumour ORR
		Months	95% CI	HR (95% CI)	Months	95% CI	HR (95% CI)	%	95% CI	%	95% CI	%	95% CI
Jeremic 200163	CTX + (HFX)RT days 1–5	20	NR	NR	NR	NR	NR	80	NR	47	NR	85	NR
	CTX + (HFX)RT days 1–7	22	NR	NR	NR	NR	NR	78	NR	49	NR	88	NR
Komaki 200250	CTX → CTX + RT	16.4	NR	NR	9.4	NR	NR	63	NR	39	NR	73	NR
	CTX + (HFX)RT	15.5	NR	NR	8.2	NR	NR	58	NR	32	NR	71	NR
Schild 200262	CTX + RT (2× daily)	14	NR	NR	9.4	NR	NR	37	29 to 47	47	NR	NR	NR
	CTX + RT (4× daily)	15	NR	NR	9.6	NR	NR	40	32 to 50	50	NR	NR	NR
Vokes 200247	CTX (GEM + CIS) → CTX + RT	18.3	13.8 to 23.6	NR	8.4	NR	NR	68	56 to 79	37	NR	74	60 to 86
	CTX (VNB + CIS) → CTX + RT	14.8	12 to 19.5	NR	9.1	NR	NR	62	50 to 75	29	NR	67	52 to 80
	CTX (PAX + CARB) → CTX + RT	17.7	12.4 to 24.7	NR	11.5	NR	NR	65	53 to 78	40	NR	73	57 to 85
Zatlouka 200451	CTX + RT	16.6.	NR	0.61 (0.39 to 0.93)	11.9a	NR	NR	69.2	NR	34.2	NR	80	62 to 98
	CTX → RT	12.9	NR	NR	8.5a	NR	NR	53	NR	14.3	NR	47	33 to 61
Belani 200552	CTX → RT	13	NR	NR	9.0	NR	NR	57	NR	30	NR	NR	NR
	CTX → CTX + RT	12.7	NR	NR	6.7	NR	NR	53	NR	25	NR	NR	NR
	CTX + RT → CTX	16.3	NR	NR	8.7	NR	NR	63	NR	31	NR	NR	NR
Fournel 200549	CTX → RT	14.5	8.3 to 27.4	NR	NR	NR	NR	59.8	50 to 69	26.5	17.9 to 35.0	54	NR
	CTX + RT → CTX	16.3	5.8 to 34.8	NR	NR	NR	NR	60.4	50.8 to 69.9	39.3	29.7 to 48.9	49	NR
Reinfuss 200546	CTX → CT	NR	NR	NR	NR	NR	NR	NR	NR	26.7	NR	NR	NR
	CTX + RT	NR	NR	NR	NR	NR	NR	NR	NR	33.3	NR	NR	NR
Dasgupta 200656	CTX → RT	NR	NR	NR	NR	NR	NR	88.4	NR	57	NR	65.7	NR
	CTX + R	NR	NR	NR	NR	NR	NR	86.1	NR	66.6	NR	66.7	NR
Gouda 200659	CTX → CTX + RT	NR	NR	NR	NR	NR	NR	55	NR	40	NR	75	NR
	CTX + RT	NR	NR	NR	NR	NR	NR	65	NR	45	NR	79	NR
Belderbos 200754	CTX → RT	16.2	12.8 to 22.6	1.06 (074 to 1.52	10.8	9.0 to 15.0	0.79 (0.56 to 1.10)	69	58.7 to 79.3	33.6	23 to 44.2	69.7	58.1 to 79.8
	CTX + RT	16.5	11.3 to 24.3		8.5	6.4 to 10.9		55.9	45.0 to 66.9	38.5	27.6 to 49.4	60.8	47.8 to 72.4
Vokes 200748	CTX + RT	12	10 to 16	NR	7.0	NR	NR	NR	NR	29	NR	67	60 to 74
	CTX → CTX + RT	14	11 to 16	NR	8.0	NR	NR	NR	NR	31	NR	61	59 to 69
Liu 200853	Low-dose weekly CTX (DOC) + RT (3D conformal) → CTX (DOC + CIS)	20	NR	NR	NR	NR	NR	69.8	NR	48.1	NR	81.8	NR
	Systemic CTX + RT (3D conformal) → CTX (DOC + CIS)	16	NR	NR	NR	NR	NR	66.5	NR	40.2	NR	86.4	NR
Socinski 2008a55	CTX → CTX (PAX + CARB) + RT	24.3	12.3 to 36.4	NR	14.9	7.9 to 24.3	NR	66.7	50.3 to 78.7	NR	NR	66.6	50.5 to 80.4
	CTX → CTX (GEM + CARB) + RT	12.5	9.4 to 27.6	NR	7.7	5.1 to 11.0	NR	50	29.9 to 67.2	NR	NR	69.2	48.2 to 85.7
Berghmans 200945	CTX + RT → CTX	17.0	9.3 to 24.6	NR	7 3s	5.0 to 9.6	NR	NR	NR	NR	NR	57	36 to 78
	CTX → CTX + RT	23.9	13.3 to 34.5	NR	13.3a	8.7 to 17.6	NR	NR	NR	NR	NR	79	64 to 94
Crvenkova 200957	CTX → RT	13	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR
	CTX + RT → CTX	22	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR	NR
Nyman 200958	CTX → CTX + accelerated RT	17.69	11.15 to 36.25	NR	8.75	7.4 to 15.16	NR	64	NR	41	NR	33	NR
	CTX → CTX daily + conventional RT	17.68	11.97 to NR	NR	10.27	8.31 to 14.3	NR	62	NR	39	NR	70	NR
	CTX → CTX weekly + conventional RT	20.63	12.72 to 25.09	NR	9.31	7.33 to 13.78	NR	62	NR	38	NR	45	NR
Zhu 200960	CTX + RT (3D conformal)	19.7	NR	NR	NR	NR	NR	70.5	NR	47.7	NR	68	NR
	CTX → RT (3D conformal)	18.2	NR	NR	NR	NR	NR	66.7	NR	42.9	NR	62	NR
Movsas 201061	CTX + RT → CTX (GEM)	16.1	9.8 to 34.0	NR	5.4	2.7 to 7.9	NR	65.6	46.9 to 79.3	40.6	23.8 to 56.8	NR	NR
	CTX + RT → CTX (GEM + DOC)	29.5	16.4 to 52.0	NR	13.4	4.6 to 23.3	NR	71.9	52.9 to 84.3	55.7	36.8 to 70.9	NR	NR

Results of evidence synthesis

Overall, population data describing just over 2000 patients in the 19 trials were eligible for consideration as part of the Assessment Group's approach to evidence synthesis. Detailed characteristics of all included trials are described in Appendix 6 and are also presented in the appendices. The Assessment Group investigated the possibility of conducting both meta-analysis and MTC analysis using the large quantity of trial data available. The Assessment Group concluded that the data available were heterogeneous: there were variations in CTX agents and different RT doses both across and within trials; number of fractions, schedules, intensity and overall treatment time also varied between trials. In summary, the 19 trials were disparate in terms of the interventions and comparators being compared (Table 10) and comprised eight distinct comparisons. As such, the conduct of a MTC was considered to be inappropriate. Direct meta-analysis using OS data was undertaken where possible: sequential CTX-RT compared with concurrent CTX-RT; sequential CTX-RT compared with concurrent/consolidation CTX-RT and sequential CTX-RT compared with concurrent CTX-RT with or without consolidation. The Assessment Group was unable to undertake any meta-analysis on PFS because of limited data.

TABLE 10 - Summary of CTX-RT combinations for each included trial by treatment option

HFXRT, hyperfractionated RT; VBL, vinblastine.

Reference ID	Concurrent CTX-RT	Sequential CTX-RT	Induction/concurrent CTX-RT	Concurrent/consolidation CTX-RT
Jeremic 200163	ETOP + CARB + HFXRT vs ETOP + CARB + HFXRT
Komaki 200250	ETOP + CIS + HFXRT		VBL + CIS → CIS + RT
Schild 200262	ETOP + CIS + RT vs ETOP + CIS + HFXRT
Vokes 200247			GEM + CIS → GEM + CIS + RT vs PAX + CIS → PAX + CIS + RT vs VNB + CIS → VNB + CIS + RT
Zatloukal 200451	VNB + CIS + RT	VNB + CIS → RT
Belani 200552		PAX + CARB → RT	PAX + CARB → PAX + CARB + RT	PAX + RT → CARB
Fournel 200549		VNB + CIS → RT		ETOP + CIS + RT → VNB + CIS
Reinfuss 200546	VNB + CIS + RT	VNB + CIS → RT
Dasgupta 200656		ETOP + CIS → RT + ETOP + CIS		ETOP + CIS + RT → ETOP + CIS
Gouda 200659	PAX + CARB + RT		PAX + CARB → PAX + CARB + RT
Belderbos 200754	CIS + RT	GEM + CIS → RT
Vokes 200748	PAX + CARB + RT		PAX + CARB → PAX + CARB + RT
Liu 200853				DOC + CIS + RT → DOC + CIS vs DOC + RT → DOC + CIS
Socinski 2008a55			GEM + CARB → GEM + RT vs PAX + CARB → PAX + CARB + RT
Berghmans 200945			GEM + VNB + CIS → GEM + VNB + CIS + RT	GEM + VNB + CIS + RT → GEM + VNB + CIS
Crvenkova 200957		ETOP + CARB—>RT		ETOP + CIS + RT → ETOP + CARB
Nyman 200958			PAX + CARB → PAX + RT vs PAX + CARB → PAX + RT vs PAX + CARB → PAX + CARB + RT
Zhu 200960	VNB + CIS + RT	VNB + CIS → RT
Movsas 201061				ETOP + CIS + RT → GEM vs ETOP + CIS + RT → GEM + DOC

Overall survival data available for inclusion in meta-analyses

Sequential chemoradiation compared with concurrent chemoradiation (n = 4)

Four trials46,51,54,60 compared sequential CTX-RT with concurrent CTX-RT. The HRs for OS for two trials51,54 were extracted directly from the published trial papers. Two studies46,60 were excluded from the meta-analysis on OS because data were unavailable and it was impossible for the Assessment Group to estimate the OS HRs based on the published summary statistics. The trial by Zatloukal et al. 51 demonstrated significantly longer OS with concurrent CTX-RT (median survival 16.6 months) than with sequential CTX-RT (median survival 12.9 months) (p = 0.023, log-rank test; HR 0.61; 95% CI 0.39 to 0.93). The results from the trial described by Belderbos et al. 54 were not statistically significant. The pooled results from the OS meta-analysis comparing concurrent CTX-RT with sequential CTX-RT were therefore based on two trials. The results of this analysis are presented in Figure 3 and appear to show an OS advantage for concurrent CTX-RT arms over sequential arms; this result is not statistically significant (HR 0.79; 95% CI 0.50 to 1.25). Visual examination of the forest plot indicates a non-statistically significant chi-squared test for heterogeneity (p = 0.096) and an I2 statistic of 63.9%; the results suggest inconsistency in the direct evidence from the two trials. 51,54

FIGURE 3.

Summary of the direct evidence results for OS for trials comparing sequential CTX-RT with concurrent CTX-RT.

Sequential chemoradiation compared with concurrent/consolidation chemoradiation (n = 4)

Four trials49,52,56,57 compared sequential CTX-RT with concurrent/consolidation CTX-RT. Concurrent/consolidation CTX-RT significantly increased median OS in a trial by Crvenkova et al. 57 Three trials49,52,56 showed non-significant trends in favour of concurrent/consolidation CTX-RT compared with sequential CTX-RT.

One52 of the four studies was excluded from the meta-analysis on OS because data were unavailable and it was impossible for the Assessment Group to estimate the OS HRs based on the published summary statistics. The OS HRs for one trial49 were extracted directly from the published trial paper, while HRs for two trials56,57 were estimated using summary statistics based on the methods described in the methods section of this report. The pooled results from the meta-analysis on OS comparing sequential CTX-RT with concurrent/consolidation CTX-RT were therefore based on data from three trials. The results of this analysis are presented in Figure 4 and appear to show a statistically significant OS advantage for concurrent/consolidation CTX-RT treatment over sequential treatment; this result is statistically significant (HR 0.68; 95% CI 0.55 to 0.83). Visual examinations of the forest plot, the chi-squared test for heterogeneity (p = 0.713) and the I2 statistic (0%) all suggest very good consistency.

FIGURE 4.

Summary of the direct evidence results for OS for trials comparing sequential CTX-RT with concurrent/consolidation CTX-RT. NR, not reported.

Sequential chemoradiation compared with concurrent chemoradiation with or without consolidation (n = 8)

Eight trials46,49,51,52,54,56,57,60 compared sequential CTX-RT with concurrent CTX-RT with or without consolidation and were considered for inclusion in the meta-analysis on OS. The HRs for OS for three trials49,51,54 were extracted directly from the published trial papers, while HRs for two trials56,57 were estimated using summary statistics based on the methods described in the methods section of this report. Three studies47,52,61 were excluded from the meta-analysis on OS because data were unavailable and it was impossible for the Assessment Group to estimate the OS HRs based on the published summary statistics. Three trials49,51,57 demonstrated significantly longer OS with concurrent CTX-RT with or without consolidation (median survival ranged from 16.3 to 22 months) than with sequential CTX-RT (median survival ranged from 12.9 to 14.5 months). The pooled results from the meta-analysis on OS comparing sequential CTX-RT with concurrent CTX-RT with or without consolidation were based on data from five trials. The results of this analysis are presented in Figure 5 and appear to show a statistically significant OS advantage for concurrent CTX-RT with or without consolidation over sequential treatment; this result is statistically significant (HR 0.72; 95% CI 0.61 to 0.84). Visual examinations of the forest plot, the chi-squared test for heterogeneity (p = 0.445) and the I2 statistic (0%) all suggest very good consistency.

FIGURE 5.

Summary of the direct evidence results for OS for trials comparing sequential CTX-RT with concurrent CTX-RT with or without consolidation. NR, not reported

Overall survival data unavailable for inclusion in direct meta-analysis

Induction/concurrent chemoradiation compared with concurrent chemoradiation (n = 3)

Three trials48,50,59 compared induction/concurrent CTX-RT with concurrent CTX-RT. None of the studies presented OS HRs and therefore no meta-analysis was undertaken because it was impossible for the Assessment Group to estimate the OS HRs based on the published summary statistics. As shown in Table 10 the induction CTX used in two of the three trials was the same (PAX plus CARB). Direct results from each of the three studies indicated that the addition of induction CTX increased toxicity and provided no survival benefit over concurrent CTX-RT alone.

Induction/concurrent chemoradiation compared with concurrent/consolidation chemoradiation (n = 2)

Two trials45,52 comparing induction/concurrent CTX-RT with concurrent/consolidation CTX-RT were considered for inclusion in the meta-analysis on OS. The studies did not present OS HRs and therefore no meta-analysis was undertaken because it was impossible for the Assessment Group to estimate the OS HRs based on the published summary statistics. It is noted that the induction and consolidation chemotherapies used in the trials were different (see Table 10). Results from both trials demonstrate a longer median survival time with concurrent/consolidation CTX-RT than with induction/concurrent CTX-RT (16.3 months vs 12.7 months; 23.9 months vs 17 months); these results were not statistically significantly different.

Induction/concurrent chemoradiation compared with induction/concurrent chemoradiation (n = 3)

Three trials47,55,58 that compared induction/concurrent CTX-RT with induction/concurrent CTX-RT were considered for inclusion in the meta-analysis on OS. None of the studies presented OS HRs data and therefore no meta-analysis was undertaken because it was impossible for the Assessment Group to estimate the OS HRs based on the published summary statistics. The three trials were very different to each other as is shown in Table 10. In the trial by Nyman et al. ,58 all patients had the same induction CTX following randomisation into three arms. Concurrent weekly CTX with conventional RT was associated with a longer median survival (20.63 months) than concurrent CTX-RT with accelerated RT (17.69 months) and concurrent daily CTX with conventional RT (17.68 months).

The trial by Vokes et al. 47 compared induction CTX using GEM, VNB or PAX in combination with cisplatin (CIS) in addition to concurrent CTX-RT; median survival for all patients was 17 months (range 14.8–18.3 months). The trial by Socinski et al. 55 evaluated induction CTX with either PAX plus CARB or GEM plus CARB. On day 43, the PAX plus CARB arm received weekly CARB plus PAX whereas the GEM plus CARB arm received biweekly GEM. Both arms received CTX concurrently with 74 Gy of thoracic RT utilising three-dimensional treatment planning. The median survival time was 24.3 months in the PAX plus CARB arm compared with 12.5 months in the GEM plus CARB arm. The GEM plus CARB arm was closed prematurely because of a high rate of grade 4/5 pulmonary toxicity.

Concurrent chemoradiation compared with concurrent chemoradiation (n = 2)

Two trials62,63 comparing concurrent CTX-RT with concurrent CRX-RT were considered for inclusion in the meta-analysis on OS. None of the studies presented OS HRs data and therefore no meta-analysis was undertaken because it was impossible for the Assessment Group to estimate the OS HRs based on the published summary statistics. The trial by Jeremic et al. 63 aimed to investigate whether or not it is advantageous to add weekend CTX consisting of ETOP plus CARB to hyperfractionated RT and concurrent daily ETOP plus CARB. No difference was found regarding median survival time or 5-year survival rates (20 vs 22 months; 20% vs 23%; p = 0.57). The trial by Schild et al. 62 demonstrated no statistically significant difference in OS between ETOP plus CIS plus RT once daily and ETOP plus CIS plus RT twice daily (14 vs 15 months).

Concurrent/consolidation chemoradiation compared with concurrent/ consolidation chemoradiation (n = 2)

Two trials53,61 comparing concurrent/consolidation CTX-RT with concurrent/consolidation CTX-RT were considered for inclusion in the meta-analysis on OS. None of the studies presented OS HRs and therefore no meta-analysis was undertaken because it was impossible for the Assessment Group to estimate the OS HRs based on the published summary statistics. The two trials were very different to each other as shown in Table 10. The trial by Movsas et al. 61 compared two different consolidation CTX interventions (GEM compared with GEM plus DOC). Patients were randomised after they had all received the same concurrent CTX-RT. Consolidation therapy with GEM was associated with a median OS of 16.1 months compared with 29.5 months for GEM plus DOC. The trial by Liu et al. 53 showed no significant difference in 1- and 2-year survival rates between low-dose weekly DOC and standard DOC plus CIS – both groups received concurrent RT and the same consolidation CTX-RT. Median survival time was 20 months for the low-dose weekly DOC group and 16 months for the standard DOC plus CIS group.

Chapter 4 Discussion

Chemoradiation treatment is common practice for stage III cancers for those patients whom clinicians believe may be curable. This review was carried out as part of a larger project32 looking at first-line treatments for patients with locally advanced and/or metastatic lung cancer. It was the opinion of the members of the clinical panel for the project that patients with stage IIIA or IIIB potentially curable disease are different from those who are considered for only palliative treatment of more advanced disease. The clinical panel was of the opinion that the review of CTX-RT treatments for patients with potentially curable disease should be reported separately.

There have been previous reviews that looked at this question. 22,35,64 However, given the advances in treatment, in the areas of both CTX and RT, it was felt worthwhile to examine the question again and to limit the dates of included trials to represent current, rather than historical, clinical practice.

Chapter 5 Conclusion

This review identified that the research conducted in the area of CTX-RT was generally of poor quality and suffered from a lack of reporting of all important clinical findings, including OS. In addition, there are within- and between-trial variations in treatment protocols including treatment duration, sequencing and length, RT exposure and type of CTX. These wide variations severely limited the combination of trial results.

Meta-analyses conducted as part of this review demonstrated a small but statistically significant improvement in OS in patients receiving concurrent/consolidation CTX-RT compared with sequential CTX-RT and statistically significantly improved OS with the use of concurrent CTX-RT (with or without consolidation) over sequential treatment. However, as noted, the variation in treatment protocols and the changes in the diagnostic criteria and staging used in NSCLC mean that the results of comparisons across these trials and with future trials need to be viewed with caution.

Acknowledgements

Expert Advisory Panel: Emer McKenna and Noelle O'Rourke. Thanks to Juliet Hockenhull for database expertise and Janet Atkinson for administrative support.

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Appendix 1 Details of clinical search strategies

Details of clinical search strategies (PDF download)

Appendix 2 Details of clinical data abstraction

Details of clinical data abstraction (PDF download)

Appendix 3 Details of clinical trial quality assessment

Details of clinical trial quality assessment (PDF download)

Appendix 4 Code from the Multi-parameter Evidence Synthesis Research Group

Code from the Multi-parameter Evidence Synthesis Research Group (PDF download)

Appendix 5 Excluded studies with reasons for exclusion

Excluded studies with reasons for exclusion (PDF download)

Appendix 6 Trial characteristics

Trial characteristics (PDF download)

Appendix 7 Intervention details

Intervention details (PDF download)

Appendix 8 Relative dose intensity

Relative dose intensity (PDF download)

Appendix 9 Patient characteristics

Patient characteristics (PDF download)

Appendix 10 Inclusion/exclusion criteria of included studies

Inclusion/exclusion criteria of included studies (PDF download)

Appendix 11 Adverse events

Adverse events (PDF download)

Appendix 12 Protocol

Protocol (PDF download)

Glossary

Adenocarcinoma

Cancer that begins in cells that line certain internal organs and which have glandular (secretory) properties.

Chemo-naive

Chemotherapy naive – having received no previous chemotherapy treatment.

Chemoradiation

Combined chemotherapy and radiation therapy.

Chemotherapy

Treatment with anticancer drugs.

Heterogeneity

Between-trial variation.

Histological diagnosis

A diagnosis made by examining a sample of tissue or cells.

Intention to treat

A method of data analysis in which all patients are analysed in the group that they were assigned to at randomisation regardless of treatment adherence.

Large cell carcinoma

A group of lung cancers in which the abnormal cells are large.

Locally advanced disease

Stages IIIA/IIIB non-small cell lung carcinoma.

Meta-analysis

A quantitative method for combining the results of many trials into one set of conclusions.

Metastasis

The spread of cancer from one part of the body to another. Tumours formed from cells that have spread are called ‘secondary tumours’ and contain cells that are like those in the original (primary) tumour. The plural is metastases.

Non-small cell lung cancer

A group of lung cancers that includes squamous cell carcinoma, adenocarcinoma and large cell carcinoma.

Non-squamous cell carcinoma

A classification of cancer that includes adenocarcinoma, which begins in the cells that line the alveoli, and large cell carcinoma that begin in types of large cells.

Radiation therapy

The use of high-energy radiation from X-rays, neutrons and other sources to kill cancer cells and shrink tumours. Radiation may come from a machine outside the body (external beam radiation therapy) or from material called radioisotopes. Radioisotopes produce radiation and are placed in or near a tumour or near cancer cells. This type of radiation treatment is called internal radiation therapy, implant radiation or brachytherapy. Systemic radiation therapy uses a radioactive substance, such as a radiolabelled monoclonal antibody, that circulates throughout the body. Also called radiotherapy.

Relative risk

The proportion of diseased people among those exposed to the relevant risk factor divided by the proportion of diseased people among those not exposed to the risk factor.

Relative risk reduction

Alternative way of expressing relative risk. It is calculated as RRR = (1 – RR) × 100%. The RRR can be interpreted as the proportion of the baseline ‘risk’ that was eliminated by a given treatment or by avoidance of exposure to a risk factor.

Squamous cell carcinoma

Cancer that begins in squamous cells, which are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma.

List of abbreviations

AE

adverse event

BSC

best supportive care

CALGB

Cancer and Leukemia Group B

CARB

carboplatin

CIS

cisplatin

CI

confidence interval

CT

computerised tomography

CTX

chemotherapy

CTX-RT

chemoradiation

DOC

docetaxel

ECOG

Eastern Cooperative Oncology Group

EGFR

epidermal growth factor receptor

ETOP

etoposide

GEM

gemcitabine

Gy

Gray (unit of absorbed radiation dose)

HART

hyperfractionated accelerated radiotheraphy

HR

hazard ratio

HRQoL

health-related quality of life

ITT

intention to treat

KPS

Karnofsky performance status

LUCADA

National Lung Cancer Data Audit

M +

mutation-positive (EGFR)

MCMC

Markov chain Monte Carlo

MTC

mixed-treatment comparison

NICE

National Institute for Health and Clinical Excellence

NSCLC

non-small cell lung cancer

ORR

overall response rate

OS

overall survival

PAX

paclitaxel

PFS

progression-free survival

PLAT

platinum (cisplatin or carboplatin)

PS

performance status

RCT

randomised controlled trial

RDI

relative dose intensity

RR

relative risk

RT

radiotherapy

TTP

time to progression

UICC

Union Internationale Contre le Cancer

VBL

vinblastine

VNB

vinorelbine

WHO

World Health Organization