13 New Directions in the Evaluation and Presentation of Clinical Research in Lung Cancer

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13 New Directions in the Evaluation and

Presentation of Clinical Research in Lung Cancer

Elinor Thompson and Fergus Macbeth

E. Thompson, MD

Iberoamerican Cochrane Centre, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

F. Macbeth, MD, FRCR

Velindre Hospital, Whitchurch, Cardiff, CF14 2TL, UK CONTENTS

13.1 Introduction 505

13.2 What the Evidence Does and Does Not Tell Us 505 13.3 A Plethora of Information but

Hardly Any Knowledge 506

13.4 Systematic Reviews and Meta-Analyses 507 13.4.1 Independent Ad Hoc Reviews 508 13.4.2 Cochrane Reviews 508

13.4.3 The Cochrane Lung Cancer Collaborative Review Group 509

13.5 A Specialised Trials Register for Lung Cancer? 510 13.5.1 What Is a Specialised Trials Register? 510 13.5.2 Reference-Based Registers and

Study-Based Registers 510

13.6 What Systematic Reviews and Meta-Analyses Can (and Cannot) Do 511

13.7 Conclusion 511 References 512

13.1

Introduction

Anyone working in oncology is only too familiar with the depressing list of statistics that is inevitably reeled off at the beginning of articles on almost any aspect of lung cancer. Globally lung cancer is the most common cancer in terms of both incidence and mortality, with more than 58% of new cases occurring in developed countries (Parkin et al. 1999). And since time trends in lung cancer reﬂ ect past exposure to cigarette smoking, the disease is likely to increase in other parts of the world over the next 20 years as rates of cigarette smoking continue to rise in many countries in the developing world and newly indus- trialised countries (Stewart and Kleihues 2003).

Equally well recognised is the fact that despite important technological developments in surgery, radiotherapy and chemotherapy over the last 20 years or more and many hundreds of clinical trials, there

has been very little overall improvement in survival in people with lung cancer. Population-based 5-year survival rates still range from about 5% to, at best, 15%. But importantly, all too little is known and published about any changes (for either better or worse) in the quality of that survival.

In this chapter we will reﬂ ect on what the published research evidence has actually told us and what its limitations are. We will then make some suggestions about how we might improve the quality, reliability and accessibility of that evidence.

13.2

What the Evidence Does and Does Not Tell Us There are a few accepted ‘truths’ in the prevention and treatment of lung cancer. Some of these ‘truths’

derive from years of accepted clinical practice and some from well-conducted randomised trials. But such is the contestable nature of clinical science and clinical practice that not everyone will agree with even these few ‘truths’.

The following are, we believe, more or less ﬁ rmly accepted in the management of patients with non- small cell lung cancer (NSCLC):

– Radical surgery (lobectomy or pneumonectomy) is an effective, potentially curative treatment for early stage disease.

– A combination of chemotherapy and radiotherapy is effective for patients with unresectable stage III disease, but there is uncertainty about which drugs and radiotherapy regimens are the best.

– Postoperative radiotherapy, using older technolo- gies, is harmful to patients who have had success- ful surgery. But there is uncertainty whether this also applies to radiotherapy with modern tech- niques.

– Cisplatin-based chemotherapy has a modest effect on survival in patients with locally advanced and metastatic disease but it is uncertain how much overall beneﬁ t there is in terms of quality of life.

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And these are the more or less ﬁ rmly accepted

‘truths’ in the management of patients with small cell lung cancer (SCLC):

– Combination chemotherapy improves survival in all patients.

– A combination of chemotherapy and thoracic radiotherapy in those with limited stage disease improves survival and results in the cure of a few patients.

– Prophylactic cranial irradiation (PCI) for those with limited disease in complete remission is likely to be beneﬁ cial.

But it is very clear that a number of important questions remain, such as:

– Does screening with helical CT scanning reduce mortality in high-risk populations?

– How much benefit do patients with stage III NSCLC derive from neoadjuvant chemotherapy?

– How much more effective is hyperfractionated and/or accelerated radiotherapy than conven- tional radical radiotherapy?

– Are the newer chemotherapy drugs more effective for both NSCLC and SCLC than the older ones either singly or in combination?

– Does dose intensiﬁ cation improve outcomes from chemotherapy in both SCLC and NSCLC?

More, and more precise, information is also needed on other important issues such as the effects of age, sex, tumour histology, patient genetic proﬁ le and co-morbidities on the relative effectiveness and morbidity of interventions. We also need a far better understanding of the effects of patient preferences, perspectives and knowledge on both cure and pal- liation. And given that so few patients with lung can-

cer are cured, we must increase our knowledge about some important and difﬁ cult end-of-life issues such as the effectiveness and desirability of second-line chemotherapy, when to stop active treatment and how best to palliate important symptoms such as breathlessness.

13.3 A Plethora of Information

but Hardly Any Knowledge

There has been a huge and accelerating growth in scientiﬁ c publications on lung cancer over the last 30 years. Searching Medline, from 1966 to the present, for ‘Lung Neoplasms/dt, rt, su, th [Drug Therapy, Radiotherapy, Surgery, Therapy]’ gave more than 31,000 hits. A quick search of PubMed using only the search terms ‘lung cancer’, limited for ‘randomised controlled trials’, revealed only one trial published in 1970 compared with 89 in 2002 (Fig. 13.1).

A search of the Cochrane Central Register of Controlled Clinical Trials identiﬁ ed around 1,575 trials and a search of PubMed for any clinical trial in lung cancer brought up more than 5,000 study reports. It is therefore surprising that the number of accepted ‘facts’ listed above is relatively short. There seems to be a lot of information but a shortage of real knowledge.

This inevitably leads both clinician and researcher to pose a number of questions:

– Which trials are of good quality and can be trusted to provide valid and robust information?

– How do I know whether the ﬁ ndings from a small study can be generalised more widely?

– Which trials asked the question that I am interested in?

Fig. 13.1. Number of randomised controlled trials in lung cancer published annually since 1970

Number of RCTs in lung cancer published annually since 1970

0 20 40 60 80 100 120 140

0791 2791 4791 6791 8791 0891 2891 4891 6891 8891 0991 2991 4991 6991 8991 0002 2002

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– Which trials looked at the effects of the treatment I am interested in, in the kinds of patients I treat?

– How do I know whether I have found all the relevant trials on this topic?

In order to be able to answer these questions we need to ﬁ nd better ways of clearing a path through the jungle of papers so that we can ﬁ nd the information we need quickly and easily and then do what we want to do – make better clinical and research decisions.

To be able to ﬁ nd our way to the information we need, every time that we need it, we must develop a very effective and ﬂ exible sorting system for manag- ing all the data. A good sorting system of the medical literature needs to be able to do the following:

– Search through all the data quickly, fi nding everything relevant and only the relevant – that is, we need sensitive and specifi c literature search strategies. Good search strategies will search all the literature, published and unpublished, in all languages and will maximise relevant fi nds while minimising irrelevant ones.

– Decide which studies are of good quality and which are of lower or poorer quality. Decisions as to study quality need the development and appli- cation of a number of valid criteria for assessing the design of a study.

– Undertake sound combinations of data from similar trials so that results (estimates of beneﬁ ts and harm) from a larger number of people can be evaluated than have been obtained from individual trials alone – these are meta-analyses.

– Repeat the sorts and collations regularly so that the information is up-to-date.

There are two important tools which can help us to construct this sorting system:

– Systematic reviews and meta-analyses – Specialised trials registers

13.4

Systematic Reviews and Meta-Analyses

Over the past 15 years or so the pitfalls of traditional

‘expert’ reviews have been clearly identiﬁ ed and well described. They are subject to a variety of biases which are usually not explicit, and the status of the authors may confer a spurious authority and validity to the conclusions. As the problems with these tradi-

tional reviews became more widely recognised, the science of systematic reviews, so-called secondary research (research on the research literature) and meta- analyses has developed and achieved widespread rec- ognition and credibility (Mulrow 1994).

Although a literature review may advertise itself as ‘systematic’, the use of this term does not guarantee either a high-quality or indeed a comprehensive approach to the retrieval of all relevant articles and a systematic assessment of their quality. This may serve to confuse the general reader who is not familiar with the methodology of systematic reviews and therefore may have difﬁ culty distinguishing the good from the bad.

Another area of confusion among general readers is with the term ‘meta-analysis’. The term meta-analysis refers to the statistical combination (or pooling) of quantitative data from more than one original study.

The reason for doing a meta-analysis is to amalgam- ate results from a larger sample of patients than was available in any of the individual original studies. A meta-analysis should therefore have greater statistical power to assess the relative risks and beneﬁ ts of interventions than the individual studies. There are drawbacks associated with pooling data from differ- ent studies, which include differences in the populations of patients in the studies, differences in the interventions given and other differences in the studies’

designs.

Meta-analyses may be undertaken in one of two ways: either by combining the data as presented in the published reports, or by combining the original data on the individual patients included in each of the original trials – an individual patient data analysis.

Most published meta-analyses are reports of pooled data from published reports as these are much quicker and easier to do, although their ﬁ ndings are less robust. An individual patient data (IPD) meta-analysis is a long and time-consuming process which requires contact with the authors of all the original studies to gain access to the original datasets. The data must then be cleaned and re-analysed on all the patients in the included trials – a process which often involves many hundreds if not thousands of patient records.

IPD analyses are therefore more robust and reliable than meta-analyses of published data. Three examples of IPD meta-analyses in lung cancer research looked at the role of postoperative radiotherapy for NSCLC (PORT Meta-Analysis Trialists’ Group 2003), at chemotherapy for NSCLC (Non-Small Cell Lung Cancer Collaborative Group 2003) and at the effectiveness of prophylactic cranial irradiation for SCLC (The Prophylactic Cranial Irradiation

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Overview Collaborative Group 2003). All three of these reviews have been very inﬂ uential in shaping clinical practice and the research agenda.

A systematic review does not always contain a meta-analysis; in fact many very good systematic reviews do not, because the pooling of quantitative data from studies included in the review would be impos- sible – as a result of differences in either the data itself or the way that data was collected, analysed and presented. Systematic reviews may be either (a) independent or ad hoc reviews or (b) Cochrane reviews.

13.4.1

Independent Ad Hoc Reviews

Independent research teams may carry out systematic reviews and meta-analyses for a variety of reasons. They are often context dependent and the context may be:

– To inform the development of clinical practice guidelines

– To inform health policy decisions

– To inform research strategy decisions within either public or private research organisations.

Depending on the reason for doing the review, dif- ferent degrees of precision may be used. The search of the literature may be more or less exhaustive, with date, language or journal restrictions. The assessment of the quality of the source studies and the accuracy of data extraction can be variable. There may be no need for updating, and given the often long times- cales for publication, the results may be rendered out of date by signiﬁ cant new papers even before they make it into the public arena. Nevertheless, these reviews usually provide some valuable insights.

13.4.2

Cochrane Reviews

The Cochrane Collaboration was set up in 1993 with the intention of meeting the global need to collect, collate, analyse and disseminate the available scien- tiﬁ c evidence in clinical medicine. An international, not-for-proﬁ t organisation, the Collaboration con- sists of a network of researchers, health professionals, consumers and others around the world who work together to prepare, maintain and promote systematic reviews of healthcare interventions. These reviews, all written in a standardised format, each provide recommendations on both research and practice that can be

accessed by anyone interested in the topic, be they clinician, health care consumer, manager, health policy maker or researcher. Working together in collaborative topic-focussed Review Groups, of which there are currently 51, Cochrane reviewers use a rigorous methodology for undertaking extensive searches of published and unpublished research, critically ap- praising abstracts and articles found, and conducting qualitative and quantitative analyses of the ﬁ ndings.

Cochrane reviews are published in electronic format (online and on a CD Rom issued quarterly) as part of the Cochrane Library and according to a recently agreed policy of co-publication, versions of reviews may also be published in a peer-reviewed journal (Clarke and Horton 2001).

The main focus of the Collaboration is on conducting reviews of randomised, controlled trials because as the accepted ‘gold standard’ of scientiﬁ c investiga- tion (Cochrane 1972), trials designed in this way are more likely to provide reliable therapeutic results than those using other designs (Mulrow and Oxman 1997). But the fact that a trial is randomised and controlled does not guarantee the validity of its results.

Cochrane reviewers are careful to apply criteria that assess the likelihood and strength of potential biases, both internal and external, and to make their recommendations with this quality assessment in mind.

Weighing up the strength of the evidence for a particular intervention requires detailed and meticulous consideration of several points. Nevertheless, while Cochrane Reviews attempt to present the evidence as objectively as possible, and, where relevant, give data on biological and cultural variation as well as on variations in compliance and baseline risks, the applicability of the recommendations to particular and individual circumstances must be decided by the reader. In other words, Cochrane reviews do not provide recipe-book medicine but rather facilitate a process in which health care decisions can be based on the best available evidence.

Cochrane reviews are based on speciﬁ c guidelines as set out in the Cochrane handbook, and in general have been found to use higher quality methods than those used by other systematic reviews. A quality assessment of 53 reviews published in the Cochrane library in 1998 (Olsen et al. 2001) showed that although there was a generally high standard, there was still room for improvement, with a tendency for reviewers to over-rate the beneﬁ ts of new interventions. As a result of this assessment, the Cochrane Collaboration has taken further steps to improve the quality of its reviews. The advantage to the general reader of a Cochrane review is that they know that

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the review has followed a pre-set procedure, including the publishing of a peer-reviewed protocol and peer reviewing by experts in both the relevant clinical ﬁ eld and the methodology of systematic reviews.

In addition to the topic-focussed Cochrane Collaborative Review Groups (CRGs) of which the Lung Cancer Collaborative Review Group is one, there are also Methods Working Groups, Fields, the Consumer Network and Cochrane Centres co-ordi- nated by a steering group (Fig. 13.2).

13.4.3

The Cochrane Lung Cancer Collaborative Review Group

The Lung Cancer Group (LCG) was formed in 1997 following an exploratory meeting held in Sabadell (Barcelona), Spain. The organisational structure of the LCG, in common with all other CRGs, includes an international, coordinating editorial team which is supported by reviewers, translators and consumers.

The LCG editorial team keeps a list that it has developed in consultation with members of the review group in which are detailed the titles registered for future systematic reviews, published review protocols and completed reviews. A list of the completed systematic reviews and published protocols, as of January 2004, is shown in Table 13.1. A further six titles have also been registered (see http//www.cochrane.es/lcg).

The scope of the LCG covers all aspects of primary and secondary prevention, therapy, supportive care, psychological interventions, biological therapy and complementary therapy for lung cancer, other intra- thoracic tumours (if not addressed by other review groups) and metastatic lung disease. Although the remit of the group covers prevention, smoking is not covered because there is a separate Cochrane Review Group addressing tobacco addiction.

Fig. 13.2. Cochrane collaboration entities Cochrane Collaboration

Entities

Fields

The Consumer

Network Centres

Methods Groups Collaborative

Review Groups

Steering Group

Table 13.1. Cochrane Lung Cancer Collaborative Review Group: systematic reviews and protocols published in the Cochrane Library (January 2004)

Topic Protocol/review

Chemotherapy for malignant pleural mesothelioma Protocol

Chemotherapy versus best supportive care for extensive SCLC Protocol

Cranial irradiation for preventing brain metastases of NSCLC in patients at high risk of cerebral metastases Protocol

Gemcitabine for NSCLC Protocol

Neo-adjuvant chemotherapy for NSCLC Protocol

Non-invasive interventions for improving well-being and quality of life in patients with lung cancer Protocol

Palliative endobronchial brachytherapy for NSCLC Protocol

Radiotherapy for malignant pleural mesothelioma Protocol

Synchronous chemoradiotherapy for NSCLC Protocol

Taxanes for advanced (metastatic and locally advanced) NSCLC Protocol

Chemotherapy for NSCLC Review

Cranial irradiation for preventing brain metastases of SCLC in patients in complete remission Review

Drugs for preventing lung cancer in healthy people Review

Palliative radiotherapy regimens for NSCLC Review

Postoperative radiotherapy for NSCLC Review

Radical radiotherapy for stage I/II NSCLC in patients not sufﬁ ciently ﬁ t for or declining surgery Review

Screening for lung cancer Review

Second-line chemotherapy for NSCLC Review

Steroids, radiotherapy, chemotherapy and stents for superior vena caval obstruction in carcinoma

of the bronchus Review

Surgical sealant for preventing air leaks after pulmonary resections in patients with lung cancer Review

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As mentioned above, the process of undertaking a Cochrane review is rigorous and structured. First, the title must be registered with the LCG to ensure that no other group is working on the same topic.

Then a detailed, peer-reviewed protocol is published in the Cochrane Library in which are outlined the research methods, including the types of study to be reviewed, the outcomes of interest and the strategy for searching the literature and selecting studies. This allows time for others to comment on and improve the protocol. Once the protocol has been published, work starts on the full systematic review. The ﬁ n- ished review is then fully peer reviewed before being published in the Cochrane Library with an obligation that it should be updated every 2 years.

The Cochrane Lung Cancer Group has laid the foundation stones and made signiﬁ cant progress in the development of an evidence-based, global information resource in lung cancer care.

13.5 A Specialised Trials Register for Lung Cancer?

13.5.1

What Is a Specialised Trials Register?

Another key resource for both investigators and clinicians who wish to fi nd their way quickly and effi - ciently through a huge bank of research evidence in a single clinical fi eld is a specialised trials register. A specialised trials register is a database of randomised controlled trials (RCTs) in any particular area of health care. A specialised register can be a useful resource for both clinicians and researchers because it offers a comprehensive and specifi c source of clinical trials for any one particular health problem.

A general search of any of the major electronic databases (Medline, Embase etc.) to identify trials for lung cancer will turn up a large number of references depending on the search terms used. Searches of the general databases may be highly sensitive, in which case a lot of unnecessary and irrelevant material must be weeded out, or highly speciﬁ c but run the risk of important references being missed. The aim of a specialised register is to collate the references of all RCTs published, by means of specially designed, exhaustive searches repeated at regular intervals. In addition to searches of the world’s major electronic databases (e.g. MEDLINE, EMBASE, CINAHL, LILACS, Current Contents, Biosis and Index to UK Theses), a specialised register includes references to reports of tri-

als (both on-going and completed) that have not been indexed, or that have been published in non-indexed journals, as well as trials found by hand searching of conference proceedings and unpublished trials.

13.5.2

Reference-Based Registers and Study-Based Registers

In its most simple form a specialised register is a reference-based database of citations of RCTs in which any one trial may have several references, one for each article published, whether a primary report, a secondary report, a review article or a let- ter. A reference-based register is the easiest and least resource-intensive register to assemble. To construct the register, electronic searches are undertaken using specially developed search strategies, and citations and/or abstracts of all references identifi ed are then downloaded and reviewed by an information specialist to ensure that they meet the criteria of the register. For a lung cancer specialised register this would be all study reports of lung cancer trials that are possibly or defi nitely randomised (or quasi-randomised). All identifi ed references meeting the criteria of the specialised register are then downloaded into the specialised register, which is searchable by author, journal, year and any of the key terms included in the abstract or the key words. In addition to those references found by electronic searching, a complementary hand search of relevant conference proceedings and journals is also undertaken to ensure that relevant references are identifi ed. The electronic searching is repeated at 3-monthly intervals to ensure that it is up-to-date. Within the Cochrane Collaboration, all review groups are expected to develop and maintain their specialised trials register and to download their contents at regular intervals into the Cochrane Central Register of Controlled Clinical Trials (CENTRAL). The specialised register is used by Cochrane review groups as a fundamental resource to support reviewers in the preparation and maintenance of reviews.

A study-based register is a more sophisticated form of register which, though more resource intensive to assemble and update, is inherently more useful than a reference-based register in that it is more ﬂ exible and can be developed to support many potential research projects. A study-based register can also be used to provide the essential background data to inform the development of a clinical research strategy. A study-based register uses each individual trial

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as the basic record, rather than every reference published. Consequently each trial will have one record, regardless of the number of publications associated with it. The record of each trial holds the same information as a reference-based register, but in this case all the identifi ed associated publications are linked to the main trial record. If a trial has 100 identifi ed publications, these will be linked to the one record relating to the main trial report. Assembling a study- based register requires a more intensive input at the level of the reference identifi cation in that someone must review the abstracts in detail (and sometimes the whole article) to see whether a reference is a primary report and, if not, to identify and link it appro- priately to the primary trial report. Depending on the level of sophistication of the register, other types of information about the trial can also be extracted at this stage and entered into separate fi elds. Extra data might include: precise condition and disease stage, number, age and sex of participants, interventions used (including agents in each arm) and outcome measures assessed. In this way an investigator consulting the register would be able to undertake very precise searches - examples of which might include:

– Trials of chemotherapy in extensive SCLC in which cisplatin was included in one arm

– Trials of people over 75 in whom quality of life was measured

Using a specialised study-based trials register, the investigator could be confi dent that she or he was consulting the most comprehensive and specifi c database of randomised trials in the fi eld of lung cancer in the world. A further possible refi nement of this kind of register, possibly within the process of undertaking a systematic review, would be to develop specifi c ‘sub-registers’ containing particular groups of trials, for example trials of chemotherapy for stage IIIB NSCLC. Such sub-registers could contain highly detailed and specifi c extracted data such as quality of the randomisation process, presence of follow-up reporting, doses and schedules of agents administered, and study power.

The establishment of a specialised register of lung cancer clinical trials, once fully assembled and with adequate processes established for ensuring its maintenance and regular updating, could be an invaluable global resource for anyone undertaking research in lung cancer. Such a register, if adequately resourced, would only need to be established once, but if adequately updated and maintained could be used by all. Just as is the case with the village ‘common’, which is owned by no-one but used by all

(Hardin 1968), a trials register, once established, could be used by all but belong to no-one. In con- trast to physical common resources, however, a common information resource would not be at risk of degradation and eventual loss to all, but would more likely be enriched by overuse!

13.6

What Systematic Reviews and Meta-Analyses Can (and Cannot) Do

Good systematic reviews can identify relevant research studies, classify them by quality, combine the data from them where appropriate and draw rea- sonable conclusions. These conclusions may have implications for clinical practice – where there are signiﬁ cant ﬁ ndings – but also, importantly implications for new research. One important conclusion from the reviews already published in the Cochrane Library is the need to improve not only the quality of individual trials (their design and reporting) but also the world-wide co-ordination of research in lung cancer so that the important questions outlined at the start of this chapter can be addressed in a more systematic way.

Systematic reviews of the type promoted and published by the Cochrane Collaboration should be an essential tool for clinicians, researchers, research funders, health policy makers and anyone with an interest in lung cancer prevention, treatment and care. They are tools to improve the quality of clinical practice and clinical research, to inform a strategic research agenda and to help streamline a more effective and efﬁ cient use of research funding. But systematic reviews are only as good as the original research from which they are derived and they can never com- pensate for poor quality professional education, poor quality clinical practice, absent research, poor quality research or a disorganised research direction and agenda.

13.7 Conclusion

Both health care professionals and clinical researchers in the ﬁ eld need access to the reliable and up-to- date information on clinical effectiveness that can be provided by systematic reviews and meta-analyses. Researchers would also undoubtedly ﬁ nd a spe-

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cialised trial register extremely helpful, especially if it were study based.

Huge challenges must be overcome in clinical research in lung cancer before we are able to solve the many unanswered questions that remain in the prevention, treatment and care of this disease. Resources are increasingly scarce, but innovations in information technology could facilitate a much more or- ganised, strategic and global approach to wider re- cruitment to soundly designed trials. The means are already at our disposal: if we really want to increase our understanding of the biggest cancer killer of our time, we must have the will to invest in a single common information management resource.

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