Methodological and trialsassociated research

Perhaps the greatest benefit of established trials centre staff conducting a series of trials is the potential this gives for developing practical and theoretical methodology that can enhance past trials and underpin future ones. A programme of clinical trials generates large amounts of data and can therefore be backed up by relevant trials-associated and methodological research to the benefit of the trials programme. Such research also provides further opportunities to involve, in a different capacity, some of the clinical collaborators who provided patients for the trials. The randomized controlled trial itself is not the only research tool the clinical researcher has to hand [2], and the appropriate tool has to be chosen according to the nature of the question being asked. Much valuable trials-associated research involves tools other than the randomized trial. Such research can include, for example, developing quality of life questionnaires [3]; undertaking surveys of clinicians' practice and attitudes; studying factors of prognostic influence; improving staging definitions; and methodological and statistical research.

Each trials centre is likely to have a programme of methodological and trials-associated research, the results of which can help to improve the design, conduct, analysis and interpretation of trials. Such a programme is likely to involve prospective methodological studies and retrospective analyses of accumulated data from large numbers of patients in many trials. Research in our own unit includes, for example, refining tumour staging and thereby greatly assisting the design of testis cancer trials [4], surveys of practice and opinions which provided invaluable information for planning future trials, particularly in lung cancer [5-8], investigating prognostic factors [9-12], long-term survival [13], and adverse effects [14], Bayesian data monitoring [15,16], and many aspects of quality of life assessment (see Chapters 6 and 9).

Part of the success of the programme of MRC testis cancer trials is attributable to the parallel programme of associated, retrospective research. While being valuable in its own right, this has, for example, provided a means by which many people, with disparate ideas about how testicular cancer should be treated, could be brought together in a large collaborative project, and become involved in planning future trials. In addition, the fact that the majority of patients are seen in a relatively small number of cancer centres makes it feasible to involve the majority of people treating the disease in the decision-making process. Two examples of how retrospective studies led on to programmes of trials are illustrated below.

Example 1: Stage I non-seminomatous germ-cell tumours (NSGCT). Until the 1980s, treatment for stage I NSGCT was typically orchidectomy with post-operative radiotherapy or extensive lymph-node dissection at the time of surgery. A policy of surveillance following orchidectomy alone with further treatment only at relapse was, however, used in some centres, with long-term survival rates apparently comparable with those in patients receiving adjuvant therapy.

In 1984, the MRC initiated both a retrospective (TE01) [17] and prospective (TE04) [18] study of patients on surveillance. The aim was, in TE01, to assess the overall relapse rate and survival rate, and to investigate possible prognostic factors to indicate if any patients were at sufficiently high risk of relapse to justify adjuvant therapy, and, in TE04, to validate any hypotheses generated by the retrospective study. In addition, in TE04, data were collected on the timing of radiological investigations. These studies together enabled a prognostic index to be defined that identified a group of patients (20-25 per cent of all stage I patients on surveillance) with a 50-60 per cent risk of relapse within two years.

As a result of these studies, the MRC conducted one of the first studies of post-operative short-course chemotherapy in these patients (TE05), which showed that two courses of bleomycin, etoposide and cisplatin (BEP) virtually eliminated the risk of relapse in high-risk patients [19]; and launched a randomized trial (TE08) investigating the impact of different CT scan schedules on stage of disease at relapse and timing of relapse, based on hypotheses formed in the TE04 study.

Example 2: Metastatic germ-cell tumours. There is a long-established practice of dividing patients with metastatic germ-cell tumours according to prognosis, and tailoring treatment accordingly. However, all the major groups worldwide had established their own prognostic criteria in different ways and considered use of their own criteria to be a prerequisite for clinical trials. This naturally inhibited collaboration. The MRC had resolved one long-running dispute by showing in a retrospective study of patients treated mainly prior to the platinum era (TE02), that volume of disease and tumour markers were complementary prognostic factors [20]. Once platinum-based chemotherapy had become established, a further retrospective study (TE07) was carried out with the specific intention of devising a prognostic classification for future trials in the platinum era [21]. The European Organization for Research and Treatment of Cancer (EORTC) were looking at data with a similar aim, and, through collaboration, the eligibility criteria for two subsequent randomized trials were developed, and the trials (TE09, TE13) run as a successful collaborative effort [22,23].

Though the MRC and EORTC were now collaborating, wider collaboration was still hindered by lack of a universally agreed prognostic classification. The MRC therefore initiated an international study to develop just such a classification. All the major germ-cell cancer treatment centres worldwide were invited, and agreed to collaborate under the name of the International Germ Cell Cancer Collaborative Group. The classification of metastatic germ-cell tumours that resulted (known as the International Germ Cell Consensus Classification) [4] was adopted by the International Union Against Cancer to form the basis of the latest TNM classification of germ-cell tumours, leading them to introduce non-anatomical factors (tumour markers) for the first time.

The basis for collaboration that this work produced has enabled large, reliable trials to be carried out rapidly, despite the rarity of the disease. Subsequently, many trials groups internationally now use the IGCCC to determine eligibility for trials. TE20, comparing three versus four courses of BEP in good-risk patients, recruited over 800 patients from twelve countries in less than three years [24]. Trials in intermediate-risk and poor-risk patients involve many of the countries collaborating in the IGCCCG project.

A further example of how involvement in a trials-related research project led on to successful new trials is the individual-patient-data meta-analysis in advanced ovarian cancer [25], the first such project to be undertaken by the MRC Clinical Trials Unit. The collaborators' meeting for the meta-analysis, held to present and discuss the results and where they should lead, brought together an international group of clinicians with a specific interest in clinical trials in ovarian cancer. Directly from discussion of the results came proposals for trials in early and advanced disease (ICON1, ICON2) which had a captive group of potential, and in due course actual, collaborators. The ICON (International Collaborative Ovarian Neoplasm) collaborative group thus formed has continued to expand and has conducted some of the largest trials in ovarian cancer ever undertaken.

In a trials centre with a programme of research in a number of types of cancer, scientific staff will be aware of many aspects of the centre's programme, not just those in which they are directly involved. This can be very beneficial, as much research can be conducted across cancer sites or is relevant to sites other than the one in which it was undertaken. Examples from the programme in our own unit include studies of hypoxic cell sensitizers, continuous hyperfractionated accelerated radiotherapy, chemotherapy dose-intensification, pre-operative chemotherapy, immediate versus delayed treatment, cytokines, the accuracy of histological reporting, comparisons of quality of life instruments, evaluation of haematological toxicity as a prognostic factor and defining quality of life endpoints.

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