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Data Quality is a central requirement of scientific research and external monitoring is essential in multicentric clinical trials (MCT). A quality control (QC) study was conducted in the main Institutions participating in EORTC-GCCG Protocol number 55863 - randomised phase III trial of vindesine, cisplatin, bleomycin and mitomycin-C (BEMP) versus cisplatin (P) in disseminated squamous cell carcinoma of the uterine cervix - in order to assess the impact of variations in data quality on the conclusions of the trial. The reliability of the different centres in following the protocol was investigated by a questionnaire covering drug prescription, local facilities and the procedure for preparation and administration of chemotherapy. The 'treatment protocol adherence' was evaluated by recalculation of the ideal protocol dose and its comparison with the actual delivered dosage at each cycle of chemotherapy. 'Data quality control' was assessed by comparison of data on case report forms (CRFs) with the corresponding items in the medical records. Eleven centres participating in the trial were visited by the same team of reviewers. Striking differences were noted in the chemotherapy administration procedures and between the type and quality of hospital files. Overall, there was an acceptable level of data quality and protocol compliance. Data accuracy was 81.8% (range: 65. 6-97%) of the 4424 items checked. Incorrect data were found in 7.0% (2.3-14.5%), data were missing on the form in 3.6% of cases (0-12%) and data was on the form but not in the file in 7.6% of cases (0. 7-17.5%). Causes of inaccuracy were analysed. Both problems in data management but also in a lack of clarity of the protocol and/or CRFs were to blame. Training and supervision of data managers, precision in writing protocols, standardisation of some aspects of CRFs and the use of a checklist for chemotherapy data and treatment toxicities would have avoided many of these errors. The need for QC in all collaborative groups performing MCT is emphasised. A literature review on QC in MCT dealing with chemotherapy is included.

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The purpose of the study was to monitor the quality of chemotherapy administration within the department of oncology, of the university hospitals in Leuven (Belgium), by focusing on prescription and documented administration of chemotherapy. First, the actors and phases of the process were identified. Then selected patient records of three different types of chemotherapy were retrospectively analysed for 453 chemotherapy administrations. Study results indicated an important need to standardize the nursing and medical guidelines concerning chemotherapy administration. A formal task force was established to work on a multidisciplinary basis. The goals were to improve the routine process by identifying practical problems at any level and to standardize procedures by replacing all poorly defined "habits" by well-structured guidelines.

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The aim of this study was to develop a standardised surgical report for breast-conserving procedures, supporting the systematic documentation of the different aspects of the surgery. The surgical procedure for tumourectomy and axillary clearance was translated into a series of steps that could be quantitatively documented. This description was submitted twice to a group of surgeons from different departments to ensure that all steps that are considered to have relevance for outcome were included and that no superfluous data were collected. After two corrective phases, a first test format was developed. Between February 1993 and May 1994, seven surgical departments, participating in EORTC trials, completed this questionnaire for a number of their patients. The data collected related to general information on the department, the tumour excision itself, the axillary dissection and, in a later phase, on pathology. 269 questionnaires (264 tumour excisions, 259 axillary dissections and 189 pathology reports) were collected and analysed. Even though the participating departments were involved in a single trial on breast-conserving surgery and had previously developed regular contacts about the practical aspects of treatment, many differences were detected. In general, variations were found in the waiting time between treatment prescription and execution, experience of the surgeon, duration of the procedure, and the use of prophylactic antibiotics. Also, in the practical execution of the procedure, major variations in the type of incision, width of tumour excision, closure of the breast tissue and skin, the use of frozen sections and the extent of the axillary dissection were found. The most relevant differences and their possible consequences are discussed. It has been proven possible and feasible to document quantitatively a surgical procedure. The fact that within a group of surgeons participating in the same clinical trials, many differences in the surgical techniques are observed, stresses the need to reach a consensus on a stricter set of guidelines for breast-conserving procedures and their documentation, especially when conducting clinical trials.

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When researching the literature, many differences within surgical techniques for breast conservation, tumour excision and axillary dissection are described in the smallest detail. Most authors have their own preferences but little clinical research has been done to evaluate the impact of those differences on outcome: local control, cosmesis, complications or costs. Even when prospective, randomized clinical trial protocols provide many instructions to perform the surgery, the case report forms almost never document the surgery actually performed. This is in contrast to radiotherapy and chemotherapy regimens, which have had higher standards of quality of care implemented. The development of more detailed and standardized procedural information should lead to more accurate and specific information, which can be easily transferred in a learning process, and enable more reliable clinical research. Documentation and guidelines for surgery are essential tools in implementing a process of quality audit for a type of surgery where accuracy is essential.

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The concept of a Master Protocol for phase III studies was raised at the Steering Committee of the EORTC Radiotherapy Group, in order to make the work of the study coordinators easier, when writing protocols and to give them more homogeneity. The Master Protocol defines and clarifies in a logical order the different steps which must be taken when designing a randomized trial--from the rationale to the references. It pays particular attention to eligibility criteria, volumes of interest defined in agreement with ICRU Report 50 (gross tumor volume, clinical target volume, planning target volume and organs at risk), simulation procedure, treatment technique, normal tissue sparing, dose computation, equipment, dose specification (also in agreement with ICRU Report 50). Last but not least, the different procedures of quality assurance for protocols and patients are also defined (site visits, dummy run procedure, in vivo dosimetry, individual case review) to allow working plans to be made in advance. We are aware that this work is not exhaustive, but hope that the contents will be of help to those who are writing a protocol.

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The purpose of this quality assurance project in the University Hospitals in Leuven, Belgium, was to describe, analyse and improve the actual routine practice of chemotherapy administration. The article focuses on analysis and improvement of role performance of nurses. The process of chemotherapy was systematically assessed by means of a retrospective analysis of patient records. This was done for 61 patient records receiving 453 chemotherapy administrations. Five aspects of the role of oncology nurses were described and analysed: data collection for prescription of chemotherapy, communication of instructions, preparation of the cytotoxic treatment, administration of cytotoxics and post-chemotherapy assessment. Data analysis showed variability in relation to several role aspects. Standardization of procedures and information was introduced to improve role performance in several areas.

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As part of a phase II study of the EORTC Soft Tissue and Bone Sarcoma Group, 15 centres took part in a programme to evaluate the quality of treatment delivered and data collected. The centres were visited and facilities for treatment and data management were reviewed. Source data in randomly selected patient hospital records were compared with information which had previously been completed on case record forms and returned to the EORTC Data Centre. The review included 71% of the patients entered into the study and 76% of the treatment cycles. Chemotherapy was prepared by nurses or clinicians in 58% and by pharmacists in 42% of the centres and was administered by specialist nurses in 67% of the hospitals. 8776 items were checked with source data. 3.4% were incorrect, 0.2% were missing and 30% could not be verified as correct (mainly related to the lack of recording of toxicity data in hospital records). The mean doses of chemotherapy delivered and treatment intervals were those stipulated in the protocol but 21% of the cycles were delayed for avoidable reasons. Several modifications to the procedures for running chemotherapy trials were suggested by this survey including the use of a systematic checklist for recording toxicity and chemotherapy administration and the development of quality assurance programmes in other collaborative groups and single centres to ensure that published results are credible.

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Blood lymphocyte subsets of early breast cancer patients and of men with stage I seminoma of the testis were studied up to 6 years after radiotherapy. Similar results were obtained in the two patient groups. After a temporary decrease, the CD4-w29 or "memory" T cells recovered completely, while the CD4-45R or "naive" T cells remained decreased up to 6 years after irradiation. The number of CD8 T lymphocytes did not change during or after treatment. Because of the decrease of a subset of CD4 cells, and the unchanged values of CD8 cells, the CD4/CD8 ratio decreased significantly after irradiation, and remained lower than before treatment up to 5-6 years after radiotherapy. The number of both HLA-DR positive CD4 and HLA-DR positive CD8 T cells ("activated" T cells) increased significantly after irradiation. The natural killer (NK) cells were not affected by treatment. We propose that the recovery of the CD4 cells is limited to the CD4-w29 ("memory") population because of thymic dysfunction in older humans. The impact of the observed immune modulation on the low susceptibility for infections after local irradiation, and on putative antitumour immune responses is discussed.

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In multicentre studies, non-compliance with the protocol may limit the chances of reaching a correct conclusion. A procedure to examine the administration of chemotherapy in multicentre EORTC protocols has been developed. General aspects are covered in a mailed questionnaire on the prescription of drugs with rounding up or down of dosages, local facilities for preparation and the procedure for preparation and administration. More detail is collected during a quality control site visit. Ten centres have been visited and there was significant variation between centres in the organisation of chemotherapy administration. However, more striking differences were noted between the type and quality of hospital files. The lack of systematic recording of sequence, timing and doses of chemotherapy and, in particular, treatment related toxicity, is a major difficulty limiting the effectiveness of quality control. These shortcomings emphasise the need for standardisation of some aspects of case records and a suggested check-list has been drafted.

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In a study initiated by the EORTC Study Group on Data Management, 15 site visits to main participating centers in ongoing cancer clinical trials have been carried out over a 1 year period. The aim was to evaluate the quality level of EORTC clinical trial data, to find out the order of magnitude of possible problems encountered and to test a technique to objectively assess the quality of data. The process of data collection and the quality of data transfer from hospital charts to EORTC case report forms (CRF) were checked. The data quality was scored and the causes of incorrectness were evaluated. Percentages of correct data ranged from 78% up to 98%; 11/15 centers had greater than 90% correct data. The median rate of error encountered in key data was 2.8% (range 0.5-7%). The main source of error was incorrect transfer of the information recorded in the patient chart to the CRF. Equally good overall results have been observed in the centers where data managers fill in the forms (DM) and those centers without an administrative trial structure (PH). The mean percentage of correct data for both types of centers is 91.4%. The wider range in percentage for incorrect data (DM mean value 3.0%, range 0.5-7%; PH mean value 2.3%, range 1.4-3.1) suggests the important impact of the knowledge and experience of the people involved in data management. The data quality evaluation was hampered by the impossibility of checking part of the data present on the CRF, 0.4-14.5%. Besides knowledge and experience, the main aspects influencing good data quality appeared to be the efficacy of the internal organization and good local data monitoring. The importance of the design of CRFs was also highlighted. As this study was run for on-going protocols, the site visiting team had the opportunity to point out and report to the trial coordinator all shortcomings and controversial points that could thus be corrected during the course of the trial.

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To investigate the feasibility and antitumoral effect of ketoconazole in the treatment of disseminated prostatic cancer, 22 patients with stage D2 disease were treated with 400 mg. ketoconazole orally every 8 hours. Of the 17 patients evaluable for antitumoral effect an initial tumor response of 88 per cent was observed (1 complete and 8 partial responses, and 6 with stable disease) with a mean duration of 15.8 months (range 5 to more than 30 months). Treatment-related side effects were encountered in 21 patients and consisted of asthenia, gastrointestinal complaints, skin reactions and cardiovascular complications. They were judged to be mild in 8 patients, moderate in 5 and severe in 8. Treatment had to be discontinued because of side effects in 7 patients (32 per cent). During treatment with ketoconazole serum testosterone levels decreased rapidly and attained nearly castrate levels at the end of week 3. However, after 1 month a steady increase was noted and the testosterone levels reached low normal ranges after 5 months. No hormonal or biochemical indications of adrenocortical insufficiency were noted. High dose ketoconazole is effective in the treatment of disseminated prostatic cancer. Its use is limited by the side effects and the inability to maintain castrate levels of testosterone.

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