1 HSK, Dr Horst Schmidt Klinik Wiesbaden, Department of Gynaecology & Gynaecological Oncology, Wiesbaden; 2 Marburg University, Coordination Centre for Clinical Trials, Marburg; 3 University of Munich Grosshadern, Department of Gynaecology & Obstetrics, Munich; 4 Magdeburg University, Department of Gynaecology & Obstetrics, Magdeburg; 5 EVK Duesseldorf, Department of Gynaecology & Obstetrics, Duesseldorf; 6 University of Munich r.d.I., Department of Gynaecology & Obstetrics, Munich; 7 Tuebingen University, Department of Gynaecology & Obstetrics, Tuebingen; 8 St Vincentius Hospital, Karlsruhe, Department of Gynaecology & Obstetrics, Karlsruhe; 9 Universitätsklinikum Schleswig-Holstein Campus Kiel, Department of Gynaecology & Obstetrics, Kiel, Germany
* Correspondence to: Dr P. Harter, Department Gynaecology & Gynaecological Oncology, HSK, Dr Horst Schmidt Klinik, Ludwig- Erhard-Strasse 100, D-65199 Wiesbaden, Germany. Tel: +49-611-432377; Fax: +49-611-432672; E-mail: p.harter{at}gmx.de
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Abstract |
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Patients and methods: We evaluated the reasons for non-enrolment of ovarian cancer patients in clinical trials. All patients with ovarian cancer not enrolled in clinical studies and treated in 2001 in the participating centres were documented retrospectively and compared with patients enrolled in clinical trials at the same institutions during the same time period.
Results: Two hundred and seventy-four patients with advanced ovarian cancer (FIGO stage IIBIV) were included, of whom 139 (51%) and 135 (49%) patients were enrolled in this study and in prospective clinical trials, respectively. Ninety-four of 274 patients (34%) did not meet the inclusion criteria for clinical trials. Of 180 eligible patients, 28 (16%) refused participation and a further 17 patients (9%) were not recruited although they met the inclusion criteria. The non-study patients were older (66.7 versus 57.2 years; P <0.0001), underwent less radical surgery (hysterectomy, oophorectomy and omentectomy performed: 61.2% versus 80.7%; P = 0.001; rate of lymphadenectomy 30.9% versus 45.2%; P = 0.015) and more frequently had bulky residual disease (residual disease >2 cm: 36.2% versus 20%; P = 0.016). However, 62% of the non-study patients were treated with the same chemotherapy as in the standard arm of the respective clinical studies.
Conclusions: Study patients differ substantially from non-study patients, thus hampering generalisation of study results. Our results suggest that at least some inclusion criteria for clinical trials should be modified to increase study participation without compromising safety.
Key words: clinical trials, ovarian cancer, study participation, trial effect
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Introduction |
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Retrospective analyses have shown participation in clinical trials to be associated with better clinical outcome [4, 5
]. This phenomenon can easily be explained in positive trials when the experimental therapy shows superior results. However, this accounts only for the minority of phase III studies in oncology. For the remaining studies, it is unclear whether this effect is an epiphenomenon owing to a selection process, or whether study participation itself has a positive effect [6
10
]. The latter might include a better quality of therapy for the individual patient or indicate a superior quality of care in hospitals participating in clinical trials, a fact that has been observed for ovarian cancer patients in Germany [5
]. Better knowledge of the differences in both patient characteristics and actual treatment strategies between study and non-study patients might improve interpretation of study results in view of daily routine care. Furthermore, identification of reasons for not participating in clinical studies might provide tools to increase and broaden recruitment, thus making results more general and accelerating new therapy development.
Non-participation in clinical trials might be attributed to four main areas: (i) lack of information on the part of the patient and/or the treating physician; (ii) lack of resources; (iii) patients' objections against trials; and (iv) selection processes. The latter, a matter of extensive discussion, could be caused by the respective inclusion and exclusion criteria [11, 12
]. A study evaluating National Surgical Adjuvant Breast and Bowel Project trials suggested that inclusion/exclusion distinction be abandoned in favour of explicitly defined inclusion criteria. They also explicitly called for more research on the impact of criteria on generalisability [13
]. It could also be owing to the physicians' choice not to enrol patients who principally meet the inclusion criteria. Taylor et al. [14
] published a study that looked at Eastern Cooperative Oncology Group (ECOG) investigators and found that all responding physician members (89%) had applied a systematic pattern of patient pre-selection for entry of clinical trials beyond the formal inclusion/exclusion trial criteria, and 83% defined randomisation and adherence to trial protocol as a serious challenge to their ability to make individualised treatment decisions. The present study focuses on quantitation of the following two complexes: (i) patients' refusal of study participation; and (ii) selection processes in a cohort of patients treated in experienced study sites where a lack of information and resources can be ruled out.
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Methods |
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Results |
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Comparison of all non-study patients with study patients revealed that non-participants were older (66.7 versus 57.2 years; P < 0.0001) and had a poorer performance status (P < 0.001). There was no difference with respect to FIGO-stage and other disease characteristics. The most commonly performed surgical procedures, including total abdominal hysterectomy, bilateral salpingo-oophorectomy and omentectomy, were performed less often in non-study patients compared with study patients (61.2% versus 80.7%; P = 0.0004). Furthermore, retroperitoneal lymphadenectomy was performed in 30.9% of the non-study patients compared with 45.2 % of the study patients (P = 0.015). However, both cohorts had similar rates of bowel resection. Both the rates of macroscopically complete resection (34.8% versus 22.5%) and debulking to residual disease with maximum diameter of <2 cm (80% versus 63.8%) differed in favour of study patients (Table 2).
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The application of the platinumpaclitaxel combination did not differ among patients failing inclusion criteria and patients not enrolled owing to the physician's decision. Fifty-three (56%) of the 94 patients failing inclusion criteria received carboplatinpaclitaxel. Patients who were not enrolled owing to their physician's decision received carboplatinpaclitaxel in 59% of cases. Patients who refused study participation were treated with carboplatinpaclitaxel in 79% of cases.
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Discussion |
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A different group of patients is represented by those who refused study participation even though they met all inclusion criteria. In contrast to some other countries, study participation does not make any difference to the patients in Germany with respect to health-care costs. The standard therapy outside a clinical trial is funded by the public health-care system. This group accounted for approximately one in six patients (16%), but the number could be higher in centres that are not as trained in study methodology as the coordinating centres. We failed to prospectively document the reasons accounting for the individual decision to refuse participation. General refusal of randomisation or data collection, as well as the wish to be treated closer to home after surgery in a centre could be assumed to be the reasons. The latter could only be overcome by increasing the number of study centres. Refusal could possibly be reduced in some patients if more information were to be provided and specific education programmes were offered [26]. Six significant items have been identified by Wright et al. [27
] correlating with participation in studies for oncology patients. Study entry was more likely when: (i) the patient perceived personal benefit; (ii) the decision was easy to make; (iii) the decision was made close to the time of study presentation; (iv) the patient did not expect to do well with standard therapy; (v) the physician believed the study was asking an important question; and (vi) the (Clinical Research Associate) (CRA) did not perceive significant side-effects.
Evidence for only partially defined selection processes could be seen in the analysis of surgical features. Later non-study patients were operated less radically and consequently finished the operation with a higher tumour burden. This adds to observed differences with respect to age and performance status, both of which were more favourable in study patients. Both surgical results and age/performance status are strong prognostic factors [2830
] and the observed differences strongly indicate the limitations when study results are translated to the general population [31
]. These observations indicate that study results might be too optimistic and this accounts especially for the results of standard chemotherapy arms that are usually used to counsel patients about prognoses and benefits from specific treatment modalities outside of trials.
This AGO-OVAR trial provides some interesting insight into possible limitations of translating study results in clinical routine and treatment recommendations. However, retrospective evaluation limits our analysis to objective factors. Consequences have already led to modification of inclusion and exclusion criteria in subsequent trials. Furthermore, a planned prospective trial will evaluate the individual reasons for refusing study participation in a more detailed way.
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Acknowledgements |
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The following additional investigators/centres contributed to the study (in alphabetical order): A. Belau (Greifswald University), U. Canzler (Dresden University), C. Jackisch (Marburg University), R. Kimmig (Essen University), S. Loibl (Frankfurt University), H. J. Lueck (MHH Hannover), W. Schröder (Bremen Zentralkrankenhaus) and J. Sehouli (Berlin University Charite).
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Notes |
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Received for publication May 3, 2005. Revision received July 11, 2005. Accepted for publication July 11, 2005.
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References |
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