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Objectives To test two methods for reporting of fecal incontinence (FI) in people with inflammatory bowel disease. Methods Consecutive patients from IBD clinics in six UK hospitals completed a short three-item case-finding survey about FI; they either completed the survey themselves or were asked the same questions face to face by a clinician. Results Of 1336 eligible patients with complete data (48% male; mean 43 years; 55% Crohn’s disease, 41% ulcerative colitis), 772 were asked about FI face to face, and 564 self-completed the survey: FI was reported in 63% and 56%, respectively (p = 0.012). In regression analyses, those aged 51–60, having Crohn’s disease and higher disease activity, were more likely to report FI. Of all respondents, 38.7% were interested in receiving help for their incontinence. Conclusions Fecal incontinence affects the majority of people with IBD. Although more patients reported fecal incontinence when asked face to face than self-reported, routine screening by either method in clinical practice is recommended. Over one-third of patients with IBD want help for bowel control problems.

Background Data collection consumes a large proportion of clinical trial resources. Each data item requires time and effort for collection, processing and quality control procedures. In general, more data equals a heavier burden for trial staff and participants. It is also likely to increase costs. Knowing the types of data being collected, and in what proportion, will be helpful to ensure that limited trial resources and participant goodwill are used wisely. Aim The aim of this study is to categorise the types of data collected across a broad range of trials and assess what proportion of collected data each category represents. Methods We developed a standard operating procedure to categorise data into primary outcome, secondary outcome and 15 other categories. We categorised all variables collected on trial data collection forms from 18, mainly publicly funded, randomised superiority trials, including trials of an investigational medicinal product and complex interventions. Categorisation was done independently in pairs: one person having in-depth knowledge of the trial, the other independent of the trial. Disagreement was resolved through reference to the trial protocol and discussion, with the project team being consulted if necessary. Key results Primary outcome data accounted for 5.0% (median)/11.2% (mean) of all data items collected. Secondary outcomes accounted for 39.9% (median)/42.5% (mean) of all data items. Non-outcome data such as participant identifiers and demographic data represented 32.4% (median)/36.5% (mean) of all data items collected. Conclusion A small proportion of the data collected in our sample of 18 trials was related to the primary outcome. Secondary outcomes accounted for eight times the volume of data as the primary outcome. A substantial amount of data collection is not related to trial outcomes. Trialists should work to make sure that the data they collect are only those essential to support the health and treatment decisions of those whom the trial is designed to inform.

IntroductionThe incidence of severe postpartum haemorrhage (PPH) that requires blood transfusion is on the increase. Fibrinogen levels have been shown to drop early and significantly during PPH, which is associated with worse outcomes. Early fibrinogen replacement could potentially improve outcomes. No studies have investigated the clinical impact of early cryoprecipitate transfusion in PPH. Prior to performing a full-scale trial, a pilot study is needed to determine feasibility of the intervention and recruitment.MethodsACROBAT is a cluster-randomised pilot study with a qualitative evaluation. Four large London maternity units are randomised to either the intervention or control group. The intervention group will adapt their major obstetric haemorrhage procedures to administer cryoprecipitate early for primary PPH. The control group will retain their standard of care.We include women at >24 weeks gestation who are actively bleeding within 24 hours of delivery and for whom transfusion of red blood cells (RBCs) has been started. We exclude women who decline blood transfusions in advance or have inherited Factor XIII or fibrinogen deficiency. Due to the emergency nature of the intervention, informed consent for administering the intervention is waived.The primary objective is to assess the feasibility of administering cryoprecipitate within 90 min of RBC request, as compared with standard treatment where cryoprecipitate is given later or not at all. Secondary objectives include the feasibility of recruitment and data collection, reasons for and barriers to consent, preliminary maternal clinical outcomes, identification of the optimal infrastructure pathways for study delivery, and acceptability of the intervention and outcomes.Ethics and disseminationThe trial has approvals from the London—Brighton & Sussex Research Ethics Committee (ref. 18/LO/2062), the Confidentiality Advisory Group (ref. 18/CAG/0199) and Health Research Authority (IRAS number 237959). Data analysis and publication of manuscripts will start in Q3 2020.Trial registration numberISRCTN12146519.

IntroductionUp to half of all women diagnosed with gestational diabetes mellitus develop type 2 diabetes within 5 years after delivery. Metformin is effective in preventing type 2 diabetes in high-risk non-pregnant individuals, but its effect when commenced in the postnatal period is not known. We plan to assess the feasibility of evaluating metformin versus placebo in minimising the risk of dysglycaemia including type 2 diabetes after delivery in postnatal women with a history of gestational diabetes through a randomised trial.Methods and analysisOptimising health outcomes with Metformin to prevent diAbetes After pregnancy (OMAhA) is a multicentre placebo-controlled double-blind randomised feasibility trial, where we will randomly allocate 160 postnatal women with gestational diabetes treated with medication to either metformin (intervention) or placebo (control) tablets to be taken until 1 year after delivery. The primary outcomes are rates of recruitment, randomisation, adherence and attrition. The secondary outcomes are maternal dysglycaemia, cost and quality of life outcomes in both arms, and acceptability of the study and intervention, which will be evaluated through a nested qualitative study. Feasibility outcomes will be summarised using descriptive statistics, point estimates and 95% CIs.Ethics and disseminationThe OMAhA study received ethics approval from the London-Brent Research Ethics Committee (18/LO/0505). Trial findings will be published in a peer-reviewed journal, disseminated at conferences, through our Patient and Public Involvement advisory group (Katie’s Team) and through social media platforms.Trial registration numberISRCTN20930880

Background: Subfertility is a common problem for which in vitro fertilisation (IVF) treatment is commonly recommended. Success rates following IVF are suboptimal and have remained static over the last few years. This imposes a considerable financial burden on overstretched healthcare resources. Time-lapse imaging (TLI) of developing embryos in IVF treatment is hypothesised to improve the success rates of treatment. This may be either by providing undisturbed culture conditions or by improving the predictive accuracy for optimal embryo selection from a cohort of available embryos. However, the current best evidence for its effectiveness is inconclusive. Methods: The time-lapse imaging trial is a pragmatic, multi-centre, three-arm parallel-group randomised controlled trial using re-randomisation. The primary objective of the trial is to determine if the use of TLI or undisturbed culture in IVF treatment results in a higher live birth rate when compared to current standard methods of embryo incubation and assessment. Secondary outcomes include measures of clinical efficacy and safety. The trial will randomise 1575 participants to detect an increase in live birth from 26.5 to 35.25%. Discussion: In the absence of high-quality evidence, there is no current national guidance, recommendation or policy for the use of TLI. The use of TLI is not consistently incorporated into standard IVF care. A large, pragmatic, multi-centre, trial will provide much needed definitive evidence regarding the effectiveness of TLI. If proven to be effective, its incorporation into standard care would translate into significant clinical and economic benefits. If not, it would allow allocation of resources to more effective interventions., Barts Charity, Chinese University of Hong Kong, Health and Medical Research Fund, Food and Health Bureau, The Government of Hong Kong SAR 07180566

Katie’s Team is funded by a grant from the Centre for Public Engagement Queen Mary University of London.

Importance The value of facedown positioning following surgery for large full-thickness macular holes is unknown. Objective To determine whether advice to position facedown postoperatively improves the outcome for large macular holes. Design, Setting, and Participants This randomized, parallel group superiority trial with 1:1 randomization stratified by site with 3 months’ follow-up was conducted at 9 sites across the United Kingdom and included participants with an idiopathic full-thickness macular hole of at least 400 μm minimum linear diameter and a duration of fewer than 12 months. All participants had vitrectomy surgery with peeling of the internal limiting membrane and injection of perfluoropropane (14%) gas, with or without simultaneous surgery for cataract. Interventions Following surgery, participants were randomly advised to position either facedown or face forward for 8 hours daily for 5 days. Main Outcomes and Measures The primary outcome was closure of the macular hole determined 3 months following surgery by masked optical coherence tomography evaluation. Secondary outcome measures at 3 months were visual acuity, participant-reported experience of positioning, and quality of life measured by the National Eye Institute Visual Function Questionnaire 25. Results A total of 185 participants (45 men [24.3%]; 156 white [84.3%]; 9 black [4.9%]; 10 Asian [5.4%]; median age, 69 years [interquartile range, 64-73 years]) were randomized. Macular hole closure was observed in 90 (85.6%) who were advised to position face forward and 88 (95.5%) advised to position facedown (adjusted odds ratio, 3.15; 95% CI, 0.87-11.41;P = .08). The mean (SD) improvement in best-corrected visual acuity at 3 months was 0.34 (0.69) logMAR (equivalent to 1 Snellen line) in the face-forward group and 0.57 (0.42) logMAR (equivalent to 3 Snellen lines) in the facedown group (adjusted mean difference, 0.22 [95 % CI, 0.05-0.38]; equivalent to 2 Snellen lines); 95% CI, 0.05-0.38;P = .01). The median National Eye Institute Visual Function Questionnaire 25 score was 89 (interquartile range, 76-94) in the facedown group and 87 (interquartile range, 73-93) in the face-forward group (mean [SD] change on a logistic scale, 0.08 [0.26] face forward and 0.11 [0.25] facedown; adjusted mean [SD] difference on a logistic scale, 0.02; 95% CI, −0.03 to 0.07;P = .41). Conclusions and Relevance The results do not prove that facedown positioning following surgery is more likely to close large macular holes compared with facing forward but do support the possibility that visual acuity outcomes may be superior. Trial Registration Isrctn.org Identifier: 12410596

Introduction Patients with IBD have difficulty revealing concerns about bowel control problems to clinicians,1 who do not actively ask about this symptom2 despite clinical guidelines recommending active-case finding in high-risk populations.3 With no available evidence to advise clinicians on how to ask, we aimed to determine the results of face-to-face or self-reported screening to identify faecal incontinence (FI) in IBD patients. We also asked about patients’ desire for interventions to improve continence. FI was defined in this study as: ‘ever having accidental passing of stool, faeces, poo into your underclothes, that you are either unaware of at the time, or unable to control’. Methods This cross-sectional survey used a study-specific questionnaire to screen participants at either face-to-face interview (by clinician/researcher) or anonymously (participant self-completed). Eligibility criteria: 18 to 80 years of age, confirmed diagnosis of IBD, no current fistula, no stoma, any level of disease activity. Disease activity was measured using the Harvey Bradshaw Index or the Simple Clinical Colitis Activity Index. Results Of 1336 participants, 48% were male; mean age 43 years (range 18–80); 55% had Crohn’s Disease (CD), 41% ulcerative colitis (UC), 4% IBD unclassified. FI (occurring ever) was reported by 63% of 772 screened face-to-face and 56% of 564 self-report participants (p=0.012). A total of 38.7% of all respondents expressed interest in an intervention for FI. Patients with CD were more likely to report FI than those with UC (p≤0.05). FI was reported by 49% of participants in remission, and by 59%, 83% and 93% of participants with mild, moderate and severe relapse of IBD respectively (p≤0.001). Conclusions Bowel control problems are very common in patients with IBD (including in remission) and these symptoms can be identified by face-to-face interview and postal screening. Interest in interventions for FI is expressed by 38.7 of patients with IBD. References . Dibley L, Norton C. Experience of fecal incontinence in people with inflammatory bowel disease: self-reported experiences among a community sample. Inflammatory Bowel Diseases2013;19(7):1450–62. . Dibley L, Norton C. Help-seeking for fecal incontinence among people with inflammatory bowel disease. JWOCN 2013;40(6):631–638. . National Institute for Health and Clinical Excellence. Management of faecal incontinence in adults. London: NICE;2007. Report No.: CG 49.

BackgroundCaesarean section is associated with blood loss and maternal morbidity. Excessive blood loss requires transfusion of donor (allogeneic) blood, which is a finite resource. Cell salvage returns blood lost during surgery to the mother. It may avoid the need for donor blood transfusion, but reliable evidence of its effects is lacking.ObjectivesTo determine if routine use of cell salvage during caesarean section in mothers at risk of haemorrhage reduces the rates of blood transfusion and postpartum maternal morbidity, and is cost-effective, in comparison with standard practice without routine salvage use.DesignIndividually randomised controlled, multicentre trial with cost-effectiveness analysis. Treatment was not blinded.SettingA total of 26 UK obstetric units.ParticipantsOut of 3054 women recruited between June 2013 and April 2016, we randomly assigned 3028 women at risk of haemorrhage to cell salvage or routine care. Randomisation was stratified using random permuted blocks of variable sizes. Of these, 1672 had emergency and 1356 had elective caesareans. We excluded women for whom cell salvage or donor blood transfusion was contraindicated.InterventionsCell salvage (intervention) versus routine care without salvage (control). In the intervention group, salvage was set up in 95.6% of the women and, of these, 50.8% had salvaged blood returned. In the control group, 3.9% had salvage deployed.Main outcome measuresPrimary – donor blood transfusion. Secondary – units of donor blood transfused, time to mobilisation, length of hospitalisation, mean fall in haemoglobin, fetomaternal haemorrhage (FMH) measured by Kleihauer–Betke test, and maternal fatigue. Analyses were adjusted for stratification factors and other factors that were believed to be prognostic a priori. Cost-effectiveness outcomes – costs of resources and service provision taking the UK NHS perspective.ResultsWe analysed 1498 and 1492 participants in the intervention and control groups, respectively. Overall, the transfusion rate was 2.5% in the intervention group and 3.5% in the control group [adjusted odds ratio (OR) 0.65, 95% confidence interval (CI) 0.42 to 1.01;p = 0.056]. In a planned subgroup analysis, the transfusion rate was 3.0% in the intervention group and 4.6% in the control group among emergency caesareans (adjusted OR 0.58, 95% CI 0.34 to 0.99), whereas it was 1.8% in the intervention group and 2.2% in the control group among elective caesareans (adjusted OR 0.83, 95% CI 0.38 to 1.83) (interactionp = 0.46, suggesting that the difference in effect between subgroups was not statistically significant). Secondary outcomes did not differ between groups, except for FMH, which was higher under salvage in rhesus D (RhD)-negative women with RhD-positive babies (25.6% vs. 10.5%, adjusted OR 5.63, 95% CI 1.43 to 22.14;p = 0.013). No case of amniotic fluid embolism was observed. The additional cost of routine cell salvage during caesarean was estimated, on average, at £8110 per donor blood transfusion avoided.ConclusionsThe modest evidence for an effect of routine use of cell salvage during caesarean section on rates of donor blood transfusion was associated with increased FMH, which emphasises the need for adherence to guidance on anti-D prophylaxis. We are unable to comment on long-term antibody sensitisation effects. Based on the findings of this trial, cell salvage is unlikely to be considered cost-effective.Future workResearch into risk of alloimmunisation among women exposed to cell salvage is needed.Trial registrationCurrent Controlled Trials ISRCTN66118656.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 22, No. 2. See the NIHR Journals Library website for further project information.

BACKGROUND: Despite the growing popularity of mixed-methods studies and considerable emphasis on the potential value of qualitative research to the trial endeavour, there remains a dearth of published studies reporting on actual contribution. This paper presents a critically reflective account of our experience of the actual value of undertaking qualitative research alongside a pilot cluster randomised controlled trial of a guided e-learning intervention for managers in an NHS Mental Health Trust to improve employee wellbeing and reduce sickness absence. For the qualitative study we undertook 36 in-depth interviews with key informants, managers and employees. We observed and took in-depth field notes of 10 meetings involving managers and employees at the Trust, and the two qualitative researchers acted as participant observers at steering committee and monthly research team meetings. We adopted a narrative methodological orientation alongside a thematic approach to data analysis, eliciting a rich account of the complexities of managing stress at work.RESULTS: We identified two key overarching roles played by the qualitative research: 'problematising' and 'contextualising'. Specifically, the qualitative data revealed and challenged assumptions embedded in the trial about the nature of the learning process, and exposed the slippery and contested nature of abstracted variables, on which a trial depends. The qualitative data challenged the trial's logic model, and provided a rich understanding of the context within which the trial and intervention took place.CONCLUSIONS: While acknowledging the ever-present tension in mixed-methods research between the requirements of quantitative research to represent the social world as abstracted variables, and the goal of qualitative research to explore and document the complexity of social phenomena, we adopted a pragmatic position that enabled us to engage with this tension in a productive and partially integrative way. Our critically reflective account of the praxis of integration illuminated opportunities and challenges for maximising the value of qualitative research to a trial. This paper sets out tangible illustrative lessons for other mixed-methods researchers endeavouring to get the most from qualitative research.TRIAL REGISTRATION: This study is registered as ISRCTN58661009 . Registration was submitted on 22 April 2013 and completed on 17 June 2013.

BACKGROUND: A phase I multicentre trial was conducted to define the recommended dose of capecitabine in combination with oxaliplatin and irinotecan (OCX) in metastatic colorectal cancer. PATIENTS AND METHODS: Patients with performance status (PS) < 2 and adequate haematological, renal and liver function received oxaliplatin 70 mg/m(2) on days 1 and 15, irinotecan 100 mg/m(2) on days 8 and 22 and one of five dose levels (DL 1-5, between 800 and 1,600 mg/ m(2)) of capecitabine on days 1-29 every 5 weeks. RESULTS: 23 patients received a median of 3 cycles. 3 dose-limiting toxicities occurred (DL 1: grade 3 (G3) elevated alkaline phosphatase; DL 5: 1 patient G4 hyperglycaemia/G3 diarrhoea and 1 sudden death). The most common severe adverse event was G3 diarrhoea (13%). Severe haematotoxicity was rare. Therapy was stopped mainly due to metastasectomy or tumour progression (7 patients each). 8 patients reached a partial response. Median time to progression and overall survival (OS) were 8.0 and 21.9 months, respectively. CONCLUSIONS: The recommended capecitabine dose in this schedule is 1,400 mg/m(2) daily. The OCX regimen is well tolerated. The response rate was surprisingly low with progression-free survival (PFS) and OS within the range of a triple combination. Further studies in combination with targeted agents are warranted.

We developed a novel diagram to depict patient flow and outcomes in clinical trials. In contrast to flow diagrams such as the CONSORT chart, our diagram enables individual patient histories to be traced and depicts important patterns of treatment administration and outcomes, such as response and adverse events. Also, it is particularly useful for multimodal treatments or a sequence of different therapies where the CONSORT flow chart is less informative and can be confusing.

BackgroundPsychosocial work environments influence employee well-being. There is a need for an evaluation of organisational-level interventions to modify psychosocial working conditions and hence employee well-being.ObjectiveTo test the acceptability of the trial and the intervention, the feasibility of recruitment and adherence to and likely effectiveness of the intervention within separate clusters of an organisation.DesignMixed methods: pilot cluster randomised controlled trial and qualitative study (in-depth interviews, focus group and observation).ParticipantsEmployees and managers of a NHS trust. Inclusion criteria were the availability of sickness absence data and work internet access. Employees on long-term sick leave and short-term contracts and those with a notified pregnancy were excluded.InterventionE-learning program for managers based on management standards over 10 weeks, guided by a facilitator and accompanied by face-to-face meetings. Three clusters were randomly allocated to receive the guided e-learning intervention; a fourth cluster acted as a control.Main outcome measuresRecruitment and participation of employees and managers; acceptability of the intervention and trial; employee subjective well-being using the Warwick–Edinburgh Mental Wellbeing Scale (WEMWBS); and feasibility of collecting sickness absence data.ResultsIn total, 424 employees out of 649 approached were recruited and 41 managers out of 49 were recruited from the three intervention clusters. Of those consenting, 350 [83%, 95% confidence interval (CI) 79% to 86%] employees completed the baseline assessment and 291 (69%, 95% CI 64% to 73%) completed the follow-up questionnaires. Sickness absence data were available from human resources for 393 (93%, 95% CI 90% to 95%) consenting employees. In total, 21 managers adhered to the intervention, completing at least three of the six modules. WEMWBS scores fell slightly in all groups, from 50.4 to 49.0 in the control group and from 51.0 to 49.9 in the intervention group. The overall intervention effect was 0.5 (95% CI –3.2 to 4.2). The fall in WEMWBS score was significantly less among employees whose managers adhered to the intervention than among those employees whose managers did not (–0.7 vs. 1.6, with an adjusted difference of 1.6, 95% CI 0.1 to 3.2). The intervention and trial were acceptable to managers, although our study raises questions about the widely used concept of ‘acceptability’. Managers reported insufficient time to engage with the intervention and lack of senior management ‘buy-in’. It was thought that the intervention needed better integration into organisational processes and practice.ConclusionsThe mixed-methods approach proved valuable in illuminating reasons for the trial findings, for unpacking processes of implementation and for understanding the influence of study context. We conclude from the results of our pilot study that further mixed-methods research evaluating the intervention and study design is needed. We found that it is feasible to carry out an economic evaluation of the intervention. We plan a further mixed-methods study to re-evaluate the intervention boosted with additional elements to encourage manager engagement and behaviour change in private and public sector organisations with greater organisational commitment.Study registrationCurrent Controlled Trials ISRCTN58661009.FundingThis project was funded by the NIHR Public Health Research programme and will be published in full inPublic Health Research; Vol. 3, No. 9. See the NIHR Journals Library website for further project information.

To determine the efficacy, impact on quality-of-life (QoL) and tolerability of two different irinotecan administration schedules in combination with capecitabine as first-line treatment of metastatic colorectal cancer.We carried out a randomized phase II trial to select one of the following treatment regimens for further investigation: weekly irinotecan at a dose of 70 mg/m(2) days 1, 8, 15, 22, 29 (arm A) or 3-weekly irinotecan at a dose of 300/240 mg/m(2) day 1 and days 22 (arm B) in combination with capecitabine 1000 mg/m(2) twice daily days 1-14 and days 22-35 every 6 weeks.Seventy-five patients with good performance status entered the trial. The two arms were well balanced for relevant patient and disease characteristics. The most frequent toxic effects were grade 3/4 diarrhea (arm A: 34%, B: 19%), grade 3/4 neutropenia (A: 5%, B: 19%) and grade 2/3 alopecia (A: 26%, B: 65%). Other grade 3/4 toxic effects were rare (5%). Response rates were 34% [95% confidence interval (CI) 20% to 51%] in arm A and 35% (95% CI: 20% to 53%) in arm B. Median time to progression was 6.9 (4.6-10.1) and 9.2 (7.9-11.5) months and median overall survival was 17.4 (12.6-23.0+) and 24.7 (16.3-26.4+) months. Patients with an objective tumor response reported better physical well-being (P0.01), mood (P0.05), functional performance (P0.05) and less effort to cope (P0.05) compared with the non-responders and stable disease patients.The primary end point of this study was the objective response rate and based on the statistical design of the trial, the 3-weekly irinotecan schedule was selected over weekly irinotecan administration. The 3-weekly irinotecan schedule also seemed advantageous in terms of grade 3/4 diarrhea, time to progression, overall survival and patient convenience, but the study was not designed to detect differences in these parameters. In addition, tumor response was shown to have a beneficial effect on QoL indicators.

Objective Excessive haemorrhage at caesarean section requires the use of donor (allogeneic) blood transfusion. The SALVO trial assessed whether the routine use of cell salvage during caesarean section can reduce the need for donor blood transfusion. Study Design We conducted a randomised controlled trial (26 UK obstetric units; June 2013 through April 2016) of routine cell salvage use (intervention) vs. current standard of care without routine salvage use (control) in caesarean section among women at risk of haemorrhage. We used multivariable models, adjusting for stratification variables and prognostic factors identified a priori, to compare rates of donor blood transfusion (primary outcome) and fetomaternal haemorrhage ≥2ml in RhD-negative women with RhD-positive baby (one of the secondary outcomes) between groups. Results Of 3028 women randomised, 2990 were analysed (after exclusions for vaginal delivery or hospital transfer after randomisation). Of 1498 assigned to intervention, 95.6% had cell salvage deployed (50.8% had salvaged blood returned; mean 259.9 ml) vs. 3.9% of 1492 assigned to control. Donor blood transfusion rates were lower in the intervention group than in control (2.5% vs. 3.5%, adjusted odds ratio [OR] 0.65, 95% confidence interval [CI] 0.42 to 1.01). No case of amniotic fluid embolism was observed. Fetomaternal haemorrhage was higher with intervention vs. control (25.6% vs. 10.5%, adjusted OR 5.63, 95% CI 1.43 to 22.14). Conclusion There was modest evidence for an effect of routine use of cell salvage during caesarean section on donor blood transfusion. The increased fetomaternal haemorrhage emphasises the need for adherence to guidance on anti-D prophylaxis and for research on risks of alloimmunisation to RhD and other red cell antigens following cell salvage. (Funder: UK National Institute of Health Research Health Technology Assessment programme, ISRCTN66118656).

BACKGROUND: To determine the activity and tolerability of adding cetuximab to the oxaliplatin and capecitabine (XELOX) combination in first-line treatment of metastatic colorectal cancer (MCC). PATIENTS AND METHODS: In a multicenter two-arm phase II trial, patients were randomized to receive oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks alone or in combination with standard dose cetuximab. Treatment was limited to a maximum of six cycles. RESULTS: Seventy-four patients with good performance status entered the trial. Objective partial response rates after external review and radiological confirmation were 14% and 41% in the XELOX and in the XELOX + Cetuximab arm, respectively. Stable disease has been observed in 62% and 35% of the patients, with 76% disease control in both arms. Cetuximab led to skin rash in 65% of the patients. The median overall survival was 16.5 months for arm A and 20.5 months for arm B. The median time to progression was 5.8 months for arm A and 7.2 months for arm B. CONCLUSION: Differences in response rates between the treatment arms indicate that cetuximab may improve outcome with XELOX. The correct place of the cetuximab, oxaliplatin and fluoropyrimidine combinations in first-line treatment of MCC has to be assessed in phase III trials.

Background: Paclitaxel and capecitabine have proven activity in the treatment of metastatic breast cancer (MBC). Paclitaxel increases the expression of thymidine phosphorylase, the enzyme that activates capecitabine. The purpose of this study was to evaluate the efficacy and tolerability of capecitabine in combination with weekly paclitaxel largely as first-line therapy in patients with MBC. Patients and Methods: From April 2002 to September 2004, 19 patients with MBC received oral capecitabine (1,000 mg/m2 twice daily on days 1–14) plus i.v. paclitaxel (80 mg/m2 on days 1, 8 and 15) in a 21-day cycle for a maximum of 6 cycles. Results: After a median follow-up of 19.3 months the overall response rate was 63% with 1 complete response (5%) and 11 partial responses (58%). Disease was stabilized in 1 patient (5%) and 3 patients had progressive disease (16%). Three patients were unable to be assessed for response to treatment. Median time to progression was 3.3 months, median time to treatment failure 3.0 months and median overall survival 13.8 months. A substantial number of patients experienced major side effects. The most common treatment-related adverse events were hand-foot syndrome (53%; grade 3: 37%), alopecia (42%; grade 3: 26%), diarrhea (32%; grade 3: 11%) and neurotoxicity (32%; grade 3: 16%). Hematologic toxicities were uncommon. Conclusion: The combination of capecitabine and paclitaxel appears to be active in MBC but the safety profile with the dosages used in this trial was unacceptably high and led to a short time to treatment failure. However, based on the efficacy data alternative schedules deserve further evaluation.

3551 Background: XELOX is a valuable alternative to continuous infusion FOLFOX type regimens in the treatment of MCC (Borner et al, JCO 2002, 1759). Cetuximab is an EGFR antibody, which has been shown to improve the efficacy of chemotherapy. A phase II study in first-line treatment of MCC has demonstrated a high response rate combining cetuximab with FOLFOX (Tabernero et al, Proc ASCO 2004, 3512). Methods: Multicenter, randomized two-arm phase II trial: OXA 130 mg/m2 day 1 and oral CAP 1000 mg/m2 bid days 1–14 every 21 days alone or in combination with cetuximab 250 mg/m2 weekly after a loading dose of 400 mg/m2. Treatment was limited to a maximum of 6 cycles. With 37 patients in each arm, the power was 90% to select the truly better arm if the true between-arm difference in response rate (RECIST) is at least 15%. The study was open for accrual until October 2005. Results: We present here the results of 74 patients included in the study. In 67 patients the first response data are available (investigators’ assessment after 3 cycles). The two arms are well balanced for relevant patient, disease and treatment characteristics. The study treatment was well tolerated with grade 3/4 toxicities in < 10% of the cycles in each arm. The frequency of side effects was balanced, but with more frequent skin toxicity in the cetuximab arm (6% versus 0% grade 3/4). Conclusions: Cetuximab seems to positively interact with XELOX in terms of efficacy but not toxicity. The cetuximab/XELOX combination appears to be a valuable option in first-line treatment of MCC especially if high response rates are a primary objective. This trial was supported in part by Merck KGaA and Sanofi-Aventis Switzerland. [Table: see text] No significant financial relationships to disclose.