Stark D.,University of Leeds |
Nankivell M.,Medical Research Council Clinical Trials Unit |
Pujade-Lauraine E.,University of Paris Descartes |
Kristensen G.,University of Oslo |
And 15 more authors.
The Lancet Oncology | Year: 2013
Background: In the Gynecologic Cancer Intergroup International Collaboration on Ovarian Neoplasms 7 (ICON7) trial, bevacizumab improved progression-free survival in patients with ovarian cancer when used in combination with first-line chemotherapy and as a single-drug continuation treatment for 18 cycles. In a preliminary analysis of a high-risk subset of patients, there was also an improvement in overall survival. This study aims to describe the health-related quality-of-life (QoL) outcomes from ICON7. Methods: ICON7 is a randomised, multicentre, open-label phase 3 trial. Between Dec 18, 2006, and Feb 16, 2009, after a surgical procedure aiming to debulk the disease, women with International Federation of Gynecology and Obstetrics (FIGO) high-risk stage I-IV epithelial ovarian cancer were randomly allocated (1:1) by computer program and block randomisation to receive either six cycles of standard chemotherapy (total 18 weeks) with carboplatin (area under the curve 5 or 6) and paclitaxel (175 mg/m2) alone or with bevacizumab (7·5 mg/kg) given intravenously with chemotherapy and continued as a single drug thereafter (total 54 weeks). The primary QoL endpoint was global QoL from the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire-core 30 at week 54, analysed by ANOVA and adjusted for baseline score. Analyses were by intention to treat. The ICON7 trial has completed recruitment and remains in follow-up. This study is registered, number ISRCTN91273375. Findings: 764 women were randomly assigned to the standard chemotherapy group and 764 to the bevacizumab group. At baseline, 684 (90%) of women in the standard chemotherapy group and 691 (90%) of those in the bevacizumab group had completed QoL questionnaires. At week 54, 502 (66%) women in the bevacizumab group and 388 (51%) women in the standard chemotherapy group provided QoL data. Overall, the mean global QoL score improved during chemotherapy by 7·2 points (SD 24·4) when analysed for all women with data at baseline and week 18. The mean global QoL score at 54 weeks was higher in the standard chemotherapy group than in the bevacizumab group (76·1 [SD 18·2] vs 69·7 [19·1] points; difference 6·4 points, 95% CI 3·7-9·0, p<0·0001). Interpretation: Bevacizumab continuation treatment seems to be associated with a small but clinically significant decrement in QoL compared with standard treatment for women with ovarian cancer. The trade-off between the prolongation of progression-free survival and the quality of that period of time needs to be considered in clinical practice when making treatment decisions. Funding: Roche and the National Institute for Health Research through the UK National Cancer Research Network. © 2013 Elsevier Ltd.
Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: A phase 3 comparison of dose intensification with 14-day versus 21-day cycles
Cunningham D.,Royal Marsden NHS Foundation Trust |
Hawkes E.A.,Royal Marsden NHS Foundation Trust |
Jack A.,St James Institute of Oncology |
Qian W.,Cambridge Cancer Trials Center |
And 13 more authors.
The Lancet | Year: 2013
Background Dose intensification with a combination of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) every 2 weeks improves outcomes in patients older than 60 years with diffuse large B-cell lymphoma compared with CHOP every 3 weeks. We investigated whether this survival benefit from dose intensification persists in the presence of rituximab (R-CHOP) in all age groups. Methods Patients (aged ≥18 years) with previously untreated bulky stage IA to stage IV diffuse large B-cell lymphoma in 119 centres in the UK were randomly assigned centrally in a one-to-one ratio, using minimisation, to receive six cycles of R-CHOP every 14 days plus two cycles of rituximab (R-CHOP-14) or eight cycles of R-CHOP every 21 days (R-CHOP-21). R-CHOP-21 was intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m 2, vincristine 1·4 mg/m2 (maximum dose 2 mg), and rituximab 375 mg/m2 on day 1, and oral prednisolone 40 mg/m 2 on days 1-5, administered every 21 days for a total of eight cycles. R-CHOP-14 was intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 2 mg, rituximab 375 mg/m 2 on day 1, and oral prednisolone 100 mg on days 1-5, administered every 14 days for six cycles, followed by two further infusions of rituximab 375 mg/m2 on day 1 every 14 days. The trial was not masked. The primary outcome was overall survival (OS). This study is registered, number ISCRTN 16017947. Findings 1080 patients were assigned to R-CHOP-21 (n=540) and R-CHOP-14 (n=540). With a median follow-up of 46 months (IQR 35-57), 2-year OS was 82·7% (79·5-85·9) in the R-CHOP-14 group and 80·8% (77·5-84·2) in the R-CHOP-21 (standard) group (hazard ratio 0·90, 95% CI 0·70-1·15; p=0·3763). No significant improvement was noted in 2-year progression-free survival (R-CHOP-14 75·4%, 71·8-79·1, and R-CHOP-21 74·8%, 71·0-78·4; 0·94, 0·76-1·17; p=0·5907). High international prognostic index, poor-prognosis molecular characteristics, and cell of origin were not predictive for benefit from either schedule. Grade 3 or 4 neutropenia was higher in the R-CHOP-21 group (318 [60%] of 534 vs 167 [31%] of 534), with no prophylactic use of recombinant human granulocyte-colony stimulating factor mandated in this group, whereas grade 3 or 4 thrombo cytopenia was higher with R-CHOP-14 (50 [9%] vs 28 [5%]); other frequent grade 3 or 4 adverse events were febrile neutropenia (58 [11%] vs 28 [5%]) and infection (125 [23%] vs 96 [18%]). Frequencies of non-haematological adverse events were similar in the R-CHOP-21 and R-CHOP-14 groups. Interpretation R-CHOP-14 is not superior to R-CHOP-21 chemotherapy for previously untreated diffuse large B-cell lymphoma; therefore, R-CHOP-21 remains the standard first-line treatment in patients with this haematological malignancy. No molecular or clinical subgroup benefited from dose intensification in this study. Funding Chugai Pharmaceutical, Cancer Research UK, National Institute for Health Research Biomedical Research Centres scheme at both University College London and the Royal Marsden NHS Foundation Trust, and Institute of Cancer Research.
A comparison of outcomes following laparoscopic and open hysterectomy with or without lymphadenectomy for presumed early-stage endometrial cancer: Results from the medical research council ASTEC trial
Kyrgiou M.,Imperial College London |
Kyrgiou M.,Hammersmith Hospital |
Swart A.-M.,University of East Anglia |
Qian W.,Cambridge Cancer Trials Center |
Warwick J.,University of Warwick
International Journal of Gynecological Cancer | Year: 2015
Objectives Laparoscopic hysterectomy (LH) is increasingly used for the management of endometrial malignancy. Its benefits may be particularly pronounced as these women are more likely to be older or obese. The aim of this study was to determine whether outcomes for LH are comparable to the open hysterectomy (OH). Design This was a prospective cohort study nested within the multicenter ASTEC (A Study in the Treatment of Endometrial Cancer) randomized controlled trial (1998-2005). Population Women with presumed early endometrial cancer were included. Methods Laparoscopic hysterectomy was compared with OH with or without systematic lymphadenectomy. Main Outcome Measures Overall survival, time to first recurrence, complication rates, and surgical outcomes were the main outcome measures. Results Of 1408 women, 1309 (93%) received OH, and 99 (7%) had LH. LH was associated with longer operating time (median, LH 105 minutes [interquartile range (IQR), 60-150] vs OH 80 minutes [IQR, 60-95]; P < 0.001) but 50% shorter hospital stay (median, LH 4 days [IQR, 3-5] vs OH 6 days [IQR, 5-7]). The number of harvested lymph nodes was similar (median, LH 13 [IQR, 10-16] vs OH 12 [IQR, 11-13]; P = 0.67). LH had fewer intraoperative and postoperative adverse events (9% difference, LH 21% vs OH 30%; borderline significance; P = 0.07). The rate of conversion to laparotomy for the LH group was high (27%). The median follow-up was 37 months. After adjusting for significant prognostic factors, the hazard ratio for overall survival in those who underwent LH compared with those who underwent OH was 0.67 (95% confidence interval, 0.31-1.43) (P = 0.30). Conclusions Laparoscopic hysterectomy for early endometrial cancer is safe. Although it requires longer operating time it is associated with shorter hospital stay and favorable morbidity profile. Further studies are required to assess the long-term safety. © 2015 by IGCS and ESGO.
Bond S.J.,Institute of Public Health |
Bond S.J.,Mundipharma Research |
Bond S.J.,Cambridge Cancer Trials Center |
White I.R.,Institute of Public Health
Clinical Trials | Year: 2010
Background Departures from randomized treatments complicate the analysis of many randomized controlled trials. Intention-to-treat analysis estimates the effect of being allocated to treatment. It is now possible to estimate the effect of receiving treatment without assuming comparability of groups defined by actual treatment. However, the methodology is largely confined to trials where the only treatment changes were switches to other trial treatments. Purpose To propose a method for comparing the effects of receiving trial treatments in an active-controlled clinical trial where some participants received nontrial treatments and others received no treatment at all, and to illustrate the method in the PENTA 5 trial in HIV-infected children. Methods We combine the instrumental variables approach, which forms unbiased estimating equations based on the randomization but does not fully identify the contrasts of trial treatment effects, with prior information about the distribution of possible effects of nontrial treatments and of one trial treatment; we do not need to use prior information about the comparisons of trial treatments. Prior information in PENTA 5 was elicited from the investigators. Results In PENTA 5, the prior information suggested that all treatments were beneficial, but there was uncertainty about the degree of benefit. Allowing for this prior information changed point estimates and increased standard errors compared with ignoring nontrial treatments. Limitations The method depends on the correct specification of the causal effect of treatment: in PENTA 5, this assumed a linear effect of dose and no interactions between treatments. This specification is hard to check from the data but can be explored in sensitivity analyses. Prior information would be better derived from the literature whenever possible. Conclusions The use of partial prior information gives a way to adjust for complex patterns of departures from randomized treatments. It should be useful in all trials where nontrial treatments are used and in active-controlled trials where trial treatments are not universally used. © The Author(s), 2010.
Wason J.M.S.,MRC Biostatistics Unit |
Mander A.P.,MRC Biostatistics Unit |
Eisen T.G.,Cambridge Cancer Trials Center
European Journal of Cancer | Year: 2011
Reducing the number of patients required for a clinical trial is important for shortening development time. Phase II cancer trials assess the tumour-shrinking effect of a novel compound through a binary end-point formed from the percentage change in total lesion diameter. We compare single-arm two-stage designs which use the binary end-point to those which directly use the continuous end-point. Using the continuous end-point results in lower expected and maximum sample sizes. For larger trials the reduction is around 37%. This assumes that the dichotomisation point of the continuous end-point is chosen to give the best sample size, with the trial design using the binary end-point performing even worse otherwise. We consider a previous trial designed using a Simon two-stage design and show that if the continuous end-point had been used, the expected and maximum sample sizes of the trial would be reduced by around 50%. Using the continuous end-point in a two-stage cancer trial results in large sample size reductions. The methods discussed in this paper work best when the number of complete responses is low, as is true in several types of cancer. We discuss what could be done if this is not the case. © 2010 Elsevier Ltd. All rights reserved.