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Kyrgiou M.,Imperial College London | Kyrgiou M.,West London Gynaecological Cancer Center | 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.

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.

Hall M.R.,Mount Vernon Cancer Center | Petruckevitch A.,Mount Vernon Cancer Center | Pascoe J.,Mount Vernon Cancer Center | Persic M.,Derby Hospitals NHS Foundation Trust | And 8 more authors.
International Journal of Gynecological Cancer | Year: 2014

Objective: New strategies are required to rapidly identify novel cytostatic agents before embarking on large randomized trials. This study investigates whether a change in rate of rise (slope) of serum CA125 from before to after starting a novel agent could be used to identify cytostatic agents. Tamoxifen was used to validate this hypothesis. Methods: Asymptomatic patients with relapsed ovarian cancer who had responded to chemotherapy were enrolled and had CA125 measurements taken every 4 weeks, then more frequently when rising. Once levels reached 4 times the upper limit of normal or nadir, they started continuous tamoxifen 20 mg daily, as well as fortnightly CA125 measurements until symptomatic progression. Because of the potentially nonlinear relationship of CA125 over time, it was felt that to enable normal approximations to be utilized a natural logarithmic standard transformation [ln(CA125)] was the most suitable to improve linearity above the common logarithmic transformation to base 10. Results: From 235 recruited patients, 81 started tamoxifen and had at least 4 CA125 measurements taken before and 4 CA125 measurements taken after starting tamoxifen, respectively. The mean regression slopes from using at least 4 1n(CA125) measurements immediately before and after starting tamoxifen were 0I0149 and 0I0093 [ln(CA125)/d], respectively. This difference is statistically significant, P = 0I001. Therefore, in a future trial with a novel agent, at least as effective as tamoxifen, using this effect size, the number of evaluable patients needed, at significance level of 5% and power of 80%, is 56. Conclusions: Further validation of this methodology is required, but there is potential to use comparison of mean regression slopes of ln(CA125) as an interim analysis measure of efficacy for novel cytostatic agents in relapsed ovarian cancer. Copyright © 2014 by IGCS and ESGO.

Meyer T.,Neuroendocrine Tumour Unit | Meyer T.,University College London | Qian W.,Cambridge Cancer Trials Center | Qian W.,Medical Research Council Biostatistics Unit Hub for Trials Methodology | And 13 more authors.
European Journal of Cancer | Year: 2014

Background Cytotoxic chemotherapy is widely used for advanced, unresectable pancreatic and other gastrointestinal foregut neuroendocrine tumours (NETs) and the most commonly used regimen combines 5-fluorouracil with streptozocin. The NET01 trial was designed to investigate whether capecitabine combined with streptozocin was an acceptable regimen with or without adding cisplatin. Methods Patients with advanced, unresectable NETs of pancreatic, gastrointestinal foregut or unknown primary site were randomised to receive three-weekly capecitabine (Cap) 625 mg/m2 twice daily orally, streptozocin (Strep) 1.0 g/m2 intravenously on day 1, with or without cisplatin (Cis) 70 mg/m2 intravenously on day 1. The primary outcome measure was objective response. Secondary outcome measures included progression-free and overall survival, quality of life, toxicity and biochemical response. Results 86 (44 CapStrep, 42 CapStrepCis) patients were randomised. Best objective response rate was 12% (95% confidence interval (CI) = 2-22%) with CapStrep and 16% (95% CI = 4-27.4%) with CapStrepCis. Disease-control rate was 80% with CapStrep and 74% with CapStrepCis. The estimated median progression-free and overall survival were 10.2 and 26.7 months for CapStrep and 9.7 and 27.5 months for CapStrepCis. 44% of CapStrep and 68% of CapStrepCis patients experienced grade ≥3 adverse events. Interpretation The efficacies of the novel CapStrep ± Cis regimens were very similar. CapStrep was better tolerated than CapStrepCis. The trial was registered as EudraCT: 2004-005202-71 and ISRCTN: 35124268. © 2014 Published by Elsevier Ltd.

Earl H.M.,University of Cambridge | Earl H.M.,National Health Research Institute | Earl H.M.,Cambridge Cancer Trials Center | Vallier A.-L.,Cambridge Cancer Trials Center | And 31 more authors.
The Lancet Oncology | Year: 2014

Background: Anthracyclines and taxanes have been the standard neoadjuvant chemotherapies for breast cancer in the past decade. We aimed to assess safety and efficacy of the addition of gemcitabine to accelerated paclitaxel with epirubicin and cyclophosphamide, and also the effect of sequencing the blocks of epirubicin and cyclophosphamide and paclitaxel (with or without gemcitabine). Methods: In our randomised, open-label, 2×2 factorial phase 3 trial (Neo-tAnGo), we enrolled women (aged >18 years) with newly diagnosed breast cancer (tumour size >20 mm) at 57 centres in the UK. Patients were randomly assigned via a central randomisation procedure to epirubicin and cyclophosphamide then paclitaxel (with or without gemcitabine) or paclitaxel (with or without gemcitabine) then epirubicin and cyclophosphamide. Four cycles of each component were given. The primary endpoint was pathological complete response (pCR), defined as absence of invasive cancer in the breast and axillary lymph nodes. This study is registered with EudraCT (2004-002356-34), ISRCTN (78234870), and ClinicalTrials.gov (NCT00070278). Findings: Between Jan 18, 2005, and Sept 28, 2007, we randomly allocated 831 participants; 207 received epirubicin and cyclophosphamide then paclitaxel; 208 were given paclitaxel then epirubicin and cyclophosphamide; 208 had epirubicin and cyclophosphamide followed by paclitaxel and gemcitabine; and 208 received paclitaxel and gemcitabine then epirubicin and cyclophosphamide. 828 patients were eligible for analysis. Median follow-up was 47 months (IQR 37-51). 207 (25%) patients had inflammatory or locally advanced disease, 169 (20%) patients had tumours larger than 50 mm, 413 (50%) patients had clinical involvement of axillary nodes, 276 (33%) patients had oestrogen receptor (ER)-negative disease, and 191 (27%) patients had HER2-positive disease. Addition of gemcitabine did not increase pCR: 70 (17%, 95% CI 14-21) of 404 patients in the epirubicin and cyclophosphamide then paclitaxel group achieved pCR compared with 71 (17%, 14-21) of 408 patients who received additional gemcitabine (p=0·98). Receipt of a taxane before anthracycline was associated with improved pCR: 82 (20%, 95% CI 16-24) of 406 patients who received paclitaxel with or without gemcitabine followed by epirubicin and cyclophosphamide achieved pCR compared with 59 (15%, 11-18) of 406 patients who received epirubicin and cyclophosphamide first (p=0·03). Grade 3 toxicities were reported at expected levels: 173 (21%) of 812 patients who received treatment and had full treatment details had grade 3 neutropenia, 66 (8%) had infection, 41 (5%) had fatigue, 41 (5%) had muscle and joint pains, 37 (5%) had nausea, 36 (4%) had vomiting, 34 (4%) had neuropathy, 23 (3%) had transaminitis, 16 (2%) had acute hypersensitivity, and 20 (2%) had a rash. 86 (11%) patients had grade 4 neutropenia and 3 (<1%) had grade 4 infection. Interpretation: Although addition of gemcitabine to paclitaxel and epirubicin and cyclophosphamide chemotherapy does not improve pCR, sequencing chemotherapy so that taxanes are received before anthracyclines could improve pCR in standard neoadjuvant chemotherapy for breast cancer. Funding: Cancer Research UK, Eli Lilly, Bristol-Myers Squibb. © 2014 Earl et al. Open Access article distributed under the terms of CC BY-NC-ND.

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