• Body mass index does not influence post-treatment survival in early stage endometrial cancer: results from the MRC ASTEC trial.

      Crosbie, E; Roberts, C; Qian, W; Swart, A; Kitchener, H; Renehan, Andrew G; Gynaecology Oncology Research Group, School of Cancer and Enabling Sciences, University of Manchester, Manchester, UK. (2012-04)
      Body mass index (BMI) is a major risk factor for endometrial cancer incidence but its impact on post-treatment survival is unclear. We investigated the relationships of BMI (categorised using the WHO definitions) with clinico-pathological characteristics and outcome in women treated within the MRC ASTEC randomised trial, which provides data from patients who received standardised allocated treatments and therefore reduces biases. The impact of BMI on both recurrence-free survival (RFS) and overall survival (OS) was analysed using the Cox regression models. An apriori framework of evaluating potential biases was explored. From 1408 participants, there were 1070 women with determinable BMI (median=29.1 kg/m(2)). Histological types were endometrioid (type 1) in 893 and non-endometrioid (type 2) in 146 women; the proportion of the latter decreasing with increasing BMI (8% versus 19% for obese III WHO category versus normal weight, p(trend)=0.003). For type 1 carcinomas, increasing BMI was associated with less aggressive histopathological features (depth of invasion, p=0.006; tumour grade, p=0.015). With a median follow-up of 34.3 months, there was no influence of BMI on RFS - adjusted HRs per 5 kg/m(2) were 0.98 (95% CI 0.86, 1.13) and 0.95 (0.74, 1.24), for type 1 and 2 carcinomas; and no influence on OS - adjusted HRs per 5 kg/m(2) were 0.96 (0.81, 1.14) and 0.92 (0.70, 1.23), respectively. These findings demonstrate an important principle: that an established link between an exposure (here, obesity) and increased incident cancer risk, does not necessarily translate into an inferior outcome following treatment for that cancer.
    • Capecitabine and streptozocin +/- cisplatin for gastroenteropancreatic neuroendocrine tumours: predictors of long-term survival in the NET01 trial.

      Meyer, T; Qian, W; Valle, Juan W; Talbot, D; Cunningham, D; Reed, N; Meyer, T; Wall, L; Waters, J; Ross, P; et al. (2016)
    • Capecitabine and streptozocin +/- cisplatin for gastroenteropancreatic neuroendocrine tumours: predictors of long-term survival in the NET01 trial.

      Meyer, T; Qian, W; Valle, Juan W; Talbot, D; Cunningham, D; Reed, N; Wall, L; Waters, J; Ross, P; Anthoney, A; et al. (2016-10-01)
    • Capecitabine and streptozocin±cisplatin in advanced gastroenteropancreatic neuroendocrine tumours.

      Meyer, T; Qian, W; Caplin, M; Armstrong, G; Lao-Sirieix, S; Hardy, R; Valle, Juan W; Talbot, D; Cunningham, D; Reed, N; et al. (2014-03)
      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.
    • Concordance between four European centres of PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma.

      Barrington, S F; Qian, W; Somer, E J; Franceschetto, A; Bagni, B; Brun, E; Almquist, H; Loft, A; Højgaard, L; Federico, M; et al. (2010-10)
      PURPOSE: To determine if PET reporting criteria for the Response Adapted Treatment in Hodgkin Lymphoma (RATHL) trial could enable satisfactory agreement to be reached between 'core' laboratories operating in different countries. METHODS: Four centres reported scans from 50 patients with stage II-IV HL, acquired before and after two cycles of Adriamycin/bleomycin/vinblastine/dacarbazine. A five-point scale was used to score response scans using 'normal' mediastinum and liver as reference levels. Centres read scans independently of each other. The level of agreement between centres was determined assuming (1) that uptake in sites involved at diagnosis that was higher than liver uptake represented disease (conservative reading), and (2) that uptake in sites involved at diagnosis that was higher than mediastinal uptake represented disease (sensitive reading). RESULTS: There was agreement that the response scan was 'positive' or 'negative' for lymphoma in 44 patients with a conservative reading and in 41 patients with a sensitive reading. Kappa was 0.85 (95% CI 0.74-0.96) for conservative reading and 0.79 (95% CI 0.67-0.90) for sensitive reading. Agreement was reached in 46 and 44 patients after discussion for the conservative and sensitive readings, respectively. CONCLUSION: The criteria developed for reporting in the RATHL trial are sufficiently robust to be used in a multicentre setting.
    • Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial.

      Rustin, G; Van der Burg, M; Griffin, C; Guthrie, D; Lamont, A; Jayson, Gordon C; Kristensen, G; Mediola, C; Coens, C; Qian, W; et al. (2010-10-02)
      BACKGROUND: Serum CA125 concentration often rises several months before clinical or symptomatic relapse in women with ovarian cancer. In the MRC OV05/EORTC 55955 collaborative trial, we aimed to establish the benefits of early treatment on the basis of increased CA125 concentrations compared with delayed treatment on the basis of clinical recurrence. METHODS: Women with ovarian cancer in complete remission after first-line platinum-based chemotherapy and a normal CA125 concentration were registered for this randomised controlled trial. Clinical examination and CA125 measurement were done every 3 months. Patients and investigators were masked to CA125 results, which were monitored by coordinating centres. If CA125 concentration exceeded twice the upper limit of normal, patients were randomly assigned (1:1) by minimisation to early or delayed chemotherapy. Patients and clinical sites were informed of allocation to early treatment, and treatment was started as soon as possible within 28 days of the increased CA125 measurement. Patients assigned to delayed treatment continued masked CA125 measurements, with treatment commencing at clinical or symptomatic relapse. All patients were treated according to standard local practice. The primary outcome was overall survival. Analysis was by intention to treat. This study is registered, ISRCTN87786644. FINDINGS: 1442 patients were registered for the trial, of whom 529 were randomly assigned to treatment groups and were included in our analysis (265 early, 264 delayed). With a median follow-up of 56·9 months (IQR 37·4-81·8) from randomisation and 370 deaths (186 early, 184 delayed), there was no evidence of a difference in overall survival between early and delayed treatment (HR 0·98, 95% CI 0·80-1·20, p=0·85). Median survival from randomisation was 25·7 months (95% CI 23·0-27·9) for patients on early treatment and 27·1 months (22·8-30·9) for those on delayed treatment. INTERPRETATION: Our findings showed no evidence of a survival benefit with early treatment of relapse on the basis of a raised CA125 concentration alone, and therefore the value of routine measurement of CA125 in the follow-up of patients with ovarian cancer who attain a complete response after first-line treatment is not proven. FUNDING: UK Medical Research Council and the European Organisation for Research and Treatment of Cancer.
    • Establishment of a UK-wide network to facilitate the acquisition of quality assured FDG-PET data for clinical trials in lymphoma.

      Barrington, S F; Mackewn, J E; Schleyer, P; Marsden, P K; Mikhaeel, N G; Qian, W; Mouncey, P; Patrick, P; Popova, B; Johnson, P; et al. (2011-03)
      Multicentre trials are required to determine how [fluorine-18]-2-fluoro-2-deoxy-D-glucose-positron emission tomography imaging can guide cancer treatment. Consistency in quality control (QC), scan acquisition and reporting is mandatory for high-quality results, which are comparable across sites.
    • The influence of sex and histology on outcomes in non-small-cell lung cancer: a pooled analysis of five randomized trials.

      Wheatley-Price, P; Blackhall, Fiona H; Lee, Siow Ming; Ma, C; Ashcroft, Linda; Jitlal, M; Qian, W; Hackshaw, A; Rudd, R; Booton, Richard; et al. (2010-03-23)
      BACKGROUND: Some non-small-cell lung cancer (NSCLC) surgical series have indicated that the positive prognostic effect of female sex is limited to patients with adenocarcinoma. We carried out a retrospective analysis to investigate the role of sex and histology on efficacy, toxicity, and dose delivery after chemotherapy. Patient and methods: Individual patient data were pooled from five randomized, phase III, advanced NSCLC chemotherapy trials. Primary outcomes were response rate, overall survival (OS), toxicity, and dose delivery. A secondary analysis examined survival by sex in histological subgroups. RESULTS: Of 2349 patients, 34% were women. Women had a higher response rate to chemotherapy (42% versus 40%, P = 0.01) and longer survival than men (median OS 9.6 versus 8.6 months, P = 0.002). The difference in OS remained after adjusting for age, stage, performance status, and histology (hazard ratio 0.83, 95% confidence interval 0.74-0.92, P = 0.0005). Upon further examination, longer survival in women was only seen in patients with adenocarcinoma (test for interaction P = 0.006). There were no differences in hematological toxicity or transfusions. Women experienced more grade 3-4 emesis than men (P < 0.0001) and more dose delays (P = 0.02) or dose reductions (P < 0.0001). CONCLUSION: The positive prognostic effect among women is confirmed in patients receiving platinum-based chemotherapy but appears confined to those with adenocarcinoma histology.
    • Ipilimumab in the real world: the UK expanded access programme experience in previously treated advanced melanoma patients.

      Ahmad, S; Qian, W; Ellis, S; Mason, Elaine; Khattak, M; Gupta, A; Shaw, H; Quinton, A; Kovarikova, J; Thillai, K; et al. (2015-10)
      Before licensing, ipilimumab was first made available to previously treated advanced melanoma patients through an expanded access programme (EAP) across Europe. We interrogated data from UK EAP patients to inform future clinical practice. Clinicians registered in the UK EAP provided anonymized patient data using a prespecified variable fields datasheet. Data collected were baseline patient characteristics, treatment delivered, toxicity, response, progression-free survival and overall survival (OS). Data were received for 193 previously treated metastatic melanoma patients, whose primary sites were cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At baseline, 88% of patients had a performance status (PS) of 0-1 and 20% had brain metastases. Of the patients, 53% received all four planned cycles of ipilimumab; the most common reason for stopping early was disease progression, including death from melanoma. Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median progression-free survival and OS were 2.8 and 6.1 months, respectively; the 1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was significantly lower for patients with poorer PS (P<0.0001), low albumin concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline. These baseline characteristics are negative predictors of benefit from ipilimumab and should be taken into consideration before prescription.
    • Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: subgroup analysis from the UK NCRI R-CHOP 14 Vs 21 trial.

      Kuehnl, A; Cunningham, D; Counsell, N; Hawkes, E; Qian, W; Smith, P; Chadwick, N; Lawrie, A; Mouncey, P; Jack, A; et al. (2015)
    • PARTNER: randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients

      Abraham, J; Vallier, AL; Qian, W; Machin, A; Grybowicz, L; Thomas, S; Weiss, M; Harvey, C; McAdam, K; Hughes-Davies, L; et al. (2019)
      Background: No specific targeted therapies are available for triple negative breast cancer (TNBC), an aggressive and diverse subgroup. The basal TNBC subgroup show some phenotypic and molecular similarities with germline BRCA mutated BC (gBRCA). In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow PARP inhibitors to work more effectively. PARTNER was designed to establish if the addition of olaparib to neoadjuvant platinum-based chemotherapy for basal TNBC and/or gBRCA BC is safe and improves efficacy (pathological complete response (pCR)). Methods: Trial design: 3-Stage open label randomised Phase II/III trial of neoadjuvant CP: Carboplatin AUC5 with weekly Paclitaxel 80mg/m2 +/- olaparib 150mgBD for 12 days x 4 cycles, followed by clinicians' choice of anthracycline regimen x 3 cycles. Basal-TNBC and / or gBRCAm patients are eligible for inclusion. Tumour infiltrating lymphocytes and basal profile are assessed at baseline. Stage 1 and 2: Patients are randomised (1:1:1) to CP: CP + olaparib from day (D) –2: or CP + olaparib from D 3. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. Primary end-points: Stage 1 – Safety; Stage 2 - Schedule selection criteria by pCR rate and completion rate of olaparib protocol treatment. 53 patients in each research arm will be evaluated within a “pick the winner” design. Null hypothesis of pCR ?35% versus alternative hypothesis of pCR ?55% will be tested with 90% power and 5% one sided significance level in each of the research arms. Stage 3 - Efficacy: anticipated pCR ~45-55% for all trial patients and ~50-60% for gBRCA patients. The trial is powered to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to chemotherapy (enriched design). Enrichment design is applied with overall significance level 0.05(?) = 0.025(?all) + 0.025(?gBRCA) and 80% power. Current enrolment: 133 of planned 527 patients. Stage 1 accrual is complete. Stage 2 began in August 2017. 19 sites open and 12 more in active set-up. Clinical trial information: NCT03150576.
    • PARTNERING/PARTNER : Phase II sub-study to establish if the addition of combinations of new agents (olaparib, cell cycle and immune checkpoint inhibitors) can improve the rate of pathological complete response (pCR) and minimal residual disease (MRD) in triple negative breast cancer (TNBC) and/or germline BRCA mutated (gBRCAm) patients with evidence of residual disease after PARTNER therapy

      Abraham, JE; Vallier, AL; Qian, W; Machin, A; Grybowicz, L; Thomas, S; Weiss, M; Harvey, C; McAdam, K; Hughes-Davies, L; et al. (2019)
      Background: In patients with TNBC, following standard neoadjuvant chemotherapy, residual disease (RD) is correlated with poor prognosis and 50% relapse within 5 years [1]. PARTNER is a neoadjuvant clinical trial which randomises TNBC and gBRCAm patients to carboplatin and paclitaxel +/- olaparib followed by anthracycline-based chemotherapy. Patients with RD after neoadjuvant treatment in this trial also face poorer survival outcomes, due to the paucity of treatment options. PARTNERING, develops a new strategy using novel agent combinations as an alternative pathway for patients with RD within the PARTNER trial. Methods: PARTNERING is a phase II open label, sub-study with a two-stage Simon design with biomarker guided treatment cohorts open only to patients in the PARTNER trial. A maximum of 15 patients will be included in each cohort. Patients with RD > 10% tumour cellularity (TC) on biopsy after neoadjuvant therapy will be eligible. Patients who have no tumour cells or < 10% TC, and those with progressive disease will be excluded. Allocation of patients into the cohorts will be based on tumour infiltrating lymphocytes (TILs) expression either on diagnostic or post treatment biopsy. Patients with tumours with TILs score ?20% are considered “non-immunogenic” They will be stratified according to HRD status and allocated to receive a cell cycle checkpoint inhibitor + olaparib. Patients with a TILs score >20% are considered “immunogenic” and will be allocated to receive an immune checkpoint inhibitor with olaparib or a cell cycle checkpoint inhibitor. Primary outcome measure is pCR / MRD rate at surgery after the administration of 2 cycles / 8 weeks of a combination of new agents. The rate of conversion to pCR/MRD will be correlated with TC, TILs, BRCA and homologous recombination deficiency (HRD) status, Ki67% and previous olaparib treatment. Progress: The PARTNERING pathway in the PARTNER trial will be open late 2018.
    • A randomised phase II feasibility study of intermittent versus continuous dosing of targeted therapy in patients with BRAFV600 mutant advanced melanoma (INTERIM)

      Corrie, P; Matin, R; Gupta, Avinash; Qian, W; Wordsworth, S; Gibbons, E; Chhabra, A; Harman, C; Mather, C; Middleton, M; et al. (2018)
    • 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; Hawkes, E; Jack, A; Qian, W; Smith, P; Mouncey, P; Pocock, C; Ardeshna, K; Radford, John A; McMillan, A; et al. (2013-05-25)
      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.