Helen Howard

The STAR trial protocol: a randomised multi-stage phase II/III study of Sunitinib comparing temporary cessation with allowing continuation, at the time of maximal radiological response, in the first-line treatment of locally advanced/metastatic Renal Cancer

BackgroundOver recent years a number of novel therapies have shown promise in advanced renal cell carcinoma (RCC). Internationally the standard of care of first-line therapy is sunitinib™, after a clear survival benefit was demonstrated over interferon-α. Convention dictates that sunitinib is continued until evidence of disease progression, assuming tolerability, although there is no evidence that this approach is superior to intermittent periods of treatment. The purpose of the STAR trial is to compare the standard treatment strategy (conventional continuation strategy, CCS) with a novel drug free interval strategy (DFIS) which includes planned treatment breaks.Methods/DesignThe STAR trial is an NIHR HTA-funded UK pragmatic randomised phase II/III clinical trial in the first-line treatment of advanced RCC. Participants will be randomised (1:1) to either a sunitinib CCS or a DFIS. The overall aim of the trial is to determine whether a DFIS is non-inferior, in terms of 2-year overall survival (OS) and quality adjusted life years (QALY) (averaged over treatment and follow up), compared to a CCS. The QALY primary endpoint was selected to assess whether any detriment in terms of OS could be balanced with improvements in quality of life (QoL). This is a complex trial with a number of design challenges, and to address these issues a feasibility stage is incorporated into the trial design. Predetermined recruitment (stage A) and efficacy (stage B) intermediary endpoints must be met to allow continuation to the overall phase III trial (stage C). An integral qualitative patient preference and understanding study will occur alongside the feasibility stage to investigate patients’ feelings regarding participation or non-participation in the trial.DiscussionThe optimal duration of continuing sunitinib in advanced RCC is unknown. Novel targeted therapies do not always have the same constraints to treatment duration as standard chemotherapeutic agents and currently there are no randomised data comparing different treatment durations. Incorporating planned treatment breaks has the potential to improve QoL and cost effectiveness, hopefully without significant detriment on OS, as has been demonstrated in other cancer types with other treatments.Trial RegistrationControlled-trials.com ISRCTN 06473203

A randomised phase II trial and feasibility study of palliative chemotherapy in frail or elderly patients with advanced gastroesophageal cancer (321GO)

Background:Elderly patients are commonly under-represented in cancer clinical trials. The 321GO was undertaken in preparation for a definitive phase three trial assessing different chemotherapy regimens in a frail and/or elderly population with advanced gastroesophageal (GO) cancer.Methods:Patients with advanced GO cancer considered unfit for conventional dose chemotherapy were randomly assigned in a 1 : 1 : 1 ratio to: epirubicin, oxaliplatin and capecitabine (EOX); oxaliplatin and capecitabine (OX); and capecitabine alone (X) (all 80% of full dose and unblinded). The primary end point was patient recruitment over an 18-month period. A registration study recorded treatment choice for all patients with advanced GO cancer at trial centres.Results:A total of 313 patients were considered for palliative chemotherapy for GO cancer over the 18-month period: 115 received full dose treatment, 89 less than standard treatment or entered 321GO and 111 no treatment. Within 321GO, 55 patients were randomly assigned (19 to OX and X; 17 to EOX). Progression-free survival (PFS) for all patients was 4.4 months and by arm 5.4, 5.6 and 3.0 months for EOX, OX and X, respectively. The number of patients with a good overall treatment utility (OTU), a novel patient-centred endpoint, at 12 weeks was 3 (18%), 6 (32%) and 1 (6%) for EOX, OX and X, respectively. At 6 weeks, 22 patients (41%) had experienced a non-haematologic toxicity ⩾grade 3, most commonly lethargy or diarrhoea. The OTU was prognostic for overall survival in patients alive at week 12 (logrank test P=0.0001).Conclusions:It is feasible to recruit elderly and/or frail patients with advanced GO cancer to a randomised clinical trial. The OX is the preferred regimen for further study. Overall treatment utility shows promise as a comparator between treatment regimens for feasibility and randomised trials in the elderly and/or frail GO cancer population.

Looking to the future: Developing an academic skills strategy to ensure information literacy survives in a changing higher education world

This paper looks at factors influencing the development of information literacy (IL) teaching within UK Higher Education (HE). It includes a review of recent literature on the current HE climate, curricula developments and the scope and breadth of IL. Using the experience at Leeds University Library as a case study, the paper outlines the development of a new strategy to deliver IL teaching and support to students. It describes the process of developing an academic skills strategy, which places IL within a broader range of academic skills, with the aim of contributing to the overall learning development of students. The case study describes the implementation of the strategy and the key stakeholders involved in this, including faculty team librarians , academic skills development officers and academic staff. The paper concludes that there were significant external and internal developments which had an impact on the direction taken by the strategy, specifically in embedding IL within an academic skills framework. In looking at the broad picture and by providing a case study from one of the few UK HE libraries to have progressed the academic skills agenda, it is hoped that the issues raised in the paper allow for reflection of the position of IL at the current time by all those involved in ensuring the acquisition of these skills by students.

The STAR trial: can quality of life benefit offset any survival detriment?

The STAR trial is a UK randomized phase II/III study of first-line sunitinib in locally advanced/metastatic clear cell renal carcinoma (mRCC). It compares the utilization of a sunitinib conventional continuation strategy (CCS) with an experimental sunitinib drug-free interval strategy (DFIS). Sunitinib is approved for the first-line treatment of mRCC and convention dictates that it is continued until disease progression or unacceptable toxicity. Duration of chemotherapy is frequently determined by cumulative toxicity, but this is not necessarily the case for targeted therapies, and the default has previously been to continue these treatments for longer. A DFIS has the potential advantage of improved quality of life (QoL) and cost-effectiveness, due to longer time-periods off-treatment. The STAR trial is unique in determining whether QoL benefits from a DFIS can offset any potential detriment in overall survival (OS). Endpoints will assess both survival and QoL separately, but will also assess averaged QALY (quality of life year). Temporarily stopping a treatment, which is working, is recognized to be potentially challenging for patients, and a qualitative substudy will be performed alongside the phase II trial, to explore patient feelings regarding trial entry and stopping treatment. Results from this will inform recruitment strategies in phase III. The multi-stage design maximizes resource efficacy by facilitating a seamless transition between the phase II and III parts, assuming attainment of the phase II endpoints (recruitment rate and time to strategy failure). It also enables the QALY data from the initial phase II part of the trial to be used to inform and verify the powering of the overall phase III trial, as minimal data was available during initial trial design to power on a QALY outcome. Other novel outcome measures (time to strategy failure and summative progression free interval) have also been required, due to the intermittent nature of the DFIS reducing the utility of the standard progression free survival endpoint. With increasing use of targeted therapies and interest in DFIS due to potential QoL and cost effectiveness benefits, these novel endpoints will be increasing required in future clinical trial designs. The STAR trial will be an exemplar trial in the evaluation of optimal treatment strategies for targeted therapies in other diseases. We will discuss issues relating to the trial design and the methodology relating to the novel endpoints in this study, as well as comment on the implications for future trial design.

Addition of gemcitabine to paclitaxel, epirubicin, and cyclophosphamide adjuvant chemotherapy for women with early-stage breast cancer (tAnGo): final 10-year follow-up of an open-label, randomised, phase 3 trial

BACKGROUND The tAnGo trial was designed to investigate the potential role of gemcitabine when added to anthracycline and taxane-containing adjuvant chemotherapy for early breast cancer. When this study was developed, gemcitabine had shown significant activity in metastatic breast cancer, and there was evidence of a favourable interaction with paclitaxel. METHODS tAnGo was an international, open-label, randomised, phase 3 superiority trial that enrolled women aged 18 years or older with newly diagnosed, early-stage breast cancer who had a definite indication for chemotherapy, any nodal status, any hormone receptor status, Eastern Cooperative Oncology Group performance status of 0-1, and adequate bone marrow, hepatic, and renal function. Women were recruited from 127 clinical centres and hospitals in the UK and Ireland, and randomly assigned (1:1) to one of two treatment regimens: epirubicin, cyclophosphamide, and paclitaxel (four cycles of 90 mg/m2 intravenously administered epirubicin and 600 mg/m2 intravenously administered cyclophosphamide on day 1 every 3 weeks, followed by four cycles of 175 mg/m2 paclitaxel as a 3 h infusion on day 1 every 3 weeks) or epirubicin, cyclophosphamide, and paclitaxel plus gemcitabine (the same chemotherapy regimen as the other group, with the addition of 1250 mg/m2 gemcitabine to the paclitaxel cycles, administered intravenously as a 0·5 h infusion on days 1 and 8 every 3 weeks). Patients were randomly assigned by a central computerised deterministic minimisation procedure, with stratification by country, age, radiotherapy intent, nodal status, and oestrogen receptor and HER-2 status. The primary endpoint was disease-free survival and the trial aimed to detect 5% differences in 5-year disease-free survival between the treatment groups. Recruitment completed in 2004 and this is the final, intention-to-treat analysis. This trial is registered with EudraCT (2004-002927-41), ISRCTN (51146252), and ClinicalTrials.gov (NCT00039546). FINDINGS Between Aug 22, 2001, and Nov 26, 2004, 3152 patients were enrolled and randomly assigned to epirubicin, cyclophosphamide, paclitaxel, and gemcitabine (gemcitabine group; n=1576) or to epirubicin, cyclophosphamide, and paclitaxel (control group; n=1576). 11 patients (six in the gemcitabine group and five in the control group) were ineligible because of pre-existing metastases and were therefore excluded from the analysis. At this protocol-specified final analysis (median follow-up 10 years [IQR 10-10]), 1087 disease-free survival events and 914 deaths had occurred. Disease-free survival did not differ significantly between the treatment groups at 10 years (65% [63-68] in the gemcitabine group vs 65% [62-67] in the control group), and median disease-free survival was not reached (adjusted hazard ratio 0·97 [95% CI 0·86-1·10], p=0·64). Toxicity, dose intensity, and a detailed safety substudy showed both regimens to be safe, deliverable, and tolerable. Grade 3 and 4 toxicities were reported at expected levels in both groups. The most common were neutropenia (527 [34%] of 1565 patients in the gemcitabine group vs 412 [26%] of 1567 in the control group), myalgia and arthralgia (207 [13%] vs 186 [12%]), fatigue (207 [13%] vs 152 [10%]), infection (202 [13%] vs 141 [9%]), vomiting (143 [9%] vs 108 [7%]), and nausea (132 [8%] vs 102 [7%]). INTERPRETATION The addition of gemcitabine to anthracycline and taxane-based adjuvant chemotherapy at this dose and schedule confers no therapeutic advantage in terms of disease-free survival in early breast cancer, although it can cause increased toxicity. Therefore, gemcitabine has not been added to standard adjuvant chemotherapy in breast cancer for any subgroup. FUNDING Cancer Research UK core funding for Clinical Trials Unit at the University of Birmingham, Eli Lilly, Bristol-Myers Squibb, and Pfizer.

A prospective evaluation of pulmonary, cardiac, and hepatic function (fn) in ‘tAnGo’: A randomized phase III trial of gemcitabine (G) in paclitaxel (T)-containing, epirubicin/cyclophosphamide (EC)-based, adjuvant chemotherapy (CT) for early stage breast cancer

821 Background: tAnGo is an ongoing 3000-patient (pt) randomized trial evaluating for the first time the role of G in adjuvant CT for breast cancer. We present the results of a preliminary prospective safety study designed to assess the incidence of any treatment (trt)-related clinical or sub-clinical disturbances of pulmonary, cardiac, or hepatic fn in the first 135 pts randomised. METHODS Pulmonary (Hb-adjusted TLCO, FEV1, FVC, CXR), cardiac (LVEF, ECG), and hepatic (AST/ALT) fn tests were conducted in 135 pts (66 EC+T, 69 EC+GT) at baseline, mid-CT, post-CT/pre-RT, and 6 months post-CT. RESULTS Pulmonary fn tests: majority normal at all time points, with no differences between trts or changes over time in FEV1 (p>0.3 and 0.9 resp) or FVC (p=0.95 and 0.5 resp). TLCO dropped marginally during trt (p<0.001), slightly lower for EC+GT pts (p=0.03). 94% of all CXRs normal with no differences between trts (p>0.25) and no changes over time (p=0.14). Cardiac fn tests: 95% of all Echo/MUGA scans and 90% of all ECGs normal, with no differences between trts (p>0.35 and >0.25 resp) and no changes in Echo/MUGAs over time (p=0.4); only a slight time effect in ECGs (p=0.03). Hepatic fn tests: 92% of all AST levels and 82% of all ALT levels normal (majority of abnormal results graded 1/2): EC+T pts show a modest increase in transaminases at mid-CT but this resolves by post-CT (AST p=0.08 and ALT p=0.38 for change over time); transaminase increases in EC+GT pts persist post-CT but resolve by 6 months (AST p=0.004 and ALT p=0.001 resp for change over time). Acute skin toxicity during RT: 87% of reports graded this as Nil/Mild; only 1% as severe; no difference between trts (p>0.1), although severity increased over time (p<0.0001). There were no trt related deaths. CONCLUSIONS These data suggest that clinically relevant trt effects on pulmonary or cardiac fn will be rare over the course of the entire study. Reported transaminase increases are both modest and reversible. Long term follow-up tests will be performed at 5 and 10 yrs. No significant financial relationships to disclose.