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Temporary drug treatment cessation might alleviate toxicity without substantially compromising efficacy in patients with cancer. We aimed to determine if a tyrosine kinase inhibitor drug-free interval strategy was non-inferior to a conventional continuation strategy for first-line treatment of advanced clear cell renal cell carcinoma. This open-label, non-inferiority, randomised, controlled, phase 2/3 trial was done at 60 hospital sites in the UK. Eligible patients (aged ≥18 years) had histologically confirmed clear cell renal cell carcinoma, inoperable loco-regional or metastatic disease, no previous systemic therapy for advanced disease, uni-dimensionally assessed Response Evaluation Criteria in Solid Tumours-defined measurable disease, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) at baseline to a conventional continuation strategy or drug-free interval strategy using a central computer-generated minimisation programme incorporating a random element. Stratification factors were Memorial Sloan Kettering Cancer Center prognostic group risk factor, sex, trial site, age, disease status, tyrosine kinase inhibitor, and previous nephrectomy. All patients received standard dosing schedules of oral sunitinib (50 mg per day) or oral pazopanib (800 mg per day) for 24 weeks before moving into their randomly allocated group. Patients allocated to the drug-free interval strategy group then had a treatment break until disease progression, when treatment was re-instated. Patients in the conventional continuation strategy group continued treatment. Patients, treating clinicians, and the study team were aware of treatment allocation. The co-primary endpoints were overall survival and quality-adjusted life-years (QALYs); non-inferiority was shown if the lower limit of the two-sided 95% CI for the overall survival hazard ratio (HR) was 0·812 or higher and if the lower limit of the two-sided 95% CI of the marginal difference in mean QALYs was -0·156 or higher. The co-primary endpoints were assessed in the intention-to-treat (ITT) population, which included all randomly assigned patients, and the per-protocol population, which excluded patients in the ITT population with major protocol violations and who did not begin their randomisation allocation as per the protocol. Non-inferiority was to be concluded if it was met for both endpoints in both analysis populations. Safety was assessed in all participants who received a tyrosine kinase inhibitor. The trial was registered with ISRCTN, 06473203, and EudraCT, 2011-001098-16. Between Jan 13, 2012, and Sept 12, 2017, 2197 patients were screened for eligibility, of whom 920 were randomly assigned to the conventional continuation strategy (n=461) or the drug-free interval strategy (n=459; 668 [73%] male and 251 [27%] female; 885 [96%] White and 23 [3%] non-White). The median follow-up time was 58 months (IQR 46-73 months) in the ITT population and 58 months (46-72) in the per-protocol population. 488 patients continued on the trial after week 24. For overall survival, non-inferiority was demonstrated in the ITT population only (adjusted HR 0·97 [95% CI 0·83 to 1·12] in the ITT population; 0·94 [0·80 to 1·09] in the per-protocol population). Non-inferiority was demonstrated for QALYs in the ITT population (n=919) and per-protocol (n=871) population (marginal effect difference 0·06 [95% CI -0·11 to 0·23] for the ITT population; 0·04 [-0·14 to 0·21] for the per-protocol population). The most common grade 3 or worse adverse events were hypertension (124 [26%] of 485 patients in the conventional continuation strategy group vs 127 [29%] of 431 patients in the drug-free interval strategy group); hepatotoxicity (55 [11%] vs 48 [11%]); and fatigue (39 [8%] vs 63 [15%]). 192 (21%) of 920 participants had a serious adverse reaction. 12 treatment-related deaths were reported (three patients in the conventional continuation strategy group; nine patients in the drug-free interval strategy group) due to vascular (n=3), cardiac (n=3), hepatobiliary (n=3), gastrointestinal (n=1), or nervous system (n=1) disorders, and from infections and infestations (n=1). Overall, non-inferiority between groups could not be concluded. However, there seemed to be no clinically meaningful reduction in life expectancy between the drug-free interval strategy and conventional continuation strategy groups and treatment breaks might be a feasible and cost-effective option with lifestyle benefits for patients during tyrosine kinase inhibitor therapy in patients with renal cell carcinoma. UK National Institute for Health and Care Research.

Improving the chances of curing patients with cancer who have had surgery to remove metastatic sites of disease is a priority area for cancer research. Pexa-Vec (Pexastimogene Devacirepvec; JX-594, TG6006) is a principally immunotherapeutic oncolytic virus that has reached late-phase clinical trials. We report the results of a single-center, nonrandomized biological end point study (trial registration: EudraCT number 2012-000704-15), which builds on the success of the presurgical intravenous delivery of oncolytic viruses to tumors. Nine patients with either colorectal cancer liver metastases or metastatic melanoma were treated with a single intravenous infusion of Pexa-Vec ahead of planned surgical resection of the metastases. Grade 3 and 4 Pexa-Vec–associated side effects were lymphopaenia and neutropaenia. Pexa-Vec was peripherally carried in plasma and was not associated with peripheral blood mononuclear cells. Upon surgical resection, Pexa-Vec was found in the majority of analyzed tumors. Pexa-Vec therapy associated with IFNα secretion, chemokine induction, and resulted in transient innate and long-lived adaptive anticancer immunity. In the 2 patients with significant and complete tumor necrosis, a reduction in the peripheral T-cell receptor diversity was observed at the time of surgery. These results support the development of presurgical oncolytic vaccinia virus-based therapies to stimulate anticancer immunity and increase the chances to cure patients with cancer.

Supplementary Figure from Neoadjuvant Intravenous Oncolytic Vaccinia Virus Therapy Promotes Anticancer Immunity in Patients

Supplementary Data from Neoadjuvant Intravenous Oncolytic Vaccinia Virus Therapy Promotes Anticancer Immunity in Patients

Improving the chances of curing patients with cancer who have had surgery to remove metastatic sites of disease is a priority area for cancer research. Pexa-Vec (Pexastimogene Devacirepvec; JX-594, TG6006) is a principally immunotherapeutic oncolytic virus that has reached late-phase clinical trials. We report the results of a single-center, nonrandomized biological end point study (trial registration: EudraCT number 2012-000704-15), which builds on the success of the presurgical intravenous delivery of oncolytic viruses to tumors. Nine patients with either colorectal cancer liver metastases or metastatic melanoma were treated with a single intravenous infusion of Pexa-Vec ahead of planned surgical resection of the metastases. Grade 3 and 4 Pexa-Vec–associated side effects were lymphopaenia and neutropaenia. Pexa-Vec was peripherally carried in plasma and was not associated with peripheral blood mononuclear cells. Upon surgical resection, Pexa-Vec was found in the majority of analyzed tumors. Pexa-Vec therapy associated with IFNα secretion, chemokine induction, and resulted in transient innate and long-lived adaptive anticancer immunity. In the 2 patients with significant and complete tumor necrosis, a reduction in the peripheral T-cell receptor diversity was observed at the time of surgery. These results support the development of presurgical oncolytic vaccinia virus-based therapies to stimulate anticancer immunity and increase the chances to cure patients with cancer.

PDF file - 129K, Supplementary Table 1. Clinical characteristics of discovery cohort. Characteristics of 10 patients from experimental arm of ICON7 trial used in MS discovery experiment; Supplementary Table 2. Number of samples in each treatment arm at each time-point; Supplementary Table 3 Associations between the baseline concentrations (time-point 1) of the serum biomarkers under investigation and the clinical characteristics in the validation study in validation cohort II; Supplementary Table 4 Associations between the baseline concentrations (time-point 1) of the serum biomarkers under investigation and the clinical characteristics in the validation study in both validation cohorts (validation cohort I and validation cohort II); Supplementary Table 5. Estimates from Cox proportional hazards regression for biomarker index (signature negative index < 3 and positive index ≥3), trial arm (standard or experimental) and signature/trial arm interaction in each validation cohort; Supplementary Table 6. Estimates from Cox proportional hazards regression for individual elements of biomarker index (score=1 if marker concentration is on the side of the cut-point favouring bevacizumab in terms of PFS in the optimal model for that marker, or a score=0 otherwise), trial arm (standard or experimental) and index element/trial arm interaction; Supplementary Table 7. Estimates from Cox proportional hazards regression for all possible combinations of the elements of the biomarker index (score=1 if the sum of the combination of elements ≥optimal split, or a score=0 otherwise, where the optimal split is recalculated for each model combination), trial arm (standard or experimental) and model combination score/trial arm interaction; Supplementary Table 8. Estimates from Cox proportional hazards regression for individual elements of biomarker index treated as continuous, trial arm (standard or experimental) and index element/trial arm interaction

Purpose: The aim of this study was to identify and validate novel predictive and/or prognostic serum proteomic biomarkers in patients with epithelial ovarian cancer (EOC) treated as part of the phase III international ICON7 clinical trial.Experimental Design: ICON7 was a phase III international trial in EOC which showed a modest but statistically significant benefit in progression-free survival (PFS) with the addition of bevacizumab to standard chemotherapy. Serum samples from 10 patients who received bevacizumab (five responders and five nonresponders) were analyzed by mass spectrometry to identify candidate biomarkers. Initial validation and exploration by immunoassay was undertaken in an independent cohort of 92 patients, followed by a second independent cohort of 115 patients (taken from across both arms of the trial).Results: Three candidate biomarkers were identified: mesothelin, fms-like tyrosine kinase-4 (FLT4), and α1-acid glycoprotein (AGP). Each showed evidence of independent prognostic potential when adjusting for high-risk status in initial (P < 0.02) and combined (P < 0.01) validation cohorts. In cohort I, individual biomarkers were not predictive of bevacizumab benefit; however, when combined with CA-125, a signature was developed that was predictive of bevacizumab response and discriminated benefit attributable to bevacizumab better than clinical characteristics. The signature showed weaker evidence of predictive ability in validation cohort II, but was still strongly predictive considering all samples (P = 0.001), with an improvement in median PFS of 5.5 months in signature-positive patients in the experimental arm compared with standard arm.Conclusions: This study shows a discriminatory signature comprising mesothelin, FLT4, AGP, and CA-125 as potentially identifying those patients with EOC more likely to benefit from bevacizumab. These results require validation in further patient cohorts. Clin Cancer Res; 19(18); 5227–39. ©2013 AACR.

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PDF file - 269K, Supplementary Figure 1: Differences in AGP, mesothelin and FLT4 concentrations between responders and non responders in the discovery sample set (n=10); Supplementary Figure 2: Progression-free survival in validation cohort I; Supplementary Figure 3: Baseline concentrations of mesothelin, FLT4, AGP and CA125 in: a). validation cohort I, b). validation cohort II, and c). both validation cohorts combined.

PDF file - 963K, Supplementary Figure 4: Correlation between biomarkers investigated in validation cohort I; Supplementary Figure 5: Longitudinal patterns in AGP concentration in validation cohort I; Supplementary Figure 6. Prognostic and predictive potential of candidate biomarkers in validation cohort I; Supplementary Figure 7. Kaplan Meier estimates of the survival function showing prognostic and predictive ability of the biomarker index in validation cohort I; Supplementary Figure 8. Prognostic and predictive potential of individual elements of biomarker index in the combined validation cohort.

PURPOSE Despite extensive randomized evidence supporting the use of treatment breaks in metastatic colorectal cancer (mCRC), they are not universally offered to patients despite improvements in quality of life without detriment to overall survival (OS). FOCUS4-N was set up to explore the impact of oral maintenance therapy in patients who are responding to first-line therapy. METHODS FOCUS4 was a molecularly stratified trial program that registered patients with newly diagnosed mCRC. The FOCUS4-N trial was offered to patients in whom a targeted subtrial was unavailable or biomarker tests failed. Patients were randomly assigned using a 1:1 ratio between maintenance capecitabine and active monitoring (AM). The primary outcome was progression-free survival (PFS) with secondary outcomes including OS toxicity and tolerability. RESULTS Between March 2014 and March 2020, 254 patients were randomly assigned (127 to capecitabine and 127 to AM) across 88 UK sites. Baseline characteristics were balanced. There was strong evidence of efficacy for PFS (hazard ratio = 0.40; 95% CI, 0.21 to 0.75; P < .0001), but no significant improvement in OS (hazard ratio, 0.93; 95% CI, 0.69 to 1.27; P = .66) was observed. Compliance with treatment was good, and toxicity from capecitabine versus AM was as expected with grade ≥ 2 fatigue (25% v 12%), diarrhea (23% v 13%), and hand-foot syndrome (26% v 3%). Quality of life showed little difference between the groups. CONCLUSION Despite strong evidence of disease control with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as safe management alternatives for patients who are stable or responding to first-line treatment for mCRC. Capecitabine without bevacizumab may be used to extend PFS in the interval after 16 weeks of first-line therapy.

Identifying pretreatment blood markers that distinguish prognostic groups of patients with advanced pancreatic ductal adenocarcinoma (PDAC) under first-line FOLFIRINOX chemotherapy has the potential to improve management of this condition. Aim of this study was to determine the prognostic utility of a range of pretreatment, inflammation-related, blood cell markers in this group of patients. Data from a training cohort were analyzed to identify potential pretreatment blood markers correlating to survival outcomes. The most informative markers were further analyzed in a validation cohort comprised patients from a geographically separate cancer center undergoing the same treatment. A total of 138 consecutive patients receiving FOLFIRINOX chemotherapy between 2010 and 2019, constituted the training cohort. Neutrophil/lymphocyte (NLR), monocyte/lymphocyte (MLR), and platelet/lymphocyte ratio (PLR) as well as the systemic inflammatory response index (SIRI) and CA19.9 showed prognostic significance in addition to tumor stage. A pretreatment SIRI score cutoff of 2.35 differentiated between a poor prognostic group with median overall survival (mOS) 5.1 months and a better prognostic group, mOS 12.5 months. SIRI ≤/> 2.35 was predictive of mOS in patients with locally advanced and metastatic PDAC. SIRI was confirmed as a prognostic marker in a validation cohort of 67 patients with mOS of 13.4 months and 6.3 months for those with SIRI ≤ 2.35 and >2.35, respectively. Additional analysis revealed baseline SIRI as being prognostic within additional subgroups of patients in both cohorts. This large, retrospective, analysis of real-world patients receiving first-line FOLFIRINOX chemotherapy for advanced PDAC has identified the pretreatment blood SIRI as a strong prognostic marker for survival. This will allow better counseling of patients with regards to the benefits of treatment, improved stratification within clinical trials, and potentially identify groups of patients for novel therapy trials as first-line treatment.

Outcomes inPatients with newly diagnosed mCRC were registered into FOCUS4 and tested forFOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) wereIn this phase II randomized trial, adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for

Highlights • Bone health should be prioritised when men with prostate cancer start long-term ADT. • Assessment by FRAX (±bone mineral density) identifies those at highest risk of fracture. • Treatment can minimise skeletal complications and reduce morbidity and mortality., Context and objective Incidence of prostate cancer (PC) is increasing, but androgen deprivation therapy (ADT) and other therapies are substantially improving survival. In this context, careful consideration of skeletal health is required to reduce the risk of treatment-related fragility fractures and their associated morbidity and mortality. This risk is currently not well-managed. ADT causes significant loss of bone mineral density (BMD). In the metastatic setting, systemic treatments (e.g. chemotherapy, abiraterone, enzalutamide) are used alongside ADT and may require concomitant glucocorticoids. Both ADT and glucocorticoids pose significant challenges to skeletal health in a population of patients already likely to have ongoing age-related bone loss and/or comorbid conditions. Current PC guidelines lack specific recommendations for optimising bone health. This guidance presents evidence for assessment and management of bone health in this population, with specific recommendations for clinical practitioners in day-to-day PC management. Methods Structured meetings of key opinion leaders were integrated with a systematic literature review. Input and endorsement was sought from patients, nursing representatives and specialist societies. Summary of guidance All men starting or continuing long-term ADT should receive lifestyle advice regarding bone health. Calcium/vitamin D supplementation should be offered if required. Fracture risk should be calculated (using the FRAX® tool), with BMD assessment included where feasible. BMD should always be assessed where fracture risk calculated using FRAX® alone is close to the intervention threshold. Intervention should be provided if indicated by local or national guidelines e.g. UK National Osteoporosis Guideline Group (NOGG) thresholds. Men requiring bone protection therapy should be further assessed (e.g. renal function), with referral to specialist centres if available and offered appropriate treatment to reduce fracture risk. Those near to, but below an intervention threshold, and patients going on to additional systemic therapies (particularly those requiring glucocorticoids), should have FRAX® (including BMD) repeated after 12–18 months. Patient summary Modern treatments for prostate cancer have led to significant improvements in survival and quality of life. However, some of these treatments may lead to weakening of patient’s bones with risk of fracture and it is therefore important to monitor patients’ bone health and provide bone protection where needed. This paper provides specific guidance to clinical teams, based on the most recent research evidence, to ensure optimal bone health in their patients.

Highlights • Lung cancer is the leading cause of cancer mortality worldwide. • Gold standard chemoradiotherapy is not deliverable for the majority of patients. • Radiation-induced DNA damage repair is an actionable mechanism of radioresistance. • Careful trial design is essential to elicit maximum impact on therapeutic index. • CONCORDE is a platform study of novel drug/radiotherapy combinations in lung cancer., Lung cancer is the leading cause of cancer mortality worldwide and most patients are unsuitable for ‘gold standard’ treatment, which is concurrent chemoradiotherapy. CONCORDE is a platform study seeking to establish the toxicity profiles of multiple novel radiosensitisers targeting DNA repair proteins in patients treated with sequential chemoradiotherapy. Time-to-event continual reassessment will facilitate efficient dose-finding.

ObjectivesStereotactic ablative radiotherapy (SABR) is a well-established treatment for medically inoperable peripheral stage I nonsmall cell lung cancer (NSCLC). Previous nonrandomised evidence supports SABR as an alternative to surgery, but high-quality randomised controlled trial (RCT) evidence is lacking. The SABRTooth study aimed to establish whether a UK phase III RCT was feasible.Design and methodsSABRTooth was a UK multicentre randomised controlled feasibility study targeting patients with peripheral stage I NSCLC considered to be at higher risk of surgical complications. 54 patients were planned to be randomised 1:1 to SABR or surgery. The primary outcome was monthly average recruitment rates.ResultsBetween July 2015 and January 2017, 318 patients were considered for the study and 205 (64.5%) were deemed ineligible. Out of 106 (33.3%) assessed as eligible, 24 (22.6%) patients were randomised to SABR (n=14) or surgery (n=10). A key theme for nonparticipation was treatment preference, with 43 (41%) preferring nonsurgical treatment and 19 (18%) preferring surgery. The average monthly recruitment rate was 1.7 patients against a target of three. 15 patients underwent their allocated treatment: SABR n=12, surgery n=3.ConclusionsWe conclude that a phase III RCT randomising higher risk patients between SABR and surgery is not feasible in the National Health Service. Patients have pre-existing treatment preferences, which was a barrier to recruitment. A significant proportion of patients randomised to the surgical group declined and chose SABR. SABR remains an alternative to surgery and novel study approaches are needed to define which patients benefit from a nonsurgical approach.

Background The combination of nivolumab, a programmed death-1 (PD-1) targeted monoclonal antibody, with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) targeted antibody, ipilimumab, represents a new standard of care in the first-line setting for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC) based on recent phase III data. Combining ipilimumab with nivolumab increases rates of grade 3 and 4 toxicity compared with nivolumab alone, and the optimal scheduling of these agents when used together remains unknown. The aim of the PRISM study is to assess whether less frequent dosing of ipilimumab (12-weekly versus 3-weekly), in combination with nivolumab, is associated with a favourable toxicity profile without adversely impacting efficacy. Methods The PRISM trial is a UK-based, open label, multi-centre, phase II, randomised controlled trial. The trial population consists of patients with untreated locally advanced or metastatic clear cell RCC, and aims to recruit 189 participants. Participants will be randomised on a 2:1 basis in favour of a modified schedule of 4 doses of 12-weekly ipilimumab versus a standard schedule of 4 doses of 3-weekly ipilimumab, both in combination with standard nivolumab. The proportion of participants experiencing a grade 3 or 4 adverse reaction within 12 months forms the primary endpoint of the study, but with 12-month progression free survival a key secondary endpoint. The incidence of all adverse events, discontinuation rates, overall response rate, duration of response, overall survival rates and health related quality of life will also be analysed as secondary endpoints. In addition, the potential of circulating and tissue-based biomarkers as predictors of therapy response will be explored. Discussion The combination of nivolumab with ipilimumab is active in patients with mRCC. Modifying the frequency of ipilimumab dosing may mitigate toxicity rates and positively impact quality of life without compromising efficacy, a hypothesis being explored in other tumour types such as non-small cell lung cancer. The best way to give this combination to patients with mRCC must be similarly established. Trial registration PRISM is registered with ISRCTN (reference ISRCTN95351638, 19/12/2017). Trial status At the time of submission, PRISM is open to recruitment and data collection is ongoing.

Importance: Older and/or frail patients are underrepresented in landmark cancer trials. Tailored research is needed to address this evidence gap. Objective: The GO2 randomized clinical trial sought to optimize chemotherapy dosing in older and/or frail patients with advanced gastroesophageal cancer, and explored baseline geriatric assessment (GA) as a tool for treatment decision-making. Design, Setting, and Participants: This multicenter, noninferiority, open-label randomized trial took place at oncology clinics in the United Kingdom with nurse-led geriatric health assessment. Patients were recruited for whom full-dose combination chemotherapy was considered unsuitable because of advanced age and/or frailty. Interventions: There were 2 randomizations that were performed: CHEMO-INTENSITY compared oxaliplatin/capecitabine at Level A (oxaliplatin 130 mg/m 2on day 1, capecitabine 625 mg/m 2twice daily on days 1-21, on a 21-day cycle), Level B (doses 0.8 times A), or Level C (doses 0.6 times A). Alternatively, if the patient and clinician agreed the indication for chemotherapy was uncertain, the patient could instead enter CHEMO-BSC, comparing Level C vs best supportive care. Main Outcomes and Measures: First, broad noninferiority of the lower doses vs reference (Level A) was assessed using a permissive boundary of 34 days reduction in progression-free survival (PFS) (hazard ratio, HR = 1.34), selected as acceptable by a forum of patients and clinicians. Then, the patient experience was compared using Overall Treatment Utility (OTU), which combines efficacy, toxic effects, quality of life, and patient value/acceptability. For CHEMO-BSC, the main outcome measure was overall survival. Results: A total of 514 patients entered CHEMO-INTENSITY, of whom 385 (75%) were men and 299 (58%) were severely frail, with median age 76 years. Noninferior PFS was confirmed for Levels B vs A (HR = 1.09 [95% CI, 0.89-1.32]) and C vs A (HR = 1.10 [95% CI, 0.90-1.33]). Level C produced less toxic effects and better OTU than A or B. No subgroup benefited from higher doses: Level C produced better OTU even in younger or less frail patients. A total of 45 patients entered the CHEMO-BSC randomization: overall survival was nonsignificantly longer with chemotherapy: median 6.1 vs 3.0 months (HR = 0.69 [95% CI, 0.32-1.48], P =.34). In multivariate analysis in 522 patients with all variables available, baseline frailty, quality of life, and neutrophil to lymphocyte ratio were independently associated with OTU, and can be combined in a model to estimate the probability of different outcomes. Conclusions and Relevance: This phase 3 randomized clinical trial found that reduced-intensity chemotherapy provided a better patient experience without significantly compromising cancer control and should be considered for older and/or frail patients. Baseline geriatric assessment can help predict the utility of chemotherapy but did not identify a group benefiting from higher-dose treatment. Trial Registration: isrctn.org Identifier: ISRCTN44687907.

3504 Background: There is extensive randomised evidence supporting the use of treatment breaks in mCRC, but breaks from treatment are not universally offered to patients despite reductions in toxicity, without detriment to OS. Prior trials have shown that the combination of Cp and bevacizumab extend PFS but not OS. FOCUS4-N explores oral maintenance Cp monotherapy in patients with disease control on first line therapy. Methods: FOCUS4 was a molecularly stratified trial programme registering patients with newly diagnosed mCRC from 88 hospitals in the UK. Whilst undergoing 16 wks of first line treatment, a sample of tumour was sent for laboratory testing to stratify their disease into molecular subtypes: MSI, BRAF, PIK3CA, TP53 and RAS mutations. For some molecular groups, a targeted therapy subtrial was available but entry into the FOCUS4-N trial was offered to those in whom a targeted subtrial was unavailable. Patients were randomised 1:1 between maintenance Cp therapy or AM. The primary outcome was PFS assessed using 8-wkly RECIST reported CT scans with quality of life (using EQ5D 8 weekly) and OS as secondary outcomes. Toxicity and tolerability were assessed 4-wkly. On progression, from the nadir, patients recommenced first line treatment. Cox regression was used to assess efficacy by intention-to-treat (ITT) with adjustment for tumour location, WHO status, metastatic burden, first line treatment and biomarker subtype. Results: Between March 2014 and March 2020, 254 patients were randomised (127 to Cp and 127 to AM). Baseline characteristics were balanced between groups but event rates were higher than anticipated in the AM group and the final analysis was triggered early as a result of the COVID-19 pandemic halting recruitment. The table presents results for PFS and OS. Compliance with treatment was good with per-protocol analysis results very similar to ITT (PFS HR=0.38 (95% CI 0.28-0.51)). Toxicity from Cp v AM was as expected with G≥2 fatigue (25% v 12%), diarrhoea (23% v 13%) and hand-foot syndrome (26% v 3%). Quality of life showed no statistically significant differences between the two arms. Conclusions: Despite strong evidence of prolongation of PFS with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as a safe management alternative for patients who are stable or responding well to first line treatment for mCRC. Cp without bevacizumab may be used to extend PFS, in the interval after 16 weeks of combination therapy. Clinical trial information: ISRCTN#90061546. [Table: see text]

Remarkable progress has been made over the past decade in cancer medicine. Personalized medicine, driven by biomarker predictive factors, novel biotherapy, novel imaging, and molecular targeted therapeutics, has improved outcomes. Cancer is becoming a chronic disease rather than a fatal disease for many patients. However, despite this progress, there is much work to do if patients are to receive continuous high-quality care in the appropriate place, at the appropriate time, and with the right specialized expert oversight. Unfortunately, the rapid expansion of therapeutic options has also generated an ever-increasing burden of emergency care and encroaches into end-of-life palliative care. Emergency presentation is a common consequence of cancer and of cancer treatment complications. It represents an important proportion of new presentations of previously undiagnosed malignancy. In the U.K. alone, 20%–25% of new cancer diagnoses are made following an initial presentation to the hospital emergency department, with a greater proportion in patients older than 70 years. This late presentation accounts for poor survival outcomes and is often associated with poor patient experience and poorly coordinated care. The recent development of acute oncology services in the U.K. aims to improve patient safety, quality of care, and the coordination of care for all patients with cancer who require emergency access to care, irrespective of the place of care and admission route. Furthermore, prompt management coordinated by expert teams and access to protocol-driven pathways have the potential to improve patient experience and drive efficiency when services are fully established. The challenge to leaders of acute oncology services is to develop bespoke models of care, appropriate to local services, but with an opportunity for acute oncology teams to engage cancer care strategies and influence cancer care and delivery in the future. This will aid the integration of highly specialized cancer treatment with high-quality care close to home and help avoid hospital admission.

Immune checkpoint inhibitors, including those targeting programmed cell death protein 1 (PD-1), are reshaping cancer therapeutic strategies. Evidence suggests, however, that tumor response and patient survival are determined by tumor programmed death-ligand 1 (PD-L1) expression. We hypothesized that preconditioning of the tumor immune microenvironment using targeted, virus-mediated interferon (IFN) stimulation, would upregulate tumor PD-L1 protein expression and increase cytotoxic T cell infiltration, improving the efficacy of subsequent checkpoint blockade. Oncolytic viruses (OVs) represent a promising form of cancer immunotherapy. For brain tumors, almost all studies to date have used direct intralesional injection of OV, because of the largely untested belief that intravenous (i.v.) administration will not deliver virus to this site. Here we show, in a window-of-opportunity clinical study, that i.v. infusion of oncolytic human Orthoreovirus (referred to herein as reovirus), leads to infection of tumor cells subsequently resected as part of standard clinical care, both in high-grade glioma (HGG) and in brain metastases, and increases cytotoxic T cell tumor infiltration relative to patients not treated with virus. We further show that reovirus upregulates IFN-regulated gene expression, as well as the PD-1/PD-L1 axis in tumors, via an IFN-mediated mechanism. Finally, we show that addition of PD-1 blockade to reovirus enhances systemic therapy in a preclinical glioma model. These results support the development of combined systemic immunovirotherapy strategies for the treatment of both primary and secondary tumors in the brain.

Background: Early phase trials are essential in drug development, determining appropriate dose levels and assessing preliminary activity. These trials are undertaken by industry and academia, with increasing collaborations between the two. There is pressure to perform these trials quickly, safely, and robustly. However, there are inherent differences between developing and managing early phase, compared to late phase, drug trials. This article describes an approach to establishing an academically led early phase trial portfolio, highlighting lessons learned and sharing experiences. Methods: In 2009, the University of Leeds Clinical Trials Research Unit became the Clinical Trials Coordinating Office for Myeloma UK’s phase I and II trials. We embarked on a transition from working extensively in phase III to early phase trials development and conduct. This involved evaluating and revising our well-established standard operating procedures, visiting other academic early phase units, and developing essential new documentation and processes. Results: A core team of trial and data managers and statisticians was established to facilitate expertise and knowledge retention. A detailed training plan was implemented focussing on essential standard practices for early phase. These included pharmacovigilance, recruitment, trial design and set-up, data and site monitoring, and oversight committees. Training in statistical methods for early phase trials was incorporated. Conclusion: Initial scoping of early phase trial management and conduct was essential in establishing this early phase portfolio. Many of the processes developed were successful. However, regular review and evaluation were implemented to enable changes and ensure efficiencies. It is recommended that others embarking on this venture build on the experiences described in this article.

Background Oncolytic viruses constitute a promising modality of cancer therapy. Pexa-Vec, a Thymidine Kinase-Deactivated Vaccinia Virus expressing GM-CSF, has been shown to target tumor tissue after intravenous (i.v.) administration (Breitbach C.J. et al., 2011). Herein, we report on the immunostimulatory effects of Pexa-Vec prior to surgical resection in patients with advanced solid tumors. Methods Patients with operable tumors (3 with metastatic melanoma and 6 with colorectal cancer metastases to the liver (CRLM)) received a single i.v. dose of 1x109 plaque forming units of Pexa-Vec, approximately 14 days prior to surgical resection. Translational and histologic assessment was performed on blood samples collected pre- and post-injection and tumor collected at surgery. Results Pexa-Vec injection was well tolerated in all cases. Pexa-Vec was detected in serum immediately after iv administration but not in PBMC. Histologic examination of tumor tissue indicates the presence of virus in tumor at the time of surgery 14 days after administration. Of the 4 evaluable CRLM, one showed complete necrosis, and another partial necrosis, within a normal background liver. Analysis of peripheral blood mononuclear cells and tumor infiltrating lymphocytes showed robust activation of Natural Killer (NK) cells and CD8+ cells, with high CD69 and PD-L1 expression. Functional assays revealed increased NK cell degranulation and elevated tumor-associated antigen recognition by T cells. Furthermore, Pexa-Vec induced a significant elevation of serum cytokines associated with immune response including IFNα, IFNβ, TRAIL and CXCL10. Conclusions When administered intravenously, Pexa-Vec exhibited a selective persistence in tumor suggesting a tumor-targeted oncolytic action. Concurrently, Pexa-Vec triggered a robust immune activation of both innate and adaptive immune cells and infiltration of lymphocytes into tumor, associated with extensive necrosis in some patient tumours. These data strongly support the rationale for sequential i.v. use of oncolytic vaccinia virus in combination with immune checkpoint modulation therapy. Clinical trial identification ISRCTN13913966. Legal entity responsible for the study University of Leeds. Funding Transgene. Disclosure A. Samson: Research grant / Funding (institution): Transgene. K. Bendjama: Full / Part-time employment: Transgene. N. Stojkowitz: Full / Part-time employment: Transgene. M. Lusky: Full / Part-time employment: Transgene. A. Melcher: Research grant / Funding (institution): Transgene. F. Collinson: Research grant / Funding (institution): Transgene. All other authors have declared no conflicts of interest.

Stage I non-small cell lung cancer (NSCLC) is potentially curable, and surgery is considered to be the standard of care for patients with good performance status and minimal co-morbidity. However, a significant proportion of patients with stage I NSCLC have a poorer performance status and significant medical co-morbidity that make them at higher risk of morbidity and mortality from surgery. Stereotactic ablative radiotherapy (SABR), which uses modern radiotherapeutic techniques to deliver large doses of radiation, has shown superiority over conventional radiotherapy in terms of local control and toxicity and is a standard of care for patients with stage I NSCLC who are at too high risk for surgery. However, it is not known whether surgery or SABR is the most effective in patients with stage I NSCLC who are suitable for surgery but are less fit and at higher risk surgical complications. Previous randomised studies have failed to recruit in this setting, and therefore, a feasibility study is required to see whether a full randomised control trial would be possible. SABRTooth is a UK-based, multi-centre, open-label, two-group individually (1:1) randomised controlled feasibility study in patients with peripheral stage I NSCLC considered to be at higher risk from surgical resection. The study will assess the feasibility of conducting a definitive large-scale phase III trial. The primary objective is to assess recruitment rates to provide evidence that, when scaled up, recruitment to a large phase III trial would be possible; the target recruitment being 54 patients in total, over a 21-month period. There are multiple secondary and exploratory objectives designed to explore the optimum recruitment and data collection strategies to help optimise the design of a future phase III trial. To know whether SABR is a better, equivalent or inferior alternative to surgery for higher risk patients is a key question in lung cancer. Other studies comparing SABR to surgery have closed early due to poor recruitment, and therefore, the SABRTooth feasibility study has been designed around the UK National Health Service (NHS) cancer pathway incorporating many design features in order to maximise recruitment for a future definitive phase III trial. controlled-trials.com ISRCTN13029788

Background Laparoscopic resection is used widely in the management of colorectal cancer; however, the data on long-term outcomes, particularly those related to rectal cancer, are limited. The results of long-term follow-up of the UK Medical Research Council trial of laparoscopically assisted versus open surgery for colorectal cancer are presented. Methods A total of 794 patients from 27 UK centres were randomized to laparoscopic or open surgery in a 2:1 ratio between 1996 and 2002. Long-term follow-up data were analysed to determine differences in survival outcomes and recurrences for intention-to-treat and actual treatment groups. Results Median follow-up of all patients was 62·9 (interquartile range 22·9 − 92·8) months. There were no statistically significant differences between open and laparoscopic groups in overall survival (78·3 (95 per cent confidence interval (c.i.) 65·8 to 106·6) versus 82·7 (69·1 to 94·8) months respectively; P = 0·780) and disease-free survival (DFS) (89·5 (67·1 to 121·7) versus 77·0 (63·3 to 94·0) months; P = 0·589). In colonic cancer intraoperative conversions to open surgery were associated with worse overall survival (hazard ratio (HR) 2·28, 95 per cent c.i. 1·47 to 3·53; P < 0·001) and DFS (HR 2·20, 1·31 to 3·67; P = 0·007). In terms of recurrence, no significant differences were observed by randomized procedure. However, at 10 years, right colonic cancers showed an increased propensity for local recurrence compared with left colonic cancers: 14·7 versus 5·2 per cent (difference 9·5 (95 per cent c.i. 2·3 to 16·6) per cent; P = 0·019). Conclusion Long-term results continue to support the use of laparoscopic surgery for both colonic and rectal cancer.

Background: Literature reviews of cancer trials have highlighted the need for better understanding of phase II statistical designs. Understanding the key elements associated with phase II design and knowledge of available statistical designs is necessary to enable appropriate phase II trial design. Methods: A systematic literature review was performed to identify phase II trial designs applicable to oncology trials. The results of the review were used to create a library of currently available designs, and to develop a structured approach to phase II trial design outlining key points for consideration. Results: A total of 122 papers describing new or adapted phase II trial designs were obtained. These were categorised into nine levels, reflecting the practicalities of implementation, and form a library of phase II designs. Key design elements were identified by data extraction. Along with detailed description of the key elements and the library of designs, a structured thought process was developed to form a guidance document for choice of phase II oncology trial design. Conclusion: The guidance offers researchers a structured and systematic approach to identifying phase II trial designs, highlighting key issues to be considered by both clinicians and statisticians and encouraging an interactive approach to more informed trial design.

3092Background: Oncolytic viruses (OV) constitute a promising modality of cancer therapy. Intra-tumoral administration has yielded encouraging clinical results, but restricted the use of OV to tumo...

Purpose of review To highlight the current antiangiogenic compounds being evaluated as single agents or in association with chemotherapy in the treatment of ovarian cancer, as well as the rationale for their development. Recent findings Several proangiogenic factors may be potential targets for antiangiogenic therapy in ovarian cancer. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has been evaluated as a single agent in two phase II clinical trials and in combination with chemotherapy in three phase II studies, with promising results. This agent is also being evaluated in association with chemotherapy in two phase III clinical trials, both in the treatment and in the maintenance settings. Heparanase inhibitors and inhibitors of platelet-derived growth factor signalling remain as potential agents to be investigated in phase II trials. The development of biomarkers to define appropriate dosing regimens and predict which patients may benefit from antiangiogenic therapies is of great importance. Summary Data from preclinical and clinical studies reported in the last 2 years demonstrate the importance of several proangiogenic factors in the prognosis of ovarian cancer, suggesting possible new targets for antiangiogenic therapy. The agents that are currently being investigated in phase II and III clinical trials include bevacizumab, erlotinib, sunitinib, sorafenib and vascular endothelial growth factor Trap, and the results of these trials will have significant implications in the future management of ovarian cancer.

Purpose: The aim of this study was to identify and validate novel predictive and/or prognostic serum proteomic biomarkers in patients with epithelial ovarian cancer (EOC) treated as part of the phase III international ICON7 clinical trial. Experimental Design: ICON7 was a phase III international trial in EOC which showed a modest but statistically significant benefit in progression-free survival (PFS) with the addition of bevacizumab to standard chemotherapy. Serum samples from 10 patients who received bevacizumab (five responders and five nonresponders) were analyzed by mass spectrometry to identify candidate biomarkers. Initial validation and exploration by immunoassay was undertaken in an independent cohort of 92 patients, followed by a second independent cohort of 115 patients (taken from across both arms of the trial). Results: Three candidate biomarkers were identified: mesothelin, fms-like tyrosine kinase-4 (FLT4), and α1-acid glycoprotein (AGP). Each showed evidence of independent prognostic potential when adjusting for high-risk status in initial (P < 0.02) and combined (P < 0.01) validation cohorts. In cohort I, individual biomarkers were not predictive of bevacizumab benefit; however, when combined with CA-125, a signature was developed that was predictive of bevacizumab response and discriminated benefit attributable to bevacizumab better than clinical characteristics. The signature showed weaker evidence of predictive ability in validation cohort II, but was still strongly predictive considering all samples (P = 0.001), with an improvement in median PFS of 5.5 months in signature-positive patients in the experimental arm compared with standard arm. Conclusions: This study shows a discriminatory signature comprising mesothelin, FLT4, AGP, and CA-125 as potentially identifying those patients with EOC more likely to benefit from bevacizumab. These results require validation in further patient cohorts. Clin Cancer Res; 19(18); 5227–39. ©2013 AACR.

Introduction: Histone deacetylase inhibitors (HDACis) have demonstrated clinical efficacy in multiple myeloma, particularly in combination with proteasome inhibitors. CHR-3996 is a class 1 selective HDACi with potent anti-myeloma activity in vitro. Aminopeptidase inhibitors act downstream of the proteasome and prevent breakdown of proteasome generated peptides into amino acids. Synergistic cytotoxicity was observed in vitro when CHR-3996 was combined with the aminopeptidase inhibitor, tosedostat through rapid activation of NFkB followed by increased expression of the repressors IκBα, A20, CYLD, BIRC3. The MUK-three study was designed to translate these pre-clinical findings into a phase 1 clinical trial. This dose escalation study aimed to determine the maximum tolerated dose, safety and preliminary activity of CHR-3996 administered in combination with Tosedostat for patients with relapsed, refractory MM. Here we present the final study results. Methods: MUK-three was an open label multi-centre UK Phase I/IIa trial for patients with relapsed and relapsed/ refractory myeloma who had failed conventional treatments. Patients were permitted to meet the haematological entry criteria using growth factor and/or blood product support. During dose escalation subjects received CHR-3996 (20-40mg days1-28) and Tosedostat (0-60mg days 1-28) (Table 1) every 28 day cycle until disease progression or withdrawal. Dose limiting toxicities (DLTs) were evaluated during cycle 1 and dose escalation followed the 3+3 design. Responses were assessed using modified IMWG uniform response criteria, with the primary endpoint for the expansion phase of stable disease (SD) rate after 4 cycles of therapy. Toxicity was graded by CTCAE V4.0. Results: The trial was open to recruitment from July 2012 to December 2015. 20 patients were treated during dose escalation, including 8 at the recommended dose (RD) and 12 at dose levels (DL) 1-3. Only 1 DLT was observed at DL3 (grade 4 thrombocytopenia); however, this DL was deemed not tolerable due to the high incidence of low grade gastrointestinal toxicities. Hence the RD was determined as DL3b, CHR-3996 20mg and Tosedostat 60mg. A further 2 patients were treated at RD during dose expansion to make the required 10 patients for the protocol defined initial analysis at which point the trial closed. At the RD (n=10) median age was 63 years (range 47-73). 80% of patients had received at least 4 prior lines of therapy (median 4, range 2-9); 50% were ISS II, 30% ISS III; 4/6 patients with evaluable FISH data had 1q gain. The median time from diagnosis to treatment for the overall population was 85.3 months (27.5-198.8). The median number of cycles received was 2.5 (range 2-8) and 2 patients remain on treatment with 8 stopped due to disease progression. The 2 patients ongoing (received 5 & 9 prior lines) had their schedule adjusted to a 5 day a week dosing to further improve tolerability. Both had a clinical response (1MR, 1PR) and remained progression free at 6 months. 3/10 patients had SD after 4 cycles, the overall response rate (≥PR) was 1/10(10%) and the clinical benefit rate (≥MR) 2/10 (20%). Overall outcomes were: PR 10%, MR 10%, and SD 30%. Median time to maximum response was 1.84 months (95% CI [1.09, 8.65]). Toxicities at the RD were manageable, 30% of patients required a dose reduction. 22 serious adverse events were reported in 16 patients across all doses, mainly infections (10/22, 45.5%). The commonest grade 3-4 toxicities reported for all 22 patients were: platelet count decrease (12, 54.5%), white blood cell decreased (6, 27.2%), diarrhoea (5, 22.7%). The most frequent grade 1-2 toxicities were fatigue (15, 68.2%), nausea (14, 63.3 %), anorexia (14, 63.6%), anaemia (13, 59.1%). 1 patient withdrew due to toxicity, and there were no treatment related deaths. Conclusions: This study demonstrated that the novel combination of CHR-3996 and tosedostat was safe and tolerable in multiply relapsed, refractory myeloma patients many of which had poor bone marrow function. The recommended dose of the combination was 20mg and 60mg, respectively. Following further adjustment to an intermittent 5 day/ week dosing schedule, treatment was well tolerated and clinical benefit observed. This suggests that further evaluation of this novel combination is warranted. Acknowledgments: This trial was part of the Myeloma UK Clinical Trial Network, ISRCTN: 24989786. Disclosures Williams: Novartis: Honoraria; Janssen: Honoraria, Other: Travel support, Speakers Bureau; Celgene: Honoraria, Other: Travel support, Speakers Bureau; Takeda: Honoraria, Other: Travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Yong:Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding. Cook:Takeda Oncology: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Glycomimetics: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Jenner:Amgen: Consultancy, Honoraria, Other: Travel support; Takeda: Consultancy, Honoraria, Other: Travel support; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Morgan:Univ of AR for Medical Sciences: Employment; Bristol Meyers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Davies:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

Background Over 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/Design The 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. Discussion The 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 Registration Controlled-trials.com ISRCTN 06473203

Laparoscopic surgery is increasingly used in the treatment of colorectal cancer and more recently robotic assistance has been advocated. However, the learning curve to achieve surgical proficiency in laparoscopic surgery is ill-defined and subject to many influences. The aim of this review was to comprehensively appraise the literature on the learning curve for laparoscopic and robotic colorectal cancer surgery, and to quantify attainment of surgical proficiency and its implications in surgical clinical trial design.A systematic review using a defined search strategy was performed. Included studies had to state an explicit numerical value of the learning curve evaluated by a single parameter or multiple parameters.Thirty-four studies were included, 28 laparoscopic and 6 robot assisted. Of the laparoscopic studies, nine defined the learning curve on the basis of a single parameter. Nine studies used more than one parameter to define learning, and 11 used a cumulative sum (CUSUM) analysis. One study used both a multiparameter and CUSUM analysis. The definition of proficiency was subjective, and the number of operations to achieve it ranged from 5 to 310 cases for laparoscopic and 15-30 cases for robotic surgery.The learning curve in laparoscopic colorectal surgery is multifaceted and often ill-defined, with poor descriptions of mentorship/supervision. Further, the quantification to attain proficiency is variable. The use of a single parameter to quantify this is simplistic. Multidimensional assessment is recommended; as part of this, the CUSUM model, which assesses trends in multiple surgical outcomes, is useful and appropriate when assessing the learning curve in a clinical setting.

Ovarian cancer is an important health concern worldwide. The majority of patients present with advanced disease, and despite initial chemosensitivity, most relapse and die from their disease. Better therapeutic options are urgently required. Maximal surgical debulking in combination with platinum/taxane chemotherapy has been the standard of care in advanced ovarian cancer since the mid-1990s. Trials investigating the addition of a third chemotherapeutic agent have disappointingly failed to demonstrate benefit. Intra-peritoneal therapy demonstrated improvements in outcomes in some trials, but at the cost of increased toxicity and inconvenience. Encouragingly, prospective data has now demonstrated benefits with bevacizumab in both the first-line and relapsed settings; however, interpretation is complex, particularly considering recent data demonstrating non-inferiority of neo-adjuvant chemotherapy with delayed primary surgery, and other data demonstrating a substantial improvement in outcome as a result of first-line paclitaxel dose fractionation. This article reviews the recent advances in ovarian cancer treatment and discusses current management and key areas for future research.

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.

There is growing enthusiasm for robotic-assisted laparoscopic operations across many surgical specialities, including colorectal surgery, often not supported by robust clinical or cost-effectiveness data. A proper assessment of this new technology is required, prior to widespread recommendation or implementation.The ROLARR trial is a pan-world, prospective, randomised, controlled, unblinded, superiority trial of robotic-assisted versus standard laparoscopic surgery for the curative treatment of rectal cancer. It will investigate differences in terms of the rate of conversion to open operation, rate of pathological involvement of circumferential resection margin, 3-year local recurrence, disease-free and overall survival rates and also operative morbidity and mortality, quality of life and cost-effectiveness. The primary outcome measure is the rate of conversion to open operation. For 80% power at the 5% (two-sided) significance level, to identify a relative 50% reduction in open conversion rate (25% to 12.5%), 336 patients will be required. The target recruitment is 400 patients overall to allow loss to follow-up. Patients will be followed up at 30 days and 6 months post-operatively and then annually until 3 years after the last patient has been randomised.In many centres, robotic-assisted surgery is being implemented on the basis of theoretical advantages, which have yet to be confirmed in practice. Robotic surgery is an expensive health care provision and merits robust evaluation. The ROLARR trial is a pragmatic trial aiming to provide a comprehensive evaluation of both robotic-assisted and standard laparoscopic surgery for the curative resection of rectal cancer.

Angiogenesis plays a role in the biology of ovarian cancer. We examined the effect of bevacizumab, the vascular endothelial growth factor inhibitor, on survival in women with this disease.We randomly assigned women with ovarian cancer to carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body-surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease. Outcome measures included progression-free survival, first analyzed per protocol and then updated, and interim overall survival.A total of 1528 women from 11 countries were randomly assigned to one of the two treatment regimens. Their median age was 57 years; 90% had epithelial ovarian cancer, 69% had a serous histologic type, 9% had high-risk early-stage disease, 30% were at high risk for progression, and 70% had stage IIIC or IV ovarian cancer. Progression-free survival (restricted mean) at 36 months was 20.3 months with standard therapy, as compared with 21.8 months with standard therapy plus bevacizumab (hazard ratio for progression or death with bevacizumab added, 0.81; 95% confidence interval, 0.70 to 0.94; P=0.004 by the log-rank test). Nonproportional hazards were detected (i.e., the treatment effect was not consistent over time on the hazard function scale) (P0.001), with a maximum effect at 12 months, coinciding with the end of planned bevacizumab treatment and diminishing by 24 months. Bevacizumab was associated with more toxic effects (most often hypertension of grade 2 or higher) (18%, vs. 2% with chemotherapy alone). In the updated analyses, progression-free survival (restricted mean) at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab (P=0.04 by log-rank test); in patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression-free survival (restricted mean) at 42 months of 14.5 months with standard therapy alone and 18.1 months with bevacizumab added, with respective median overall survival of 28.8 and 36.6 months.Bevacizumab improved progression-free survival in women with ovarian cancer. The benefits with respect to both progression-free and overall survival were greater among those at high risk for disease progression. (Funded by Roche and others; ICON7 Controlled-Trials.com number, ISRCTN91273375.).

Despite advances in management over recent years, epithelial ovarian cancer remains the most lethal gynaecological malignancy. Methods of early detection, as well as improved therapeutic options, are urgently needed.Currently, a number of targeted therapies, including vascular endothelial growth factor inhibitors, poly-ADP-ribose polymerase inhibitors and folate receptor inhibitors look promising in this arena and this article will review a number of these drugs and the evidence pertaining to their use.Much further research is required to define if, when and how best to integrate these novel therapies, and also to define associated biomarkers that predict toxicity and select patients most likely to derive benefit. Individualized therapy is not an impossible dream, but there is still a long way to go.