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New technologies and techniques in radiation oncology and imaging offer opportunities to enhance the benefit of loco-regional treatments, expand treatment to new patient populations such as those with oligometastatic disease and decrease normal tissue toxicity. Furthermore, novel agents have become available which may be combined with radiation therapy, and identification of radiation-related biomarkers can be studied to refine treatment prescriptions. Finally, the use of artificial intelligence (AI) capabilities may also improve treatment quality assurance or the ease with which radiation dosing is prescribed. All of these potential advances present both opportunities and challenges for academic clinical researchers. Recently, the European Organisation for Research and Treatment of Cancer addressed these topics in a meeting of multiple stakeholders from Europe and North America. The following five themes radiobiology-based biomarkers, new technologies – particularly proton beam therapy, combination systemic and radiation therapy, management of oligometastatic disease and AI opportunities in radiation oncology were discussed in a State of Science format to define key controversies, unanswered questions and propose clinical trial priorities for development. Priorities for clinical trials implementing new science and technologies have been defined. Solutions to integrate the multidimensional complexity of data have been explored. New types of platforms and partnerships can support innovative approaches for clinical research in radiation oncology. • Biomarkers of radiation sensitivity are ready for randomised prospective evaluation. • RCTS (Randomised Clinical Trials) of proton therapy should examine impacts on toxicity and efficacy. • Artificial intelligence may improve the quality of radiation treatment delivery. • Cure is the key end-point for trials of ablative radiation in oligometastases. • New systemic therapy plus radiation should be evaluated to improve disease control. [ABSTRACT FROM AUTHOR]

Abstract: Background: Clinical benefit (CB) was first successfully used as an end-point in 1997 in the pivotal study of gemcitabine in advanced pancreas cancer. In the trial by Burris et al. CB was a composite measure of pain, performance status and weight. Here we describe how CB has been used in oncology trials since that time. Methods: We performed an electronic search (www.jco.org) for reports of all clinical trials (phase I, II and III) published in the Journal of Clinical Oncology 1997–2008 citing ‘clinical benefit’. Eligible trials were those reporting clinical benefit as an end-point. Details related to study methodology, sponsorship and end-points were abstracted. Use of CB was classified as patient centred if it referred to improvement in the clinical parameters used by Burris et al. or in other disease-related symptoms. CB was classified as tumour centred if it relatedtoobjective tumour criteria for partial/complete response and/or stable disease. Descriptive statistics were used to summarise findings and the chi-square test was used to compare proportions. Results: Seventy-one trials reporting CB as an end-point were identified: 37in breast, 8in pancreasand 26 in other cancers. The definition of CB was patient centred in 20 trials (28%) and tumour centred in 51 trials (72%). Only 20% (14/71) of trials (including all 8 pancreas studies) used the original Burris definition. Among the 71 trials reporting clinical benefit, in only 31 (44%) cases was the end-point defined as a primary or secondary study objective. Trials with a patient-centred definition of CB were considerably more likely to do so than trials with a tumour-centred definition (19/20, 95% versus 12/51, 24%, p <0.0001). Study variables associated with the use of a tumour-centred definition include: disease site (breast 35/37, 95%; all others 16/34, 47%, p <0.001) andintervention (hormone or targeted agent 38/40, 95%; chemotherapy 13/31, 42%, p <0.001). There has been a steady increase in the number of trials using CB as an end-point; in the second half of the study period the number of trials increased from 17 to 54, along with the proportion of trials with a tumour-centred definition (10/17, 59% to 41/54, 76%, p =0.09). Conclusions: Despite its initial definition, clinical benefit is often used to describe objective tumour findings. Clinical trials should use end-points in a consistent manner to enable clear communication between investigators, clinicians and patients about the benefit of novel therapies. [Copyright &y& Elsevier]

The emergence of the precision medicine paradigm in oncology has led to increasing interest in the integration of real-world data (RWD) into cancer clinical research. As sources of real-world evidence (RWE), such data could potentially help address the uncertainties that surround the adoption of novel anticancer therapies into the clinic following their investigation in clinical trials. At present, RWE-generating studies which investigate antitumour interventions seem to primarily focus on collecting and analysing observational RWD, typically forgoing the use of randomisation despite its methodological benefits. This is appropriate in situations where randomised controlled trials (RCTs) are not feasible and non-randomised RWD analyses can offer valuable insights. Nevertheless, depending on how they are designed, RCTs have the potential to produce strong and actionable RWE themselves. The choice of which methodology to employ for RWD studies should be guided by the nature of the research question they are intended to answer. Here, we attempt to define some of the questions that do not necessarily require the conduct of RCTs. Moreover, we outline the strategy of the European Organisation for Research and Treatment of Cancer (EORTC) to contribute to the generation of robust and high-quality RWE by prioritising the execution of pragmatic trials and studies set up according to the trials-within-cohorts approach. If treatment allocation cannot be left up to random chance due to practical or ethical concerns, the EORTC will consider undertaking observational RWD research based on the target trial principle. New EORTC-sponsored RCTs may also feature concurrent prospective cohorts composed of off-trial patients. • The role of real-world data (RWD) in cancer clinical research is increasing. • A false dichotomy exists between RWD studies and randomised controlled trials (RCTs). • There are different methodologies for RWD studies, including RCT designs. • The methodology to be employed should be determined by the research question. • We outline the RWD strategy of a large academic clinical cancer research organisation. [ABSTRACT FROM AUTHOR]

Progression-free survival (PFS) is an end-point in an increasing number of cancer clinical trials, informing both regulatory bodies and clinical practice. PFS is utilised both as a surrogate end-point for overall survival and as a primary trial end-point in itself. Understanding the history of clinical trial definitions of progression provides some context for how PFS may be applied to clinical practice as well as some of its limitations that need to be considered in patient care decisions. This commentary reviews recent drug approval for anti-cancer agents in solid tumours, reviews various concepts of progression in clinical trials and outlines some future directions for patient care and clinical trial research using progression free survival. [ABSTRACT FROM AUTHOR]

Disease-free survival (DFS) is an end-point for an increasing number of clinical trials in adjuvant and curative intent cancer treatment informing both regulatory bodies and clinical practice. DFS is seen both as a surrogate end-point and as an end-point in itself in clinical trials. Understanding the history of DFS, and some of the assumptions, limitations, and vulnerabilities for studies designed with this primary end-point are required. This commentary reviews recent drug approvals for anti-cancer agents in solid tumours in the adjuvant and curative settings, and considers the meaning of DFS from the perspectives of clinical trials and clinical practice. [ABSTRACT FROM AUTHOR]

Progression-free survival (PFS) is an end-point in an increasing number of cancer clinical trials, informing both regulatory bodies and clinical practice. PFS is utilised both as a surrogate end-point for overall survival and as a primary trial end-point in itself. Understanding the history of clinical trial definitions of progression provides some context for how PFS may be applied to clinical practice as well as some of its limitations that need to be considered in patient care decisions. This commentary reviews recent drug approval for anti-cancer agents in solid tumours, reviews various concepts of progression in clinical trials and outlines some future directions for patient care and clinical trial research using progression free survival. [ABSTRACT FROM AUTHOR]

Abstract: Cancer for many patients is still a lethal disease, and we are at the edge of the time that it will be the leading cause of death in the western world. One of the hallmarks of cancer is its ability to spread to other organs, turning cancer in essence to a systemic disease. For this reason, systemic therapy plays an important role in our efforts to either obtain cure or to prolong life and palliate symptoms. The ultimate goal in the development of such new treatments is cure or prolongation of life, but the process to ascertain this may be lengthy. This presents a limitation to the rapid assessment of the potential benefit of new cancer treatments, which is why investigators and regulators have been interested in clinical trial measures that could provide early readouts of drug activity or efficacy, in other words for surrogate indicators for the ultimately desired outcome. [Copyright &y& Elsevier]

Background Women with breast cancer and diabetes mellitus (DM) have poorer survival. Mechanisms include insulin dysregulation and/or DM related co-morbidities (CM). In MA.17 adjuvant letrozole (LET) after 5 years of tamoxifen (TAM) reduced the risk of recurrence and improved survival. We evaluated DM, hypertension (HTN), and coronary artery disease (CAD) as prognostic and predictive factors in MA.17. Patients and methods Disease free survival, distant disease free survival (DDFS) and overall survival (OS) were compared using Cox regression model adjusting for other prognostic factors: in women treated by placebo (PLAC) based on the presence or absence of baseline DM (n = 462), HTN (n = 1627), CAD (n = 604) or any one of these CM (n = 2049), and between LET and PLAC groups in each CM. Analyses based on nodal status were performed. Results DM was neither prognostic nor predictive for women on extended LET. Women with one CM had similar outcomes on LET compared to women free of CM. For node positive women, the difference between LET and PLAC in DDFS was greater among women with one CM (hazard ratio [HR] = 0.30 [0.15–0.60], p = 0.001) compared to those without CM (HR = 0.72 [0.45–1.16], p = 0.17, p interaction = 0.04). Women on PLAC with HTN trended towards lower DDFS (HR = 1.50 [0.98–2.3], p = 0.06) and OS (HR = 1.61 [0.95–2.72], p = 0.08) than non-HTN women. HTN women had better DDFS on LET than non-HTN women. Women with one CM on PLAC had lower OS (HR = 2.10 [1.26–3.51], p = 0.004) than those free of CM. Conclusions DM was not prognostic or predictive of outcomes. Women with CM who remain disease free after 5 years of TAM should be offered LET. HTN trended towards a negative prognosticator and outcomes among this group were improved on LET. More studies are needed to assess impact of adrenergic stimulation as a possible link to poorer breast cancer outcomes. [ABSTRACT FROM AUTHOR]

Abstract: The Methodology for the Development of Innovative Cancer Therapies (MDICT) task force considered aspects of the design and conduct of early (phase I and II) studies of combinations of molecular targeted agents during their 2012 meeting. The task force defined necessary non-clinical data, such as evidence of additive or synergistic effects in multiple molecularly credentialed and validated models, and appropriate pharmacodynamic marker development. A robust hypothesis was considered critical while non-clinical pharmacokinetic studies were also considered valuable. Clinical trials should include clear objectives that will prove or disprove the hypothesis. Predictive biomarkers/classifiers should be explored in phase I studies, rather than used to select patients. Trial design should be efficient and flexible rather than based on a strict progression from phase I to II to III; researchers could consider phase I studies with an expansion cohort, Phase I/II designs or phase II studies with a safety run in. Pharmacokinetics are recommended when interactions or overlapping toxicity is expected. Pharmacodynamic evaluations should be considered especially in a subset of patients closest to the recommended dose; an attempt should be made to validate surrogate tissues to enable inclusion for all patients. Schedule and or dose should be formally explored for e.g. with a randomised or an adaptive design. Data and knowledge sharing was strongly recommended, including the creation of formal or informal consortia of laboratories with individual expertise in pathway or target based models, collaboration between companies to ensure that agents which are ‘best in class’ are combined, and the development of databases which will be able to inform the development of future recommendations/guidelines. [Copyright &y& Elsevier]

Abstract: There has been a significant shift within oncology drug development away from empiric screening of cytotoxic compounds to the era of genomics and molecularly targeted agents. The drug development process is evolving with greater emphasis on proof-of-mechanism studies in both preclinical and early clinical development. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Task Force, established as a forum for academic and pharmaceutical leaders to discuss methodological issues in targeted anticancer therapy development, met in March 2010 to review what were the minimal data required to make appropriate decisions about moving new targeted cancer agents from late preclinical development into phase I and from phase I into phase II trials. A number of specific questions were posed, and responses to each developed through survey, literature review and discussion at the face to face meeting of the MDICT Task Force. Consensus emerged around the necessity to demonstrate proof-of-mechanism and obtain information on key pharmacokinetic aspects of drug behaviour in late preclinical and early clinical trials. However, controversy remains on the extent of in vivo anti-tumour efficacy required to support clinical development of targeted agents. A systematic review of the data in this area would be informative. Further, while objective response in phase I trials may be a favourable signal about the potential activity of a new agent, debate exists around the weight that should be placed on the observation of stable disease or functional imaging changes in driving drug development decisions in the absence of observing either responses or convincing pharmacodynamic data in phase I. MDICT made a number of recommendations that may aid in future development of targeted agents. [Copyright &y& Elsevier]

Aim: The impact of PTEN status and microsatellite instability (MSI) on the prognosis of women with endometrial cancer is controversial. The aim of this study was to investigate MSI and PTEN expression in two patient populations using data from NCIC CTG studies. Methods: Archival paraffin embedded tumour from women with endometrial cancer enrolled in NCIC CTG studies: EN5 (stage I/II) and IND 126, 148 and 160 (advanced/recurrent disease) were examined for MSI using BAT25/26 and for PTEN expression using immunohistochemistry. PTEN and MSI status were correlated with clinicopathologic variables and survival using data from NCIC CTG trial databases. Results: PTEN and MSI results were available from 128 and 163 patients, respectively. MSI+ tumours were more common in women enrolled in EN5 compared to the IND studies (p =0.01). PTEN negative tumours were associated with improved survival in both univariate (hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.32–0.94; p =0.03) and multivariate (adjusted HR 0.54, 95% CI 0.30–0.96; p =0.03) analyses in women enrolled in IND studies. Microsatellite stable tumours were associated with an improved prognosis in univariate (HR 0.18, 95% CI 0.06–0.51; p <0.0001) and multivariate (adjusted HR 0.16, 95% CI 0.05–0.5; p <0.0001) analyses in women enrolled in EN5. There was no significant correlation between MSI and PTEN status. Conclusions: PTEN negative tumours in women with advanced disease are associated with improved survival. MSI+ tumours are more common in early stage disease and in this group of women are associated with a worse prognosis. [Copyright &y& Elsevier]

Summary: Background: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. Methods: Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353. Findings: Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27·2% (95% CI 22·2–32·5) at 2 years, 16·0% (12·0–20·6) at 3 years, 12·1% (8·5–16·4) at 4 years, and 9·8% (6·4–14·0) at 5 years with temozolomide, versus 10·9% (7·6–14·8), 4·4% (2·4–7·2), 3·0% (1·4–5·7), and 1·9% (0·6–4·4) with radiotherapy alone (hazard ratio 0·6, 95% CI 0·5–0·7; p<0·0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60–70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. Interpretation: Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. Funding: EORTC, NCIC, Nélia and Amadeo Barletta Foundation, Schering-Plough. [Copyright &y& Elsevier]

Abstract: Background: After the initial RECIST 1.0 were published in 2000, the criteria were widely implemented in the scientific oncology community. Since then, the RECIST working group has identified several issues to examine further. Two key issues that required careful, data-based assessment were the maximum number of lesions that should be assessed at each evaluation and the added value of requiring confirmation of response. Methods: To address these questions, data were obtained from 16 clinical trials in metastatic cancer, with patients enrolled between 1993 and 2005. A total of 6512 patients were included in the primary analysis dataset, accounting for over 18,000 potential target lesions. Nine percent of the included patients (n =585) had six or more reported target lesions. The response and progression outcomes in the database were calculated using an adjusted RECIST methodology with a maximum of 5 (or 3) target lesions with/without confirmation and this was compared to the original RECIST version 1.0 which required up to 10 target lesions plus confirmation of response. Results: Assessment of 5 lesions per patient led to a difference in best overall response assignment for an estimated 209 (3.2%) patients as compared to RECIST version 1.0. However, these changes did not affect the overall response rate. Progression-free survival was only minimally affected by measuring fewer lesions. In contrast, removing the requirement for response confirmation led to a significant increase in the numbers of patients classified as responders, resulting in a relative increase of approximately 19% in response rate. An algorithm using a maximum of three target lesions shows high concordance with the 10 lesions requirement in terms of response and TTP assignment. Concern that appropriate assessment of disease within an organ requires two lesions to be followed per organ suggests the approach of following two target lesions per organ, up to a maximum of five target lesions overall. Both strategies seem reasonable based on the data warehouse. The requirement of response confirmation in trials where this is a primary end-point is recommended to be maintained as its removal would substantially increase reported response rates. [Copyright &y& Elsevier]

Abstract: The Methodology for the Development of Innovative Cancer Therapies (MDICT) task force considered aspects of the design and conduct of phase II studies for molecular targeted agents during their 2007 meeting. The task force recommended that multinomial endpoints and designs should be considered for phase II studies of targeted agents, that both single arm as well as randomised designs remain appropriate in certain settings, and that further assessment of novel endpoints (tumour growth kinetic assessment, biomarker or functional imaging) and designs (randomised discontinuation or Bayesian adaptive design) be encouraged. The MDICT cautioned on the use of small randomised trials which have a number of statistical pitfalls and dangers and strongly encouraged the complete reporting, including negative trials, in the scientific literature. [Copyright &y& Elsevier]

Abstract: Oncology drug development has seen a paradigm shift in the past decade from traditional cytotoxic agents to molecular targeted therapies. Given the different mechanisms and toxicities of these agents, drug development methodology may also require novel approaches. To address emerging issues in oncology drug development the ‘Methodology for the Development of Innovative Cancer Therapies’ (MDICT) task force was established to provide a forum for academic leaders involved in cancer drug development to discuss methodological issues inherent to the study of targeted anticancer therapy. At the inaugural MDICT meeting in 2006, discussion focused on the most appropriate primary endpoints for first-in-man phase I studies of targeted anticancer agents and organisational issues of such studies. This report summarises the scientific reviews and discussions as well as the recommendations regarding phase I trial design formulated by the MDICT task force. [Copyright &y& Elsevier]

Background: A randomised trial published by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) Clinical Trials Group (trial 26981-22981/CE.3) showed that addition of temozolomide to radiotherapy in the treatment of patients with newly diagnosed glioblastoma significantly improved survival. We aimed to undertake an exploratory subanalysis of the EORTC and NCIC data to confirm or identify new prognostic factors for survival in adult patients with glioblastoma, derive nomograms that predict an individual patient's prognosis, and suggest stratification factors for future trials.Methods: Data from 573 patients with newly diagnosed glioblastoma who were randomly assigned to radiotherapy alone or to the same radiotherapy plus temozolomide in the EORTC and NCIC trial were included in this subanalysis. Survival modelling was done in three patient populations: intention-to-treat population of all randomised patients (population 1); patients assigned temozolomide and radiotherapy (population 2, n=287); and patients assigned temozolomide and radiotherapy who had assessment of MGMT promoter methylation status and who had undergone tumour resection (population 3, n=103). Cox proportional hazards models were fitted with and without O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Nomograms were developed to predict an individual patient's median and 2-year survival probabilities. No nomogram was developed in the radiotherapy-alone group because combined treatment is now the new standard of care.Findings: Independent of the MGMT promoter methylation status, analysis in all randomised patients (population 1) identified combined treatment with temozolomide, more extensive tumour resection, younger age, Mini-Mental State Examination (MMSE) score of 27 or higher, and no corticosteroid treatment at baseline as independent prognostic factors correlated with improved survival outcome. In patients assigned temozolomide and radiotherapy (population 2), younger age, better performance status, more extensive tumour resection, and MMSE score of 27 or higher were associated with better survival. In patients who had tumours resected, who were assigned temozolomide and radiotherapy, and who had available MGMT promoter methylation status (population 3), methylated MGMT, better performance status, and MMSE score of 27 or higher were associated with improved survival. Nomograms were developed and are available at http://www.eortc.be/tools/gbmcalculator.Interpretation: MGMT promoter methylation status, age, performance status, extent of resection, and MMSE are suggested as eligibility or stratification factors for future trials in patients with newly diagnosed glioblastoma. Stratifying by MGMT promoter methylation status should be mandatory in all glioblastoma trials that use alkylating chemotherapy. Nomograms can be used to predict an individual patient's prognosis, and they integrate pertinent molecular information that is consistent with a paradigm shift towards individualised patient management. [ABSTRACT FROM AUTHOR]

Summary: Background: A randomised controlled trial of radiotherapy alone versus radiotherapy with concomitant and adjuvant temozolomide for patients with glioblastoma showed that survival was higher for patients assigned combination treatment compared with those assigned standard radiotherapy alone. This paper reports the health-related quality of life (HRQOL) of the patients in this trial. Methods: 573 patients with newly diagnosed glioblastoma were randomly allocated either radiotherapy alone or radiotherapy and temozolomide. The primary endpoint was survival, and HRQOL was a secondary endpoint. We assessed HRQOL at baseline and at every 3 months during treatment until progression using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 (QLQ-C30) and the EORTC brain cancer module (EORTC BN-20). We calculated changes from baseline score for seven predefined HRQOL measures (fatigue, overall health, social function, emotional function, future uncertainty, insomnia, and communication deficit) and differences between groups for these measures at every time point. The significance of, and proportions of patients with, improved HRQOL scores—defined as a change of 10 points or more—were recorded. This trial is registered on the US National Cancer Institute website http://www.cancer.gov/search/NewClinicalTrials, NCT00006353. Findings: Baseline questionnaires were available for 490 (86%) patients. Baseline HRQOL scores did not differ between groups. At first follow-up, groups differed only in social functioning, favouring the radiotherapy-only group (mean score 79·0 [SD 3·2] for patients assigned radiotherapy vs 67·4 [2·7] for those assigned radiotherapy and temozolomide; difference between groups 11·6 points [95% CI 3·5–19·7], p=0·0052). Over subsequent assessments, HRQOL was much the same between treatment groups. Interpretation: Addition of temozolomide during and after radiotherapy for patients with newly diagnosed glioblastoma significantly improved survival without a negative effect on HRQOL. [Copyright &y& Elsevier]