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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]

We undertook a phase I/II study of the EGFR/erbB2 inhibitor lapatinib in patients with recurrent glioblastoma multiforme (GBM) to determine response rate, pharmacokinetics (PK) and recommended dose in patients taking enzyme-inducing anti-epileptic drugs (EIAEDs) and to explore relationships of molecular genetics to outcome. Recurrent GBM patients taking EIAEDs were enrolled on the phase I portion (starting dose of lapatinib 1,000 mg po bid). In the absence of dose-limiting toxicity (DLT), escalation continued in cohorts of three patients. Patients not on EIAEDs enrolled in the phase II arm (lapatinib 750 mg bid po). Immunohistochemical and quantitative RT PCR studies were performed on tumor to determine PTEN and EGFRvIII status, respectively. Lapatinib PK was analyzed using HPLC with tandem mass spectrometry. Phase II: Of 17 patients, 4 had stable disease and 13 progressed. Accrual ceased because of no responses. Phase I: Four patients received 1,000 mg bid and three, 1,500 mg bid. No DLT occurred, but escalation stopped because of lack of phase II efficacy. Lapatinib apparent oral clearance in patients taking EIAEDs was 106.9 L h−1 m−2 in comparison to 12.1 L h−1 m−2 in those not on EIAEDs. In 16 phase II patients, PTEN loss was seen in 6 and EGFRvIII expression in 4. No correlation was seen with outcome and molecular results. Lapatinib apparent oral clearance increased by approximately tenfold when given with EIAEDs. In this small sample, EGFRvIII expression and PTEN loss did not predict a favorable subtype. Overall, lapatinib did not show significant activity in GBM patients. [ABSTRACT FROM AUTHOR]

RECIST (response evaluation criteria in solid tumours) uses a unidimensional approach to tumour measurement and has been widely adopted for assessing the response rate of new therapies in solid tumour clinical trials. For lymphoma, the IWC (International Workshop Criteria), based on bidimensional product assessment, is generally utilised. We adapted RECIST for use in lymphoma and compared responses with the IWC in three Phase II lymphoma trials (n = 115). Measures of agreement estimated the concordance between the adapted RECIST and the IWC response assessments. A Pearson's coefficient estimated the correlation between changes in uni- and bidimensional measurements in a subset of patients (n = 75). All measures of agreement were very high [κ = 0.86 (95% CI: 0.76 - 0.95), percent agreement 0.93 (95% CI: 0.87 - 0.97), positive agreement 0.90 (95% CI: 0.87 - 0.98), negative agreement 0.92 (95% CI: 0.89 - 0.98)]. Pearson's coefficient was 0.92 (95% CI: 0.87, 0.95). The lymphoma-adapted RECIST is simpler to apply than the IWC and yields near identical response rates. The adapted RECIST should be considered for inclusion into any new draft of the IWC. [ABSTRACT FROM AUTHOR]

Summarizes the issues discussed at the workshop 10th National Cancer Institute-European Organization for Research and Treatment of Cancer Symposium on New Drugs in Cancer Therapy held in the United States. Preclinical assessment; Phase I trial design of an anticancer drug; Lessons from nononcology drugs.

Explains the Gynaecologic Cancer Intergroup's stand that definitions for response and progression of ovarian cancer according to serum CA 125 levels should be incorporated into ovarian cancer clinical trial protocols for relapse therapy. Definition of response; Rules for calculating CA 125 levels; Recommendation that CA 125 measurements be taken at specific time intervals.

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]

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]

Summary: 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. [Copyright &y& Elsevier]