Integration of Translational Research in the European Organization for Research and Treatment of Cancer Research (EORTC) Clinical Trial Cooperative Group Mechanisms

The landscape for cancer research is profoundly different today from that only one decade ago. Basic science is moving rapidly and biotechnological revolutions in molecular targeting and immunology have completely modified the opportunities and concepts for cancer treatment. In contrast to the recent past where cytotoxic molecules were screened in the laboratory and then tested in early clinical studies with toxicity as endpoint instead of the often poorly defined mechanism for its potential anti-tumor effect, we now have entered the age of molecular therapeutics, rationally designed to target "strategic" checkpoints that underlie the malignant phenotype. Translational research in early clinical trials (Phase I and II) is an integral aspect of the development of the new generation of cancer drugs as it is necessary to implement radically different early phase clinical trial design and to validate new biological end-points if the full potential of these new agents is to be realized. The "proof of principle with mechanistic analysis" strategy will allow optimisation of therapy from the beginning, and provide important feedback to pre-clinical drug developers. Translational research is also essential in late (phase III) clinical trials in defining different patient populations that may benefit to differing degrees from new treatments, and thus provide further insight and refine clinical practice in a more and more patient-tailored approach. In this editorial we will discuss the integration of Translational Research in the Organization for Research and Treatment of Cancer (EORTC)

Response assessment in cancer clinical trials

Most anticancer agents developed over the last four decades are cytotoxic drugs inducing tumor regression, sometimes also resulting in prolongation of survival. Historically, the direct therapeutic efficacy of such treatments has been monitored through successive evaluations of the tumor burden quantified through the measurement of the size of tumor lesions that were clinically or radiologically evaluable. By the end of the 1970’s, a group of breast cancer specialists, under the auspices of International Union Against Cancer (UICC), set the principles under which response to treatment in breast cancer should be evaluated. This work was subsequently adopted and integrated into the recommendations set by the World Health Organisation (WHO) for the evaluation of cancer treatment in solid tumors. After 1981, many new anticancer drugs have been developed, and many researchers have also started to investigate different combinations of treatments. The experience acquired over the years and the lack of details in the WHO recommendations has stimulated the development of modified versions of the WHO criteria. Over the years, the use of the different versions of the original WHO criteria have rendered the accuracy of the relative comparison of the results of investigations based on the same therapy very unreliable. The evolution of cancer imaging, the importance given to “response rate” as an endpoint of early clinical trials and the rapidly increasing number of new anticancer agents to be tested have also justified the initiative to revisit, update the existing response criteria. This thesis focuses on the development and the implementation of a new set of response criteria (RECIST)

INCIDENCE AND PREVENTION OF DEEP VEIN THROMBOSIS IN RESTRAINED PSYCHIATRIC PATIENTS

Background: Although physical restraint is still used in psychiatric inpatient settings, it sometimes causes serious side effects, including deep vein thrombosis (DVT) and resulting pulmonary embolism. The aim of this study was to review the literature investigating the incidence of the DVT in restrained psychiatric patients, to identify the risk factors of this condition and the effectiveness of routine prophylaxis. Subjects and methods: Studies investigating associations between deep vein thrombosis and restrained psychiatric patients were searched in the Pubmed database. More than 700 articles were sorted independently by two of the authors using predefined criteria. Only research articles, reviews and meta-analyses were selected for this review. Results: 5 articles published between 2010 and 2016 were selected. Although antipsychotics and restrain are known to be thrombogenenic, in all retrospective studies, with anticoagulant prophylaxis for those restrained for more than 12 or 24 h, incidence of DVT in restrained psychiatric patients was almost not existent. Controversially, in a comparative study by Ishida, although deep sedation and physical comorbidities were associated with the occurrence of DVT, not using of anticoagulants was not associated with any increased incidence of DVT. DVT may be overlooked because psychiatric patients are often unaware of leg symptoms because of their psychiatric disease and induced sedation. Furthermore most DVT, in particular distal DVT are asymptomatic. When screened and assessed with more appropriate methods such as plasma D Dimer and ultrasound scanning the incidence of DVT reaches 11.6%. Conclusion: The incidence of DVT in restrained psychiatric patients was not low in spite of prophylaxis. These findings emphasize the importance of regular screening of and thorough assessments of DVT, especially in restrained psychiatric patients

INCIDENCE AND PREVENTION OF DEEP VEIN THROMBOSIS IN RESTRAINED PSYCHIATRIC PATIENTS

Background: Although physical restraint is still used in psychiatric inpatient settings, it sometimes causes serious side effects, including deep vein thrombosis (DVT) and resulting pulmonary embolism. The aim of this study was to review the literature investigating the incidence of the DVT in restrained psychiatric patients, to identify the risk factors of this condition and the effectiveness of routine prophylaxis. Subjects and methods: Studies investigating associations between deep vein thrombosis and restrained psychiatric patients were searched in the Pubmed database. More than 700 articles were sorted independently by two of the authors using predefined criteria. Only research articles, reviews and meta-analyses were selected for this review. Results: 5 articles published between 2010 and 2016 were selected. Although antipsychotics and restrain are known to be thrombogenenic, in all retrospective studies, with anticoagulant prophylaxis for those restrained for more than 12 or 24 h, incidence of DVT in restrained psychiatric patients was almost not existent. Controversially, in a comparative study by Ishida, although deep sedation and physical comorbidities were associated with the occurrence of DVT, not using of anticoagulants was not associated with any increased incidence of DVT. DVT may be overlooked because psychiatric patients are often unaware of leg symptoms because of their psychiatric disease and induced sedation. Furthermore most DVT, in particular distal DVT are asymptomatic. When screened and assessed with more appropriate methods such as plasma D Dimer and ultrasound scanning the incidence of DVT reaches 11.6%. Conclusion: The incidence of DVT in restrained psychiatric patients was not low in spite of prophylaxis. These findings emphasize the importance of regular screening of and thorough assessments of DVT, especially in restrained psychiatric patients

Clinical validation of a software for quantitative follow-up of abdominal aortic aneurysm maximal diameter and growth by CT angiography

Purpose To compare the reproducibility and accuracy of abdominal aortic aneurysm (AAA) maximal diameter (D-max) measurements using segmentation software, with manual measurement on double-oblique MPR as a reference standard. Materials and methods The local Ethics Committee approved this study and waived informed consent. Forty patients (33 men, 7 women; mean age, 72 years, range, 49–86 years) had previously undergone two CT angiography (CTA) studies within 16 ± 8 months for follow-up of AAA ≥35 mm without previous treatment. The 80 studies were segmented twice using the software to calculate reproducibility of automatic D-max calculation on 3D models. Three radiologists reviewed the 80 studies and manually measured D-max on double-oblique MPR projections. Intra-observer and inter-observer reproducibility were calculated by intraclass correlation coefficient (ICC). Systematic errors were evaluated by linear regression and Bland–Altman analyses. Differences in D-max growth were analyzed with a paired Student's t-test. Results The ICC for intra-observer reproducibility of D-max measurement was 0.992 (≥0.987) for the software and 0.985 (≥0.974) and 0.969 (≥0.948) for two radiologists. Inter-observer reproducibility was 0.979 (0.954–0.984) for the three radiologists. Mean absolute difference between semi-automated and manual D-max measurements was estimated at 1.1 ± 0.9 mm and never exceeded 5 mm. Conclusion Semi-automated software measurement of AAA D-max is reproducible, accurate, and requires minimal operator intervention

The epidemiology of pseudallescheriasis complicating transplantation: Nosocomial and community‐acquired infection

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141586/1/myc1990336296.pd

The value of source data verification in a cancer clinical trial

Background Source data verification (SDV) is a resource intensive method of quality assurance frequently used in clinical trials. There is no empirical evidence to suggest that SDV would impact on comparative treatment effect results from a clinical trial. Methods Data discrepancies and comparative treatment effects obtained following 100% SDV were compared to those based on data without SDV. Overall survival (OS) and Progression-free survival (PFS) were compared using Kaplan-Meier curves, log-rank tests and Cox models. Tumour response classifications and comparative treatment Odds Ratios (ORs) for the outcome objective response rate, and number of Serious Adverse Events (SAEs) were compared. OS estimates based on SDV data were compared against estimates obtained from centrally monitored data. Findings Data discrepancies were identified between different monitoring procedures for the majority of variables examined, with some variation in discrepancy rates. There were no systematic patterns to discrepancies and their impact was negligible on OS, the primary outcome of the trial (HR (95% CI): 1.18(0.99 to 1.41), p = 0.064 with 100% SDV; 1.18(0.99 to 1.42), p = 0.068 without SDV; 1.18(0.99 to 1.40), p = 0.073 with central monitoring). Results were similar for PFS. More extreme discrepancies were found for the subjective outcome overall objective response (OR (95% CI): 1.67(1.04 to 2.68), p = 0.03 with 100% SDV; 2.45(1.49 to 4.04), p = 0.0003 without any SDV) which was mostly due to differing CT scans. Interpretation Quality assurance methods used in clinical trials should be informed by empirical evidence. In this empirical comparison, SDV was expensive and identified random errors that made little impact on results and clinical conclusions of the trial. Central monitoring using an external data source was a more efficient approach for the primary outcome of OS. For the subjective outcome objective response, an independent blinded review committee and tracking system to monitor missing scan data could be more efficient than SDV

Designing exploratory cancer trials using change in tumour size as primary endpoint

In phase III cancer clinical trials, overall survival is commonly used as the definitive endpoint. In phase II clinical trials, however, more immediate endpoints such as incidence of complete or partial response within 1 or 2 months or progression-free survival (PFS) are generally used. Because of the limited ability to detect change in overall survival with response, the inherent variability of PFS and the long wait for progression to be observed, more informative and immediate alternatives to overall survival are desirable in exploratory phase II trials. In this paper, we show how comparative trials can be designed and analysed using change in tumour size as the primary endpoint. The test developed is based on the framework of score statistics and will formally incorporate the information of whether patients survive until the time at which change in tumour size is assessed. Using an example in non-small cell lung cancer, we show that the sample size requirements for a trial based on change in tumour size are favourable compared with alternative randomized trials and demonstrate that these conclusions are robust to our assumptions

Osteoblastic flare in a patient with advanced gastric cancer after treatment with pemetrexed and oxaliplatin: implications for response assessment with RECIST criteria

<p>Abstract</p> <p>Background</p> <p>The RECIST guidelines are commonly used in phase II and III clinical trials. The correct definition of response can be controversial in some situations, as in the case we describe.</p> <p>Case presentation</p> <p>A 43 year-old man with advanced gastric cancer was enrolled in a phase II trial where he was treated with pemetrexed 500 mg/m²plus oxaliplatin 120 mg/m²every 3 weeks. At baseline, the target lesions were lymph-nodes, and the non-target lesions were small pulmonary nodules. At first re-evaluation, the target lesions showed partial response and the non-target lesions showed complete response, but new diffuse osteoblastic lesions appeared. The investigator decided to continue treatment until the second re-evaluation. CT scan confirmed the response of the target and non-target lesions, while the osteoblastic lesions did not change.</p> <p>Conclusion</p> <p>The appearance of osteoblastic lesions after an active antitumor treatment, a phenomenon known as flare, can complicate the definition of the best overall response using RECIST criteria. This possibility should be considered by oncologists involved in clinical trials.</p

Phase II trial of biweekly gemcitabine and paclitaxel with recurrent or metastatic squamous cell carcinoma of the head and neck: Southwest Oncology Group study S0329

Background A phase I study and an institutional pilot study in patients with metastatic/recurrent squamous cell carcinoma of the head and neck (SCCHN) utilizing biweekly gemcitabine and paclitaxel (GEMTAX), showed an overall response rate of 53%. 1 This phase II trial was conducted to determine the feasibility, tolerability, and efficacy of this combination. Methods Patients with metastatic/recurrent SCCHN were treated with gemcitabine (3000 mg/m2) and paclitaxel (150 mg/m2) on days 1 and 15 of every 28‐day cycle. Results In 57 patients with measurable disease, median progression‐free survival (PFS) was 4 months and median overall survival (OS) was 8 months. Overall response rate of 28% and disease stabilization in 19% were seen. There were no treatment‐related deaths with grade 3/4 hematologic toxicity seen in 20% of the patients. Conclusion Biweekly GEMTAX is feasible, well tolerated, and demonstrated reasonable efficacy. This may be an alternative for patients who are not candidates for platinum‐based chemotherapy. © 2014 Wiley Periodicals, Inc. Head Neck 36: 1712–1717, 2014Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109649/1/hed23522.pd