Comparative assessment of early mortality risk upon immune checkpoint inhibitors alone or in combination with other agents across solid malignancies: a systematic review and meta-analysis.

BACKGROUND: The early crossing of survival curves in randomised clinical trials (RCTs) with immune checkpoint blockers suggests an excess of mortality in the first months of treatment. However, the exact estimation of the early death (ED) rate, the comparison between ED upon immune checkpoint inhibitors (ICI) alone or in combination with other agents and the impact of tumour type, and PD-L1 expression on ED are unknown. METHODS: RCTs comparing ICI alone (ICI-only group) or in combination with other non-ICI therapies (ICI-OT group) (experimental arms) versus non-ICI treatments (control arm) were included. ED was defined as death within the first 3 months of treatment. The primary outcome was the comparison of ED between experimental and control arms, and the secondary outcome was the comparison of ED risk between ICI-only and ICI-OT. ED rates estimated by risk ratio (RR) were pooled by random effect model. RESULTS: A total of 56 RCTs (40,215 participants, 14 cancer types) were included. ED occurred in 14.2% and 6.7% of patients in ICI-only and ICI-OT groups, respectively. ED risk significantly increased with ICI-only (RR: 1.29, 95% CI 1.05-1.57) versus non-ICI therapies, while it was lower with ICI-OT versus non-ICI treatments (RR: 0.81, 95% CI 0.73-0.90). ED risk was significantly higher upon ICI-only compared to ICI-OT (RR: 1.57, 95% CI 1.26-1.95). Gastric and urothelial carcinoma were at higher risk of ED. PD-L1 expression and ICI drug classes were not associated with ED. CONCLUSIONS: ED upon first-line ICI is a clinically relevant phenomenon across solid malignancies, not predictable by PD-L1 expression but preventable through the addition of other treatments to ICI.

Assessment of assumptions of statistical analysis methods in randomised clinical trials: the what and how.

When analysing and presenting results of randomised clinical trials, trialists rarely report if or how underlying statistical assumptions were validated. To avoid data-driven biased trial results, it should be common practice to prospectively describe the assessments of underlying assumptions. In existing literature, there is no consensus on how trialists should assess and report underlying assumptions for the analyses of randomised clinical trials. With this study, we developed suggestions on how to test and validate underlying assumptions behind logistic regression, linear regression, and Cox regression when analysing results of randomised clinical trials.Two investigators compiled an initial draftbased on a review of the literature. Experienced statisticians and trialists from eight different research centres and trial units then participated in a anonymised consensus process, where we reached agreement on the suggestions presented in this paper.This paper provides detailed suggestions on 1) which underlying statistical assumptions behind logistic regression, multiple linear regression and Cox regression each should be assessed; 2) how these underlying assumptions may be assessed; and 3) what to do if these assumptions are violated.We believe that the validity of randomised clinical trial results will increase if our recommendations for assessing and dealing with violations of the underlying statistical assumptions are followed.

Supporting Clinical Decision-Making during the SARS-CoV-2 Pandemic through a Global Research Commitment: The TERAVOLT Experience.

To understand the real impact of COVID-19 on cancer patients, an entirely new data collection effort was initiated within the Thoracic Cancers International COVID-19 Collaboration (TERAVOLT). TERAVOLT reported high mortality related to COVID-19 infection in thoracic cancer patients and identified several negative prognostic factors. In this commentary, we discuss the importance and limits of patient registries to support decision-making in thoracic cancer during the SARS-CoV-2 pandemic.

TERAVOLT: Thoracic Cancers International COVID-19 Collaboration.

Prior publications on small subsets of cancer patients infected with SARS CoV-2 have shown an increased risk of mortality compared to the general population. Furthermore, patients with thoracic malignancies are thought to be at particularly high risk given their older age, smoking habits, and pre-existing cardio-pulmonary comorbidities. For this reason, physicians around the world have formed TERAVOLT, a global consortium dedicated to understanding the impact of COVID-19 on patients with thoracic malignancies.

Prospective observational study on the impact of the 21-gene assay on treatment decisions and resources optimization in breast cancer patients in Lombardy: The BONDX study.

PURPOSE: Adjuvant treatment decisions in early breast cancer (eBC) have traditionally been driven by risk stratification based on clinical and pathological risk factors. The 21-gene Oncotype DX® assay has been validated as a predictive test for benefit from adjuvant chemotherapy (CT), hence assessing its impact in clinical decisions is of high interest. The objective of this study was to estimate the rate of adjuvant treatment decision modification impacted by the Recurrence Score® result, and the consequent budget impact. METHODS: The study was a multicentre, prospective, real-life experience in Lombardy (Italy) including consecutive patients with T1-T3, N0-N1a, and ER+/HER2-eBC with clinical-pathologic "intermediate risk" of relapse. The change in treatment recommendations was assessed before and after availability of Recurrence Score result. A budget model evaluated the implications of 21-gene testing in the study population. RESULTS: The overall proportion of CT recommendations was reduced from 24.6% to 15.2% after 21-gene testing, with a major impact in patients initially considered for CT plus hormone therapy (CHT). In these patients, the total budget was reduced, leading to a net saving of -€81,017. The greater the physician propensity to prescribe CHT, the higher the potential savings for the health system from sparing CT in most tested patients. CONCLUSIONS: Our real-life experience suggests that all intermediate-risk ER+/HER2-eBC patients who are initially deemed candidates for CHT should be tested with the 21-gene test. The potential to spare CT in at least half of them offers relevant advantages for patients and national health services.

Assessment of proportional hazard assumption in aggregate data: a systematic review on statistical methodology in clinical trials using time-to-event endpoint.

BACKGROUND: The evaluation of the proportional hazards (PH) assumption in survival analysis is an important issue when Hazard Ratio (HR) is chosen as summary measure. The aim is to assess the appropriateness of statistical methods based on the PH assumption in oncological trials. METHODS: We selected 58 randomised controlled trials comparing at least two pharmacological treatments with a time-to-event as primary endpoint in advanced non-small-cell lung cancer. Data from Kaplan-Meier curves were used to calculate the relative hazard at each time point and the Restricted Mean Survival Time (RMST). The PH assumption was assessed with a fixed-effect meta-regression. RESULTS: In 19% of the trials, there was evidence of non-PH. Comparison of treatments with different mechanisms of action was associated (P = 0.006) with violation of the PH assumption. In all the superiority trials where non-PH was detected, the conclusions using the RMST corresponded to that based on the Cox model, although the magnitude of the effect given by the HR was systematically greater than the one from the RMST ratio. CONCLUSION: As drugs with new mechanisms of action are being increasingly employed, particular attention should be paid on the statistical methods used to compare different types of agents.

Brain Gliomas: Multicenter Standardized Assessment of Dynamic Contrast-enhanced and Dynamic Susceptibility Contrast MR Images.

Purpose To evaluate the feasibility of a standardized protocol for acquisition and analysis of dynamic contrast material-enhanced (DCE) and dynamic susceptibility contrast (DSC) magnetic resonance (MR) imaging in a multicenter clinical setting and to verify its accuracy in predicting glioma grade according to the new World Health Organization 2016 classification. Materials and Methods The local research ethics committees of all centers approved the study, and informed consent was obtained from patients. One hundred patients with glioma were prospectively examined at 3.0 T in seven centers that performed the same preoperative MR imaging protocol, including DCE and DSC sequences. Two independent readers identified the perfusion hotspots on maps of volume transfer constant (Ktrans), plasma (vp) and extravascular-extracellular space (ve) volumes, initial area under the concentration curve, and relative cerebral blood volume (rCBV). Differences in parameters between grades and molecular subtypes were assessed by using Kruskal-Wallis and Mann-Whitney U tests. Diagnostic accuracy was evaluated by using receiver operating characteristic curve analysis. Results The whole protocol was tolerated in all patients. Perfusion maps were successfully obtained in 94 patients. An excellent interreader reproducibility of DSC- and DCE-derived measures was found. Among DCE-derived parameters, vp and ve had the highest accuracy (are under the receiver operating characteristic curve [Az] = 0.847 and 0.853) for glioma grading. DSC-derived rCBV had the highest accuracy (Az = 0.894), but the difference was not statistically significant (P > .05). Among lower-grade gliomas, a moderate increase in both vp and rCBV was evident in isocitrate dehydrogenase wild-type tumors, although this was not significant (P > .05). Conclusion A standardized multicenter acquisition and analysis protocol of DCE and DSC MR imaging is feasible and highly reproducible. Both techniques showed a comparable, high diagnostic accuracy for grading gliomas. © RSNA, 2018 Online supplemental material is available for this article.

High-grade soft-tissue sarcomas: tumor response assessment--pilot study to assess the correlation between radiologic and pathologic response by using RECIST and Choi criteria.

PURPOSE: To compare radiologic response as defined according to both Response Evaluation Criteria in Solid Tumors (RECIST) and the new Choi criteria recently proposed for gastrointestinal stromal tumors with pathologic response in high-grade soft-tissue sarcomas (STSs) treated with preoperative chemotherapy and radiation therapy. MATERIALS AND METHODS: The institutional ethical committee approved the trial in which patients were enrolled. Signed informed consent was obtained. Thirty-seven patients (21 men, 16 women; mean age, 44.2 years) enrolled in a collaborative randomized trial on preoperative chemotherapy and radiation therapy in localized high-risk STS at a single institution were selected for this retrospective analysis. Tumor response to preoperative treatment was assessed by using both RECIST and Choi criteria at computed tomography (CT) and was adapted to be used at magnetic resonance (MR) imaging. Pathologic response was assessed as either good or very good. Sensitivity, specificity, and predictive value of RECIST and Choi criteria were calculated with pathologic response as the reference standard and were reported with 95% confidence intervals. RESULTS: For 28 patients without synovial sarcomas, sensitivity of RECIST versus adapted Choi criteria was 32.0% versus 88.0% for good response and 41.2% versus 82.4% for very good response, respectively; specificity for pathologic response was 100% versus 100% for not a good response and 90.9% versus 27.3% for not a very good response, respectively. In synovial sarcoma, the nontreatment-related neoplastic cystic component of the tumor was a major obstacle for both RECIST and Choi criteria. CONCLUSION: In STS treated with chemotherapy and radiation therapy, tumor size may be insufficient to render actual tumor response. Tumor attenuation at CT or tumor contrast material enhancement at MR imaging may complement tumor size, thus making Choi criteria more predictive of pathologic response.

Cost of insurance policies for investigator-initiated cancer clinical trials in Italy.

BACKGROUND: Clinical trials with non-profit promoters are frequently performed in oncology and represent a highly valuable source of information. METHODS: To describe the costs of insurance policies and their determinants, data were collected from 12 Italian non-profit promoters of cancer trials. The cost of policies was expressed as per-patient premium. RESULTS: Sixty-two quotations issued by only two companies were collected, relative to 44 trials proposed for quotation between December 1998 and February 2003. Only the date of quotation was significantly associated with the cost (P = 0.0003) of quotations by Company A for policies with a deductible, with cost increasing over time. Date of quotation (P = 0.0002), sample size (P = 0.008) and number of study arms (P = 0.02) were independently associated with the cost of no-deductible policies quoted by Company A. Only the number of study arms was significantly associated with cost (P = 0.0001) in no-deductible policies quoted by Company B. CONCLUSION: There is insufficient competition among companies for insurance of cancer trials with non-profit promoters. Many variables that affect the trial risk profile from a clinical perspective are not associated with insurance cost. Date of quotation is among the strongest determinants of the cost, which has sharply increased over time. This trend may become a serious problem for non-profit promoters of cancer clinical trials.

the impact of definition of primary open-angle glaucoma on the cross-sectional assessment of diagnostic validity of Heidelberg retinal tomography.

PURPOSE: To evaluate the impact of different definitions of primary open angle glaucoma (POAG) on assessment of the diagnostic validity of Heidelberg Retinal Tomography (HRT). DESIGN: Retrospective, cross-sectional study. METHODS: A search of medline (1992-2003) led to the retrieval of 181 papers containing definitions of POAG, including the eight visual field (VF)-based definitions used for this study. A sample of 193 normal subjects, 222 patients with suspected POAG, and 103 with POAG underwent HRT and the 24 II Humphrey VF examinations to assess the diagnostic validity of HRT. POAG was defined on the basis of Glaucoma Hemifield Test (GHT) "out of normal limits" associated with corrected pattern standard deviation (CPSD) > 2 dB and intraocular pressure (IOP) > or =22 mm Hg. The VFs were re-analyzed and categorized according to the other eight definitions of POAG: IOP formed part of all the definitions, whereas the appearance of the optic disk did not. The sensitivity and specificity of each scenario were calculated by standard procedures. RESULTS: The definitions of POAG found in the literature included 17 IOP criteria, more than 15 optic disk criteria, and more than 30 VF criteria. The sensitivity of HRT ranged from 0.51 to 0.80, and its specificity from 0.94 and 0.95 when the patients with suspected POAG were excluded; diagnostic validity was much lower and still variable when the POAG suspects were included with the normal or the POAG groups. CONCLUSIONS: The most commonly used VF-based definitions of POAG led to substantial differences in the sensitivity and specificity of HRT when using the same large sample of normal subjects and POAG patients. A standard definition of POAG is needed to make diagnostic investigations more accurate and comparable.