Navigating the landscape of liver cancer management: Study designs in clinical trials and clinical practice.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death worldwide and its prognosis is highly heterogeneous, being related not only to tumour burden but also to the severity of underlying chronic liver disease. Moreover, advances in systemic therapies for HCC have increased the complexity of patient management. Randomised-controlled trials represent the gold standard for evidence generation across all areas of medicine and especially in the oncology field, as they allow for unbiased estimates of treatment effect without confounders. Observational studies have many problems that could reduce their internal and external validity. However, large prospective (well-conducted) observational real-world studies can detect rare adverse events or monitor the occurrence of long-term adverse events. How best to harness real world data, which refers to data generated from the routine care of patients, and real-world 'evidence', which is the evidence generated from real-world data, represents an open challenge. In this review article, we aim to provide an overview of the benefits and limitations of different study designs, particularly focusing on randomised-controlled trials and observational studies, to address important and not fully resolved questions in HCC research.

Risk factors for more rapid progression of severe liver fibrosis in children with cystic fibrosis-related liver disease: A multi-center study validated by liver biopsy.

BACKGROUND AND AIMS: Early identification of risk factors for the development of severe fibrosis in children with cystic fibrosis-related liver disease (CFLD) is crucial as promising therapies emerge. METHODS: This multi-center cohort study of children with a priori defined CFLD from 1999 to 2016, was designed to evaluate the clinical utility of CF-specific characteristics and liver biomarkers assessed years prior to liver biopsy-proven CFLD to predict risk of developing severe fibrosis (F3-4) over time. Fibrosis was staged by Metavir classification. RESULTS: The overall study cohort of 42 patients (F0-2 (n = 22) and F3-4 (n = 20)) was 57% male (n = 24) with median age of 7.6 years at baseline visit versus 10.3 years at biopsy. Median FEV1 % predicted was lower in F3-4 participants at baseline versus F0-2 (59% vs. 85%; p = .002), while baseline FIB-4, APRI and GGT were higher in F3-4. Median splits for FIB-4 (≥.13), APRI (≥.36), GPR (≥.09), GGT (≥25.5), and FEV1 % (<64%) were associated with more rapid progression to F3-4 (p < .01 for all). Using a combination of change/year in FIB-4, APRI, and GPR to predict F3-4, the AUROC was .81 (95% CI, .66, .96; p < .0001). For up to 5.8 years prior, thresholds for GPR were met 6.5-fold more rapidly, and those for APRI and FIB-4 were met 2.5-fold more rapidly, in those who progressed to F3-4 than those that did not. CONCLUSIONS: This study suggests mild-moderate pulmonary dysfunction and higher liver biomarker indices at baseline may be associated with faster progression of CFLD.

Estimating the distribution of ratio of paired event times in phase II oncology trials.

With the rapid development of new anti-cancer agents which are cytostatic, new endpoints are needed to better measure treatment efficacy in phase II trials. For this purpose, Von Hoff (1998) proposed the growth modulation index (GMI), that is, the ratio between times to progression or progression-free survival times in two successive treatment lines. An essential task in studies using GMI as an endpoint is to estimate the distribution of GMI. Traditional methods for survival data have been used for estimating the GMI distribution because censoring is common for GMI data. However, we point out that the independent censoring assumption required by traditional survival methods is always violated for GMI, which may lead to severely biased results. In this paper, we construct both nonparametric and parametric estimators for the distribution of GMI, accounting for the dependent censoring of GMI. Extensive simulation studies show that our nonparametric estimators perform well in practical situations and outperform existing estimators, and our parametric estimators perform better than our nonparametric estimators and existing estimators when the parametric model is correctly specified. A phase II clinical trial using GMI as the primary endpoint is provided for illustration.

Inappropriate Expression of PD-1 and CTLA-4 Checkpoints in Myeloma Patients Is More Pronounced at Diagnosis: Implications for Time to Progression and Response to Therapeutic Checkpoint Inhibitors.

Multiple myeloma (MM) is a hematologic malignancy characterized by severely profound immune dysfunction. Therefore, the efficacy of drugs targeting the immune environments, such as immune checkpoint inhibitors (ICIs), is of high clinical importance. However, several clinical trials evaluating ICIs in MM in different therapeutic combinations revealed underwhelming results showing a lack of clinical efficacy and excessive side effects. The underlying mechanisms of resistance to ICIs observed in the majority of MM patients are still under investigation. Recently, we demonstrated that inappropriate expression of PD-1 and CTLA-4 on CD4 T cells in active MM is associated with adverse clinical outcomes and treatment status. The aim of the current study was to determine the usefulness of immune checkpoint expression assessment as a predictive biomarker of the response to therapeutic inhibitors. For this purpose, along with checkpoint expression estimated by flow cytometry, we evaluated the time to progression (TTP) of MM patients at different clinical stages (disease diagnosis and relapse) depending on the checkpoint expression level; the cut-off point (dividing patients into low and high expressors) was selected based on the median value. Herein, we confirmed the defective levels of regulatory PD-1, CTLA-4 receptors, and the CD69 marker activation in newly diagnosed (ND) patients, whereas relapsed/refractory patients (RR) exhibited their recovered values and reactivity. Additionally, substantially higher populations of senescent CD4+CD28- T cells were found in MM, primarily in NDMM subjects. These observations suggest the existence of two dysfunctional states in MM CD4 T cells with the predominance of immunosenescence at disease diagnosis and exhaustion at relapse, thus implying different responsiveness to the external receptor blockade depending on the disease stage. Furthermore, we found that lower CTLA-4 levels in NDMM patients or higher PD-1 expression in RRMM patients may predict early relapse. In conclusion, our study clearly showed that the checkpoint level in CD4 T cells may significantly affect the time to MM progression concerning the treatment status. Therefore, when considering novel therapies and potent combinations, it should be taken into account that blocking PD-1 rather than CTLA-4 might be a beneficial form of immunotherapy for only a proportion of RRMM patients.

Factors Associated with Time to Progression and Overall Survival in Patients with De Novo Metastatic Breast Cancer: A Colombian Cohort.

PURPOSE: About 10% of breast cancer (BC) is diagnosed in stage IV. This study sought to identify factors associated with time to progression (TTP) and overall survival (OS) in a cohort of patients diagnosed with de novo metastatic breast cancer (MBC), from a single cancer center in Colombia, given that information on this aspect is limited. METHODOLOGY: An observational, analytical, and retrospective cohort study was carried out. Time to progression and OS rates were estimated using the Kaplan-Meier survival functions. Cox models were developed to assess association between time to progression and time to death, using a group of fixed variables. RESULTS: Overall, 175 patients were included in the study; 33.7% of patients had luminal B HER2-negative tumors, 49.7% had bone involvement, and 83.4% had multiple metastatic sites. Tumor biology and primary tumor surgery were the variables associated with TTP and OS. Patients with luminal A tumors had the lowest progression and mortality rates (10 per 100 patients/year (95% CI: 5.0-20.0) and 12.6 per 100 patients/year (95% CI: 6.9-22.7), respectively), and patients with triple-negative tumors had the highest progression and mortality rates (40 per 100 patients/year (95% CI: 23.2-68.8) and 44.1 per 100 patients/year (95% CI: 28.1-69.1), respectively). Across the cohort, the median TTP was 2.1 years (95% CI: 1.6; the upper limit cannot be reached) and the median OS was 2.4 years (95% CI: 2-4.3). CONCLUSIONS: In this cohort, patients with luminal A tumors and those who underwent tumor surgery given that they presented clinical benefit (CB) after initial systemic treatment, had the lowest progression and mortality rates. Overall, OS was inferior to other series due to high tumor burden and difficulties in accessing and continuing oncological treatments.

Ten-Year Survivorship in Patients with Metastatic Gastrointestinal Stromal Tumors.

INTRODUCTION: Patients developing metastatic gastrointestinal stromal tumors (mGIST) have heterogenous disease biology and oncologic outcomes; prognostic factors are incompletely characterized. We sought to evaluate predictors of 10-year metastatic survivorship in the era of tyrosine kinase inhibitor (TKI) therapy. METHODS: We reviewed patients with mGIST treated at our Comprehensive Cancer Center from 2003 to 2019, including only patients with either mortality or 10 years of follow-up. Ten-year survivorship was evaluated with logistic regression. RESULTS: We identified 109 patients with a median age of 57 years at mGIST diagnosis. Synchronous disease was present in 57% (n = 62) of patients; liver (n = 48, 44%), peritoneum (n = 40, 37%), and liver + peritoneum (n = 18, 17%) were the most common sites. Forty-six (42%) patients were 10-year mGIST survivors. Following mGIST diagnosis, radiographic progression occurred within 2 years in 53% (n = 58) of patients, 2-5 years in 16% (n = 17), and 5-10 years in 16% (n = 17), with median survival of 32, 76, and 173 months, respectively. Seventeen (16%) patients had not progressed by 10 years. Fifty-two (47%) patients underwent metastasectomy, which was associated with improved progression-free survival (hazard ratio 0.63, p = 0.04). In patients experiencing progression, factors independently associated with 10-year survivorship were age (odds ratio [OR] 0.96, p = 0.03) and time to progression (OR 1.71/year, p < 0.001). CONCLUSIONS: Ten-year survivorship is achievable in mGIST in the era of TKIs and is associated with younger age and longer time to first progression, while metastasectomy is associated with longer time to first progression. The role of metastasectomy in the management of patients with disease progression receiving TKI therapy merits further study.

Single medium-sized hepatocellular carcinoma treated with sequential conventional transarterial chemoembolization (cTACE) and microwave ablation at 4 weeks versus cTACE alone: a propensity score.

BACKGROUND: Microwave ablation (MWA) is a potentially curative treatment for unresectable patients with hepatocellular carcinoma (HCC) ≤ 3 cm, while its therapeutic efficacy decreases significantly for HCC > 3cm. Previous studies have demonstrated that conventional transarterial chemoembolization (cTACE) combined with MWA (cTACE-MWA) may improve local tumor control rate and reduce the recurrence rate for HCC > 3cm. However, there have been few study designs to analyze the clinical efficacy of cTACE-MWA for medium-sized HCC (3-5cm). Therefore, this study aims to compare the clinical efficacy and safety of cTACE-MWA with cTACE alone for a single medium-sized HCC of 3-5 cm in diameter. METHODS: We retrospectively investigate the data of 90 patients with a single medium-sized HCC who were referred to our hospital and underwent cTACE-MWA or cTACE alone from December 2017 to March 2020. Then, patients were identified with propensity score-matched (1:1). The local tumor response to treatment and time to progression (TTP) were compared using mRECIST criteria between the cTACE-MWA group and the cTACE group. RESULTS: A total of 42 patients were included after matching (cTACE-MWA: 21; cTACE: 21). Comparing with cTACE, cTACE-MWA demonstrate significantly better local tumor control (ORR: 95.2% vs 61.9%, p = 0.02; DCR: 95.2% vs 66.7%, p = 0.045) and TTP (median 19.8 months vs 6.8 months, p < 0.001). The 1- and 2-year cumulative probabilities of OS were 100% and 95% in the cTACE-MWA group, which were significantly higher than those in the cTACE group (95% and 76%) (p = 0.032). Multivariate Cox regression analysis illustrates that cTACE-MWA was associated with better TTP (hazard ratio, 0.28; 95% CI: 0.1, 0.76; p = 0.012), but tumor size was associated with worse TTP (hazard ratio, 1.71; 95% CI: 1.01, 2.89; p = 0.045). CONCLUSIONS: cTACE followed by MWA improved TTP and OS in patients with a single medium-sized HCC, and no major complication was observed in this study.

Estimation of time to progression and post progression survival using joint modeling of summary level OS and PFS data with an ordinary differential equation model.

measures such as progression-free survival (PFS) and overall survival (OS) are commonly reported in literature for oncology trials, while time to progression (TTP) and post progression survival (PPS) are not usually reported. A time-variant transition hazard model was developed using an ordinary differential equation (ODE) model to estimate TTP and PPS from summary level PFS and OS. The model was applied to published data from immune checkpoint inhibitor trials for non-small cell lung cancer (NSCLC) in a meta-analysis framework. This model-based method was able to robustly estimate TTP and PPS from summary level OS and PFS data, provided a quantitative approach for understanding the patterns of disease progression across different treatments through the time-variant disease progression rate function, and provided a summary of how different treatments affect TTP and PPS. The proposed method can be generalized to characterize and quantify multiple time-to-event endpoints jointly in oncology trials and improve our understanding of disease prognostics for different treatments.

Effects of systemic therapy and local therapy on outcomes of 873 breast cancer patients with metastatic breast cancer to brain: MD Anderson Cancer Center experience.

Outcomes of treatments for patients with breast cancer brain metastasis (BCBM) remain suboptimal, especially for systemic therapy. To evaluate the effectiveness of systemic and local therapy (surgery [S], stereotactic radiosurgery [SRS] and whole brain radiotherapy [WBRT]) in BCBM patients, we analyzed the data of 873 BCBM patients from 1999 to 2012. The median overall survival (OS) and time to progression in the brain (TTP-b) after diagnosis of brain metastases (BM) were 9.1 and 7.1 months, respectively. WBRT prolonged OS in patients with multiple BM (hazard ratio [HR], 0.68; 95% CI, 0.52-0.88; P = .004). SRS alone, and surgery or SRS followed by WBRT (S/SRS + WBRT), were equivalent in OS and TTP-b (median OS, 14.9 vs 17.2 months; median TTP-b, 8.2 vs 8.6 months). Continued chemotherapy prolonged OS (HR, 0.35; 95% CI, 0.30-0.41; P < .001) and TTP-b (HR, 0.48; 95% CI, 0.33-0.70; P < .001), however, with no advantage of capecitabine over other chemotherapy agents used (median OS, 11.8 vs 12.4 months; median TTP-b, 7.2 vs 7.4 months). Patients receiving trastuzumab at diagnosis of BM, continuation of anti-HER2 therapy increased OS (HR, 0.53; 95% CI, 0.34-0.83; P = .005) and TTP-b (HR, 0.41; 95% CI, 0.23-0.74; P = .003); no additional benefit was seen with switching over between trastuzumab and lapatinib (median OS, 18.4 vs 22.7 months; median TTP-b: 7.4 vs 8.7 months). In conclusion, SRS or S/SRS + WBRT were equivalent for patients' OS and local control. Continuation systemic chemotherapy including anti-HER2 therapy improved OS and TTP-b with no demonstrable advantage of capecitabine and lapatinib over other agents of physicians' choice was observed.

Individualized Prediction of Early Alzheimer's Disease Based on Magnetic Resonance Imaging Radiomics, Clinical, and Laboratory Examinations: A 60-Month Follow-Up Study.

BACKGROUND: Accurately predicting whether and when mild cognitive impairment (MCI) will progress to Alzheimer's disease (AD) is of vital importance to help developing individualized treatment plans to defer the occurrence of irreversible dementia. PURPOSE: To develop and validate radiomics models and multipredictor nomogram for predicting the time to progression (TTP) from MCI to AD. STUDY TYPE: Retrospective. POPULATION: One hundred sixty-two MCI patients (96 men and 66 women [median age, 72; age range, 56-88 years]) were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. FIELD STRENGTH/SEQUENCE: T1 -weighted imaging and T2 -weighted fluid-attenuation inversion recovery imaging acquired at 3.0 T. ASSESSMENT: During the 5-year follow-up, 68 patients converted to AD and 94 remained stable. Patients were randomly divided into the training (n = 112) and validation datasets (n = 50). Radiomic features were extracted from the whole cerebral cortex and subcortical nucleus of MR images. A radiomics model was established using least absolute shrinkage and selection operator (LASSO) Cox regression. The clinical-laboratory model and radiomics-clinical-laboratory model were developed by multivariate Cox proportional hazard model. The performance of each model was assessed by the concordance index (C-index). A multipredictor nomogram derived from the radiomics-clinical-laboratory model was constructed for individualized TTP estimation. STATISTICAL TESTS: LASSO cox regression, univariate and multivariate Cox regression, Kaplan-Meier analysis and Student's t test were performed. RESULTS: The C-index of the radiomics, clinical-laboratory and radiomics-clinical-laboratory models were 0.924 (95% confidence interval [CI]: 0.894-0.952), 0.903 (0.868-0.938), 0.950 (0.929-0.971) in the training cohort and 0.811 (0.707-0.914), 0.901 (0824-0.977), 0.907 (0.836-0.979) in the validation cohort, respectively. A multipredictor nomogram with 15 predictors was established, which had high accuracy for individual TTP prediction with the C-index of 0.950 (0.929-0.971). DATA CONCLUSION: The prediction of individual TTP from MCI to AD could be accurately conducted using the radiomics-clinical-laboratory model and multipredictor nomogram. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: 2.

Are radiological endpoints surrogate outcomes of overall survival in hepatocellular carcinoma treated with transarterial chemoembolization?

BACKGROUND& AIMS: Time to progression (TTP) and progression-free survival (PFS) are commonly used as surrogate endpoints in oncology trials. We aimed to assess the surrogacy relationship of TTP and PFS with overall survival (OS) in studies of transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (u-HCC) by innovative methods. METHODS: A search of databases for studies of TACE for u-HCC reporting both OS and TTP or PFS was performed. Individual patient data were extracted from TTP/PFS and OS Kaplan-Meier curves of TACE arms. Pooled median TTP and OS were obtained from random-effect model. The surrogate relationships of hazard ratios (HRs) and median TTP for OS were evaluated by the coefficient of determination R2 . RESULTS: We identified 13 studies comparing TACE vs systemic therapy or vs TACE plus systemic therapy and including 1932 TACE-treated patients. Pooled median OS was 11.2 months (95% confidence interval [95%CI] 7.9-17.8), and pooled median TTP was 5.4 months (95%CI 3.8-8.0). Heterogeneity among studies was highly significant for both outcomes. The correlation between HR TTP and HR OS was moderate (R2  = 0.65. 95%CI 0.08-0.81). R2 value was 0.04 (95%CI 0.00-0.35) between median TTP and median OS. CONCLUSION: In studies of TACE for u-HCC, the surrogate relationship of radiology-based endpoints with OS is moderate. Multiple endpoints including hepatic decompensation, macrovascular invasion and extrahepatic spread are needed for future trials comparing systemic therapies or combination of TACE with systemic therapies vs TACE alone.

Assessment of the information theory approach to evaluating time-to-event surrogate and true endpoints in a meta-analytic setting.

In many disease areas, commonly used long-term clinical endpoints are becoming increasingly difficult to implement due to long follow-up times and/or increased costs. Shorter-term surrogate endpoints are urgently needed to expedite drug development, the evaluation of which requires robust and reliable statistical methodology to drive meaningful clinical conclusions about the strength of relationship with the true long-term endpoint. This paper uses a simulation study to explore one such previously proposed method, based on information theory, for evaluation of time to event surrogate and long-term endpoints, including the first examination within a meta-analytic setting of multiple clinical trials with such endpoints. The performance of the information theory method is examined for various scenarios including different dependence structures, surrogate endpoints, censoring mechanisms, treatment effects, trial and sample sizes, and for surrogate and true endpoints with a natural time-ordering. Results allow us to conclude that, contrary to some findings in the literature, the approach provides estimates of surrogacy that may be substantially lower than the true relationship between surrogate and true endpoints, and rarely reach a level that would enable confidence in the strength of a given surrogate endpoint. As a result, care is needed in the assessment of time to event surrogate and true endpoints based only on this methodology.

Biomarkers Associated With Response to Regorafenib in Patients With Hepatocellular Carcinoma.

BACKGROUND & AIMS: In a phase 3 trial (RESORCE), regorafenib increased overall survival compared with placebo in patients with hepatocellular carcinoma (HCC) previously treated with sorafenib. In an exploratory study, we analyzed plasma and tumor samples from study participants to identify genetic, microRNA (miRNA), and protein biomarkers associated with response to regorafenib. METHODS: We obtained archived tumor tissues and baseline plasma samples from patients with HCC given regorafenib in the RESORCE trial. Baseline plasma samples from 499 patients were analyzed for expression of 294 proteins (DiscoveryMAP) and plasma samples from 349 patients were analyzed for levels of 750 miRNAs (miRCURY miRNA PCR). Tumor tissues from 7 responders and 10 patients who did not respond (progressors) were analyzed by next-generation sequencing (FoundationOne). Forty-six tumor tissues were analyzed for expression patterns of 770 genes involved in oncogenic and inflammatory pathways (PanCancer Immune Profiling). Associations between plasma levels of proteins and miRNAs and response to treatment (overall survival and time to progression) were evaluated using a Cox proportional hazards model. RESULTS: Decreased baseline plasma concentrations of 5 of 266 evaluable proteins (angiopoietin 1, cystatin B, the latency-associated peptide of transforming growth factor beta 1, oxidized low-density lipoprotein receptor 1, and C-C motif chemokine ligand 3; adjusted P ≤ .05) were significantly associated with increased overall survival time after regorafenib treatment. Levels of these 5 proteins, which have roles in inflammation and/or HCC pathogenesis, were not associated with survival independently of treatment. Only 20 of 499 patients had high levels and a reduced survival time. Plasma levels of α-fetoprotein and c-MET were associated with poor outcome (overall survival) independently of regorafenib treatment only. We identified 9 plasma miRNAs (MIR30A, MIR122, MIR125B, MIR200A, MIR374B, MIR15B, MIR107, MIR320, and MIR645) whose levels significantly associated with overall survival time with regorafenib (adjusted P ≤ .05). Functional analyses of these miRNAs indicated that their expression level associated with increased overall survival of patients with tumors of the Hoshida S3 subtype. Next-generation sequencing analyses of tumor tissues revealed 49 variants in 27 oncogenes or tumor suppressor genes. Mutations in CTNNB1 were detected in 3 of 10 progressors and VEGFA amplification in 1 of 7 responders. CONCLUSION: We identified expression patterns of plasma proteins and miRNAs that associated with increased overall survival times of patients with HCC following treatment with regorafenib in the RESORCE trial. Levels of these circulating biomarkers and genetic features of tumors might be used to identify patients with HCC most likely to respond to regorafenib. ClinicalTrials.gov number NCT01774344. NCBI GEO accession numbers: mRNA data (NanoString): GSE119220; miRNA data (Exiqon): GSE119221.

Higher number of multidisciplinary tumor board meetings per case leads to improved clinical outcome.

BACKGROUND: This analysis aims at evaluating the impact of multidisciplinary tumor boards on clinical outcome of multiple tumor entities, the effect of the specific number of multidisciplinary tumor boards and potential differences between the tumor entities. METHODS: By a matched-pair analysis we compared the response to treatment, overall survival, relapse or disease free survival and progression free survival of patients whose cases were discussed in a tumor board meeting with patients whose cases were not. It was performed with patients registered in the cancer registry of the University of Bonn and diagnosed between 2010 and 2016. After the matching process with a pool of 7262 patients a total of 454 patients with 66 different tumor types were included in this study. RESULTS: First, patients with three or more multidisciplinary tumor board meetings in their history show a significantly better overall survival than patients with no tumor board meeting. Second, response to treatment, relapse free survival and time to progression were not found to be significantly different. Third, there was no significant difference for a specific tumor entity. CONCLUSION: This study revealed a positive impact of a higher number of multidisciplinary tumor boards on the clinical outcome. Also, our analysis hints towards a positive effect of multidisciplinary tumor boards on overall survival.

Overweight is associated with better prognosis in metastatic colorectal cancer patients treated with bevacizumab plus FOLFOX chemotherapy.

INTRODUCTION: Previous studies showed that high and low body mass index (BMI) was associated with worse prognosis in metastatic CRC (mCRC). Whether BMI is a prognostic or predictive factor in mCRC is unclear. We aimed to assess efficacy outcomes according to BMI in patient with metastatic colorectal cancer treated with bevacizumab plus FOLFOX chemotherapy regimen in second-line treatment. MATERIAL AND METHODS: The analysis of 237 patients with metastatic colorectal cancer treated with bevacizumab plus FOLFOX in the second line (treated from January 2014 to August 2018) in 4 reference oncological centers in Poland. RESULTS: The median age of the patients was 65 years (range 34-82). The median overall survival (OS) and progression-free survival (PFS) of the all 237 patient was 14.6 and 8.8 months, respectively. Comparison of obese patient (BMI > 30 kg/m2) vs. overweight patients (BMI ≥ 25 to < 30 kg/m2) vs. normal BMI range patients revealed a significant improvement of median OS (17.5 vs. 14.3 vs. 13.1 months, p = 0.01) and median PFS (9.4 vs. 9.1 vs. 7.3 months, p = 0.03). The Cox hazard model showed that the BMI class is an important risk factor. However, the Cox model also showed that the significance of the BMI class applies only to patients with BMI < 25 kg/m2. This rule applies to both OS and PFS. The regression analysis also confirmed that there is a statistically significant relationship between the length of OS and PFS and the BMI value. Higher BMI was associated with a better prognosis. There were no differences in responses to treatment bevacizumab and FOLFOX chemotherapy and number adverse events according to BMI values. CONCLUSIONS: Patients with mCRC treated with chemotherapy with bevacizumab in second-line treatment with higher BMI compared with normal weight patients have better prognosis in terms of PFS and OS. In this group, we found no evidence of changes in safety profile depending on BMI. Nevertheless, further large randomized studies are needed to assess the body weight on the effectiveness of chemotherapy in combination with bevacizumab.

Outcomes of hepatocellular carcinoma patients treated with sorafenib: a meta-analysis of Phase III trials.

Aim: To benchmark overall survival (OS) and time to radiological progression (TTP) of patients enrolled in randomized controlled trials (RCTs) assessing sorafenib in advanced hepatocellular carcinoma using individual participant survival data, and to meta-analyze prognostic factors for OS and TTP. Methods: RCTs were identified through literature search until December 2018. Individual participant survival was reconstructed with an algorithm from published Kaplan-Meier curves. Results: Ten RCTs were included. Median OS was 10.0 months (95% CI: 9.6-10.5), and median TTP was 4.1 months (95% CI: 3.8-4.3). Multivariable analyses showed HCV positivity, absence of macrovascular invasion and extra-hepatic disease as predictors of longer OS. Conclusion: We provided a benchmark for future studies on sorafenib. The present results can be used in the decision making for the early shift to second-line strategy.

The pretreatment platelet count is an independent predictor of tumor progression in patients undergoing transcatheter arterial chemoembolization with hepatitis B virus-related hepatocellular carcinoma.

AIM: To explore the prognostic value of the pretreatment platelet (PLT) count in patients undergoing transcatheter arterial chemoembolization (TACE) with hepatocellular carcinoma (HCC). MATERIALS & METHODS: We prospectively analyzed 317 hepatitis B virus-related HCC patients undergoing TACE. Time to progression (TTP) was selected to evaluate the clinical significance of PLT level in HCC patients. RESULTS: PLT was the only parameter showing statistical significance of all the clinical characteristics between two distinct tumor response groups. After ruling out cirrhosis as a potential major confounding factor, the conclusion was further established. Higher pretreatment PLT level, portal vessel invasion and higher stratification of α-fetoprotein level were independently associated with longer TTP. The prognostic score model combining the three risk factors revealed that higher risk scores might mean shorter TTP. CONCLUSION: The pretreatment PLT level is a potentially useful biomarker to predict the prognostic outcomes in HCC patients undergoing TACE and deserves to be further explored in subsequent works.

Dynamic contrast-enhanced magnetic resonance imaging perfusion characteristics in meningiomas treated with resection and adjuvant radiosurgery.

OBJECTIVEThere is a need for advanced imaging biomarkers to improve radiation treatment planning and response assessment. T1-weighted dynamic contrast-enhanced perfusion MRI (DCE MRI) allows quantitative assessment of tissue perfusion and blood-brain barrier dysfunction and has entered clinical practice in the management of primary and secondary brain neoplasms. The authors sought to retrospectively investigate DCE MRI parameters in meningiomas treated with resection and adjuvant radiation therapy using volumetric segmentation.METHODSA retrospective review of more than 300 patients with meningiomas resected between January 2015 and December 2018 identified 14 eligible patients with 18 meningiomas who underwent resection and adjuvant radiotherapy. Patients were excluded if they did not undergo adjuvant radiation therapy or DCE MRI. Demographic and clinical characteristics were obtained and compared to DCE perfusion metrics, including mean plasma volume (vp), extracellular volume (ve), volume transfer constant (Ktrans), rate constant (kep), and wash-in rate of contrast into the tissue, which were derived from volumetric analysis of the enhancing volumes of interest.RESULTSThe mean patient age was 64 years (range 49-86 years), and 50% of patients (7/14) were female. The average tumor volume was 8.07 cm3 (range 0.21-27.89 cm3). The median Ki-67 in the cohort was 15%. When stratified by median Ki-67, patients with Ki-67 greater than 15% had lower median vp (0.02 vs 0.10, p = 0.002), and lower median wash-in rate (1.27 vs 4.08 sec-1, p = 0.04) than patients with Ki-67 of 15% or below. Logistic regression analysis demonstrated a statistically significant, moderate positive correlation between ve and time to progression (r = 0.49, p < 0.05). Furthermore, there was a moderate positive correlation between Ktrans and time to progression, which approached, but did not reach, statistical significance (r = 0.48, p = 0.05).CONCLUSIONSThis study demonstrates a potential role for DCE MRI in the preoperative characterization and stratification of meningiomas, laying the foundation for future prospective studies incorporating DCE as a biomarker in meningioma diagnosis and treatment planning.

Phase II trial design with growth modulation index as the primary endpoint.

Molecularly targeted, genomic-driven, and immunotherapy-based clinical trials continue to be advanced for the treatment of relapse or refractory cancer patients, where the growth modulation index (GMI) is often considered a primary endpoint of treatment efficacy. However, there little literature is available that considers the trial design with GMI as the primary endpoint. In this article, we derived a sample size formula for the score test under a log-linear model of the GMI. Study designs using the derived sample size formula are illustrated under a bivariate exponential model, the Weibull frailty model, and the generalized treatment effect size. The proposed designs provide sound statistical methods for a single-arm phase II trial with GMI as the primary endpoint.

Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience.

Background Immunotherapy is emerging as the cornerstone for treatment of patients with advanced cancer, but significant toxicity (immune-related adverse events [irAEs]) associated with unbridled T cell activity remains a concern. Patients and methods A retrospective review of the electronic medical records of 290 patients with advanced cancer treated on an immunotherapy-based clinical trial in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center between February 2010 and September 2015 was performed. Clinical and laboratory parameters were collected to determine the incidence of irAEs, risk factors, and their association with treatment outcomes. Results Ninety eight of 290 patients (34%) experienced any grade irAEs. Among the 15 (5.2%) patients with grade ≥ 3 irAEs, the most common irAEs were dermatitis and enterocolitis. Although 80% of the patients with grade ≥ 3 irAEs required systemic corticosteroids, all the 15 patients recovered from the irAEs. On re-challenge, 4 of the 5 patients who had received systemic corticosteroids for irAE continued to respond. There were no irAE-related deaths. Importantly, patients with grade ≥ 3 irAEs had improved overall response rate (25 vs. 6%; p = 0.039) and longer median time to progression (30 weeks vs. 10 weeks; p = 0.0040) when compared to those without grade ≥ 3 irAEs. Conclusion Incidence of irAEs with immunotherapeutic agents indicates an active immune status, suggestive of potential clinical benefit to the patient. Further validation of this association in a large prospective study is warranted.