A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS)
Cherny N.I.,Shaare Zedek Medical Center |
Sullivan R.,Kings College London |
Dafni U.,National and Kapodistrian University of Athens |
Kerst J.M.,Antoni van Leeuwenhoek Hospital |
And 5 more authors.
Annals of Oncology
The value of any new therapeutic strategy or treatment is determined by the magnitude of its clinical benefit balanced against its cost. Evidence for clinical benefit from new treatment options is derived from clinical research, in particular phase III randomised trials, which generate unbiased data regarding the efficacy, benefit and safety of new therapeutic approaches. To date, there is no standard tool for grading the magnitude of clinical benefit of cancer therapies, which may range from trivial (median progression-free survival advantage of only a few weeks) to substantial (improved longterm survival). Indeed, in the absence of a standardised approach for grading the magnitude of clinical benefit, conclusions and recommendations derived from studies are often hotly disputed and very modest incremental advances have often been presented, discussed and promoted as major advances or 'breakthroughs'. Recognising the importance of presenting clear and unbiased statements regarding the magnitude of the clinical benefit from new therapeutic approaches derived from high-quality clinical trials, the European Society for Medical Oncology (ESMO) has developed a validated and reproducible tool to assess the magnitude of clinical benefit for cancer medicines, the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS). This tool uses a rational, structured and consistent approach to derive a relative ranking of the magnitude of clinically meaningful benefit that can be expected from a new anti-cancer treatment. The ESMO-MCBS is an important first step to the critical public policy issue of value in cancer care, helping to frame the appropriate use of limited public and personal resources to deliver cost-effective and affordable cancer care. The ESMO-MCBS will be a dynamic tool and its criteria will be revised on a regular basis. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source
Garbarino S.,University of Genoa |
Garbarino S.,CNR Institute of Neuroscience |
Caviglia G.,University of Genoa |
Sambuceti G.,IRCCS San Martino IST |
And 4 more authors.
Physics in Medicine and Biology
This paper introduces a novel compartmental model describing the excretion of 18F-fluoro-deoxyglucose (FDG) in the renal system and a numerical method based on the maximum likelihood for its reduction. This approach accounts for variations in FDG concentration due to water re-absorption in renal tubules and the increase of the bladder's volume during the FDG excretion process. From the computational viewpoint, the reconstruction of the tracer kinetic parameters is obtained by solving the maximum likelihood problem iteratively, using a non-stationary, steepest descent approach that explicitly accounts for the Poisson nature of nuclear medicine data. The reliability of the method is validated against two sets of synthetic data realized according to realistic conditions. Finally we applied this model to describe FDG excretion in the case of animal models treated with metformin. In particular we show that our approach allows the quantitative estimation of the reduction of FDG de-phosphorylation induced by metformin. © 2014 Institute of Physics and Engineering in Medicine. Source
Gennari A.,Galliera Hospital |
Gennari A.,Romagna Cancer Institute |
Nanni O.,Romagna Cancer Institute |
Puntoni M.,Galliera Hospital |
And 6 more authors.
Cancer Epidemiology Biomarkers and Prevention
Background: The effect of body mass index (BMI) on the prognosis of metastatic breast cancer (MBC) has not been explored so far. Methods: The relationship between BMI (kg/m2) and progression-free survival (PFS) or overall survival (OS) was assessed in 489 patients with MBC enrolled in three clinical trials of first-line chemotherapy. World Health Organization BMI categories were used: normal, 18.5-24.9 kg/m2; overweight, 25-29.9 kg/m2; and obese, 30- kg/m2. Univariate PFS and OS curves were estimated; multivariate Cox analysis was conducted adjusting for age, menopausal status, performance status (PS), hormonal status and site, and number of metastases. Results: Overall, 39.9% of the patients were normal or underweight, 37.8% were overweight, and 22.3% were obese. Median age was 57 years (range 25-73); median PS was 0. Median PFS was 10.9 months [interquartile range (IQR) 5.5 to 19.9] in normal weight women, 13.0 months (IQR 7.8 to 23.7) in overweight, and 12.2 (IQR 7.1 to 23.0) in obese women, P = 0.17. Median OS was 32.0 months [95% confidence interval (CI), 14.5-88.3] versus 33.2 months (95% CI, 19.4-81.1) and 30.7 (95% CI, 17.6-50.8), respectively. In multivariate analyses, no statistically significant association between BMI category and PFS or OS was observed. Conclusions: In this study, BMI was not associated with the outcome of patients withMBCtreated with firstline chemotherapy. Impact: In the absence of any evidence in support of a prognostic role of obesity in patients with MBC treated with chemotherapy, dietary restrictions, medical interventions aimed at reducing BMI/insulin resistance, or specific anticancer treatment strategies do not seem to be appropriate. © 2013 American Association for Cancer Research. Source
Raiola A.M.,Istituto Ricerca Carattere Scientifico |
Dominietto A.,Istituto Ricerca Carattere Scientifico |
di Grazia C.,Istituto Ricerca Carattere Scientifico |
Lamparelli T.,Istituto Ricerca Carattere Scientifico |
And 11 more authors.
Biology of Blood and Marrow Transplantation
We studied 459 consecutive patients with hematologic malignancies, median age 44years (range, 15 to 71years), who underwent transplantation with grafts from identical sibling donors (SIB; n=176), matched unrelated donors (MUD; n=43), mismatched unrelated donors (mmUD; n=43), unrelated cord blood (UCB; n=105) or HLA-haploidentical family donors (HAPLO; n=92). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate in the SIB recipients; antithymocyte globulin for the MUD, mmUD, and UCB recipients; and post-transplantation cyclophosphamide, cyclosporine, and mycophenolate in the HAPLO recipients. Conditioning regimens were mostly myeloablative (69%). Advanced disease phase was more frequent, but not significantly so, in the HAPLO and mmUD groups (P=08). Acute GVHD grade II-IV was significantly less frequent in the HAPLO, UCB, and MUD groups (14% to 21%) compared with the SIB (31%) and mmUD (42%) groups (P<.001), and there was a trend toward less moderate-severe chronic GVHD in the HAPLO and UCB groups (P=053). The proportion of patients off cyclosporine at 1year ranged from 55% for the SIB group to 81% for the HAPLO group (P<.001). Transplantation-related mortality at 2years was lower in the HAPLO and SIB groups (18% to 24%) compared with the MUD, mmUD, and UCB groups (33% to 35%; P=10). Relapse rate was comparable in the 5 groups (P=80). The 4-year actuarial survival was 45% in the SIB group, 43% in the MUD group, 40% in the mmUD group, 34% in the UCB group, and 52% in the HAPLO group (P=10). In multivariate analysis, advanced disease was a negative predictor of survival (hazard ratio [HR], 2.4; P<.0001), together with a diagnosis of acute leukemia (HR, 1.8; P=0001); HAPLO grafts were comparable to SIB (P=80), whereas UCB had inferior survival (P=03). In conclusion, unmanipulated haploidentical family donor transplants are an additional option for patients lacking a matched sibling donor. © 2014 American Society for Blood and Marrow Transplantation. Source
Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: A retrospective, exploratory analysis of the CORRECT trial
Tabernero J.,Autonomous University of Barcelona |
Lenz H.-J.,University of Southern California |
Siena S.,Niguarda Cancer Center |
Siena S.,University of Milan |
And 17 more authors.
The Lancet Oncology
Background: Tumour mutational status is an important determinant of the response of metastatic colorectal cancer to targeted treatments. However, the genotype of the tissue obtained at the time of diagnosis might not accurately represent tumour genotype after multiple lines of treatment. This retrospective exploratory analysis investigated the clinical activity of regorafenib in biomarker subgroups of the CORRECT study population defined by tumour mutational status or plasma protein levels. Methods: We used BEAMing technology to identify KRAS, PIK3CA, and BRAF mutations in DNA obtained from the plasma of 503 patients with metastatic colorectal cancer who enrolled in the CORRECT trial. We quantified total human genomic DNA isolated from plasma samples for 503 patients using a modified version of human long interspersed nuclear element-1 (LINE-1) quantitive real-time PCR. We also measured the concentration of 15 proteins of interest-angiopoietin 2, interleukin 6, interleukin 8, placental growth factor, soluble TIE-1, soluble VEGFR1, VEGF-A, VEGF-C, VEGF-D, VEGF-A isoform 121, bone morphogenetic protein 7, macrophage colony-stimulating factor, stromal cell-derived factor-1, tissue inhibitor of metalloproteinase 2, and von Willebrand factor-in plasma samples from 611 patients. We did correlative analyses of overall survival and progression-free survival in patient subgroups based on mutational status, circulating DNA concentration, and protein concentrations. The CORRECT trial was registered with ClinicalTrials.gov, number NCT01103323. Findings: Tumour-associated mutations were readily detected with BEAMing of plasma DNA, with KRAS mutations identified in 349 (69%) of 503 patients, PIK3CA mutations in 84 (17%) of 503 patients, and BRAF mutations in 17 (3%) of 502 patients. We did not do correlative analysis based on BRAF genotype because of the low mutational frequency detected for this gene. Some of the most prevalent individual hot-spot mutations we identified included: KRAS (KRAS G12D, 116 [28%] of 413 mutations; G12V, 72 [17%]; and G13D, 67 [16%]) and PIK3CA (PIK3CA E542K, 27 [30%] of 89 mutations; E545K, 37 [42%]; and H1047R, 12 [14%]). 41 (48%) of 86 patients who had received anti-EGFR therapy and whose archival tumour tissue DNA was KRAS wild-type in BEAMing analysis were identified as having KRAS mutations in BEAMing analysis of fresh plasma DNA. Correlative analyses suggest a clinical benefit favouring regorafenib across patient subgroups defined by KRAS and PIK3CA mutational status (progression-free survival with regorafenib vs placebo: hazard ratio [HR] 0·52, 95% CI 0·35-0·76 for KRAS wild-type; HR 0·51, 95% CI 0·40-0·65 for KRAS mutant [KRAS wild type vs mutant, pinteraction=0·74]; HR 0·50, 95% CI 0·40-0·63 for PIK3CA wild-type; HR 0·54, 95% CI 0·32-0·89 for PIK3CA mutant [PIK3CA wild-type vs mutant, pinteraction=0·85]) or circulating DNA concentration (progression-free survival with regorafenib vs placebo: HR 0·53, 95% CI 0·40-0·71, for low circulating DNA concentrations; HR 0·52, 95% CI 0·40-0·70, for high circulating DNA concentrations; low vs high circulating DNA, pinteraction=0·601). With the exception of von Willebrand factor, assessed with the median cutoff method, plasma protein concentrations were also not associated with regorafenib activity in terms of progression-free survival. In univariable analyses, the only plasma protein that was associated with overall survival was TIE-1, high concentrations of which were associated with longer overall survival compared with low TIE-1 concentrations. This association was not significant in multivariable analyses. Interpretation: BEAMing of circulating DNA could be a viable approach for non-invasive analysis of tumour genotype in real time and for the identification of potentially clinically relevant mutations that are not detected in archival tissue. Additionally, the results show that regorafenib seems to be consistently associated with a clinical benefit in a range of patient subgroups based on mutational status and protein biomarker concentrations. Funding: Bayer HealthCare Pharmaceuticals. © 2015 Elsevier Ltd. Source