Abstract Antiangiogenic agents (AAs) have reported grater efficacy compared to interferon. Despite these advances, radiological complete response to therapy is rare. We meta-analyzed the incidence of ...complete response in patients treated with AAs and in controls in main randomized clinical trials for first-line therapy in metastatic renal cell carcinoma. PubMed was reviewed for phase II–III randomized clinical trials with AAs vs. non-AAs in patients with good or intermediate prognosis. We calculated the relative risk of events in patients assigned to AAs compared to control. Five RCTs were found; four were phase III and one was phase II. A total of 2747 patients was valuable for final analysis and randomized to receive AAs or control. Patients in the control-group had interferon (85%) or placebo (15%); patients in the AAs-group received bevacizumab (48%), sunitinib (26%), pazopanib (20%) or sorafenib (6%). The incidence of complete response in patients treated with AAs was 2.0% (95% CI, 1.2–2.8) compared to 1.4% (95% CI, 0.7–2.1) in the control arm. Comparing the different type of AAs, the incidence of complete response was 2.5% (95% CI, 1.2–3.8) in the bevacizumab group and 1.6% (95% CI, 0.1–2.5) in the TKIs group. The relative risk to have a complete response was 1.52 (95% CI, 0.85–2.73; p = 0.16) in patients treated with AAs compared to controls; this was found higher in patients treated with TKIs compared to bevacizumab. The complete response is a rare event in metastatic kidney tumor, even if AAs reported greater efficacy in terms of progression-free survival and of overall response rate, they did not increase the curative rate of metastatic disease. Probably, some biologic factors other than angiogenesis may influence the complete response in this disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Purpose The primary analysis of the ASPECCT study demonstrated that panitumumab was non-inferior to cetuximab for overall survival (OS) in patients with chemotherapy-refractory wild-type ...KRAS exon 2 metastatic colorectal cancer (mCRC). Here, we report the final analysis results of ASPECCT. Patients and methods Patients with wild-type KRAS exon 2 mCRC who progressed on or were intolerant to irinotecan- or oxaliplatin-based chemotherapy were randomised to receive panitumumab 6 mg/kg once every 2 weeks or cetuximab (400 mg/m2 ) followed by 250 mg/m2 weekly. The primary end-point was OS assessed for non-inferiority. Patients were followed for survival for 24 months after the last patient was randomised and a final analysis was conducted. No formal hypothesis testing was done. Post hoc analyses of outcomes by prior bevacizumab exposure, worst-grade skin toxicity (0–1 versus 2–4) and worst-grade hypomagnesaemia (0 versus 1–4) were conducted. Results Nine hundred ninety-nine patients were randomised and received ≥1 treatment dose (panitumumab, n = 499; cetuximab, n = 500). Median OS was 10.2 months with panitumumab versus 9.9 months with cetuximab (hazard ratio = 0.94; 95% confidence interval = 0.82–1.07). Median progression-free survival was 4.2 months with panitumumab and 4.4 months with cetuximab (hazard ratio = 0.98; 95% confidence interval = 0.87–1.12). Longer OS was observed for patients with increased skin toxicity and with hypomagnesaemia in both arms. Furthermore, OS was longer for patients with prior bevacizumab exposure treated with panitumumab than with cetuximab. The observed safety profiles were consistent with previous studies. Conclusion Consistent with the primary analysis, the final analysis of ASPECCT showed panitumumab was non-inferior to cetuximab for OS for patients with chemotherapy-refractory, wild-type KRAS exon 2 mCRC. Trial registration: ClinicalTrials.gov , NCT01001377.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Pancreatic ductal adenocarcinoma is associated to dismal prognosis despite the use of palliative chemotherapy, partly due to the lack of knowledge of biological processes underlying disease ...progression. Exosomes have been identified as biomarkers sources in different cancer types. Aim of the study was to analyse the contents of circulating exosomes in patients with pancreatic cancer who received palliative chemotherapy.
Patients were submitted to blood sample collection before chemotherapy (T0) and after 3 months (T3). We quantified by an ELISA-based technique specific proteins of cancer-derived exosomes (CD44,CD44v6,EpCAM,CD9,CD81,Tspan8,Integrin α6,Integrin β4,CD24,CXCR4). We correlated the baseline levels of these factors and changes between T3 and T0 and survival outcomes. Survival analyses were performed by Kaplan-Meier method. Correlation was assessed by log-rank test and level of statistical significance was set at 0.05. Multivariate analysis was performed by logistic regression analysis.
Nineteen patients were enrolled. EpCAM T0 levels and increased EpCAM levels from T0 to T3 were those mostly associated with differences in survival. Patients having higher EpCAM had median progression free survival (PFS) of 3.18vs7.31 months (HR:2.82,95%CI:1.03-7.73,p = 0.01). Overall survival (OS) was shorter for patients having higher EpCAM (5.83vs16.45 months,HR:6.16,95%CI:1.93-19.58,p = 0.0001) and also response rates (RR) were worse (20%vs87%,p = 0.015). EpCAM increase during treatment was associated with better median PFS (2.88vs7.31 months,HR:0.24,95%CI:0.04-1.22,p = 0.003). OS was also better (8.75vs11.04 months, HR:0.77,95%CI:0.21-2.73,p = 0.66) and RR were 60%vs20% (p = 0.28). Among clinical factors that might determine changes on PFS and OS, only ECOG PS was associated to significantly worse PFS and OS (p = 0.0137and<0.001 respectively).Multivariate analysis confirmed EpCAM T0 levels and EpCAM T0/T3 changes as independent prognostic factors for PFS.
Pancreatic cancer patients exosomes express EpCAM, whose levels change during treatment. This represents a useful prognostic factor and also suggests that future treatment modalities who target EpCAM should be tested in pancreatic cancer patients selected by exosome EpCAM expression.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The present study aims to investigate the role of the prognostic nutritional index (PNI) on survival in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib.
This multicentric ...study included a training cohort of 194 HCC patients and three external validation cohorts of 129, 76 and 265 HCC patients treated with Sorafenib, respectively. The PNI was calculated as follows: 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm3). Univariate and multivariate analyses were performed to investigate the association between the covariates and the overall survival (OS).
A PNI cut-off value of 31.3 was established using the ROC analysis. In the training cohort, the median OS was 14.8 months (95% CI 12-76.3) and 6.8 months (95% CI 2.7-24.6) for patients with a high (>31.3) and low (<31.3) PNI, respectively. At both the univariate and the multivariate analysis, low PNI value (p = 0.0004), a 1-unit increase of aspartate aminotransferase (p = 0.0001), and age > 70 years (p< 0.0038) were independent prognostic factors for OS. By performing the same multivariate analysis of the training cohort, the PNI <31.3 versus >31.3 was found to be an independent prognostic factor for predicting OS in all the three validation cohorts.
PNI represents a prognostic tool in advanced HCC treated with first-line Sorafenib. It is readily available and low-cost, and it could be implemented in clinical practice in patients with HCC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction: Since 2007 Sorafenib has represented the only approved drug for first-line treatment of advanced hepatocellular carcinoma (HCC). Lenvatinib, an orally active inhibitor of multiple ...receptor tyrosine kinases (VEGFR 1-3, FGFR 1-4, PDGFRa, RET and KIT), showed preclinical and clinical activity in the treatment of solid tumors, including HCC.
Areas covered: In this review, we summarize the current therapeutic paradigm for the systemic treatment of advanced HCC, focusing on Lenvatinib pre-clinical and clinical development. Keywords 'Lenvatinib', ' Target therapy', 'REFLECT trial', 'Hepatocellular carcinoma', 'HCC', 'Sorafenib' were used for literature search on PubMed.
Expert commentary: In Phase-III multicentric REFLECT trial Lenvatinib demonstrated a non-inferior overall survival (OS) compared to Sorafenib in the first-line treatment of advanced HCC, with a manageable toxicity profile, becoming a valid alternative option in the therapeutic repertoire of this disease. Nevertheless, the potential role of Lenvatinib in real-life clinical practice has still to be defined, especially in the light of the positive results that have been achieved with other new therapeutic agents (e.g. immunotherapy).
Background
Atezolizumab plus bevacizumab showed superior progression-free and overall survival compared to sorafenib in the IMbrave150 trial. It would therefore be useful to compare the efficacy of ...lenvatinib and that of atezolizumab plus bevacizumab to determine if a benefit of one therapy against the other exists.
Objective
The aim of the present report was to apply a matching-adjusted indirect comparison (MAIC) to individual participant data (IPD) from patients treated with lenvatinib outside of randomized trials, to aggregate results derived from the IMbrave150 trial.
Patients and methods
Data from 455 patients who received lenvatinib as first-line systemic therapy for unresectable HCC represented the present IPD. Data inclusion were adapted to those reported in the IMbrave150 trial.
Results
Overall survival on atezolizumab plus bevacizumab proved to be superior to lenvatinib (log-rank: 0.001) with a hazard ratio of 0.59 (95% confidence interval 0.46–0.75). The number needed to treat ranged between seven in the first 12 months and five at the 15th month.
Conclusions
The present MAIC highlights that the combination of atezolizumab plus bevacizumab is superior to lenvatinib. However, updated data or sub-analyses of the IMbrave150 trial would provide more robust estimates for such a treatment comparison.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Background
An accurate risk‐stratification is key to optimize the benefit‐to‐risk ratio of palliative treatment in advanced biliary cancer. We aimed at assessing the impact of the prognostic ...nutritional index (PNI) on survival and treatment response in advanced biliary cancer (ABC) receiving first‐line chemotherapy.
Methods
Medical records of ABC treated with standard chemotherapy at the Modena Cancer Centre were retrospectively reviewed for variables deemed of potential interest, including the PNI. Univariate and multivariate analyses were performed to investigate the association between the covariates and overall survival (OS).
Results
114 ABC fulfilled the inclusion criteria and made up the training cohort. A PNI cut‐off value of 36.7 was established using the receiver operating characteristic (ROC) analysis. At both the univariate and the multivariate analysis, low PNI value (<36.7) was associated with shorter OS (P = .0011), together with increased NLR (P = .0046) and ECOG >1 (P < .0001). The median OS was 5.4 vs 12.1 months in the low‐ vs high PNI‐group. Moreover, a PNI value >36.7 resulted in a higher disease control in patients treated with gemcitabine/platinum combination (61.4% vs 34.3%). These results were validated in an independent cohort of 253 ABC.
Conclusions
We demonstrated and externally validated a prognostic role for the PNI in ABC treated with first‐line chemotherapy. Although the PNI turned out to be predictive in the subset of patients receiving platinum/gemcitabine combination, future prospective confirmation is needed.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Background
EOX (epirubicin, oxaliplatin, and capecitabine) is one of the standard regimens for metastatic or locally advanced gastric cancer (GC). A new combination based on fractional docetaxel ...(low-TOX) has been developed in an attempt to increase the efficacy of EOX and reduce the heavy toxicity of classical docetaxel regimens.
Methods
Overall, 169 previously untreated GC patients were randomized between EOX (
arm A
) and low-TOX (
arm B
). The primary endpoint was progression-free survival (PFS), while secondary ones were overall survival (OS), overall response rate (ORR), disease control rate (DCR), and tolerability. The study was designed to detect a 35% (80% power at a two-sided 5% significance level) PFS increase with low-TOX and an interim analysis for futility was planned after the first 127 events.
Results
At the cut-off date of interim analysis, median PFS was 6.3 months 95% confidence interval (CI) 5.0–8.1 in
arm A vs
6.3 months (95% CI 5.0–7.8) in
arm B
, without statistical difference. OS was comparable in the two arms: 12.4 in
arm A
(95% CI 9.1–19.2)
vs
11.5 months in
arm B
(95% CI 8.6–15.0). ORR was 33% and 24%, while DCR was 68% and 67%, respectively. Treatment modification (91% vs 78%,
P
= 0.017) and number of patients with CTC grade ≥ 3 adverse events (42 vs 35) were higher in arm B.
Conclusions
A triplet regimen based on the fractional dose of docetaxel achieves no improvement over EOX which remains a potential standard treatment in many patients with inoperable, locally advanced or metastatic GC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In a previous cohort study, we proposed that responsiveness of metastatic colorectal cancer (mCRC) to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies has a genetic basis, being ...associated with increased EGFR gene copy number (GCN) as measured by fluorescence in situ hybridization (FISH) in individual tumors. The present study was aimed at assessing the predictive role of EGFR GCN, in terms of clinical outcome, in patients treated with panitumumab.
Patients with mCRC refractory to standard therapies were a subset of patients from a phase III trial of panitumumab plus best supportive care (BSC; n = 58) versus BSC alone (n = 34) who were selected on the basis of availability of tumor samples adequate for FISH.
In patients treated with panitumumab, a mean EGFR GCN of less than 2.5/nucleus or less than 40% of tumor cells displaying chromosome 7 polysomy within the tumor predicted for shorter progression-free survival (PFS; P = .039 and P = .029, respectively) and overall survival (P = .015 and P = .014, respectively). None of the treated patients with mean EGFR GCN of less than 2.47/nucleus or less than 43% of tumor cells displaying chromosome 7 polysomy obtained objective response compared with six of 20 and six of 19 patients with values greater than these cutoff limits, respectively (P = .0009 and P = .0007, respectively). Evaluation of BSC-treated patients showed no correlation between EGFR GCN or chromosome 7 polysomy status and PFS.
In a larger and more homogeneous series than in previous studies, present exploratory data suggest that mCRC patients with tumors distinguishable by FISH analysis of EGFR as homogenously disomic or with low chromosome 7 polysomy have a reduced likelihood of response to panitumumab.
In recent years, the study of genomic alterations and protein expression involved in the pathways of breast cancer carcinogenesis has provided an increasing number of targets for drugs development in ...the setting of metastatic breast cancer (i.e., trastuzumab, everolimus, palbociclib, etc.) significantly improving the prognosis of this disease. These drugs target specific molecular abnormalities that confer a survival advantage to cancer cells. On these bases, emerging evidence from clinical trials provided increasing proof that the genetic landscape of any tumor may dictate its sensitivity or resistance profile to specific agents and some studies have already showed that tumors treated with therapies matched with their molecular alterations obtain higher objective response rates and longer survival. Predictive molecular biomarkers may optimize the selection of effective therapies, thus reducing treatment costs and side effects. This review offers an overview of the main molecular pathways involved in breast carcinogenesis, the targeted therapies developed to inhibit these pathways, the principal mechanisms of resistance and, finally, the molecular biomarkers that, to date, are demonstrated in clinical trials to predict response/resistance to targeted treatments in metastatic breast cancer.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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