De novo metastatic head and neck squamous cell carcinoma: Why does locoregional control "always" matter?

De novo metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) constitutes 10% of recurrent/metastatic (RM) cases. Radiotherapy (RT) has a crucial role in the treatment of locally advanced HNSCC, however its application on RM diseases is still limited. The advent of immune checkpoint inhibitors (ICIs) improves the survival of RM HNSCC, however median overall survival is still limited. Integration of locoregional RT with ICIs in de novo metastatic HNSCC represents a promising treatment option. This perspective aims to explore the role of the combination of locoregional and systemic treatment in improving outcomes for synchronous de novo metastatic HNSCC patients and highlights the principal crucial point in decision making.

Immune-related adverse events as potential surrogates of immune checkpoint inhibitors' efficacy: a systematic review and meta-analysis of randomized studies.

BACKGROUND: Immune-related adverse events (irAEs) are frequently reported during immune checkpoint inhibitor (ICI) therapy and are associated with long-term outcomes. It is unknown if the irAE occurrence is a valid surrogate of ICIs' efficacy. METHODS: We identified articles reporting the results of randomized trials of experimental ICI therapy in solid tumors with a systematic search. The control arms could be placebo, cytotoxic/targeted therapy, or ICI therapy. We extracted the hazard ratios for overall survival (OS) with the number of OS events per arm and the number and percentages of overall and specific irAEs of grade 1-2 and grade 3-4 per arm. We estimated the treatment effect on the potential surrogate outcome with the odds ratio of the irAE rate between the experimental and the control arm. The statistical analysis consisted of weighted linear regression on a logarithmic scale between treatment effects on irAE rate and treatment effects on OS. RESULTS: Sixty-two randomized trials were included for a total of 79 contrasts and 42 247 patients. The analyses found no significant association between the treatment effects for overall grade 1-2 or grade 3-4 irAE rates or specific (skin, gastrointestinal, endocrine) irAE rates. In the non-small-cell lung cancer (NSCLC) trial subset, we observed a negative association between treatment effects on overall grade 1-2 irAEs and treatment effects on OS in studies with patients selected for programmed death-ligand 1 expression (R2 = 0.55; 95% confidence interval 0.20-0.95; R = -0.69). In the melanoma trial subset, a negative association was shown between treatment effects on gastrointestinal grade 3-4 irAEs and treatment effects on OS in trials without an ICI-based control arm (R2 = 0.77; 95% confidence interval 0.24-0.99; R = -0.89). CONCLUSIONS: We found low-strength correlations between the ICI therapy effects on overall or specific irAE rates and the treatment effects on OS in several cancer types.

Characterization of the HER2 status in BRCA-mutated breast cancer: a single institutional series and systematic review with pooled analysis.

BACKGROUND: Pathogenic variants (PVs) in BRCA1/2 genes account for ∼6% of breast and 20% of ovarian cancers. Most breast tumors developed by BRCA1 carriers are triple negative. BRCA2 tumors have similar rates of estrogen receptor positivity as sporadic controls but are less likely to be human epidermal growth factor receptor 2 (HER2)-positive. Prevalence of HER2 positivity among breast cancers (BCs) in BRCA1/2 mutation carriers is poorly and variably described, ranging from 0% to 10% and 0% to 13% in BRCA1 and BRCA2 carriers, respectively. PATIENTS AND METHODS: We assessed the prevalence of HER2 positivity among a single institutional cohort of 398 BCs developed in carriers of BRCA1/2 PVs (240 BRCA1, 158 BRCA2). Subsequently, a systematic review of the literature and pooled analysis was carried out. RESULTS: In our series we found a 7% HER2 positivity rate among all first BRCA1/2 BCs overall. In BRCA1 carriers, 5.4% of BCs were HER2-positive compared with 9.5% in BRCA2-mutated patients. Among bilateral BCs, HER2-positive cases were 15.2% in the BRCA1 group and 23.1% in the BRCA2 group. Notably, six BRCA1 and eight BRCA2 carriers showed discordant HER2 status between BC and bilateral BC (23.7%, 14/59). The systematic review included 21 083 BRCA1/2 patients from 73 eligible studies. The pooled rate of BRCAmut/HER2-positive BCs is 9.1% (95% confidence interval 7.3% to 11.2%). BRCA1 and BRCA2 when reported as separate data ranged from 0% to 33.3% (mean 8.3%) and from 0% to 86% (mean 10.3%), respectively. CONCLUSIONS: As compared with sporadic cases, BCs occurring in BRCA1 and/or BRCA2 PVs carriers are less frequently HER2-positive. Prevalence of HER2 positivity in our series was consistent with pooled analysis and did not exceed 10%. Although not common, co-existence of BRCA mutations and HER2 overexpression and/or gene amplification should be acknowledged. More research is needed to better characterize this subgroup of patients who should not be excluded a priori from clinical trials of targeted therapy for BRCA1/2-driven cancers.

Efficacy and activity of PD-1 blockade in patients with advanced esophageal squamous cell carcinoma: a systematic review and meta-analysis with focus on the value of PD-L1 combined positive score.

BACKGROUND: Recently, several randomized controlled trials (RCTs) investigated immunotherapy-based regimens versus chemotherapy alone in patients with advanced esophageal squamous cell carcinoma (ESCC). Here we conducted a systematic review and meta-analysis on the efficacy and activity of programmed cell death protein 1 blockade in these patients, with focus on the value of programmed death-ligand 1 combined positive score (CPS) for selecting patients who may benefit the most. METHODS: RCTs investigating treatment with or without immune checkpoint inhibitors for advanced ESCC were selected. The hazard ratio (HR) and the odds ratio were used to compare the treatment effect on survival outcomes and tumor response, respectively, for immunotherapy-based regimens compared with standard chemotherapy, overall and according to geographic region or treatment line. We carried out a subgroup analysis comparing patients with CPS ≥10 or <10 and the evidence for treatment effect was evaluated by interaction test. RESULTS: A total of 5257 patients and 10 RCTs were included. Overall, the HR for overall survival benefit with immunotherapy-based regimens was 0.71 [95% confidence interval (CI) 0.66-0.76] compared with chemotherapy alone; such effect was independent from geographical region (Asia versus rest of the world) and treatment line (upfront versus second/further lines). The HR for progression-free survival benefit and the odds ratio for overall response rate increase were 0.78 (95% CI 0.66-0.93) and 1.50 (95% CI 1.22-1.83), respectively. The HR for overall survival benefit with immunotherapy-based treatment was 0.60 (95% CI 0.51-0.70) for CPS ≥10 subgroup versus 0.83 (95% CI 0.69-1.00) for CPS <10 (P for interaction 0.009). CONCLUSIONS: Immune checkpoint inhibitors have a consistent benefit in reducing the risk of death for ESCC patients which is dependent on programmed death-ligand 1 CPS status. Further investigations of biomarkers for immunotherapy in the subgroup of patients with CPS <10 are needed.

Predictive role of microsatellite instability for PD-1 blockade in patients with advanced gastric cancer: a meta-analysis of randomized clinical trials.

BACKGROUND: Several post hoc analyses of randomized controlled trials (RCTs) suggested the importance of microsatellite instability (MSI) as a positive predictive factor to immunotherapy in patients with advanced gastric cancer (GC); however, individually these have low statistical power. METHODS: RCTs investigating treatment with or without an anti-programmed cell death protein 1 (PD-1) agent for advanced GC and providing outcome according to MSI status were selected. The hazard ratio (HR) and the odds ratio were used to compare the treatment effect on survival outcomes and tumor response, respectively, for anti-PD-1-based therapy compared with standard therapy. Evidence for treatment effect by MSI status was evaluated by a test of interaction. RESULTS: The phase III KEYNOTE-062, CheckMate-649, JAVELIN Gastric 100 and KEYNOTE-061 trials were included. A total of 2545 patients with evaluable MSI status were included and 123 (4.8%) had MSI-high cancers. The HR for overall survival benefit with anti-PD-1-based regimens was 0.34 (95% CI: 0.21-0.54) for MSI-high cancers versus 0.85 [95% confidence interval (CI): 0.71-1.00] for microsatellite stable. The treatment effect was significantly different in the two subgroups (P for interaction 0.003). In the MSI-high subgroup, the HR for progression-free survival was 0.57 (95% CI: 0.33-0.97; P = 0.04) and the odds ratio for response was 1.76 (95% CI: 1.10-2.83; P = 0.02). CONCLUSIONS: Patients with MSI-high GC should be regarded as a specific and highly immunosensitive population worthy of dedicated clinical trials.

Overall survival with 3 or 6 months of adjuvant chemotherapy in Italian TOSCA phase 3 randomised trial.

BACKGROUND: Oxaliplatin-based adjuvant chemotherapy is the standard treatment of high-risk colon cancer (CC). A shorter duration (3 months) can achieve a similar outcome [in terms of relapse-free survival (RFS)] to a longer duration. This study reports the overall survival (OS) analysis of the three or six colon adjuvant (TOSCA) phase III study. It assessed different adjuvant chemotherapy durations in patients with resected high-risk stage II and stage III CC. MATERIAL AND METHODS: TOSCA was an open-label, phase III, multicentre, non-inferiority trial conducted in 130 Italian centres. Patients were randomly assigned, in a 1 : 1 ratio, to receive 3 months of standard doses of FOLFOX/CAPOX, or 6 months of FOLFOX/CAPOX. Patients with histologically confirmed high-risk stage II and III CC were included, with RFS being the primary end point. OS was a secondary end point. RESULTS: From June 2007 to March 2013, 3759 patients were accrued. At a median follow-up of 7 years, the hazard ratio (HR) for RFS of the 3-month versus 6-month arms was 1.13; 95% confidence interval (CI) 0.99-1.29, P for non-inferiority = 0.380, P for superiority = 0.068, crossing the non-inferiority limit of 1.20. This result did not allow us to reject the null hypothesis of the inferiority of the 3-month arm. The HR for OS of the 3-month versus 6-month arms was 1.09 (95% CI 0.93-1.26, P for superiority = 0.288). At the last follow-up analysis, the absolute OS difference between arms was <1%. CONCLUSIONS: The present analysis of the TOSCA trial does not indicate any significant difference in OS between the treatment groups. The extra benefit provided by the longer treatment should be balanced against the extra toxicity of more prolonged therapy. The trial is registered with ClinicalTrials.gov, registration number: NCT0064660.

Network indirect comparison of 3 BRAF + MEK inhibitors for the treatment of advanced BRAF mutated melanoma.

BACKGROUD: Synergistic combinations between BRAF and MEK inhibitors, such as dabrafenib plus trametinib, vemurafenib plus cobimetinib or encorafenib plus binimetinib, represent the current standard of care in metastatic or locally advanced BRAF V600 mutated malignant melanomas (MM). However, no studies explored the direct head-to-head comparison between the three different combinations. In this paper, we performed a network meta-analysis to evaluate their efficacy in terms of overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and safety profile. METHOD: We performed a systematic review of the literature about published first line trials of BRAF and MEK inhibitors doublets in advanced mutated malignant melanoma. We compared then the results with an adjusted indirect analysis of randomized-controlled trials. Our primary survival outcome was OS. Secondary endpoints were PFS, ORR, G3-4 toxicities described in at least 5% of patients in experimental arms. RESULTS: We identified three phase-3 trials: coBRIM (vemurafenib and cobimetinib), COMBI-v (dabrafenib and trametinib) and Columbus study (encorafenib and binimetinib) for a total of 1230 included patients. The control arm was vemurafenib in all studies. The indirect comparison revealed no statistically differences for OS, PFS and ORR across trials, while safety profile differed between the three couples of agents. CONCLUSION: This indirect adjusted meta-analysis suggests a similar efficacy and a slightly different safety profile, related to specific molecular properties of the three different BRAF and MEK inhibitors currently approved in the management of advanced MM.

Lipomatous Hypertrophy: An Accidental Finding in Heart.

Lipomatous hypertrophy is an uncommon benign lesion of the atrium, generally asymptomatic, characterized by unencapsulated accumulation of adipose tissue entrapping cardiomyocytes. This pathology generally remains unnoticed and often emerges as an occasional finding. Here, we report two cases from our hospital including a review of the available literature.

The pharmacist's role in health information, vaccination and health promotion.

On the subject of vaccination, owing to complex issues connected to vaccine refusal and vaccine hesitancy, the pharmacist is seen as a professional figure in the health sector who is qualified to improve social accountability with the aim of increasing the consent. In order to provide accurate information, Law no. 119/2007 has confirmed the central role of the pharmacist in the promotion of prophylactic vaccination, explicitly stating under art. 2 that the Ministry will be able to count on the collaboration of pharmacists as well as general practitioners and paediatricians. Pharmacists are pinpointed as new professional figures who could assist the national health service in its vaccine awareness and administration campaigns. Art. 5 comma 1 of Law no.119/2017 states that to meet vaccine goals, each Region will be able to allow vaccines to be booked through the Italian booking system (CUP) and administered free-of-charge in authorized pharmacies.

Lifestyles and discomfort in a sample of young Romanian students.

INTRODUCTION: The 40.3% of the Romanian youth population is at risk of poverty or social exclusion, and, in addition, the abuse of substances increases. It was interesting to evaluate the attitudes shared by pupils as well as their knowledge of these substances with a view to analyzing causes and types of risky behaviour in young people. METHODS: This is an observational study on the harassment influence in the lifestyle of a sample of Craiova high-school students The Fagerström Test was applied to evaluate the degree of nicotine dependence, and the data processed to assess the Odds Ratio. RESULTS: The sample was composed by 1,980 students with an average age of 17, of which 1,727 correctly responded to the questionnaire. The 37.4% of students admit to smoke, and the 67% to drink alcohol. The Fagerström test showed that the 68.2% of respondents are not highly addicted to smoke while the 31.8% was associated with a middle-to-high addiction level. A worrying weekly consumption of beer has been registered in the students. Regarding psychological distress caused by harassment a high Odds Ratio was recorded between the smokers and the drug users. CONCLUSIONS: More than half of students did not know about the health consequences of smoking, and the same result was recorded about the consumption of alcohol. A special attention should be done to the understanding of harassment problem in the young people. In fact, almost all the respondents declared to have suffered abuse and admits to use drug and cigarettes.

Implications of modified food choices and food-related lifestyles following the economic crisis in the Marche Region of Italy.

BACKGROUND: The economic crisis in Italy has led to profound changes in resource management not only at the macro level but also for individual families, causing substantial changes in different habits of Italians. STUDY DESIGN: The purpose of this research was to conduct a study on changes in family eating habits potentially triggered by the economic crisis was conducted in an area of the Marche Region in central Italy. METHODS: The research was conducted in the period 2016 - 2017 by administering a specific and anonymous questionnaire. RESULTS: The interviewed people has reduced its food consumption. In particular, analyzing the results for the animal protein food group, there has been a reduction in purchase of beef, and an increase in that of pork. Overall fish consumption has decreased by 44%, with a decrease in the purchase of fresh fish, and an increase in that of canned fish products. Finally, consumers have reduced their purchases of fresh and canned legumes, fresh vegetables, and fresh fruit. CONCLUSION: The economic crisis seems to have changed the eating habits and food-related lifestyle choices of the subjects studied, especially in the urban area affected by the deeper economic depression. These changes are likely to have permanent social consequences, and deserve to be analyzed also in smaller territories in order to better understand the dynamics of individual choices and the social framework.

Tumor regression grade and survival after neoadjuvant treatment in gastro-esophageal cancer: A meta-analysis of 17 published studies.

INTRODUCTION: Major pathologic regression after neoadjuvant therapy is a strong and favorable prognostic factor in several types of cancer (breast, rectal and bladder). This information is less clear and has yet to be systematically evaluated in upper gastrointestinal tumors. We performed a meta-analysis to evaluate the prognostic impact of tumor regression after preoperative therapy on disease-free survival (DFS) and overall survival (OS) in gastro-esophageal cancer patients. METHODS: we searched for relevant articles in PubMed, SCOPUS, Web of Science, CINAHL, LILACS, Ovid, Cochrane Library, Google Scholar and Embase up to June 2, 2016. Data of tumor regression (complete or near-complete pathologic response) that independently correlated with OS and DFS in multivariate analysis were extracted, and the proper hazard ratios (HRs) with corresponding 95% confidence intervals (95% CIs) were pooled according to the random effect model. RESULTS: a total of 17 studies-which included 3145 patients-were considered in the final analysis. Major pathologic response was significantly related with better OS (HR 0.46, 95% CI 0.32-0.66, P < 0.001) and DFS (HR = 0.40, 95% CI 0.26-0.62, P < 0.001). Pathologic complete response (pCR) or major tumor regression were associated with the same degree of benefit in outcome compared to no or minimal pathologic regression, regardless of histology. CONCLUSION: major pathologic response is associated with a significant improvement in OS compared to no response or minor pathologic changes after neoadjuvant therapy in gastro-esophageal cancers. This should be considered a robust prognostic factor to guide postoperative treatment and follow-up.

Estimating 12-week death probability in patients with refractory metastatic colorectal cancer: the Colon Life nomogram.

Background: Regorafenib and TAS-102 have recently demonstrated statistically significant survival gains in patients with refractory metastatic colorectal cancer (mCRC). Life expectancy ≥12 weeks was an inclusion criterion in registrative trials, and the identification of proper clinical selection tools for the daily use of these drugs in heavily pre-treated patients is needed to improve the cost-benefit ratio. We aimed at building a nomogram able to predict death probability within 12 weeks from the date of assessment of refractory mCRC. Patients and methods: Four hundred eleven refractory mCRC patients with ECOG performance status (PS) ≤2 receiving regorafenib, TAS-102 or other treatments were used as developing set. Putative prognostic variables were selected using a random forest model and included in a binary logistic model from which the nomogram was developed. The nomogram was externally validated and its performance was evaluated by examining calibration (how close predictions were to the actual outcome) and discriminative ability (Harrell C index) both on developing (internal validation) and validating (external validation) sets. Results: Four variables were selected and included in the nomogram: PS (P < 0.0001), primary tumor resection (P = 0.027), LDH value (P = 0.0001) and peritoneal involvement (P = 0.081). In the developing set, the nomogram discriminative ability was high (C = 0.778), and was confirmed in the validating set (C = 0.778), where the overall outcome was better as a consequence of the enrichment in patients receiving regorafenib or TAS-102 (46% versus 34%; P < 0.0001). Conclusions: Our nomogram may be a useful tool to predict the probability of death within 12 weeks in patients with refractory mCRC. Based on four easy-to-collect variables, the 'Colon Life' nomogram and free app for smartphones may improve mCRC patients' selection for later-line therapies and assist researchers for the enrollment in clinical trials in this setting.

Antibiotic prophylaxis for skin toxicity induced by antiepidermal growth factor receptor agents: a systematic review and meta-analysis.

Topical and systemic prophylactic measures, which are administered before the development of epidermal growth factor receptor (EGFR)-related acneiform rash, are appropriate interventions to mitigate the intensity of skin toxicity. We have performed a systematic review and meta-analysis to evaluate whether prophylactic antibiotics may reduce the occurrence and severity of anti-EGFR drug-related skin rashes. A systematic review was performed by searching Medline, Scopus, Embase, CINAHL, LILACS, Web of Science and the Cochrane Library from inception until March 2016 for publications regarding the pre-emptive role of antibiotics for EGFR-induced skin rashes. Fixed- or random-effects meta-analyses, according to heterogeneity, were used to summarize odds ratios of skin toxicity with antibiotic use. Of the 827 citations found in the search, 13 studies comprising 1073 patients were included in the analysis. In 12 studies, patients in the prophylactic antibiotic arms had a lower risk of developing a skin rash (odds ratio 0·53, 95% confidence interval 0·39-0·72, P < 0·01) than patients without antibiotic prophylaxis. In particular, moderate-to-severe toxicities (grades 2-4) were reduced by nearly two-thirds (odds ratio 0·36, 95% confidence interval 0·22-0·60, P < 0·01) in 13 studies. This translated to a 26% absolute difference of high-grade skin rash compared with the control arms (from 50% to 24%). The results of this meta-analysis show that the risk of skin rash after treatment with anti-EGFR agents for solid tumours was significantly lower in patients taking prophylaxis with antibiotics than in those who were not. Therefore, taking pre-emptive tetracyclines for several weeks at the start of anti-EGFR treatment can significantly reduce the incidence and severity of cutaneous acneiform rash.

Tumour Budding and Survival in Stage II Colorectal Cancer: a Systematic Review and Pooled Analysis.

PURPOSE: Tumour budding is defined as the presence of isolated or small clusters of malignant cells at the invasive edge of the tumour. It is considered a negative prognostic factor in colorectal cancer (CRC) and is associated with a poor outcome and adverse pathological features. Here, we report a meta-analysis of the association of tumour budding and survival in stage II CRC patients. METHODS: PubMed, EMBASE, Web of Science and SCOPUS were searched for studies that assessed the relationship between tumour budding and 5-year overall survival (OS) in stage II CRC patients. Published data were extracted and used to compute odds ratios (ORs) for death at 5 years and hazard ratios (HRs) for survival amongst patients with respect to the extent of tumour budding, using multivariate analysis. Data were pooled using the Mantel-Haenszel random effect model. RESULTS: We analysed 12 studies that included a total of 1652 patients. High-grade budding was associated with worse OS at 5 years (OR for death, 6.25; 95 % confidence interval [CI], 4.04-9.67; P < 0.00001). The absolute difference in 5-year OS was -25 % (95 % CI, -18- - 33 %, P < 0.00001). It was particularly noteworthy that the presence of high-grade budding was associated with an increased risk of death (HR for death, 3.68; 95 % CI, 2.16-6.28, P < 0.00001). CONCLUSIONS: Tumour budding is associated with worse survival in stage II CRC, in particular in pT3N0M0 patients. It could therefore potentially be used when deciding whether to administer adjuvant chemotherapy in high-risk node negative CRC patients.

Oxaliplatin-based chemotherapy: a new option in advanced hepatocellular carcinoma. a systematic review and pooled analysis.

Advanced hepatocellular carcinoma (HCC), for which locoregional treatment is not an option, is a candidate for palliative systemic therapy, but an accepted chemotherapy regimen does not exist. We have conducted a systematic literature review and meta-analyses to quantify the benefits of oxaliplatin (OXA)-based chemotherapy in advanced HCC in patients not exposed to sorafenib. Studies that enrolled advanced HCC patients treated with first-line OXA-based chemotherapy were identified using PubMed, Web of Science, SCOPUS, The Cochrane Register of Controlled Trials and EMBASE. A systematic review was conducted to calculate the pooled response rate and 95% confidence interval. The pooled median progression-free survival (PFS) and overall survival, weighted on the number of patients of each selected trials, were also calculated. We tested for significant heterogeneity by Cochran's chi-squared test and I-square index. Thirteen studies were included in this review, with a total of 800 patients analysed. The pooled response rate was 16.8%. The median PFS and overall survival were 4.2 and 9.3 months, respectively, with a 1 year overall survival of 37%. The weighted median PFS/overall survival and response rate were 4.5/11 months and 20% in Western patients. Conversely, in Asiatic studies, the median PFS/overall survival and response rate were 2.43/6.47 months and 13.2%, respectively. OXA-based chemotherapy is effective in advanced HCC and represents a viable option in these patients. A head to head comparison with sorafenib or a second-line agent should be verified in prospective trials.

The predictive role of skin rash with cetuximab and panitumumab in colorectal cancer patients: a systematic review and meta-analysis of published trials.

Skin rash is an early and frequent phenomenon during treatment with anti-epidermal growth factor receptor monoclonal antibodies. The objective of this review is to assess the predictive value of skin rash in patients with advanced colorectal cancer treated with cetuximab and panitumumab. We searched PubMed and ASCO Meetings for publications reporting the correlation of skin rash with survival and/or response rate. Hazard ratios (HRs) with 95% confidence intervals for progression and/or survival, and/or risk ratios (RRs) for response rate in patients with rash were obtained from publications and pooled in a meta-analysis. Fourteen publications (for a total of 3,833 patients) were included in this meta-analysis. The occurrence of skin toxicity represents a predictive factor for survival (HR 0.51; p<0.00001) and progression (HR 0.58; p<0.00001). Similarly, patients who developed moderate or severe rash had an increased chance of response (35 vs 13%; RR 2.23, p<0.00001). The occurrence of skin rash during treatment with cetuximab and panitumumab represents a significant predictor of the efficacy of these drugs. The hypothesis that, in patients who lack substantial skin toxicity, this treatment is not beneficial and requires early discontinuation deserves further study.

Correlation of progression-free and post-progression survival with overall survival in advanced colorectal cancer.

BACKGROUND: Polychemotherapy and biological drugs have increased therapeutic options and outcomes of advanced colorectal cancer (CRC). We examined the relation between progression-free survival (PFS), post-progression survival (PPS) and overall survival (OS) in trials of modern (oxaliplatin- and irinotecan-based) chemotherapy alone or with targeted therapies for advanced CRC. We also evaluated surrogacy of PFS and OS. PATIENTS AND METHODS: A PubMed search identified 34 randomized trials. We split the OS, PFS and PPS and evaluated the correlation between OS and either PFS or PPS. RESULTS: The median PPS and PFS were 10.75 and 8.4 months, respectively. For all trials, PPS was strongly associated with OS [regression coefficient (R2)=0.8; Spearman's rank correlation coefficient (r)=0.88], whereas PFS was moderately associated with OS (R2)=0.43; r=0.64). In trials with targeted therapies, the correlation of PPS with OS was 0.88. However, across all trials, correlation between differences in median PFS (ΔPFS) and median OS (ΔOS) is 0.59 (P=0.0007), confirming PFS/OS surrogacy. CONCLUSION: Our findings indicate that in recent first-line, phase III, trials, OS becomes more associated with PPS than PFS. However, improvements in PFS are strongly associated with improvements in OS. In this setting so, PFS may be an appropriate surrogate for OS.

Role of HER2-neu as a prognostic factor for survival and relapse in pT1a-bN0M0 breast cancer: a systematic review of the literature with a pooled-analysis.

High levels of human epidermal growth receptor 2 (HER2) expression are associated with recurrence and death in breast cancer (BC) patients. We have performed a systematic review and meta-analysis in order to evaluate the prognosis for HER2+ pT1a-bN0M0 BC patients. A search of PubMed and Embase was performed. Studies were included if they reported hazard ratios (HRs) with a 95% confidence interval (CI) for multivariate analyses of relapse or survival in pT1a-bN0M0, HER2+ BC patients treated with surgery and chemotherapy and/or endocrine therapy, but not with trastuzumab. A total of 764 patients from seven studies were included in the meta-analysis. In the pooled analysis, HER2 had a detrimental effect on relapse-free (HR 4.68, 95% CI 3.05-7.18; p<0.00001) and distant relapse-free survival, with a HR of 5.6 (95% CI 2.65-11.85; p<0.00001). HER2+ status was also linked to increased risk of death (HR 3.4, 95% CI 0.86-13.41; p=0.08) and worst BC-specific survival (HR 2.61, 95% CI 1.51-4.51; p=0.0006), but these data were presented in few studies. HER2+ pT1a-bN0M0 BC is associated with a dismal prognosis. In these patients, HER2 has to be taken into account when deciding on adjuvant therapy, and trastuzumab should be considered.