The clinical value of combination of immune checkpoint inhibitors in cancer patients: A meta‐analysis of efficacy and safety

The use of immune checkpoint inhibitors (ICIs) in combination therapy is an emerging trend in tumor immunology. However, the value of combination immunotherapy remains controversial, because of the toxic effects induced by combination. The added benefit of each additional drug has not been assessed against the added toxicity. We searched for clinical trials that evaluated ICI monotherapies and combination therapies in lung cancer and melanoma patients. The overall response rate (ORR), grade 3/4 treatment‐related adverse event rate, overall survival (OS), and progression‐free survival (PFS) were extracted from the most recently published studies to determine the relative risk (RR), hazard ratios (HRs), and 95% confidence intervals (CIs). Seven randomized controlled trials and one open‐label study were identified (n = 3,097). Treatments included combinations of several ICIs, a combination of an ICI and dacarbazine, two combinations of an ICI, paclitaxel and carboplatin, and a combination of an ICI and gp100 vaccine. Higher ORR (RR: 1.51, 95% CI: 1.03–2.20, p = 0.034), OS (HR: 0.86, 95% CI: 0.78–0.95, p = 0.000), and PFS (HR: 0.93, 95% CI: 0.72–1.14, p = 0.000) values were observed in combination therapy than in monotherapy. In addition, the toxicity of combination ICI immunotherapy was higher (RR: 1.50, 95% CI: 1.03–2.19, p = 0.036) than that of monotherapy. This meta‐analysis showed that the addition of nivolumab to ipilimumab better benefits PFS and ORR. Adding sargramostim was associated with better OS and safety. The efficacy and safety of a nivolumab‐ipilimumab‐sargramostim combination should be investigated further.     

Prognostic value of phospho‐Akt in patients with non‐small cell lung carcinoma: A meta‐analysis

Previous studies have been inconsistent with respect to the reported associations between phospho‐Akt (p‐Akt) overexpression and lung cancer prognosis. In this study, we conducted a systematic review and meta‐analysis to assess the prognostic value of p‐Akt in patients with non‐small cell lung carcinoma (NSCLC). Relevant articles were identified by searching MEDLINE. Hazard risks (HRs) from individual studies were calculated and pooled by using a random‐effect model, and heterogeneity and publication bias analyses were also performed. Finally, 18 studies comprising 2,353 patients were included in the meta‐analysis. p‐Akt overexpression was associated with worse survival in NSCLC patients, and the pooled HRs for all the studies was 1.38 (95% confidence interval [CI]: 1.11–1.70; p < 0.01). After subgroup analysis, the association was strengthened in the surgery treatment group, with an HR of 1.44 (95% CI: 1.19–1.75; p < 0.01), while in the tyrosine kinase inhibitors treatment group, the statistical significance disappeared (HR: 1.22, 95% CI: 0.70–2.14; p = 0.48). The HR in cases of early stage disease (I–III) was 1.35 (95% CI: 1.08–1.69; p = 0.04); however, in cases of late stage disease (III–IV), the association became non‐significant (HR: 1.22, 95% CI: 0.64–2.33; p = 0.54). Our results suggest that there was a significantly inverse association between p‐Akt overexpression and the prognosis of NSCLC patients, and that this association appeared to be limited in early‐stage patients who underwent surgery.     

Influence of mRNA expression of epiregulin and amphiregulin on outcome of patients with metastatic colorectal cancer treated with 5‐FU/LV plus irinotecan or irinotecan plus oxaliplatin as first‐line treatment (FIRE 1‐trial)

Our aim was to investigate the impact of EREG and AREG mRNA expression (by RT‐qPCR) in patients with metastatic colorectal cancer (mCRC). In addition, epidermal growth factor receptor (EGFR) expression (by immunohistochemistry) as well as RAS‐and PIK3CA‐mutations (by pyrosequencing) were assessed. Tumors of 208 mCRC patients receiving 5‐fluorouracil/leucovorin plus irinotecan (FUFIRI) or irinotecan plus oxaliplatin (mIROX) within the FIRE‐1 trial were analyzed for mutations. Molecular characteristics were correlated with response, progression‐free survival (PFS), overall survival (OS). mRNA expression was evaluated using ROC‐analysis in 192 tumors (AREG high n = 31 vs. low n = 161; EREG high n = 89 vs. low n = 103). High versus low AREG expression was associated with PFS of 10.0 versus 8.0 months (HR = 0.62, 95% CI: 0.402–0.940, p = 0.03) and OS of 24.6 versus 18.7 months (HR = 0.72, 95% CI: 0.476–1.078, p = 0.11). High versus low EREG expression correlated with prolonged PFS (9.4 vs. 6.8 months, HR = 0.62, 95% CI: 0.460–0.846, p = 0.002) and OS (25.8 vs. 15.5 months, HR = 0.48, 95% CI: 0.351–0.657, p < 0.001). The positive prognostic effect of high EREG expression was confirmed in a multivariate analysis and was neither affected by EGFR expression nor by mutations of RAS‐ and PIK3CA‐genes. EREG expression appears as an independent prognostic marker in patients with mCRC receiving first‐line irinotecan‐based chemotherapy.     

Efficacy and safety of anti‐EGFR agents administered concurrently with standard therapies for patients with head and neck squamous cell carcinoma: a systematic review and meta‐analysis of randomized controlled trials

Agents targeting epidermal growth factor receptor (EGFR) are used to treat head and neck squamous cell carcinoma (HNSCC); however, their efficacy and safety is poorly understood. Here we evaluated the efficacy and safety of anti‐EGFR agents administered concurrently with standard therapies for HNSCC. Randomized controlled trials that evaluated addition of EGFR targeted therapy versus standard therapy alone were included. The primary outcome was overall survival (OS). Secondary outcomes were progression‐free survival (PFS), overall response rate (ORR), locoregional control, and severe adverse events (SAEs, grade ≥ 3). Sixteen eligible trials with 4031 patients were included. Addition of anti‐EGFR regimens to standard therapy significantly improved OS of patients with HNSCC (HR = 0.89; 95% CI, 0.82–0.96), with a moderately elevated rate of SAEs (RR = 1.08; 95% CI, 1.03–1.13). Subgroup analysis indicated that the survival benefit was observed when cetuximab was administered concurrently with radiotherapy (RT) for stage III/IV patients (HR = 0.76; 95% CI, 0.61–0.94; p = 0.01), or with chemotherapy for recurrent or metastatic (R/M) HNSCC (HR = 0.86; 95% CI, 0.78–0.95; p = 0.005). Significantly increased ORR (RR = 1.51; 95% CI 1.05–2.18) and PFS (HR = 0.72; 95% CI, 0.59–0.88) were found in R/M HNSCC patients treated with anti‐EGFR plus chemotherapy, while no significant improvements were found in stage III/IV patients treated with anti‐EGFR plus standard therapy. In conclusion, addition of cetuximab to standard therapy may improve outcomes for R/M HNSCC patients, while causing a moderate increase in SAEs. For stage III/IV patients, anti‐EGFR mAb plus RT can improve OS compared with RT alone, while replacement of chemotherapy with EGFR mAb or adding EGFR mAb to combined chemotherapy and RT did not improve outcomes.     

Survival benefit from S‐1 as compared to Fluorouracil in Asian patients with advanced gastrointestinal cancer: A meta‐analysis

Whether S‐1 could replace 5‐Fluorouracil (5‐Fu) or not in the treatment of advanced gastrointestinal (GI) cancer (including advanced gastric cancer [AGS] and metastatic colorectal cancer [mCRC]) in Asian patients has been controversial. This meta‐analysis was performed to compare the activity, efficacy and toxicity of S‐1‐based versus 5‐Fu‐based chemotherapy in those Asian patients. Randomized controlled trials (RCTs) were identified by electronic search of Pubmed. Relevant abstracts were manually searched to identify relevant trials. A total of 2182 patients from eight RCTs were included, and our results demonstrated that S‐1‐based chemotherapy significantly improved overall survival (OS) (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.77–1.00) and overall response rate (ORR) (odds ratio [OR], 1.72; 95% CI, 1.09–2.70), but no significant progression‐free survival (PFS) benefit was found between arms (HR, 0.87; 95% CI, 0.72–1.06). Subgroup analyses revealed that S‐1‐based chemotherapy significantly improved OS and ORR in subgroups of patients with non‐platinum containing regimens (P = 0.041; P = 0.034) and patients with no prior chemotherapy history (P = 0.025; P = 0.016). Statistically significant improvements of PFS and ORR in the S‐1‐based chemotherapy were observed in the subgroup of patients with AGC (P < 0.001; P = 0.005). S‐1‐based chemotherapy was characterized by significantly higher incidences of diarrhea, fatigue and thrombocytopenia, and a lower incidence of nausea. This analysis provided strong evidence for survival benefits of S‐1, and S‐1‐based chemotherapy could be considered to replace 5‐Fu‐based therapy for the treatment of advanced GI cancer in Asian patients.     

Folic acid supplementation and cancer risk: A meta‐analysis of randomized controlled trials

There are growing data and a continuing controversy over the effect of folic acid supplementation on cancer risk. We conducted a meta‐analysis based on up‐to‐date published relevant randomized trials to further examine this issue. Relative risk (RR) was used to measure the effect of folic acid supplementation on risk of cancer using a random‐effects model. Overall, folic acid supplementation had no significant effect on total cancer incidence (13 trials, n = 49,406, RR = 1.05; 95% CI: 0.99–1.11, p = 0.13), colorectal cancer (seven trials, n = 33,824, 1.01; 0.82–1.23, p = 0.95), other gastrointestinal cancer (two trials, n = 20,228, 1.00; 0.75–1.33, p = 0.99), prostate cancer (five trials, n = 27,065, 1.17; 0.84–1.62, p = 0.35), other genitourinary cancer (two trials, n = 20,228, 0.97; 0.75–1.27, p = 0.84), lung cancer (five trials, n = 31,864, 1.00; 0.84–1.21, p = 0.97), breast cancer (four trials, n = 19,800, 0.82; 0.63–1.07, p = 0.15), hematological malignancy (three trials, n = 25,670, 0.87; 0.64–1.17, p = 0.35) and total cancer mortality (six trials, n = 31,930, 1.02; 0.90–1.15, p = 0.81). However, a significantly reduced risk was observed for melanoma (three trials, n = 19,128, 0.47; 0.23–0.94, p = 0.03). Furthermore, higher total cancer incidence risk was observed among those trials with a higher percent use of lipid‐lowering drugs (>60%, 1.10; 1.00–1.20, p = 0.04), or with lower percent baseline hypertension (≤70%, 1.08; 1.00–1.16, p = 0.057).Consistently, meta‐regression analyses suggested that the similar trend between percent use of lipid‐lowering drugs (p = 0.084) or percent baseline hypertension (p = 0.056) and log‐RR for total cancer incidence associated with folic acid supplementation. Our findings indicate that folic acid supplementation has no significant effect on total cancer incidence, colorectal cancer, prostate cancer, lung cancer, breast cancer or hematological malignancy, but reduces the risk of melanoma.     

Promising biomarkers for predicting the outcomes of patients with KRAS wild‐type metastatic colorectal cancer treated with anti‐epidermal growth factor receptor monoclonal antibodies: A systematic review with meta‐analysis

KRAS mutations have been established as a major predictive biomarker for resistance to the treatment of metastatic colorectal cancer (mCRC) with anti‐epidermal growth factor receptor monoclonal antibodies (anti‐EGFR MoAbs). However, many patients with KRAS wild‐type tumors still do not respond to the treatment. We conducted a systematic review with meta‐analysis to assess whether BRAF mutations, PIK3CA mutations and PTEN loss can predict the outcomes of patients with KRAS wild‐type mCRC treated with anti‐EGFR MoAbs. Studies that explored the association of one or more of the three biomarkers with progression‐free survival (PFS), overall survival (OS) and/or objective response rate (ORR) were identified through August 2012. Summary hazard ratios (HRs) and rate differences (RDs) and corresponding 95% confidence intervals (CIs) were calculated by using the random‐effects model. BRAF mutations, PIK3CA exon 20 mutations and PTEN loss were all associated with shorter PFS (HR = 2.59, 95% CI 1.67–4.03; HR = 2.52, 95% CI 1.33–4.78 and HR = 1.75, 95% CI 1.19–2.56, respectively), shorter OS (HR = 2.74, 95% CI 1.79–4.19; HR = 3.29, 95% CI 1.60–6.75 and HR = 1.85, 95% CI 1.30–2.64, respectively) and lower ORR (RD = ?36%, 95% CI ?44 to ?28%; RD = ?38%, 95% CI ?51 to ?24% and RD = ?41%, 95% CI ?68 to ?14%, respectively). PIK3CA exon 9 mutations were associated with none of the outcomes. Studies with relevant data consistently demonstrated a stronger predictive power of combined multiple biomarkers as compared to one alteration alone. These results suggest that BRAF mutations, PIK3CA exon 20 mutations and PTEN loss are predictive of better outcomes in KRAS wild‐type mCRC treated with anti‐EGFR MoAbs. However, the quality of included studies varied, and some of the meta‐analyses were limited by significant between‐study heterogeneity. In the future, well‐designed large randomized controlled trials conducted in KRAS wild‐type mCRC patients with subgroup analysis according to BRAF, PIK3CA exon 20 and PTEN status are essential to fully assess the clinical relevance of these biomarkers.     

Calcium intake and colorectal adenoma risk: Dose‐response meta‐analysis of prospective observational studies

Evidence from randomized controlled trials suggests that calcium may protect against recurrence of colorectal adenomas, which could lead to the subsequent prevention of cancer. Yet the trials used only a large single dose and were of small sizes, and thus, knowledge of the dose‐response relationship and influence on high‐risk adenomas is limited. To address these issues, we conducted linear and nonlinear dose‐response meta‐analyses primarily based on prospective observational studies published up to July 2014 identified from PubMed and Embase. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated for total and supplemental calcium intake, respectively, using a random‐effects model. For total calcium intake, summary RR for each 300 mg/day increase was 0.95 (95% CI = 0.92–0.98; I² = 45%; eight studies with 11,005 cases; range of intake = 333–2,229 mg/day). Evidence of nonlinearity was indicated: approximately, compared to 550 mg/day of total calcium intake, the summary RR was 0.92 (95% CI = 0.89–0.94) at 1,000 mg/day and 0.87 (95% CI = 0.84–0.90) at 1,450 mg/day (p_nonlinearity < 0.01). Associations were stronger for high‐risk adenomas (≥1 cm in diameter, (tubulo)villous histology, dysplasia, or multiplicity): approximately, compared to 550 mg/day of total calcium intake, the summary RR was 0.77 (95% CI = 0.74–0.81) at 1,000 mg/day and reduced to 0.69 (95% CI = 0.66–0.73) at 1,450 mg/da (p_nonlinearity < 0.01). For supplemental calcium intake, summary RR of total adenoma risk for each 300 mg/day increase was 0.96 (95% CI = 0.93–0.99; I² = 0%; three studies with 4,548 cases; range of supplementation = 0–1,366 mg/day). In conclusion, calcium intake may continue to decrease the risk of adenomas, particularly high‐risk adenomas, over a wide range of calcium intake.     

Correlation between sex and efficacy of immune checkpoint inhibitors (PD‐1 and CTLA‐4 inhibitors)

Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on immune response, which is affected by sex difference, where both biological and sociological factors are involved. The role of sex in ICI trials has been overlooked. How sex correlates with ICI efficacy is incompletely understood. Clinical trials evaluating ICI versus other therapies in male and female patients were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS) and progression‐free survival (PFS) were used. Six thousand and ninety‐six patients from 11 trials were included. More improvement of OS was observed in males (HR, 0.62; 95% CI, 0.53–0.71; p < 0.001) treated with ICI versus controls than females (HR, 0.74; 95% CI, 0.65–0.84; p < 0.001). ICIs improved PFS more in males (HR, 0.57; 95% CI, 0.43–0.71; p < 0.001) than females (HR, 0.71; 95% CI, 0.52–0.91; p < 0.001). The sex difference had more effect on the overall survival in melanoma patients versus NSCLC patients. Overall survival of patients treated with CTLA‐4 inhibitor was more influenced by sex variable compared with PD‐1 inhibitors. A significant sex‐related efficacy difference was observed between female and male melanoma patients. Although male patients had longer OS and PFS than females when treated with ICIs versus controls, the difference was not significant. Sex difference should be more considered in future clinical trials, guidelines and clinical practice.     

Association between metformin use after surgery for colorectal cancer and oncological outcomes: A nationwide register‐based study

Colorectal cancer is one of the most common malignancies in the Western world, and even after surgical removal, there is a high recurrence rate. Metformin treatment has been associated with a reduced risk of developing cancer, but whether metformin influences the risk of recurrence is unknown. The aim of our study was to examine the association between treatment with metformin and recurrence‐free, disease‐free survival and all‐cause mortality after surgery for colorectal cancer. The study was an observational register‐based study and included 25,785 patients, of which 1,116 had medically treated diabetes and 966 started metformin treatment at some point postoperatively. Diabetes was not associated with neither disease‐free (HR_adjusted = 1.09, 95% CI 0.97–1.21, p = 0.15) nor recurrence‐free survival (HR_adjusted = 1.13, 95% CI 0.95–1.35, p = 0.17). The study found no difference in regards to disease‐free or recurrence‐free survival between the metformin treated group (HR_RFS = 1.06, 95% CI 0.87–1.15, p = 0.57, HR_DFS = 1.01, 95% CI 0.89–1.15, p = 0.85) and non‐diabetic patients. Patients with diabetes had increased all‐cause mortality (HR_adjusted = 1.29, 95% CI 1.16–1.45, p < 0.0001). Metformin treatment did not affect all‐cause mortality (HR = 1.07, 95% CI 0.94–1.22, p = 0.33) compared to non‐diabetic patients. In conclusion, our study did not find an association between diabetes or metformin treatment and recurrence‐free or disease‐free survival after surgery for colorectal cancer. However, diagnosis of diabetes is associated with increased all‐cause mortality.     

Adolescent and mid‐life diet and subsequent risk of thyroid cancer in the NIH‐AARP diet and health study

Although thyroid cancer is suspected to have a nutritional etiology, prospective studies examining the relationship between diet and thyroid cancer are lacking. During 1996–1997, NIH‐AARP Diet and Health Study participants, ages 51–72 years, completed a 37‐item food frequency questionnaire about diet at ages 12–13 years (adolescence) and 10 years before baseline (mid‐life). Over a median 10 years of follow‐up, 325 individuals (143 men and 182 women) were diagnosed with thyroid cancer. Multivariable‐adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for intakes of foods and food groups comparing the highest to the lowest quartiles. Adolescent intakes of chicken/turkey (HR = 1.59, 95% CI: 0.97–2.60; p_trend < 0.01) and sweet baked goods (HR = 1.59, 95% CI: 1.09–2.34; p_trend = 0.04) were positively associated with thyroid cancer risk, while intake of butter/margarine was inversely associated with risk (HR = 0.64, 95% CI: 0.44–0.91; p_trend < 0.02). Similar to adolescent diet, mid‐life intake of sweet baked goods was nonsignificantly associated with an increased risk of thyroid cancer (HR = 1.39, 95% CI: 0.96–2.00; p_trend = 0.11), but intake of butter/margarine was inversely associated with risk (HR = 0.66, 95% CI: 0.46–0.95; p_trend = 0.03). Among men, higher adolescent consumption of canned tuna was positively associated with risk of thyroid cancer (HR = 1.69, 95% CI: 1.01–2.83; p_trend = 0.03), and greater mid‐life intake of broccoli was associated with a twofold increased risk (HR = 2.13, 95% CI: 1.13–3.99; p_trend < 0.01). This large prospective study suggests that several components of the adolescent and mid‐life diet, including iodine‐rich foods and goitrogens, may influence thyroid cancer risk.     

Comparing cytotoxic backbones for first‐line trastuzumab‐containing regimens in human epidermal growth factor receptor 2‐positive advanced oesophagogastric cancer: A meta‐analysis

According to the Trastuzumab for Gastric Cancer (ToGA) study, trastuzumab plus cisplatin and capecitabine/5‐fluorouracil (5‐FU) is standard first‐line treatment for human epidermal growth factor receptor 2 (HER2)‐positive advanced oesophagogastric cancer. We examined the relative efficacy and safety of alternative trastuzumab‐based cytotoxic backbone regimens compared to the standard ToGA regimen using meta‐analysis. We searched Medline, EMBASE, CENTRAL and ASCO and ESMO up to March 2017 for studies investigating alternative first‐line trastuzumab‐based regimens for HER2‐positive oesophagogastric cancer, defined as high protein expression IHC3+ or IHC2+ and gene amplification by in situ hybridisation. We compared primary outcome overall survival (OS) of alternative trastuzumab‐based regimens to the ToGA regimen. Hazard ratios (HRs) and 95% confidence intervals (95%CI) were calculated by extraction of the published Kaplan‐Meier curves. Incidence counts and toxicity sample‐sizes were extracted for adverse events and compared using single‐arm proportion meta‐analysis in R. Fifteen studies (N = 557 patients) were included. OS was significantly longer with regimen trastuzumab plus doublet oxaliplatin and capecitabine/5‐FU (median OS = 20.7 months) versus ToGA (16.0 months, HR = 0.75, 95% CI = 0.59–0.99) and was less toxic. Trastuzumab plus doublet cisplatin and S‐1 showed no OS difference versus ToGA, but showed a different toxicity profile, including less hand‐foot syndrome. Trastuzumab plus cisplatin or capecitabine as singlet backbone showed significantly worse survival and more toxicity versus ToGA regimen. Trastuzumab with triplet cytotoxic backbones or with bevacizumab and doublet cytotoxic backbone showed no survival benefit and more toxicity. In conclusion, trastuzumab plus doublet cytotoxic backbone containing oxaliplatin is preferable over the ToGA regimen with cisplatin. S‐1 can substitute capecitabine or 5‐FU when specific toxicities are encountered.     

A preclinical evaluation of a novel multikinase inhibitor,SKLB‐329, as a therapeutic agent against hepatocellular carcinoma

We previously reported that lower post‐diagnostic circulating 25‐hydroxyvitamin D [25(OH)D] concentrations were associated with higher risk of overall mortality and distant disease in stage I–IV postmenopausal breast cancer survivors. This association was now re‐examined in an extended dataset to investigate potential effect modification by tumor characteristics and lifestyle factors. A prospective cohort study was conducted in Germany including 2,177 incident stage I–IV postmenopausal breast cancer patients aged 50–74 years. Patients were diagnosed between 2001 and 2005 and median follow‐up time was 5.3 years. Cox proportional hazards models were stratified by age at diagnosis, study center and season of blood collection and adjusted for other prognostic factors. A meta‐analysis of studies on circulating 25(OH)D and mortality in breast cancer patients was performed to summarize evidence. Lower concentrations of 25(OH)D were significantly associated with higher risk of overall mortality [hazard ratio (HR) lowest vs. highest tertile = 1.86; 95% confidence interval (CI): 1.22, 2.82; p‐trend = 0.002] and distant disease (HR = 1.76; 95% CI: 1.24, 2.49; p‐trend = 0.003) in stage I–IIIa but not in stage IIIb–IV breast cancer patients. No significant interaction by lifestyle factors was observed (all p‐interaction > 0.05). The meta‐analysis yielded significant associations with overall and breast cancer‐specific mortality (lowest vs. highest quantile: HR = 1.52; 95% CI: 1.22, 1.88 and HR = 1.74; 95% CI: 1.23, 2.40, respectively). In conclusion, post‐diagnostic circulating 25(OH)D concentrations were associated with overall mortality and distant disease in stage I–IIIa postmenopausal breast cancer patients. This association was not strongly modified by lifestyle factors.     

Body mass index and survival in patients with renal cell carcinoma: A clinical‐based cohort and meta‐analysis

Growing evidence suggests that obesity, an established cause of renal cell cancer (RCC), may also be associated with a better prognosis. To evaluate the association between RCC survival and obesity, we analyzed a large cohort of patients with RCC and undertook a meta‐analysis of the published evidence. We collected clinical and pathologic data from 1,543 patients who underwent nephrectomy for RCC between 1994 and 2008 with complete follow‐up through 2008. Patients were grouped according to BMI (kg/m²): underweight <18.5, normal weight 18.5 to <23, overweight 23 to <25 and obese ≥25. We estimated survival using the Kaplan–Meier method and Cox proportional hazard models to examine the impact of BMI on overall survival (OS) and cancer‐specific survival (CSS) with adjustment for covariates. We performed a meta‐analysis of BMI and OS, CSS and recurrence‐free survival (RFS) from all relevant studies using a random‐effects model. The 5‐year CSS increased from 76.1% in the lowest to 92.7% in the highest BMI category. A multivariate analysis showed higher OS [hazard ratio (HR) = 0.45; 95% CI: 0.29–0.68) and CSS (HR = 0.47; 95% CI: 0.29–0.77] in obese patients than in normal weight patients. The meta‐analysis further corroborated that high BMI significantly improved OS (HR = 0.57; 95% CI: 0.43–0.76), CSS (HR = 0.59; 95% CI: 0.48–0.74) and RFS (HR = 0.49; 95% CI: 0.30–0.81). Our study shows that preoperative BMI is an independent prognostic indicator for survival among patients with RCC.     

Antiviral therapy improves overall survival in hepatitis C virus‐infected patients who develop diffuse large B‐cell lymphoma

Chronic Hepatitis C virus (HCV) infection is associated with increased incidence of non‐Hodgkin lymphoma. Several studies have demonstrated regression of indolent lymphoma with antiviral therapy (AVT) alone. However, the role of AVT in HCV‐infected patients with diffuse large B‐cell lymphoma (DLBCL) is unclear. We therefore analyzed AVT's impact on oncologic outcomes of HCV‐infected patients (cases) who developed DLBCL. Cases seen at our institution (June 2004–May 2014) were matched with uninfected counterparts (controls) and then divided according to prior AVT consisting of interferon‐based regimens. We studied 304 patients (76 cases and 228 controls). More cases than controls had extranodal (79% vs. 72%; p = 0.07) and upper gastrointestinal (GI; 42% vs. 24%; p = 0.004) involvement. Cases never given AVT had DLBCL more refractory to first‐line chemotherapy than that in the controls (33% vs. 17%; p = 0.05) and exhibited a trend toward more progressive lymphoma at last examination compared to controls (50% vs. 32%; p = 0.09) or cases given AVT (50% vs. 27%; p = 0.06). Cases never given AVT had worse 5‐year overall survival (OS) rates than did the controls (HR, 2.3 [95% CI, 1.01–5.3]; p = 0.04). Furthermore, AVT improved 5‐year OS rates among cases in both univariate (median [Interquartile range]: 39 [26–56] vs. 16 [6–41] months, p = 0.02) and multivariate analyses (HR = 0.21 [95% CI, 0.06–0.69]; p = 0.01). This study highlights the negative impact of chronic HCV on survival of DLBCL patients and shows that treatment of HCV infection is associated with a better cancer response to chemotherapy and improves 5‐year OS.     

Clinical impact of anti-epidermal growth factor receptor monoclonal antibodies in first-line treatment of metastatic colorectal cancer: meta-analytical estimation and implications for therapeutic strategies

BACKGROUND:

Antiepidermal growth factor receptor (anti‐EGFR) monoclonal antibodies (MoAbs) are indicated for the treatment of metastatic colorectal cancer patients, but some scientific issues concerning their efficacy are currently unsolved.

METHODS:

A literature‐based meta‐analysis was conducted. Hazard ratios (HRs) were extracted from randomized trials for progression‐free survival (PFS) and overall survival (OS); the event‐based risk ratio was derived for response. Sensitivity analyses to look for interactions according to KRAS status and chemotherapy association regimens were performed.

RESULTS:

Eight trials (6609 patients) were identified. A significant interaction according to KRAS status was found for PFS (wild type vs mutant, P = .001) and response rate (wild type vs mutant, P < .0001). The addition of an anti‐EGFR MoAb to first‐line chemotherapy increased PFS in the KRAS wild‐type population (HR, 0.91; 95% confidence interval [CI], 0.84‐0.99; P = .03), and had a detrimental effect in the KRAS mutant population (HR, 1.13; 95% CI, 1.03‐1.25; P = .013). A significant increase in the probability of achieving a response was evident in KRAS wild‐type patients (relative risk, 1.17; 95% CI, 1.04‐1.33; P = .011). In this population, the interaction in response rate according to adopted chemotherapy favored irinotecan‐containing regimens (P = .01), and at meta‐regression analysis the relative increase in response rate was significantly related to PFS (P = .00001) and OS (P = .00193) benefit.

CONCLUSIONS:

The addition of an anti‐EGFR MoAb to first‐line chemotherapy produces a clear benefit in response rate. This advantage is restricted to KRAS wild‐type patients and translates into a small benefit in PFS. At present, irinotecan‐based backbone chemotherapy could be a preferable option. The correlation between activity and survival parameters corroborates the hypothesis that anti‐EGFR MoAbs might be more suitable for patients needing tumoral shrinkage. Cancer 2011;. © 2011 American Cancer Society.     

The European Medicines Agency Approval of Axitinib (Inlyta) for the Treatment of Advanced Renal Cell Carcinoma After Failure of Prior Treatment With Sunitinib or a Cytokine: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use

Axitinib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR‐1), VEGFR‐2, and VEGFR‐3. Based on the positive opinion from the European Medicines Agency (EMA), a marketing authorization valid throughout the European Union (EU) was issued for the treatment of advanced renal cell carcinoma (RCC) after failure of prior treatment with sunitinib or a cytokine. The demonstration of clinical benefit for axitinib was based on a phase III, randomized, open‐label, multicenter study of axitinib compared with sorafenib in patients with advanced RCC after failure of a prior systemic first‐line regimen containing one or more of the following agents: sunitinib, bevacizumab plus interferon‐α, temsirolimus, or cytokines. In the primary analysis, a 2‐month increase in median progression‐free survival (PFS) was observed for axitinib compared with sorafenib (hazard ratio [HR]: 0.665; 95% confidence interval [CI]: 0.544–0.812; p < .0001). In the subgroup of patients with a prior cytokine‐containing regimen, the increase in median PFS associated with axitinib was 5.4 months (updated analysis, HR: 0.519; 95% CI: 0.375–0.720; p < .0001). In the subgroup of patients with prior sunitinib treatment, the increase in median PFS was 1.4 months (updated analysis, HR: 0.736; 95% CI: 0.578–0.937; p = .0063). The analysis of overall survival showed no statistically significant survival benefit of axitinib over sorafenib in patients previously treated with cytokine‐containing regimens (HR: 0.813; 95% CI: 0.556–1.191) or sunitinib (HR: 0.997; 95% CI: 0.782–1.270). The most common treatment‐related adverse events associated with axitinib included diarrhea, hypertension, fatigue, nausea, decreased appetite, dysphonia, and palmar‐plantar erythrodysesthesia. Most of these events were mild or moderate in severity. This paper summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website ( http://www.ema.europa.eu ).     

Adherence to Mediterranean diet and risk of cancer: A systematic review and meta‐analysis of observational studies

The aim of this research study was to meta‐analyze the effects of adherence to Mediterranean diet (MD) on overall cancer risk, and different cancer types. Literature search was performed using the electronic databases MEDLINE, SCOPUS and EMBASE until January 10, 2014. Inclusion criteria were cohort or case–control studies. Study specific risk ratios (RRs) were pooled using a random effect model by the Cochrane software package Review Manager 5.2. Twenty‐one cohort studies including 1,368,736 subjects and 12 case–control studies with 62,725 subjects met the objectives and were enclosed for meta‐analyses. The highest adherence to MD category resulted in a significantly risk reduction for overall cancer mortality/incidence (cohort; RR: 0.90, 95% CI 0.86–0.95, p < 0.0001; I² = 55%), colorectal (cohort/case–control; RR: 0.86, 95% CI 0.80–0.93, p < 0.0001; I² = 62%], prostate (cohort/case–control; RR: 0.96, 95% CI 0.92–0.99, p = 0.03; I² = 0%) and aerodigestive cancer (cohort/case–control; RR: 0.44, 95% CI 0.26–0.77, p = 0.003; I² = 83%). Nonsignificant changes could be observed for breast cancer, gastric cancer and pancreatic cancer. The Egger regression tests provided limited evidence of substantial publication bias. High adherence to a MD is associated with a significant reduction in the risk of overall cancer mortality (10%), colorectal cancer (14%), prostate cancer (4%) and aerodigestive cancer (56%).     

Alcohol drinking and pancreatic cancer risk: a meta‐analysis of the dose‐risk relation

In order to provide a more precise quantification of the association between alcohol consumption and pancreatic cancer risk, we performed a meta‐analysis of relevant dose‐risk results. We conducted a PubMed search of all case‐control (N=21) and cohort (N=11) studies published up to March 2009. We computed summary relative risk (RR) estimates using either fixed‐ or, in the presence of heterogeneity, random‐effects models. The pooled RR was 0.92 (95% confidence interval, 95% CI, 0.86–0.97) for <3 drinks/day and 1.22 (95% CI, 1.12–1.34) for ≥3 drinks/day. The increased risk for heavy drinking was similar in women and men, but apparently stronger in cohort studies (RR=1.29), in studies with high quality index (RR=1.30), and did not appear to be explained by residual confounding by either history of pancreatitis or tobacco smoking. This meta‐analysis provides strong evidence for the absence of a role of moderate drinking in pancreatic carcinogenesis, coupled to an increased risk for heavy alcohol drinking. Given the moderate increase in risk and the low prevalence of heavy drinkers in most populations, alcohol appears to be responsible only for a small fraction of all pancreatic cancers.     

Association between physical activity and mortality in colorectal cancer: A meta‐analysis of prospective cohort studies

Several prospective cohort studies have examined the association between prediagnosis and/or postdiagnosis physical activity (PA) on colorectal cancer outcomes and reported conflicting results. To quantitatively assess this association, we have conducted a meta‐analysis of prospective studies. Databases and reference lists of relevant studies were searched using MEDLINE and EMBASE up to January 2013. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated using random‐effects models. For this meta‐analysis, a total of seven prospective cohort studies were included. The analysis included 5,299 patients for prediagnosis PA and 6,348 patients for postdiagnosis PA, followed up over a period ranging from 3.8 to 11.9 years. The analyses showed that patients who participated in any amount of PA before diagnosis had a RR of 0.75 (95% CI: 0.65–0.87, p < 0.001) for colorectal cancer‐specific mortality compared to patients who did not participate in any PA. Those who participated in high PA before diagnosis (vs. low PA) had a RR of 0.70 (95% CI: 0.56–0.87, p = 0.002). Similarly, patients who participated in any PA after diagnosis had a RR of 0.74 (95% CI: 0.58–0.95, p = 0.02) for colorectal cancer‐specific mortality compared to patients who did not participate in any PA. Those who participated in high PA after diagnosis (vs. low PA) had a RR of 0.65 (95% CI: 0.47–0.92, p = 0.01). Similar inverse associations of prediagnosis or postdiagnosis PA were found for all‐cause mortality. In conclusion, both prediagnosis and postdiagnosis PA were associated with reduced colorectal cancer‐specific mortality and all‐cause mortality.