Survival after radiotherapy in gastric cancer: Systematic review and meta-analysis

Background and purpose

A systematic review and meta-analysis was performed to assess the impact of radiotherapy on both 3- and 5-year survival in patients with resectable gastric cancer.

Methods

Randomized Clinical Trials (RCTs) in which radiotherapy, (preoperative, postoperative and/or intraoperative), was compared with surgery alone or surgery plus chemotherapy in resectable gastric cancer were identified by searching web-based databases and supplemented by manual examination of reference lists. Meta-analysis was performed using Risk Ratios (RRs). Random or fixed effects models were used to combine data. The methodological quality was evaluated by Chalmers’ score.

Results

Radiotherapy had a significant impact on 5-year survival. Using an intent to treat (ITT) and a Per Protocol (PP) analysis, the overall 5-year RR was 1.26 (95% CI: 1.08-1.48; NNT = 17) and 1.31 (95% CI: 1.04-1.66; NNT = 13), respectively. Although the quality of the studies was variable, the data were consistent and no clear publication bias was found.

Conclusion

This meta-analysis showed a statistically significant 5-year survival benefit with the addition of radiotherapy in patients with resectable gastric cancer. Radiotherapy remains a standard component in the treatment of resectable gastric cancer and new RCTs need to address the impact of new conformal radiotherapy technologies.     

Empirical antifungal therapy for patients with neutropenia and persistent fever: Systematic review and meta-analysis

ObjectivesTo assess the evidence for the current standard of practice of using empirical antifungal treatment in febrile neutropenic cancer patients.MethodsSystematic review and meta-analysis of randomised controlled trials comparing empirical or preemptive antifungal treatment with placebo, no intervention, or another antifungal. The primary outcomes were all-cause mortality and invasive fungal infections (IFI) (documented or probable). Relative risks (RR) with 95% confidence intervals (CI) were pooled.ResultsSix trials assessed the efficacy of empirical treatment compared to no treatment and one compared empirical to preemptive therapy. Empirical treatment did not decrease mortality significantly (RR 0.82, 95% CI 0.50–1.34), but significantly decreased IFIs (RR 0.25, 0.12–0.54). Twenty-three trials assessed the efficiency of different antifungals. All-cause mortality was lower with azoles compared to amphotericin B (AB) (RR 0.81, 0.65–1.01); IFI rates were not different while adverse events were less frequent with azoles (RR 0.40; 0.34–0.66). Liposomal AB was associated with lower mortality and IFIs than other AB formulations (RR 1.57, 1.10–2.23 and 1.48, 0.98–2.25, respectively). Caspofungin was associated with fewer adverse events, but otherwise comparable to liposomal AB. All trials included patients with haematological malignancies. Major limitations included per-protocol analysis, non-blinded design and inconsistent definitions of IFIs.ConclusionsEmpirical antifungal treatment is associated with a lower rate of IFIs but no significant difference in overall mortality. The assessment of IFIs in these trials may have been biased, offering only weak support to standard practice. Azoles, liposomal amphotericin B or caspofungin should be preferred. Pre-emptive antifungal therapy should be considered and further investigated.     

Population attributable risk of aflatoxin-related liver cancer: Systematic review and meta-analysis

BackgroundOver 4 billion people worldwide are exposed to dietary aflatoxins, which cause liver cancer (hepatocellular carcinoma, HCC) in humans. However, the population attributable risk (PAR) of aflatoxin-related HCC remains unclear.MethodsIn our systematic review and meta-analysis of epidemiological studies, summary odds ratios (ORs) of aflatoxin-related HCC with 95% confidence intervals were calculated in HBV+ and HBV− individuals, as well as the general population. We calculated the PAR of aflatoxin-related HCC for each study as well as the combined studies, accounting for HBV status.ResultsSeventeen studies with 1680 HCC cases and 3052 controls were identified from 479 articles. All eligible studies were conducted in China, Taiwan, or sub-Saharan Africa. The PAR of aflatoxin-related HCC was estimated at 17% (14–19%) overall, and higher in HBV+ (21%) than HBV− (8.8%) populations. If the one study that contributed most to heterogeneity in the analysis is excluded, the summarised OR of HCC with 95% CI is 73.0 (36.0–148.3) from the combined effects of aflatoxin and HBV, 11.3 (6.75–18.9) from HBV only and 6.37 (3.74–10.86) from aflatoxin only. The PAR of aflatoxin-related HCC increases to 23% (21–24%). The PAR has decreased over time in certain Taiwanese and Chinese populations.ConclusionsIn high exposure areas, aflatoxin multiplicatively interacts with HBV to induce HCC; reducing aflatoxin exposure to non-detectable levels could reduce HCC cases in high-risk areas by about 23%. The decreasing PAR of aflatoxin-related HCC reflects the benefits of public health interventions to reduce aflatoxin and HBV.     

Venous thromboembolism prophylaxis in brain tumor patients undergoing craniotomy: a meta-analysis

Brain tumor patients undergoing craniotomy generally receive prophylaxis against venous thromboembolism (VTE), but modalities in use differ widely and have been debated in the literature. A systematic review and meta-analysis was conducted to assess the efficacy and safety of VTE prophylaxis among brain tumor patients undergoing craniotomy. Ten randomized controlled trials were included in the final efficacy analysis. The various prophylactic measures employed in these studies reduced the risk for thrombosis compared to controls with an overall risk ratio of 0.61 (95?% CI: 0.47–0.79) in the fixed effect model. Although Cochrane Q-test showed unimportant heterogeneity across studies (p?=?0.19) and the I², a measure of heterogeneity between studies, was reasonably low at 28?%, subgroup analysis indicated that intervention type was a potential effect modifier for efficacy (p?=?0.04). Unfractionated heparin alone showed a stronger reduction in VTE risk compared to placebo (RR?=?0.27; 95?% CI: 0.10–0.73), and LMWH combined with mechanical prophylaxis showed a lower VTE risk as compared to mechanical prophylaxis alone (0.61; 95?% CI: 0.46–0.82). This meta-analysis demonstrates a statistically significant VTE risk reduction among brain tumor patients receiving prophylaxis, with chemical prophylaxis showing the strongest risk reduction. Five studies were included in the safety analysis, which showed an overall increased risk of bleeding comparing different prophylactic measures to different controls (RR?=?2.02; 95?% CI: 1.14–3.58; I²?=?0?%; p?=?0.86). Interventions in these studies were associated with an increased risk of post-operative, minor hemorrhage (RR?=?2.20; 95?% CI?=?1.00; 4.85), while the risk of major hemorrhage was not increased by chemoprophylaxis.     

Intensity-modulated radiation therapy for head and neck cancer: Systematic review and meta-analysis

Background and purpose

Intensity-modulated radiation therapy (IMRT) provides the possibility of dose-escalation with better normal tissue sparing. This study was performed to assess whether IMRT can improve clinical outcomes when compared with two-dimensional (2D-RT) or three-dimensional conformal radiation therapy (3D-CRT) in patients with head and neck cancer.

Methods and materials

Only prospective phase III randomized trials comparing IMRT with 2D-RT or 3D-CRT were eligible. Combined surgery and/or chemotherapy were allowed. Two authors independently selected and assessed the studies regarding eligibility criteria and risk of bias.

Results

Five studies were selected. A total of 871 patients were randomly assigned for 2D-RT or 3D-CRT (437), versus IMRT (434). Most patients presented with nasopharyngeal cancers (82%), and stages III/IV (62.1%). Three studies were classified as having unclear risk and two as high risk of bias. A significant overall benefit in favor of IMRT was found (hazard ratio – HR = 0.76; 95% CI: 0.66, 0.87; p < 0.0001) regarding xerostomia scores grade 2–4, with similar loco-regional control and overall survival.

Conclusions

IMRT reduces the incidence of grade 2–4 xerostomia in patients with head and neck cancers without compromising loco-regional control and overall survival.     

Use of laser-assisted indocyanine green angiography in breast reconstruction: Systematic review and meta-analysis

Laser-assisted indocyanine green angiography allows surgeons to determine intraoperative flap perfusion and achieve the best outcomes in breast reconstruction. This study stratified outcomes based on a meta-analysis of complications including longitudinal trials comparing the clinical assessment of skin flaps during breast reconstruction. Nine studies met inclusion criteria and reported outcomes of interest (n = 2256). The risk of flap necrosis and the necessity of reoperation was statistically significantly higher in the control group.     

Systematic review and meta-analysis of insulin therapy and risk of cancer

Recent epidemiological studies suggest that treatment with insulin may promote cancer growth. The present systematic review and meta-analysis of published observational studies was conducted to assess the risk of cancer during treatment with insulin. A search of online database through January 2011 was performed and examined the reference lists of pertinent articles, limited to observational studies in humans. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated with a random-effects model. Fifteen studies (five case-control and ten cohort studies) were included, with 562,043 participants and 14,085 cases of cancer. Insulin treatment was associated with an increased risk of overall cancer [summary RR (95% CI)=1.39 (1.14, 1.70)]. Summary RR (9% CI) for case-control studies was 1.83 (0.99, 3.38), whereas RR for cohort studies was 1.28 (1.03, 1.59). These results were consistent between studies conducted in the USA and in Europe. For studies that included combined type 1 and 2 diabetes, the summary estimate was stronger than studies including only type 2 diabetes mellitus. The association between insulin treatment and cancer was stronger for pancreatic cancer [summary RR (95% CI)=4.78 (3.12, 7.32)] than for colorectal cancer [1.50 (1.08, 2.08)]. Insulin treatment was not associated with breast, prostate, and hepatocelluar cancer, and their effect estimates were not statistically significant. Our findings support an association between insulin use and increased risk of overall, pancreatic, and colorectal cancer.     

Systematic review and meta-analysis of immunohistochemical prognostic biomarkers in resected oesophageal adenocarcinoma

Background:

Oesophageal adenocarcinoma (OAC) is one of the fastest rising malignancies with continued poor prognosis. Many studies have proposed novel biomarkers but, to date, no immunohistochemical markers of survival after oesophageal resection have entered clinical practice. Here, we systematically review and meta-analyse the published literature, to identify potential biomarkers.

Methods:

Relevant articles were identified via Ovid medline 1946–2013. For inclusion, studies had to conform to REporting recommendations for tumor MARKer (REMARK) prognostic study criteria. The primary end-point was a pooled hazard ratio (HR) and variance, summarising the effect of marker expression on prognosis.

Results:

A total of 3059 articles were identified. After exclusion of irrelevant titles and abstracts, 214 articles were reviewed in full. Nine molecules had been examined in more than one study (CD3, CD8, COX-2, EGFR, HER2, Ki67, LgR5, p53 and VEGF) and were meta-analysed. Markers with largest survival effects were COX-2 (HR=2.47, confidence interval (CI)=1.15–3.79), CD3 (HR=0.51, 95% CI=0.32–0.70), CD8 (HR=0.55, CI=0.31–0.80) and EGFR (HR=1.65, 95% CI=1.14–2.16).

Discussion:

Current methods have not delivered clinically useful molecular prognostic biomarkers in OAC. We have highlighted the paucity of good-quality robust studies in this field. A genome-to-protein approach would be better suited for the development and subsequent validation of biomarkers. Large collaborative projects with standardised methodology will be required to generate clinically useful biomarkers.     

Impact of antifungal prophylaxis on the gastrointestinal yeast colonisation in patients with haematological malignancies

Patients with haematological malignancies are at high risk for developing invasive Candida infections. They are often colonised with Candida spp. in the gastrointestinal (GI) tract. In order to prevent infection, the prophylactic use of antifungal agents has been established. The widespread use of fluconazole may lead to the emergence of resistant Candida isolates. We studied the yeast colonisation of the GI tract in patients with haematological malignancies receiving antifungal prophylaxis (AP) in comparison with healthy controls. The study cohort included 46 neutropenic patients with 52 stool samples under 52 episodes of AP and 110 healthy controls. The patients received amphotericin B orally (n = 8), amphotericin B and fluconazole (n = 7), amphotericin B and itraconazole (n = 5), fluconazole orally (n = 15) and itraconazole orally (n = 17). Yeasts were cultured from the stool samples of 63.5% of the patients and 60% of the controls with a mean yeast load of 1.6 x 10(3) and 0.4 x 10(3) cfu g(-1), respectively (P = 0.045). Patients and controls had a low faecal yeast load of 10(3) to 10(4) cfu g(-1) in 19.3% and 37.3%, respectively (P = 0.021), and yeast overgrowth of >10(5) cfu g(-1) in 28.9% and 10.9%, respectively (P = 0.004). The rate of Candida albicans was 32.6% and 54.1% in the patients and controls, respectively (P = 0.021). The rates of fluconazole-resistant yeast species were higher in the patient group than in the control group: C. glabrata 20.9% vs. 11.7% (P = 0.168), C. krusei 25.6% vs. 4.7% (P = 0.001). Not a single patient under AP suffered from proven or probable invasive candidosis. In conclusion, oral AP in haematological patients resulted in a higher colonisation rate with fluconazole-resistant Candida species but efficiently prevented invasive candidosis.     

Antiviral prophylaxis in patients with haematological malignancies and solid tumours: Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Oncology (DGHO).

Morbidity and mortality in patients with malignancies are increased by viral infections. These mostly are reactivations of asymptomatic latent infections. They primarily concern clinical entities associated with the reactivation of herpes viruses, such as varicella zoster virus (VZV) and cytomegalovirus (CMV). Respiratory tract infections caused by influenza, parainfluenza or respiratory syncytial virus (RSV) are less common. Since reactivation of latent infections has major clinical impact, antiviral prophylaxis is an attractive approach for patients expecting immunosuppression. The main risk factor for clinically relevant reactivation is profound disruption of cellular immune response. Duration and severity of chemotherapy induced neutropenia are of lesser importance. The risk of viral complications rises significantly in the presence of sustained suppression of T-cell function, e.g. in recipients of allogeneic stem cell transplants or of alemtuzumab (Campath-1H) antibody therapy. The objective of this guideline is to review the basis of prophylactic strategies and to provide recommendations for clinicians treating patients with haematological malignancies and solid tumors.     

Serum 25-hydroxyvitamin D levels and survival in colorectal and breast cancer patients: Systematic review and meta-analysis of prospective cohort studies

AimTo estimate the association between serum 25-hydroxyvitamin D (25(OH)D) levels and survival among colorectal and breast cancer patients.MethodsWe performed a comprehensive literature search of prospective cohort studies assessing the association of serum 25(OH)D levels with survival in colorectal and breast cancer patients. Study characteristics and results were extracted and dose–response relationships were graphically displayed in a standardised manner. Meta-analyses using random effects models were performed to estimate pooled hazard ratios.ResultsThe systematic search yielded five studies including 2330 colorectal cancer patients and five studies including 4413 breast cancer patients all of which compared mortality across two to five categories of 25(OH)D levels. Among colorectal cancer patients, pooled hazard ratios (95% confidence intervals) comparing highest with lowest categories were 0.71 (0.55–0.91) and 0.65 (0.49–0.86) for overall and disease-specific mortality, respectively. For breast cancer patients, the corresponding pooled estimates were 0.62 (0.49–0.78) and 0.58 (0.38–0.84), respectively. No significant evidence of heterogeneity between studies was observed.ConclusionHigher 25(OH)D levels (>75 nmol/L) were associated with significantly reduced mortality in patients with colorectal and breast cancer. Randomised controlled trials are needed to evaluate whether vitamin D supplementation can improve survival in colorectal and breast cancer patients with low vitamin D status (25(OH)D < 50 nmol/L) at diagnosis and before treatment.     

Systematic review and meta-analysis of the complications of salvage total laryngectomy

Background and objectives

Management paradigms in laryngeal cancer have shifted to “organ preservation” chemoradiotherapy protocols. In the event of treatment failure, salvage total laryngectomy remains the only curative treatment option. However a comprehensive review of the complications of this procedure has not been reported.

Systematic review and meta-analysis on vitamin D receptor polymorphisms and cancer risk

The vitamin D receptor (VDR) can influence cancer susceptibility through binding to vitamin D. However, the previous studies were contradictory. Therefore this meta-analysis was conducted to clarify the association between VDR polymorphisms (BsmI, TaqI, FokI, and ApaI) and cancer risk. One hundred twenty-six studies were enrolled through PubMed. For VDR BsmI polymorphism, significantly increased cancer risks were observed in the overall analysis. In the further stratified analysis, increased risks were observed in colorectal and skin cancer, especially in Caucasian population. However, no significant associations were observed in other VDR polymorphisms in the overall analysis. In the further subgroup analysis, increased risks were found in oral, breast, and basal cell cancer while decreased risk was found in prostate cancer in t allele carriers of TaqI polymorphism. For VDR FokI polymorphism, increased risks were found in ovarian and skin cancer while decreased risk in glioma in f allele carriers. For VDR ApaI polymorphism, increased risk was observed in basal cell cancer, especially in Asian population in a allele carriers. In conclusion, these results indicated that b allele of BamI polymorphism was a risk factor for cancer susceptibility. Meanwhile, t allele of TaqI polymorphism was a risk factor for oral, breast, and basal cell cancer and a protective factor for prostate cancer. Moreover, f allele of FokI polymorphism was a risk factor for ovarian and skin cancer and a protective factor for glioma. Finally, a allele of ApaI polymorphism was a risk factor for basal cell cancer in Asian population.     

Conventional cardiac risk factors associated with trastuzumab-induced cardiotoxicity in breast cancer: Systematic review and meta-analysis

Background: Trastuzumab has had a major impact on the treatment of human epidermal growth factor receptor 2 (HER2) positive breast cancer patients. However, it is associated with cardiotoxicity, expressed as an asymptomatic decrease in left ventricular ejection fraction (LVEF) and less often as clinical HF. The aim of this meta-analysis is to identify the association of conventional cardiovascular risk factors with the development of trastuzumab-induced cardiotoxicity (TIC). Methods: A literature search of PubMed was conducted to identify studies examining the association between cardiovascular risk factors and TIC. Data were extracted and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated examining the odds of developing TIC for each of the risk factors. Results: A total of 35 studies were included in the analysis. Age (OR:0.7; 95%CI 0.318-1.09; P= 0.0004), hypertension (OR:0.69; 95%CI 0.26-1.12; P = 0.001), smoking(OR:0.35; 95%CI 0.01- 0.69; P = 0.038), diabetes mellitus (OR:0.44; 95%CI 0.24- 0.68; P = 0.0001) and family history of CAD (OR:5.51, 95%CI 1.76-17.25; P< 0.00001)were significantly associated with the development of cardiotoxicity. Known history of CAD (OR: 3.72; 95%CI 2.11-6.57; P = 0.0005) was also associated with the development of TIC. Conclusion(s): Identifying women at risk for TIC have several important potential applications. Clinicians may decide to assess LVEF more frequently in patients at highest risk for TIC in order to detect LV systolic dysfunction earlier. Additionally, this could help identify patients who would benefit most from prophylactic therapy for preventing TIC.     

Systematic review and meta-analysis of monotherapy compared with combined androgen blockade for patients with advanced prostate carcinoma

BACKGROUND: The current systematic review and meta-analysis compared monotherapy and combined androgen blockade in the treatment of men with advanced prostate carcinoma. Outcomes of interest included overall, cancer specific, and progression-free survival; time to treatment failure; adverse events; and quality of life. METHODS: The literature search identified randomized trials comparing monotherapy (orchiectomy and luteinizing hormone-releasing hormone [LHRH] agonists) with combination therapy using orchiectomy or a LHRH agonist plus a nonsteroidal or steroidal antiandrogen. Dual independent review occurred. The meta-analysis used a random effects model. RESULTS: Twenty-one trials compared survival after monotherapy with survival after combined androgen blockade (n = 6871 patients). The meta-analysis found no statistically significant difference in survival at 2 years between patients treated with combined androgen blockade and those treated with monotherapy (20 trials; hazard ratio [HR] = 0.970; 95% confidence interval [95% CI], 0.866-1.087). The authors determined a statistically significant difference in survival at 5 years that favored combined androgen blockade (10 trials; HR = 0.871; 95% CI, 0.805-0.942). For the subgroup of patients with a good prognosis, there was no statistically significant difference in survival. Adverse effects leading to withdrawal from therapy occurred more often with combined androgen blockade. To the authors' knowledge there is little evidence published to date comparing the effects of combined androgen blockade and monotherapy on quality of life, but the single randomized trial that adequately addressed this outcome reported an advantage for monotherapy over combined androgen blockade. CONCLUSIONS: A thorough examination of the usefulness of combined androgen blockade must balance the modest increase in expected survival observed at 5 years against the increased risk of adverse effects and the potential for adversely affecting the patient's overall quality of life.     

Induction chemotherapy prior to surgery with or without postoperative radiotherapy for oral cavity cancer patients: Systematic review and meta-analysis

BackgroundLocoregionally advanced oral cavity cancers are aggressive tumours with high risk of relapse after definitive treatment. This study was performed to assess the effectiveness and safety of induction chemotherapy prior to surgery for untreated oral cavity cancer patients.Material and methodsOnly prospective phase III randomised studies comparing induction chemotherapy followed by surgery with or without postoperative radiotherapy (Chemo Group) compared with surgery with or without postoperative radiotherapy (Control Group) were eligible. Two of the authors independently selected and assessed the studies regarding eligibility criteria and risk of bias.ResultsTwo studies were selected. A total of 451 patients were randomly assigned to Chemo Group (n = 226) versus Control Group (n = 225). Most patients had tumours at clinical stages III/IV (89.1%). Both trials were classified as having low risk of bias. No significant overall benefit in favour of induction chemotherapy was found regarding loco-regional recurrence, disease-free survival and overall survival. A subgroup analysis of individual data from cN2 patients showed statistically significant overall survival benefit in favour of induction chemotherapy. The included studies did not directly compare toxicity between the groups and no statistical analysis was performed regarding safety outcomes.ConclusionsBased on the available studies, induction chemotherapy when administered before surgery with curative intent did not improve clinical outcomes in locoregionally advanced oral cavity cancer patients. Clinically assessed N2 patients might benefit from induction chemotherapy.