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.     

Efficacy of interventions for prevention of chemotherapy‐induced alopecia: A systematic review and meta‐analysis

Chemotherapy‐induced alopecia (CIA) is a highly distressing event for cancer patients, and hence, we here aimed to assess the efficacy of various interventions in the prevention of CIA. We searched PubMed, EMBASE and the Cochrane Library, from June 20, 2013 through August 31, 2013. Two of the authors independently reviewed and selected clinical trials that reported the efficacy of any intervention for prevention of CIA compared with that of controls. Two authors extracted data independently on dichotomized outcome in terms of CIA occurrence. Relative risks (RRs) and 95% confidential intervals (CIs) were calculated for efficacy of CIA prevention by using random‐effect or fixed‐effect models. Out of 691 articles retrieved, a total of eight randomized controlled trials and nine controlled clinical trials involving 1,098 participants (616 interventions and 482 controls), were included in the final analyses. Scalp cooling, scalp compression, a combination of cooling and compression, topical minoxidil and Panicum miliaceum were used as interventions. The participants were mainly breast cancer patients receiving doxorubicin‐ or epirubicin‐containing chemotherapy. Scalp cooling, which is the most popular preventive method, significantly reduced the risk of CIA (RR = 0.38, 95% CI = 0.32–0.45), whereas topical 2% minoxidil and other interventions did not significantly reduce the risk of CIA. No serious adverse effects associated with scalp cooling were reported. Our results suggest that scalp cooling can prevent CIA in patients receiving chemotherapy. However, the long‐term safety of scalp cooling should be confirmed in further studies.     

Frontline treatment for transplant‐eligible multiple myeloma: A 6474 patients network meta‐analysis

Autologous transplantation continues to be the cornerstone of younger and fit multiple myeloma patients. It is known that frontline induction therapy before transplantation can influence post‐transplant results. Therefore, best frontline treatment for transplant‐eligible patients should be based on best available evidence to guide therapy. Furthermore, until now due to data scarcity, it was not possible to thoroughly compare lenalidomide to other regimens in this setting. We performed a systematic review and network (mixed treatment comparison) meta‐analysis of 21 clinical trial publications, enrolling 6474 patients and comparing 11 different treatment frontline setting regimens regarding survival, response, and safety outcomes. OS analysis showed superiority of CRD (cyclophosphamide‐lenalidomide‐dexamethasone) over TD‐based (thalidomide‐dexamethasone, HR = 0.76,0.62‐0.90), VAD‐based (HR = 0.71,0.52‐0.90), and Z‐Dex (idarubicin‐dexamethasone, HR = 0.37,0.17‐0.76) regimens. Concerning PFS, VTD (bortezomib‐thalidomide‐dexametasone) showed superior results when compared with TD‐based (HR = 0.66,0.51‐0.84), VAD‐based (HR = 0.61,0.46‐0.82), Z‐Dex (HR = 0.42,0.22‐0.78), and high dose dexamethasone (Dex, HR = 0.62,0.41‐0.90) regimens. Bortezomib/thalidomide regimens were not superior to lenalidomide, considering these outcomes. Also, concerning complete and overall response, VTD ranked first among other regimens, showing clear superiority over thalidomide‐only containing protocols. Safety outcome evaluated infectious, cardiac, gastrointestinal, neurological, thrombotic, and hematological grade 3 to 4 adverse events. Risk of thrombotic events was higher with TAD (thalidomide‐doxorubicin‐dexamethasone), neurological with PAD (bortezomib‐doxorubicin‐dexamethasone), infectious with Dex, hematological with Z‐Dex, gastrointestinal with VTD, and cardiac with PAD regimens. Our study endorses current recommendations on combined immunomodulatory drugs and proteasome inhibitors frontline regimens (in triplets) in transplant‐eligible multiple myeloma patients, but also formally demonstrates the favorable performance of lenalidomide in overall and progression‐free survival, when compared with bortezomib/thalidomide protocols.     

A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma

BACKGROUND: The use of adjuvant chemotherapy to treat adults with localized resectable soft-tissue sarcoma remains controversial. The objective of this systematic review was to update the 1997 meta-analysis of randomized controlled trials (RCTs) to reassess the efficacy of doxorubicin-based chemotherapy with respect to recurrence and survival. METHODS: A comprehensive literature search was performed to identify RCTs of adjuvant chemotherapy for adult patients diagnosed with localized resectable soft-tissue sarcoma. Two reviewers independently assessed eligibility and quality of the studies using a modified version of the Detsky Quality Scale. The outcome measures were local, distant, and overall recurrence and survival calculated through the fixed effect or random effect model. RESULTS: Four new eligible trials were identified allowing for a total of 18 trials representing 1953 patients to be included in the analysis. The odds ratios (OR) for local recurrence was 0.73 (95% confidence interval [CI] 0.56-0.94; P = .02) in favor of chemotherapy. For distant and overall recurrence the OR was 0.67 (95% CI 0.56-0.82; P = .0001) in favor of chemotherapy. In terms of survival, doxorubicin alone had an OR of 0.84 (95% CI, 0.68-1.03; P = .09), which as not statistically significant. However, the OR for doxorubicin combined with ifosfamide was 0.56 (95% CI, 0.36-0.85; P = .01) in favor of chemotherapy. CONCLUSIONS: This updated meta-analysis confirms the marginal efficacy of chemotherapy in localized resectable soft-tissue sarcoma with respect to local recurrence, distant recurrence, overall recurrence, and overall survival. These benefits are further improved with the addition of ifosfamide to doxorubicin-based regimens, but must be weighed against associated toxicities.     

Neoadjuvant treatments for locally advanced,resectable esophageal cancer: A network meta‐analysis

The relative survival benefits and postoperative mortality among the different types of neoadjuvant treatments (such as chemotherapy only, radiotherapy only or chemoradiotherapy) for esophageal cancer patients are not well established. To evaluate the relative efficacy and safety of neoadjuvant therapies in resectable esophageal cancer, a Bayesian network meta‐analysis was performed. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched for publications up to May 2016. ASCO and ASTRO annual meeting abstracts were also searched up to the 2015 conferences. Randomized controlled trials that compared at least two of the following treatments for resectable esophageal cancer were included: surgery alone, surgery preceded by neoadjuvant chemotherapy, neoadjuvant radiotherapy or neoadjuvant chemoradiotherapy. The primary outcome assessed from the trials was overall survival. Thirty‐one randomized controlled trials involving 5496 patients were included in the quantitative analysis. The network meta‐analysis showed that neoadjuvant chemoradiotherapy improved overall survival when compared to all other treatments including surgery alone (HR 0.75, 95% CR 0.67–0.85), neoadjuvant chemotherapy (HR 0.83. 95% CR 0.70–0.96) and neoadjuvant radiotherapy (HR 0.82, 95% CR 0.67–0.99). However, the risk of postoperative mortality increased when comparing neoadjuvant chemoradiotherapy to either surgery alone (RR 1.46, 95% CR 1.00–2.14) or to neoadjuvant chemotherapy (RR 1.58, 95% CR 1.00–2.49). In conclusion, neoadjuvant chemoradiotherapy improves overall survival but may also increase the risk of postoperative mortality in patients locally advanced resectable esophageal carcinoma.     

How to conduct meta‐analysis for studies with multiple intervention groups

In this letter, we will introduce how to conduct a correct meta‐analysis for studies with multiple intervention groups.     

Adjuvant chemotherapy for patients with primary hepatocellular carcinoma: A meta‐analysis

Numerous studies have investigated the effects of adjuvant chemotherapy for primary hepatocellular carcinoma (HCC) patients. We conducted this analysis to evaluate the efficacy of adjuvant chemotherapy in HCC patients after hepatectomy. PubMed/MEDLINE, EMBASE, Cochrane, and other databases were searched for eligible studies. The major endpoints were overall survival (OS) and disease‐free survival (DFS). The pooled odds ratio (OR) was calculated using a random‐effects model to summarize the results. In the meta‐analysis of 13 randomized control trials (RCTs) and 35 observational studies with 4747 patients, hepatectomy plus adjuvant chemotherapy showed superiority over hepatectomy alone in 1‐year DFS (OR = 1.86, 1.38–2.51, p < 0.001), 3‐year DFS (OR = 2.37, 1.73–3.24, p < 0.001) and 5‐year DFS (OR = 1.99, 1.55–2.55, p < 0.001), as well as 1‐year OS (OR = 2.16, 95% confidence interval 1.75–2.68, p < 0.001), 3‐year OS (OR = 1.77, 1.48–2.13, p < 0.001) and 5‐year OS (OR = 1.92, 1.44–2.56, p < 0.001). Subgroup and sensitivity analysis revealed that only adjuvant TACE had significant survival benefits. The meta‐analysis of studies involving patients with portal vein tumor thrombus (PVTT), but not other factors related to recurrence risk, revealed favorable outcomes of the Treatment arm over the Control arm. The present study shows that adjuvant chemotherapy can improve outcomes for HCC patients. The benefits of adjuvant TACE have been confirmed whereas the effects of other adjuvant chemotherapy modalities remain uncertain. Adjuvant chemotherapy is likely to be more applicable to certain patient populations for instance those with PVTT, but further research in identifying these patient factors is of importance for tailoring adjuvant therapies to individual patients in the future.     

旋覆代赭汤加味防治肿瘤化疗后恶心呕吐随机对照试验的Meta分析

目的:评价旋覆代赭汤加味防治肿瘤化疗引起的恶心、呕吐的疗效.方法:计算机检索中国期刊全文数据库和维普中文期刊数据库、万方学术期刊全文数据库2001-01-2010-12的相关文献,收集中药旋覆代赭汤预防肿瘤化疗引起的恶心、呕吐的随机对照试验(RCT).按纳入排除标准筛选试验、评价研究质量、提取有效数据,并采用RevMan 5.0进行统计分析.结果:最终纳入12个RCTs,Meta分析显示,有效率(RR)为1.20,95％CI(1.13～1.27),差异有统计学意义,P＜0.01.进行敏感性分析,结果稳定.漏斗图显示不对称,提示纳入评价的文献存在发表性偏倚.结论:中药旋覆代赭汤预防肿瘤化疗引起的恶心、呕吐有效,但由于本系统评价纳入研究的方法学质量较低,尚需开展更多设计合理、执行严格的多中心大样本且随访时间足够长的RCTs验证其疗效及安全性.     

Treatment of hepatocellular carcinoma: A systematic review of randomized controlled trials

Background: Hepatocellular carcinoma (HCC) is a leading cause ofcancer-related death. Many treatments have been proposed but considerableuncertainty still remains about their effectiveness. In this review weevaluated the quality, clinical coherence, consistency and results ofRandomized Controlled Trials (RCT) of non-surgical treatments for HCC.Methods: Thirty-seven RCTs examining the effect of differenttreatments were retrieved using MEDLINE (November 1978 to December 1995) anda review of reference lists. Selected aspects of the quality of design,conduct and reporting were examined. The odds ratio for the probability ofsurviving up to one year was calculated according to theMantel–Haenszel–Peto method and displayed using l'Abbéplots.Results: The 37 RCTs overall included 2803 patients (median 56, range20–289). Patients prognosis varied widely across studies which alsofailed to report on important information about their characteristics. Only10 RCTs had an untreated control group; the remaining 27 compared differentregimens of intravenous or intraarterial chemotherapy with or withoutembolization of hepatic artery, hormono- and immunotherapy regimens. Someevidence of a moderate benefit emerged only from RCTs using tamoxifen andtranscatheter arterial embolization vs. no treatment in unresectable patients:pooled odds ratio for 1-year survival were, respectively, 2.0 (95%confidence intervals (CI) 1.1–3.6) and 2.0 (95% CI1.1–3.6). At 2 years, however, pooled odds ratio were no longerstatistically significant for tamoxifen 1.2 (95% CI 0.6–2.6) butwas significant for embolization 2.3 (95% CI 1.2–4.6). Noevidence of efficacy was detected for embolization as adjuvant therapy inresected or transplantated patients nor for chemotherapy added tointraarterial embolization.Conclusions: This systematic review of RCTs on HCC, mostly in nonresectable patients, indicate that the non-surgical current treatments areineffective or minimally uncertainly effective. The three treatment modalitiesminimally and uncertainly effective (i.e., embolization, tamofixen, and IFN)can deserve further assessment by larger and methodologically more soundrandomized trials     

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.     

Safety and efficacy of nivolumab in the treatment of cancers: A meta‐analysis of 27 prospective clinical trials

Immune checkpoint inhibition therapy has benefited people and shown powerful anti‐tumor activity during the past several years. Nivolumab, a fully human IgG4 monoclonal antibody against PD‐1, is a widely studied immune checkpoint inhibitor for the treatment of cancers. To assess the safety and efficacy of nivolumab, 27 clinical trials on nivolumab were analyzed. Results showed that the summary risks of all grade adverse effects (AEs) and grade ≥3 AEs were 0.65 and 0.12. The rate of nivolumab‐related death was 0.25%. The most common any grade AEs were fatigue (25.1%), rush (13.0%), pruritus (12.5%), diarrhea (12.1%), nausea (11.8%) and asthenia (10.4%). The most common grade ≥3 AEs were hypophosphatemia (only 2.3%) and lymphopenia (only 2.1%). The pooled objective response rate (ORR), 6‐month progression‐free survival (PFS) rate and 1‐year overall survival (OS) rate were 0.26, 0.40 and 0.52, respectively. The odds ratio of ORR between PD‐L1 positive and negative was 2.34 (95% CI 1.77–3.10, p < 0.0001). The odds ratios of ORR, 6‐month PFS rate and 1‐year OS rate between nivolumab and chemotherapeutics were 2.77 (95% CI 1.69–4.56, p < 0.0001), 1.97 (95% CI 1.02–3.81, p = 0.04) and 1.87 (95% CI 1.46–2.40, p <0.0001), respectively. In conclusion, nivolumab has durable outcomes with tolerable AEs and drug‐related deaths in cancer patients. Nivolumab monotherapy has better treatment response compared with chemotherapy, whereas chemotherapeutics have significantly higher risk of adverse effects than nivolumab.     

Overall survival benefits for irinotecan‐containing regimens as first‐line treatment for advanced gastric cancer: An updated meta‐analysis of ten randomized controlled trials

The standard treatment for patients with advanced gastric cancer (AGC) is still debated, and the available data on the benefit of irinotecan‐containing regimen as first‐line treatment for those patients are controversial. We performed a systematic review and meta‐analysis of randomized controlled trials to determine the survival benefits of irinotecan‐containing regimens in this setting. A total of 1,837 patients from ten trials were included in the analysis. Our results showed that irinotecan‐containing regimens significantly improved overall survival [OS: hazard ratio (HR) 0.86, 95% CI = 0.78–0.94, p = 0.002] and progression‐free survival [HR = 0.82, 95% CI = 0.69–0.97, p = 0.026); however, the improvement of time to failure (HR = 0.90; 95% CI = 0.77–1.04, p = 0.15), 1‐year survival rate [1‐year SR: relative risk (RR) 1.10, 95% CI = 0.97–1.24, p = 0.13] and overall response rate (RR = 1.16, 95% CI = 0.91–1.49, p = 0.24] were nonsignificant. Equivalent frequencies of toxicities were found between the two groups excluding more Grade 3 or 4 fatigue (p = 0.001) in irinotecan‐containing regimens. This updated meta‐analysis provided strong evidence for a survival benefit of irinotecan‐containing regimen as first‐line treatment for AGC. A clear advantage of irinotecan‐containing over nonirinotecan‐containing regimen had not been established. These results should help to inform decisions about patient management and design of future trials.     

Hematologic toxicity assessment in solid tumor patients treated with cetuximab: A pooled analysis of 18 randomized controlled trials

The role of cetuximab in treatment‐related hematologic toxicity is not clear. We performed a meta‐analysis of published randomized controlled trials (RCTs) to determine the overall risk of ≥grade 3 hematologic toxicity events (HTEs) associated with cetuximab. PubMed, EMBASE, and Web of Knowledge databases as well as abstracts presented at American Society of Clinical Oncology conferences and ClinicalTrials.gov were searched to identify relevant studies. Eligible studies included RCTs in which cetuximab in combination with chemotherapy or chemoradiotherapy was compared with chemotherapy or chemoradiotherapy alone. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using fixed‐ or random‐effects models. A total of 11,234 patients with a variety of advanced solid tumors from 18 RCTs were included in the meta‐analysis. Compared with chemotherapy alone, the addition of cetuximab was associated with increased risks of ≥grade 3 leucopenia/neutropenia and anemia events in colorectal cancer, with RRs of 1.16 (95% CI 1.05–1.27, p = 0.002; incidence, 21.0 vs. 18.0%) and 2.67 (95% CI 1.53–4.65, p = 0.01; incidence, 4.0 vs. 2.0%), respectively. Cetuximab was also associated with an increased risk of leucopenia/neutropenia in nonsmall cell lung cancer (NSCLC) (RR: 1.15; 95% CI 1.08–1.22, p < 0.01). Additionally, K‐ras wild type in the case of colorectal cancer patients was more vulnerable to ≥grade 3 leucopenia or neutropenia events in cetuximab group (RR: 1.31; 95% CI 1.11–1.54, p = 0.001). With present evidence, cetuximab in conjunction with chemotherapy or chemoradiotherapy, compared with chemotherapy or chemoradiotherapy alone, was associated with increased slight risk of ≥grade 3 HTEs, especially in colorectal cancer and NSCLC.     

香菇多糖治疗恶性胸腔积液随机对照试验的Meta分析

目的:运用系统评价Meta分析的方法评价香菇多糖(LNT)单药或联合其他药物治疗恶性胸腔积液(MPE)的临床疗效及安全性。方法:应用Pubmed、Cochrane图书馆、Embase、CBM、CNKI、维普及万方数据库系统,全面收集有关LNT单药或联合其他药物治疗MPE的临床对照研究。结果:本系统评价共纳入17篇随机对照试验,共计978例患者,其中LNT组500例,顺铂组478例。Meta分析结果显示,LNT组临床有效率明显优于顺铂组(OR=3.68,95%CI=2.75～4.94;P<0.000 01);LNT组治疗后Karnofsky评分升高患者例数均显著多于顺铂组患者(OR=3.79,95%CI=2.46～5.84,P<0.000 01),其降低及稳定患者例数明显低于顺铂组患者(OR=0.41,95%CI=0.21～0.78,P=0.007;OR=0.37,95%CI=0.22～0.60,P<0.000 1);LNT组胃肠道反应和血液学毒性发生率较顺铂组明显减少(OR=0.31,95%CI=0.21～0.47,P<0.000 01;OR=0.49,95%CI=0.28～0.84,P=0.01)。结论:现有证据表明,LNT单药或联合其他药物治疗MEP的临床疗效及安全性均优于顺铂单药,可广泛应用于临床治疗晚期肿瘤恶性胸腔积液。