Real-World Use of Fedratinib for Myelofibrosis Following Prior Ruxolitinib Failure: Patient Characteristics, Treatment Patterns, and Clinical Outcomes.

BACKGROUND: There is a lack of established clinical outcomes for patients with myelofibrosis (MF) receiving fedratinib following ruxolitinib failure. This study examined real-world patient characteristics, treatment patterns, and clinical outcomes of patients with MF treated with fedratinib following ruxolitinib failure in US clinical practice. PATIENTS AND METHODS: This retrospective patient chart review included adults with a physician-reported diagnosis of MF, who initiated fedratinib after discontinuing ruxolitinib. Descriptive analyses characterized patient characteristics, clinical outcomes, and treatment patterns from MF diagnosis through ruxolitinib and fedratinib treatment. RESULTS: Twenty-four physicians abstracted data for 150 eligible patients. Approximately 55.3% of the patients were male, 68.0% were White, and median age at MF diagnosis was 68 (range, 35-84) years. Median duration of ruxolitinib therapy was 7.6 (range, 0.7-65.5) months. At initiation of fedratinib, 88.0% of patients had palpable spleen and a mean spleen size of 16.0 (standard deviation [SD], 5.9) cm. Spleen size decreased by 19.4% to 13.2 (SD, 7.9) cm at month 3 (P = .0001) and by 53.4% to 7.2 (SD, 7.4) cm at month 6 (P = .01) of fedratinib treatment, respectively. Almost one-third (26.8%) of patients had achieved ≥ 50% spleen reduction by month 6. Mean number of symptoms also decreased significantly at month 3 (P < .0001) and month 6 (P = .01). CONCLUSION: Fedratinib appears to deliver spleen and symptom benefits in real-world patients with MF previously treated with ruxolitinib.

Real-world outcomes with fedratinib therapy in patients who discontinued ruxolitinib for primary myelofibrosis.

Aim: Fedratinib is an oral selective JAK2 inhibitor approved in the USA for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis (MF). Methods: This observational study assessed adult US patients who received ruxolitinib for primary MF (Flatiron Health database: 1 January 2011-31 October 2020). Patients were stratified by post-ruxolitinib treatment (fedratinib vs non-fedratinib). Results: Characteristics were comparable between fedratinib (n=70) and non-fedratinib (n=159) groups (median age: 71.0 vs 70.0 years; females: 55.7 vs 50.3%; median follow-up: 7.0 vs 6.0 months). Median overall survival (not reached vs 17 months) and 12 month survival (71.6 vs 53.5%) were improved with fedratinib versus the non-fedratinib therapies. Conclusion: In MF patients who received frontline ruxolitinib, survival was improved with subsequent fedratinib versus non-fedratinib care.

Real-world clinical outcomes of patients with myelofibrosis treated with ruxolitinib: a medical record review.

Aim: To assess real-world ruxolitinib treatment patterns and outcomes in patients diagnosed with primary or secondary myelofibrosis. Materials & methods: Patient medical records were reviewed in six countries. Results: Eligible patients (n = 469) had a mean age of 63.5 years, and most were male (66.5%) with primary myelofibrosis (78.5%). Median duration of ruxolitinib treatment was 13.1 months; 40% of patients initiated treatment at the recommended dose. The Kaplan-Meier estimate of median survival from ruxolitinib initiation was 44.4 months (95% CI, 38.8-50.2 months). Approximately one quarter (23%) of patients continued ruxolitinib after progression. Conclusion: These results suggest an unmet need for more effective treatments for patients with myelofibrosis who failed ruxolitinib.

Real-world outcomes with second-line therapy in advanced esophageal squamous cell carcinoma using SEER-Medicare data.

Aim: To characterize real-world patterns of second-line treatment and outcomes in older patients with advanced/metastatic esophageal squamous cell carcinoma (ESCC). Patients and methods: Patients aged ≥66 years diagnosed with advanced/metastatic ESCC between 2010 and 2015 and followed through 2016 were included in this retrospective analysis using SEER-Medicare data. Results: Of 756 patients with advanced/metastatic ESCC, 104 (14%) received second-line therapy; median duration of treatment was 1.5 months. Median overall survival was 5.7 months for all patients receiving second-line treatment, and 4.5, 5.6 and 8.5 months, respectively, for patients receiving taxane monotherapy, taxane combination therapy and nontaxane therapy. Conclusion: A small proportion of patients with advanced/metastatic ESCC received second-line therapy, which was associated with short duration of treatment and poor overall survival.

This study assessed how US physicians have been treating a common type of esophageal cancer, known as squamous cell carcinoma, which has spread from the esophagus to other parts of the body (advanced/metastatic cancer). We looked at information from US cancer registry data on 756 people who were 66 years and older and diagnosed between 2010 and 2015. Only 14% of people received a second kind of chemotherapy after their first chemotherapy was stopped. People received their second chemotherapy for a short period (approximately 6 weeks) and lived for approximately 6 months on average from start of treatment. This research highlights that more effective treatments are needed for older people with advanced/metastatic esophageal squamous cell carcinoma.

Cost-effectiveness of nivolumab monotherapy in the third-line treatment of small cell lung cancer.

AIMS: Present cost-effectiveness analysis of nivolumab monotherapy vs. commonly prescribed third-line (3 L+) treatment in small cell lung cancer (SCLC). MATERIALS AND METHODS: A three health states partitioned survival model (progression-free, progressed disease, and death; US payer perspective) was developed. The systematic literature review identified no randomized controlled or single-arm trials with separate outcomes for 3 L + SCLC patients. Topotecan was chosen as a comparator because it is frequently prescribed in real-world practice for 3 L SCLC. Clinical inputs for topotecan were derived from the Flatiron database with inclusion/exclusion criteria matched to patients treated with 3 L + nivolumab in CheckMate 032. Intravenous (IV) and oral topotecan clinical efficacy were assumed equivalent. Base-case analysis used a 20-year lifetime horizon. An annual discount rate of 3.0% for costs and outcomes was applied. Uncertainty was assessed using sensitivity analyses adjusted for key parameters. RESULTS: Incremental cost per quality-adjusted life-year (QALY) gained with nivolumab was US$153,312 vs. IV topotecan and US$123,003 vs. oral topotecan, respectively. When results were disaggregated, nivolumab-related costs were mainly driven by drug acquisition costs, and topotecan-related costs were primarily due to adverse event treatment. Mean overall survival (OS) was 21.69 months with nivolumab and 5.80 months with IV or oral topotecan. More favorable outcomes were found by the landmark response analyses. Deterministic sensitivity analyses showed that changes to the discount rate for costs and outcomes and body weight had the greatest impacts on results. LIMITATIONS: Included use of real-world data for OS outcomes associated with 3 L topotecan, use of second-line topotecan data for progression-free survival, and no indirect costs. CONCLUSIONS: Based on the literature on willingness-to-pay for a QALY in metastatic cancer, nivolumab monotherapy might represent a cost-effective option for 3 L + treatment of SCLC compared with IV and oral topotecan. Sensitivity analysis using response-based methods yielded further favorable cost-effectiveness estimates.

Patient-reported Effects of Fedratinib, an Oral, Selective Inhibitor of Janus Kinase 2, on Myelofibrosis-related Symptoms and Health-related Quality of Life in the Randomized, Placebo-controlled, Phase III JAKARTA Trial.

Patients with myelofibrosis (MF) experience an array of symptoms that impair health-related quality of life (HRQoL). Fedratinib, an oral, selective Janus-kinase 2 (JAK2) inhibitor, was investigated in the randomized, placebo-controlled, phase III JAKARTA study in adult patients with intermediate- or high-risk JAK-inhibitor-naïve MF. The effect of fedratinib 400 mg/d on patient-reported MF symptoms and HRQoL in JAKARTA was assessed. Participants completed the modified Myelofibrosis Symptom Assessment Form (MFSAF v2.0), which evaluates 6 key MF symptoms (night sweats, early satiety, pruritus, pain under ribs on the left side, abdominal discomfort, bone/muscle pain). The modified MFSAF v2.0 was completed during the first 6 treatment cycles and at end of cycle 6 (EOC6). Symptom response was a ≥50% improvement from baseline in total symptom score (TSS). Overall HRQoL was assessed by EQ-5D-3L health utility index (HUI) score. The MFSAF-evaluable population comprised 91/96 patients randomized to fedratinib 400 mg and 85/96 patients randomized to placebo. Mean baseline TSS was 17.6 and 14.7 for fedratinib and placebo, respectively, and mean EQ-5D-3L HUI was 0.70 and 0.72. Fedratinib elicited statistically significant and clinically meaningful improvements in TSS from baseline versus placebo at all postbaseline visits. Symptom response rates at EOC6 were 40.4% with fedratinib and 8.6% with placebo (OR 7.0 [95% CI, 2.9-16.9]; P < 0.001), and a significantly higher proportion of fedratinib-treated patients achieved clinically meaningful improvement from baseline on the EQ-5D-3L HUI at EOC6 (23.2% versus 6.5%; P = 0.002). Fedratinib provided clinically meaningful improvements in MF symptoms and overall HRQoL versus placebo in patients with JAK-inhibitor-naïve MF.

Fedratinib Improves Myelofibrosis-related Symptoms and Health-related Quality of Life in Patients with Myelofibrosis Previously Treated with Ruxolitinib: Patient-reported Outcomes from the Phase II JAKARTA2 Trial.

Myelofibrosis symptoms compromise health-related quality of life (HRQoL). Ruxolitinib can reduce myelofibrosis symptom severity, but many patients discontinue ruxolitinib due to loss of response or unacceptable toxicity. Fedratinib is an oral, selective JAK2 inhibitor approved in the United States for treatment of patients with intermediate-2 or high-risk myelofibrosis. The single-arm, phase II JAKARTA2 trial assessed fedratinib 400 mg/d (starting dose) in patients with myelofibrosis previously treated with ruxolitinib. Patient-reported changes in myelofibrosis symptom severity using the modified Myelofibrosis Symptom Assessment Form (MFSAF), and overall HRQoL and functional status using the EORTC QLQ-C30, were evaluated at each cycle. Clinically meaningful changes from baseline HRQoL scores were based on effect sizes. Ninety patients were MFSAF-evaluable. Myelofibrosis symptoms were mild-to-moderate at baseline. Patients showed statistically significant and clinically meaningful improvements in total symptom scores from baseline on the MFSAF at all post baseline visits through the end of cycle 6 (EOC6). Baseline global health status/QoL and functional domain scores on the EORTC QLQ-C30 were meaningfully worse than in the general population. At EOC6, 44% of patients reported clinically meaningful improvements in global health status/QoL, and 30%-53% of patients experienced clinically meaningful improvement in QLQ-C30 functional domains across post baseline timepoints. Over 80% of ongoing patients perceived fedratinib as beneficial on the Patient's Global Impression of Change questionnaire. Fedratinib effects were consistent among prognostically relevant patient subgroups. Patients with myelofibrosis previously treated with ruxolitinib experienced clinically meaningful improvements in myelofibrosis symptom burden, overall HRQoL, and functional status in the first 6 months of fedratinib treatment.

Healthcare utilization and total costs of care among patients with advanced metastatic gastric and esophageal cancer.

Aim: Study first-line (1L) treatment patterns and economic outcomes among patients with advanced metastatic gastric cancer (GC) and esophageal cancer (EC). Materials & methods: Newly diagnosed patients with systemic GC and EC treatments were identified between 1 January 2011 and 31 July 2017; costs were presented as per patient per month (PPPM) basis. Results: Study included 392 GC and 436 EC patients. Most frequently used 1L regimens were: 5-fluorouracil (5-FU) + oxaliplatin (22.5%) and epirubicin + cisplatin + 5-FU (ECF)/ECF modifications (21.9%) in patients with GC; and carboplatin + paclitaxel (29.6%) and 5-FU + oxaliplatin (11.5%) in EC patients. Mean all-cause costs were US$16,242 PPPM for GC, and $18,384 PPPM for EC during 1L treatment. Conclusion: GC and EC were resource intensive and costly. High costs and short treatment durations underscored a gap in care in 1L treatment.

A Comparison of Real-World Treatment Patterns and Clinical Outcomes in Patients Receiving First-Line Therapy for Unresectable Advanced Gastric or Gastroesophageal Junction Cancer Versus Esophageal Adenocarcinomas.

INTRODUCTION: Management of locally advanced, unresectable, or metastatic (adv/met) esophageal adenocarcinoma (EAC) follows clinical guidance for gastric cancer (GC) and gastroesophageal junction cancer (GEJC). However, evidence for these guidelines is based largely on patients with adv/met GC/GEJC, and generally excludes patients with EAC. It is currently unclear whether patients with adv/met GC/GEJC and adv/met EAC have similar demographics and clinical outcomes in real-world practice. METHODS: Adult patients diagnosed with adv/met GC/GEJC and adv/met EAC between January 1, 2011 and November 30, 2018 were identified (Flatiron Health database); patients with confirmed human epidermal growth factor receptor 2 (HER2)-positive tumors were excluded, and index was date of adv/met diagnosis. Median overall survival (OS) from start of first-line therapy until death/censoring was estimated by the Kaplan-Meier method. Multivariable analysis (Cox proportional hazards) was conducted to identify factors associated with OS. RESULTS: In total, 3052 patients were identified (adv/met GC/GEJC, n = 2083; adv/met EAC, n = 969). Patients with EAC were more likely to be male, have a history of smoking, have a higher body weight and body mass index, and were less likely to be Hispanic/Latino or Medicaid enrollees than patients with GC/GEJC. A similar proportion of patients with adv/met GC/GEJC (75%; n = 2326) and adv/met EAC (77%; n = 1573) received first-line therapy. Fluoropyrimidine plus platinum combinations were the most frequent first-line regimen in both groups (36%). Median OS was similar for patients with adv/met GC/GEJC and adv/met EAC (9.7 vs. 9.1 months, respectively; hazard ratio [95% confidence interval] 0.96 [0.87-1.06]; p = 0.4320). CONCLUSION: Despite minor differences in baseline demographics, clinical outcomes for patients with adv/met GC/GEJC and EAC are similar. This supports the inclusion of patients with adv/met EAC in clinical trials assessing adv/med GC/GEJC.

Comparative effectiveness of nivolumab versus standard of care for third-line patients with small-cell lung cancer.

Aim: To estimate the comparative effectiveness of nivolumab versus standard of care (SOC) in terms of overall survival (OS) for small-cell lung cancer patients treated with two prior lines of chemotherapy, in other words, third line in the USA. Materials & methods: Data were from CheckMate 032, a single-arm trial of nivolumab, and real-world electronic patient records. Comparisons of OS were conducted using three different methods to adjust for differences (regression, weighting and doubly robust) between the populations. Results: Nivolumab was associated with longer survival compared with SOC (hazard ratio for OS: 0.58-0.70) across all methods for adjustment. Conclusion: Nivolumab was more efficacious in terms of OS as third-line treatment for small-cell lung cancer compared with current SOC in the USA.

Real-World Treatment Patterns and Outcomes in Patients Receiving Second-Line Therapy for Advanced/Metastatic Esophageal Squamous Cell Carcinoma.

INTRODUCTION: Currently available second-line (2L) therapies for advanced/metastatic esophageal squamous cell carcinoma (adv/met ESCC) include the taxanes paclitaxel and docetaxel. In clinical trials, such therapies have provided only modest improvements in survival. Few studies have assessed outcomes in routine clinical practice in the USA. We compared real-world clinical outcomes in the US for patients receiving taxane or non-taxane 2L therapy for adv/met ESCC. METHODS: The Flatiron Health database was used to identify patients diagnosed with adv/met ESCC (1 January 2011-31 January 2019) who received 2L therapy; index date was date of adv/met diagnosis. Baseline variables and treatment regimens received were identified. Overall survival (OS; 2L start until death or last recorded medical activity) and duration of therapy (DoT; start of 2L therapy until last administration date of 2L therapy) in patients receiving taxane vs. non-taxane-based therapies in the 2L setting were estimated by Kaplan-Meier method. RESULTS: There were no clear differences in baseline characteristics between patients who received 2L taxane therapy (n = 37) and 2L non-taxane therapy (n = 49). Median (95% CI) 2L OS was significantly longer with 2L taxanes (7.3 [5.9-11.5] months) vs. 2L non-taxanes (5.1 [2.9-7.6] months); median (95% CI) 2L DoT was 2.1 (1.8-3.0) months vs. 3.3 (2.6-6.7) months, respectively. CONCLUSION: Survival was generally poor in patients receiving 2L therapy for adv/met ESCC and was longer in patients receiving 2L taxanes than 2L non-taxane therapy. Efficacious, tolerable therapies for ESCC in the 2L setting are urgently needed.

Cost-effectiveness analysis of nivolumab for the treatment of squamous cell carcinoma of the head and neck in the United States.

Aim: To assess the cost-effectiveness of nivolumab monotherapy for recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) in the US.Methods: We constructed a cohort-based partitioned survival model for three health states (progression-free, progressed disease, and death). Using overall survival and progression-free survival data from the nivolumab and investigator's choice (IC) arms of the CheckMate 141 study, the proportion of patients in each health state was estimated by parametric modeling over a 25-year period. Cost, utility, adverse event, and disease management data inputs were obtained from relevant literature and applied to patients in each health state. A scenario analysis was conducted assuming increased uptake of subsequent immunotherapies. A one-way deterministic sensitivity analysis assessed the impact of variation in multiple parameters. A probabilistic sensitivity analysis in which probabilistic distributions were applied to each input during 1,000 model iterations was also conducted.Results: Total costs incurred were higher with nivolumab ($101,552) than with IC ($38,067). Nivolumab was associated with a higher number of life-years (LY; 1.21) and quality-adjusted life-years (QALYs; 0.89), compared with IC (0.68 and 0.42, respectively). The incremental cost-effectiveness ratio for nivolumab compared with IC was $134,438 per QALY, and this remained qualitatively similar when increased uptake of subsequent immunotherapies was assumed ($129,603 per QALY). Sensitivity analyses supported these findings.Conclusions: These results suggest that, at a willingness-to-pay threshold of $150,000 per QALY, nivolumab is a cost-effective option for therapy of SCCHN in the US.

Developing real-world comparators for clinical trials in chemotherapy-refractory patients with gastric cancer or gastroesophageal junction cancer.

BACKGROUND: There are few third-line or later (3L+) treatment options for advanced/metastatic (adv/met) gastric cancer/gastroesophageal junction cancers (GC/GEJC). 3L+ Nivolumab demonstrated encouraging results in Asian patients in the ATTRACTION-2 study compared with placebo (12-month survival, 26% vs 11%), and in Western patients in the single-arm CheckMate 032 study (12-month survival, 44%). This analysis aimed to establish comparator cohorts of US patients receiving routine care in real-world (RW) clinical practice. METHODS: A 2-step matching process generated RW cohorts from Flatiron Health's oncology database (January 1, 2011-April 30, 2017), for comparison with each trial: (1) clinical trial eligibility criteria were applied; (2) patients were frequency-matched with trial arms for baseline variables significantly associated with survival. Median overall survival (OS) was calculated by Kaplan-Meier analysis from last treatment until death. RESULTS: Of 742 adv/met GC/GEJC patients with at least 2 prior lines of therapy, matching generated 90 US RW ATTRACTION-2-matched patients (median OS: 3.5 months) versus 163 ATTRACTION-2 placebo patients (median OS: 4.1 months), and 100 US RW CheckMate 032-matched patients (median OS: 2.9 months) versus 42 CheckMate 032 nivolumab-treated patients (median OS: 8.5 months). Baseline characteristics were generally similar between clinical trial arms and RW-matched cohorts. CONCLUSIONS: We successfully developed RW cohorts for comparison with data from clinical trials, with comparable baseline characteristics. Survival in US patients receiving RW care was similar to that seen in Asian patients receiving placebo in ATTRACTION-2; survival with nivolumab in CheckMate 032 appeared favorable compared with US RW clinical practice.

Real-world treatment patterns, cost of care and effectiveness of therapies for patients with squamous cell carcinoma of head and neck pre and post approval of immuno-oncology agents.

Aims: In 2016, nivolumab and pembrolizumab were approved for the treatment of squamous cell carcinoma of the head and neck (SCCHN) following progression after initial platinum-based therapy. We sought to explore the uptake, effectiveness, and impact on healthcare resource utilization (HRU) and total costs of care pre and post introduction of immuno-oncology (IO) agents.Materials and Methods: Recurrent/metastatic SCCHN patients were identified from a healthcare claims clearinghouse by selecting patients with a claim for distant metastases or who initiated systemic therapy at least 120 days following discontinuation of platinum-based therapy. Two cohorts were created according to the date of post-platinum therapy (PPT) initiation: pre-IO = 08/01/2014-07/31/2015; post-IO = 08/01/2016-07/31/2017. Treatment patterns and effectiveness (duration of treatment, time to next treatment) during first-line (1 L) PPT, HRU, and costs were compared between propensity-score matched patients from each cohort.Results: Of 716 patients identified (pre-IO = 265, post-IO = 451) 46.3% of post-IO patients received IO post-platinum. In 229 matched patients 20.0% of the post-IO compared to 10.7% of the pre-IO (p=.02) had at least a 6 month duration of 1 L PPT. Inpatient admissions during 1 L PPT: 34.1% post-IO versus 48.0% pre-IO (p= <.01). PPPM total costs of care in 1 L PPT were significantly greater post-IO ($11,535) compared to pre-IO ($9,054, p=.002). Time to next treatment (from 1 L PPT start) was 6.1 months pre-IO versus 7.4 months post-IO (p=.046).Limitations: Recurrent SCCHN patients were identified using a validated claims-based algorithm but misclassification may occur. Requiring patients to have received 1 L PPT the pre-IO cohort may be systematically different that the post-IO cohort as pre-IO patients were more likely to have not received further treatment beyond 1 L PPT.Conclusions: The significant uptake of IO therapy resulted in longer durations of therapy, lower rates of hospitalizations although higher treatment costs. The results suggest IO treatment provides additional clinical benefits to recurrent/metastatic SCCHN patients.

Correction to: Developing real-world comparators for clinical trials in chemotherapy-refractory patients with gastric cancer or gastroesophageal junction cancer.

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Real-world Treatment Patterns and Clinical Outcomes Across Lines of Therapy in Patients With Advanced/Metastatic Gastric or Gastroesophageal Junction Cancer.

BACKGROUND: First-line (1L) and second-line (2L) therapies for advanced/metastatic gastric cancer (GC) and gastroesophageal junction cancer (GEJC) have modest efficacy, and therapeutic options in subsequent lines are limited as disease progresses. We assessed real-world treatment patterns and outcomes for advanced/metastatic GC/GEJC. PATIENTS AND METHODS: Adult patients diagnosed with advanced/metastatic GC/GEJC between January 1, 2011 and April 30, 2018 were identified using the Flatiron Health database. Median overall survival (OS) from start of each line of therapy until death was estimated by the Kaplan-Meier method. Duration of therapy (DoT) was time from start date until end date of each line. RESULTS: We identified 3291 patients with advanced/metastatic GC/GEJC adenocarcinoma. At diagnosis, the median age was 68 years, 60% were white, 53% had initial stage IV disease, and 57% had GC. Of these 3291 patients, most (75%) received at least 1 therapy; 32% received 2L, 14% received third-line (3L) therapy, and 6% received at least 4 lines of therapy (4L+). The median OS from start of 1L was 10.7 months (2L, 7.6 months; 3L, 6.1 months; 4L+, 2.8 months). The median DoT in 1L was 2.2 months (2L, 2.1 months; 3L, 1.7 months; 4L+, 3.0 months). Use of targeted and immunotherapies generally increased progressively with each subsequent line of therapy. CONCLUSION: One-quarter of patients with advanced/metastatic GC/GEJC remained untreated, and only approximately one-half of patients receiving 1L therapy received subsequent treatment. In all lines of therapy, OS was generally poor and DoT was short. More effective treatment options are needed across all lines of therapy for this highly burdensome disease.

Comparative effectiveness of nivolumab versus clinical practice for advanced gastric or gastroesophageal junction cancer.

Aim: To determine the effectiveness of nivolumab compared with routine clinical practice (RCP) for patients with gastric or gastroesophageal cancer refractory to, or intolerant of, two or more previous regimens, using real-world electronic patient records from a US population, a single-arm trial (CheckMate 032) and a randomized controlled trial in an Asian setting (ATTRACTION-2). Materials & methods: A simulated treatment comparison was conducted to predict overall survival for patients treated with nivolumab compared with RCP in the USA. Results: Results of the indirect simulated treatment comparison suggest that nivolumab is associated with a 50% reduction in the risk of all-cause mortality relative to RCP (Hazard ratio: 0.50; 95% CI: 0.36, 0.68). Conclusion: The survival benefit of nivolumab may extend more generally to the USA.

Antibacterial prophylaxis for gram-positive and gram-negative infections in cranial surgery: A meta-analysis.

BACKGROUND: Perioperative antibiotic prophylaxis against gram positive and gram negative infections is considered standard of care in the perioperative management of patients undergoing cranial surgery. The antibiotic regimen which best reduces the risk of surgical site infections (SSIs) remains controversial. OBJECTIVES: A systematic literature review and meta-analysis were conducted to examine the effect of various prophylactic antibiotics on infection incidence among patients undergoing cranial surgeries. METHODS: A comprehensive search was conducted on Pubmed, EMBASE and Cochrane databases through October 2014 for studies that evaluated the efficacy of antibiotic prophylaxis among patients undergoing cranial surgeries. Pooled effect estimates using both fixed- and random-effect models were calculated. RESULTS: Eight articles were included in the meta-analysis, with a combined total of 1655 cranial procedures. Among these, 74 cases of SSIs were reported after patients received a single antibiotic or a combination of 2 or more antibiotics (pooled incidence of SSIs=6.00%; 95% CI=4.80%, 7.50%; fixed-effects model; I2=73.7%; P-heterogeneity<0.01). Incidence of SSI was 1.00% (95% CI=0.40%, 2.60%) for non-MRSA gram-positive bacterial infections; 2.70% (95% CI=0.90%, 8.00%) for gram-negative bacterial infections; 6.00% (95% CI=4.50%, 7.80%) for gram negative, and non-MRSA gram-positive bacterial infections; and 11.3% (95% CI=7.20%, 17.4%) for gram negative and MRSA gram-positive bacterial infections. Subgroup analysis revealed an effect modification by drug class (P=0.05) and infection type (P-interaction=0.01). More specifically, lincosamides (2.70%; n=1 group), glycopeptides (2.80%; n=1), third generation cephalosporins (5.30%; n=2), antibiotics combination (4.90%; n=4), and penicillin-family antibiotics (5.90%, n=1) offered better coverage against infections than first generation cephalosporins (22.0%; n=2). A meta-regression analysis on study length was not significant (P=0.13). Random-effect models were not materially different form fixed-effects. No evidence of publication bias was found. CONCLUSION: Lincosamides, glycopeptides, third generation cephalosporins, other combinations of prophylactic antibiotics, or penicillin-family antibiotics alone offer better coverage against SSIs than first generation cephalosporin among cranial surgery patients.