Aspirin Use and Risk of Breast Cancer: A Meta-analysis of Observational Studies from 1989 to 2019

BackgroundSome evidence shows that aspirin can reduce the morbidity and mortality of different cancers, including breast cancer. Aspirin has become a new focus of cancer prevention and treatment research at present, however, clinical studies found conflicting conclusions of its anticancer characteristics.Materials and MethodsA systematic literature search was performed in 8 electronic databases. The pooled relative risk (RR) with 95% confidence interval (CI) was calculated using the random effects model to estimate the effect of aspirin on breast cancer.ResultsForty-two published articles with 99,769 patients were identified. The meta-analysis showed a significant decrease in breast cancer risk with aspirin use (RR, 0.92; 95% CI, 0.89-0.96; I² = 72%). Aspirin use decreased the risk of hormone receptor–positive tumors (estrogen receptor [ER]-positive RR, 0.89; 95% CI, 0.82-0.97; I²=54%; progesterone receptor [PR]–positive RR, 0.86; 95% CI, 0.78-0.95; I²=32%; ER- and PR-positive RR, 0.92; 95% CI, 0.85-1.00; I²=45%) and reduced the risk of breast cancer in postmenopausal women (RR, 0.92; 95% CI, 0.86-0.98; I²=59%). Further analysis showed that for the in situ breast cancer, regular-dose and more than 3 years use of aspirin were associated with the reduced risk of breast cancer.ConclusionThis meta-analysis suggested that aspirin may reduce the overall risk of breast cancer, reduce the risk of breast cancer in postmenopausal women, hormone receptor–positive tumors, and in situ breast cancer. Larger, multicenter clinical studies are needed to find the optimal dose range, frequency, and duration of the aspirin use to explore the best benefit–risk ratio.     

Prognostic Value of Primary Tumor Volume Changes on kV-CBCT during Definitive Chemoradiotherapy for Stage III Non–Small Cell Lung Cancer

IntroductionKilovoltge cone beam computed tomography (kV-CBCT) allows for tumor localization and response assessment during definitive chemoradiotherapy for locally advanced NSCLC. We hypothesize that significant tumor volume loss occurs early during radiotherapy and that the extent of volume loss correlates with clinical outcomes.MethodsA total of 52 patients with locally advanced NSCLC treated with definitive chemoradiotherapy were reviewed. kV-CBCT images were used to contour primary gross tumor volumes at four time points during treatment. Patients were dichotomized according to absolute and relative volume changes at each time point. Statistical analyses were performed to evaluate correlations between volume changes and clinical outcomes.ResultsThe median gross tumor volumes were 77.1, 48.3, 42.5, and 29.9 cm³ for fractions 1, 11, 21, and final, respectively. Greater relative volume loss between fractions 1 and 21 correlated with improved distant control (hazard ratio [HR] = 0.35, 95% confidence interval [CI]: 0.13–0.94, p = 0.038) and overall survival (HR = 0.40, 95% CI: 0.16–0.98, p = 0.046). Greater relative volume loss between fractions 11 and 21 correlated with improved progression-free survival (HR = 0.39, 95% CI: 0.17–0.88, p = 0.02) and trended toward improved overall survival (HR = 0.43, 95% CI: 0.17–1.06, p = 0.07). On multivariate analysis, greater relative volume loss between fractions 11 and 21 correlated with improved progression-free survival (HR = 0.39, 95% CI: 0.16–0.97, p = 0.041) and overall survival (HR = 0.31, 95% CI: 0.11–0.88, p = 0.027).ConclusionsSignificant primary tumor volume loss occurs early during radiotherapy for locally advanced NSCLC. Greater relative tumor volume loss during treatment correlates with improved disease control and overall survival. Thus, kV-CBCT has potential to be used as a practical prognostic imaging marker.     

Two stage hepatectomy (TSH) versus ALPPS for initially unresectable colorectal liver metastases: A systematic review and meta-analysis

BackgroundAlthough numerous comparisons between conventional Two Stage Hepatectomy (TSH) and Associating Liver Partition and Portal Vein Ligation for staged hepatectomy (ALPPS) have been reported, the heterogeneity of malignancies previously compared represents an important source of selection bias. This systematic review and meta-analysis aimed to compare perioperative and oncological outcomes between TSH and ALPPS to treat patients with initially unresectable colorectal liver metastases (CRLM).MethodsMain electronic databases were searched using medical subject headings for CRLM surgically treated with TSH or ALPPS. Patients treated for primary or secondary liver malignancies other than CRLM were excluded.ResultsA total of 335 patients from 5 studies were included. Postoperative major complications were higher in the ALPPS group (relative risk [RR] 1.46, 95% confidence interval [CI] 1.04–2.06, I² = 0%), while no differences were observed in terms of perioperative mortality (RR 1.53, 95% CI 0.64–3.62, I² = 0%). ALPPS was associated with higher completion of hepatectomy rates (RR 1.32, 95% CI 1.09–1.61, I² = 85%), as well as R0 resection rates (RR 1.61, 95% CI 1.13–2.30, I² = 40%). Nevertheless, no significant differences were achieved between groups in terms of overall survival (OS) (RR 0.93, 95% CI 0.68–1.27, I² = 52%) and disease-free survival (DFS) (RR 1.08, 95% CI 0.47–2.49, I² = 54%), respectively.ConclusionALPPS and TSH to treat CRLM seem to have comparable operative risks in terms of mortality rates. No definitive conclusions regarding OS and DFS can be drawn from the results.     

Prophylactic Cranial Irradiation for Patients with Surgically Resected Small Cell Lung Cancer

IntroductionData on prophylactic cranial irradiation (PCI) after complete resection of SCLC are limited. The purpose of this study was to investigate the impact of PCI in this population.MethodsWe retrospectively identified completely resected SCLC at the Shanghai Chest Hospital between January 2006 and January 2014.ResultsA total of 349 patients (115 patients who received PCI [the PCI-treated cohort] and 234 patients who did not [the non–PCI-treated cohort]) were included in the study. The results demonstrated that the PCI-treated cohort had longer overall survival than the non–PCI-treated cohort among patients with pathologic stage (p-stage) II (hazard ratio [HR] = 0.54, 95% confidence interval [CI]: 0.30–0.99, p = 0.047) and p-stage III (HR = 0.54, 95% CI: 0.34–0.86, p = 0.009) disease. Among patients with p-stage III disease, there was a significantly higher risk for cerebral recurrence from the time of diagnosis in the non–PCI-treated cohort (p = 0.018). With regard to patients with p-stage I disease, neither overall survival benefit (HR = 1.61, 95% CI: 0.68–3.83, p = 0.282) nor risk for cerebral recurrence (p = 0.389) was significant between the PCI-treated and non–PCI-treated cohorts.ConclusionsThe data presented in the current study support using PCI in patients with p-stage II/III disease but not in patients with p-stage I disease. A relatively lower risk for brain metastases in p-stage I patients might explain the inferior efficacy of PCI in this population.     

Dietary fructose, carbohydrates, glycemic indices and pancreatic cancer risk: a systematic review and meta-analysis of cohort studies

BackgroundDietary carbohydrates, glycemic load and glycemic index have been hypothesized to influence pancreatic cancer risk, but epidemiological studies have been inconsistent. We conducted a systematic review and meta-analysis of prospective studies to clarify these results.MethodsPubMed and several other databases were searched for prospective studies of intake of carbohydrates, glycemic index and glycemic load and pancreatic cancer up to September 2011. Summary relative risks were estimated using a random effects model.ResultsTen cohort studies (13 publications) were included in the meta-analysis. The summary relative risk (RR) per 10 glycemic index units was 1.02 [95% confidence interval (CI): 0.93–1.12, I² = 0%], per 50 glycemic load units was 1.03 (95% CI: 0.93–1.14, I² = 10%), per 100 g/day of total carbohydrates was 0.97 (95% CI: 0.81–1.16, I² = 35%), and per 25 g/day of sucrose intake was 1.05 (95% CI: 0.85–1.23, I² = 53%). A positive association was observed with fructose intake, summary RR = 1.22 (95% CI: 1.08–1.37, I² = 0%) per 25 g/day.ConclusionsThis meta-analysis does not support an association between diets high in glycemic index, glycemic load, total carbohydrates or sucrose and pancreatic cancer risk. The finding of an increased risk with fructose intake warrants further investigation in studies with better adjustment for confounding and in non-American populations.     

Propensity-score Matched Comparison of Salvage Chemotherapy Regimens in Relapsed/Refractory Acute Myeloid Leukemia

BackgroundRelapsed/refractory acute myeloid leukemia (AML) confers a poor prognosis, and there is no single standard of care first-line salvage regimen. FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) is a common salvage regimen with a favorable toxicity and efficacy profile in poor-risk AML.Materials and MethodsWe conducted a single-center, retrospective analysis of first relapse/primary refractory patients with AML that received salvage chemotherapy from January 2009 to July 2019. We propensity-score matched patients 1:1 (based on age at diagnosis, cytogenetic risk group, Charlson comorbidity index, de novo vs. secondary AML, and whether or not they received an allogeneic stem cell transplant in first complete remission) into 2 groups, FLAG (Group 1) or non-FLAG (Group 2) as first-line salvage regimen, with 66 patients in each group. The primary endpoint was overall response rate (complete response and complete response with incomplete hematologic recovery).ResultsThe median patient age was 59 years (range, 19-80 years). Patients treated with FLAG had a higher overall response rate (complete response/complete response with incomplete hematologic recovery) (71.2% vs. 50.0%; odds ratio, 2.47; 95% confidence interval [CI], 1.21-5.08; P = .013), longer event-free survival (8.9 vs. 2.1 months; hazard ratio [HR], 0.58; 95% CI, 0.39-0.86; P = .005), and longer overall survival (14.2 vs. 5.9 months; HR, 0.62; 95% CI, 0.41-0.93; P = .019). Patients who received FLAG had a shorter median duration of neutropenia (22 vs. 34 days; HR, 0.43; 95% CI, 0.29-0.64; P < .001).ConclusionThis analysis supports the FLAG regimen as an effective and well-tolerated salvage therapy for patients with relapsed/refractory AML.     

Efficacy and Safety of Ceritinib (450 mg/d or 600 mg/d) With Food Versus 750-mg/d Fasted in Patients With ALK Receptor Tyrosine Kinase (ALK)–Positive NSCLC: Primary Efficacy Results From the ASCEND-8 Study

IntroductionIn an earlier report of the ASCEND-8 study (open-label, phase I, three-arm study, treatment-naive patients and pre-treated patients with advanced/metastatic NSCLC), it was shown that ceritinib 450 mg with food had comparable exposure and better gastrointestinal tolerability than 750-mg fasted.MethodsHere, we report efficacy and updated safety data from primary efficacy analysis of the ASCEND-8 study. Key secondary endpoints were overall response rate and duration of response, assessed by blinded independent review committee (BIRC) using Response Evaluation Criteria in Solid Tumors 1.1.ResultsIn total, 306 patients were randomized to ceritinib 450-mg fed (n = 108) or 600-mg fed (n = 87) or 750-mg fasted (n = 111), of which 304 patients were included in safety analysis and 198 treatment-naive patients (ALK receptor tyrosine kinase [ALK]–positive by immunohistochemistry) were included in the efficacy analysis (450-mg fed [n = 73], 600-mg fed [n = 51], and 750-mg fasted [n = 74]). The BIRC-assessed overall response rate was 78.1% (95% confidence interval [CI]: 66.9–86.9), 72.5% (95% CI: 58.3–84.1), and 75.7% (95% CI: 64.3–84.9), respectively; and the median duration of response (months) by BIRC was not estimable (NE) (95% CI: 11.2–NE), 20.7 (95% CI: 15.8–NE), and 15.4 (95% CI: 8.3–NE), respectively. Based on the safety analysis (n = 304), the 450-mg fed arm showed the highest median relative dose intensity (100% versus 78.5% versus 83.7%), lowest proportion of patients with dose reductions (24.1% versus 65.1% versus 60.9%), and lowest proportion of patients with gastrointestinal toxicities (75.9% versus 82.6% versus 91.8%).ConclusionCeritinib at a dose of 450 mg with food compared to 750-mg fasted showed consistent efficacy and less gastrointestinal toxicity.     

Sarcopenia and obesity among patients with soft tissue sarcoma – Association with clinicopathologic characteristics,complications and oncologic outcome: A systematic review and meta-analysis

Background and aimsSarcopenia and obesity may be associated with negative outcomes in many cancers, but their prevalence and impact in modern regimens for soft-tissue sarcoma (STS) have not been systematically studied. This study summarises and critically evaluates the current evidence-based literature on body mass index (BMI) and body composition among patients with STS, with respect to clinical and pathologic characteristics, treatment-associated morbidity and oncologic outcome.MethodsA systematic literature search of the PubMed, Embase and Cochrane databases was performed. Meta-analysis of the relationship between BMI, body composition and pathologic characteristics, operative morbidity and oncologic outcome was undertaken using RevMan v.5.4 using fixed or random effects methods as appropriate.Results14 studies including 3598 patients met inclusion criteria. Ten studies reported on BMI, two on CT and two on PET-CT assessment of body composition. BMI ranged from 14.6 to 63.7 kg/m², with obesity in 18%–39% of patients. Although some studies demonstrated larger tumours among patients with obesity, this was not significant on meta-analysis (P = 0.31, I² = 99%). There was no significant difference in tumour grade or histologic type according to BMI. Postoperatively, obesity was associated with increased risk of overall morbidity (odds ratio (OR) 2.03 [95% CI 1.41–2.92], P = 0.0001, I² = 22%), and wound morbidity (OR 1.32 [95% CI 1.02–1.71], P = 0.03, I² = 0%). Similar effects were observed in studies of visceral adiposity. No differences in functional outcomes were observed. There was a trend towards reduced local recurrence among patients with obesity (HR 0.64 [95% CI 0.38–1.08], P = 0.10, I² = 0%), but no difference in distant metastasis (HR 1.00 [95% CI 0.76–1.30], P = 0.98, I² = 0%) or overall survival (HR 0.98 [95% CI 0.43–2.22], P = 0.95, I² = 64%). Various measures of sarcopenia were associated with poorer survival outcomes.ConclusionWhile obesity is associated with increased postoperative morbidity, it had no significant association with long-term oncologic outcomes. Sarcopenia may be associated with a poorer long-term prognosis. A greater understanding of the impact of nutritional status on disease characteristics and treatment outcomes is essential to facilitate improvements in clinical care for patients with STS.     

WJOG13219G: The Efficacy and Safety of FOLFOXIRI or Doublet plus Anti-VEGF Therapy in Previously Untreated BRAFV600E Mutant Metastatic Colorectal Cancer: A Multi-Institutional Registry-Based Study (BRACELET Study)

BackgroundThe real-world survival benefit of FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus anti-VEGF therapy (Triplet) over doublet chemotherapy (Doublet) remains controversial in patients with BRAF^V600E mutant metastatic colorectal cancer (mCRC).Patients and MethodsWJOG13219G was a multicenter, retrospective, registry-based study of patients with BRAF^V600E mutant mCRC who received first-line triplet or doublet chemotherapy from January 2014 to December 2019 in Japan. Inverse probability of treatment weighting (IPTW) was used to adjust for patient background.ResultsThe analysis included 79 and 91 patients in the Triplet and Doublet groups, respectively. The Triplet group was significantly younger and had better performance status. No statistical difference was noted in progression-free survival (PFS; HR, 0.82; 95% CI, 0.60–1.13; P = .22) and overall survival (OS; HR, 0.88; 95% CI, 0.62–1.25; P = .48) between both groups. IPTW analysis also showed no difference between the 2 groups in PFS (HR, 0.86; 95% CI, 0.69–1.08; P = .20) and OS (HR, 0.93; 95% CI, 0.73–1.20; P = .59). The Triplet and Doublet groups had an objective response rate of 53% and 41%, respectively (P = .10). At least one grade 3 or 4 adverse event was seen in 51 (65%) and 43 (47%) patients in the Triplet and Doublet groups, respectively, with the incidence of neutropenia being significantly higher in the former.ConclusionTriplet therapy had no survival benefit versus doublet therapy in the overall and IPTW cohorts or specific subgroups for real-world patients with BRAF^V600E mutant mCRC.     

Postoperative Radiotherapy for Completely Resected Masaoka/Masaoka-Koga Stage II/III Thymoma Improves Overall Survival: An Updated Meta-Analysis of 4746 Patients

IntroductionOur systematic review and meta-analysis aimed to evaluate the effect of postoperative radiotherapy (PORT) on completely resected Masaoka/Masaoka-Koga (M/MK) stage II/III thymomas.MethodsWe systematically searched four online databases and included studies that compared surgery alone versus surgery plus a PORT for completely resected M/MK stage II/III thymoma. The multivariate-adjusted hazard ratios (HRs) of overall survival (OS) and disease-free survival were evaluated as the primary and secondary end points, respectively. We performed a subgroup analysis for OS with respect to M/MK stage II, III, and inseparable II/III cases. A generic inverse variance meta-analysis using a random model was conducted.ResultsFive studies including 4746 patients (among them, 2408 patients received PORT) met our selection criteria. A meta-analysis of these five studies revealed that PORT was associated with a significantly better OS (HR = 0.68, 95% confidence interval [CI]: 0.57–0.83, p < 0.001, I² = 0%, p for heterogeneity = 0.97). Subgroup analyses for M/MK stage II disease (HR = 0.63, 95% CI: 0.44–0.91, p = 0.01, I² = 0%, p for heterogeneity = 0.80) and M/MK stage III disease (HR = 0.72, 95% CI: 0.55–0.95, p = 0.02, I² = 0%, p for heterogeneity = 0.84) revealed similar results. PORT was not associated with an improved disease-free survival (HR = 0.96, 95% CI: 0.70–1.33, p = 0.83, I² = 0%, p for heterogeneity = 0.72).ConclusionsCurrently available evidence from observational studies suggests PORT for patients with completely resected M/MK stage II/III thymoma. A randomized trial is warranted.     

Comparison of Chemotherapy Plus Pembrolizumab vs. Chemotherapy Alone in EGFR-Mutant Non–small-Cell Lung Cancer Patients

IntroductionPlatinum doublet chemotherapy is the standard of care in patients with non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation who had disease progression after tyrosine kinase inhibitor (TKI). We aimed to assess immune checkpoint inhibitors efficacy in EGFR-mutant advanced NSCLC.Materials and MethodsWe retrospectively reviewed the data of sensitive EGFR-mutant NSCLC patients who progressed after EGFR-TKIs and received platinum doublet chemotherapy plus immunotherapy between 2015 and 2021. Efficacy outcomes, including overall response rate, progression-free survival, and overall survival, were assessed and compared with those of patients who had received platinum-based doublet chemotherapy.ResultsOf the total 869 patients, 82 treated with pembrolizumab and chemotherapy and 82 with only chemotherapy were selected. The median progression-free survival in patients administered pembrolizumab was significantly longer than those not administered pembrolizumab (6.7 months; 95% confidence interval [CI] 5.0-8.5 vs. 4.2 months; 95% CI 3.3-5.0, hazard ratio [HR] 0.64, 95% CI 0.46-0.89, P = .0076). Improved median overall survival was also observed in patients receiving pembrolizumab plus chemotherapy (26.7 [95% CI 22.6-30.8] vs. 13.4 months [95% CI 10.4-16.4], HR, 0.49 [95% CI 0.31-0.75], P = .0052). In addition, the overall response rate was higher in patients treated with than patients treated without pembrolizumab (34.1% and 20.7%, respectively).ConclusionThe combination of pembrolizumab with chemotherapy is associated with improved efficacy and survival in patients with EGFR-mutant NSCLC after TKI resistance, but these findings need to be confirmed in further prospective studies.     

Phase II Trial of Combination Nab-paclitaxel and Gemcitabine in Non–squamous Non–small Cell Lung Cancer After Progression on Platinum and Pemetrexed

BackgroundBetter therapies are needed to improve survival in metastatic non–small cell lung cancer (NSCLC). Given the synergy of combination nab-paclitaxel and gemcitabine in metastatic pancreatic cancer and their individual activity in advanced NSCLC, we sought to determine whether the same combination would confer a therapeutic benefit in the second-line therapy of recurrent or metastatic non–squamous (NSQ) NSCLC.Materials and MethodsThis single-arm phase II trial of nab-paclitaxel and gemcitabine was performed from June 2015 to April 2020 at an academic referral cancer center. Patients with advanced NSQ-NSCLC whose disease progressed on first-line pemetrexed plus platinum +/- immunotherapy were enrolled. Patients received intravenous nab-paclitaxel 100 mg/m² and gemcitabine 1000 mg/m² on days 1 and 8 of each 21-day cycle. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Safety and tolerability were evaluated by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.ResultsThirty-seven patients (15 men [41%] and 22 women [59%]; median age, 66 years [range, 41-81 years]) were accrued. ORR was 13.5% (95% CI, 2.5-24.5%). DCR was 59.5% (95% CI, 43.5-75.5%). Median PFS was 2.6 months (95% CI, 1.4-3.8 months). Median OS was 6.2 months (95% CI, 4.2-8.2 months). 1-year OS was 24% (95% CI, 10-38%). Safety and tolerability were similar to other second-line chemotherapies, although there was an 11% incidence of grade 2-3 pneumonitis.ConclusionCombination nab-paclitaxel and gemcitabine after platinum and pemetrexed for NSQ-NSCLC was not associated with greater efficacy than would be expected for single-agent chemotherapy in this setting. The higher-than-expected risk of pneumonitis was also concerning.Trial RegistrationClinicalTrials.gov Identifier: NCT02303977Micro-AbstractIn this phase II trial, 37 patients with metastatic non–squamous non–small cell lung cancer were treated with nab-paclitaxel/gemcitabine in second-line. ORR = 13.5% (95% CI, 2.5%-24.5%). Median PFS = 2.6 months (95% CI, 1.4-3.8 months). Median OS = 6.2 months (95% CI, 4.2-8.2 months). Nab-paclitaxel and gemcitabine was not associated with greater efficacy than would be expected for single-agent chemotherapy in this setting.     

Non-linear dose–response relationship between cigarette smoking and pancreatic cancer risk: Evidence from a meta-analysis of 42 observational studies

BackgroundQuestion remains about the shape of the dose–response relationship between cigarette smoking and pancreatic cancer risk.MethodsRelevant studies were identified by searching PubMed, ISI Web of Science and China National Knowledge Infrastructure (CNKI) databases and by reviewing the reference lists of retrieved articles. Random-effects models were applied to estimate summary relative risks (RRs).ResultsForty-two publications were finally included. The overall meta-analysis showed evidence of non-linear association between smoking intensity and pancreatic cancer risk (P for non-linearity = 0.000). Compared with non-smokers, the summary RRs were 1.5 (95% confidence interval (CI): 1.4, 1.6) for 10 cigarettes/day, 1.9 (95% CI: 1.8, 2.0) for 20 cigarettes/day, 2.0 (95% CI: 1.9, 2.1) for 30 cigarettes/day and 2.1 (95% CI: 1.9, 2.3) for 40 cigarettes/day with marginal between-study heterogeneity (I² = 29%). Similar results were also found for smoking duration and cumulative amount of cigarettes smoked. Besides, the summary RR for former smokers reduced with increasing time since quitting smoking compared with current smokers without heterogeneity (P for non-linearity = 0.008, I² = 0%). The results of stratified analysis by study design were comparable to those of overall meta-analysis. When stratified by sex, non-linear dose–response associations were detected for all metrics of cigarette smoking in women, while linear relationships were observed for smoking duration and cumulative amount of cigarettes smoked in men except for smoking intensity.ConclusionThis meta-analysis reveals a non-linear dose–response association between cigarette smoking and pancreatic cancer risk, but it might differ between sexes.     

Outcomes According to ALK Status Determined by Central Immunohistochemistry or Fluorescence In Situ Hybridization in Patients With ALK-Positive NSCLC Enrolled in the Phase 3 ALEX Study

IntroductionWe retrospectively examined progression-free survival (PFS) and response by ALK fluorescence in situ hybridization (FISH) status in patients with advanced ALK immunohistochemistry (IHC)-positive NSCLC in the ALEX study.MethodsA total of 303 treatment-naive patients were randomized to receive twice-daily alectinib 600 mg or crizotinib 250 mg. ALK status was assessed centrally using Ventana ALK (D5F3) CDx IHC and Vysis ALK Break Apart FISH Probe Kit. Primary end point is investigator-assessed PFS. Secondary end points of interest are objective response rate and duration.ResultsInvestigator-assessed PFS was significantly prolonged with alectinib versus crizotinib in ALK IHC-positive and FISH-positive tumors (n = 203, 67%) (hazard ratio [HR] = 0.37, 95% confidence interval [CI]: 0.25–0.56; p < 0.0001) and ALK IHC-positive and FISH-uninformative tumors (n = 61, 20%) (HR = 0.39, 95% CI: 0.20–0.78) but not in ALK IHC-positive and FISH-negative tumors (n = 39, 13%) (HR = 1.33, 95% CI: 0.6–3.2). Objective response rates were higher with alectinib versus crizotinib in ALK IHC-positive and FISH-positive tumors (90.6% versus 81.4%; stratified OR = 2.22, 95% CI: 0.97–5.07) and ALK IHC-positive and FISH-uninformative tumors (96.0% versus 75.0%; OR = 9.29, 95% CI: 1.05–81.88) but not in ALK IHC-positive and FISH-negative tumors (28.6% versus 44.4%; OR = 0.45, 95% CI: 0.12–1.74). Next-generation sequencing was performed in 35 of 39 patients with ALK IHC-positive and FISH-negative tumors; no ALK fusion was identified in 20 of 35 patients (57.1%) by next-generation sequencing, but 10 of 20 (50.0%) had partial response or stable disease.ConclusionsOutcomes of patients with ALK IHC-positive and FISH-positive and ALK IHC-positive and FISH-uninformative NSCLC were similar to those of the overall ALEX population. These results suggest that Ventana ALK IHC is a standard testing method for selecting patients for treatment with alectinib.     

A systematic review and meta-analysis on the impact of pre-operative neutrophil lymphocyte ratio on long term outcomes after curative intent resection of solid tumours

IntroductionThere is increasing evidence to suggest that cancer-associated inflammation is associated with poorer long-term outcomes. Various markers have been studied over the past decade in an attempt to improve selection of patients for surgery. This meta-analysis explored the association between the neutrophil-lymphocyte ratio and prognosis following curative-intent surgery for solid tumours.MethodsStudies were identified from US National Library of Medicine (Medline) and the Exerpta Medica database (EBASE) performed in March 2013. A systematic review and meta-analysis were performed to generate combined hazard ratios for overall survival (OS) and disease-free survival (DFS).ResultsForty-nine studies containing 14282 patients were included. Elevated NLR was associated with poorer overall survival [HR: 1.92, 95% CI (1.64–2.24)] (p < 0.001) and disease-free survival [HR: 1.99, 95% CI (1.80–2.20)] (p < 0.001). Significant heterogeneity was found with an I² of 77% and 97% for OS and DFS respectively. Subgroup analyses demonstrated that gastro-intestinal malignancies; mainly gastric [HR: 1.97, 95% CI (1.41–2.76)], colorectal [HR: 1.65, 95% CI (1.21–2.26)] and oesophageal [HR: 1.48, 95% CI (0.91–2.42)] cancers were predictive of OS (I² = 54.3%). A separate analysis for studies using an NLR cutoff of 5 demonstrated significantly poorer outcomes [HR: 2.18, 95% CI (1.74–2.73)] (p = 0.002) with less heterogeneity (I² = 58%).ConclusionElevated NLR correlates with poorer prognosis. It potentially represents a simple, robust and reliable measure that may be useful in identifying high-risk groups who could benefit from adjuvant therapy.     

Randomised phase III trial of second-line irinotecan plus cisplatin versus irinotecan alone in patients with advanced gastric cancer refractory to S-1 monotherapy: TRICS trial

AimThe optimal second-line regimen for treating advanced gastric cancer (AGC) remains unclear. While irinotecan (CPT-11) plus cisplatin (CDDP) combination therapy and CPT-11 monotherapy have been explored in the second-line setting, the superiority of second-line platinum-based therapies for AGC patients initially treated with S-1 monotherapy has not yet been evaluated; therefore, we aimed to examine the survival benefit of CPT-11/CDDP combination over CPT-11 monotherapy.MethodsAGC patients showing progression after S-1 monotherapy for advanced cancer or recurrence within 6 months after completion of S-1 adjuvant therapy were randomly allocated to CPT-11/CDDP (CPT-11, 60 mg/m²; CDDP, 30 mg/m², q2w) or CPT-11 (150 mg/m², q2w).ResultsSixty-eight advanced and 95 recurrent cases were evaluated. The median overall survivals were 13.9 (95% confidence interval [CI]: 10.8–17.6) and 12.7 (95% CI: 10.3–17.2) months for CPT-11/CDDP and CPT-11, respectively (hazard ratio: 0.834; 95% CI: 0.596–1.167, P = 0.288). No significant differences were observed in the secondary end-points, including progression-free survival (4.6 [95% CI: 3.4–5.9] versus 4.1 [95% CI: 3.3–4.9] months) and response rate (16.9% [95% CI: 8.8–28.3] versus 15.4% [95% CI: 7.6–26.5]). The incidences of grade 3–4 anaemia (16% versus 4%) and elevated serum lactate dehydrogenase levels (5% versus 0%) were higher for CPT-11/CDDP than for CPT-11. Exploratory subgroup analysis revealed that CPT-11/CDDP was significantly more effective for intestinal-type AGC, compared with CPT-11 (overall survival: 15.8 versus 14.0 months; P = 0.019).ConclusionNo survival benefit was observed upon adding CDDP to CPT-11 after S-1 monotherapy failure.     

Analysis of Predictive Factors for Early Response to Ruxolitinib in 320 Patients with Myelofibrosis From the Polish Adult Leukemia Group (PALG) Registry

IntroductionRuxolitinib is widely used in myelofibrosis (MF). However, some patients do not optimally respond and require more efficacious treatment. Our analysis aimed to establish predictors of ruxolitinib response.Patients and MethodsWe designed a multicenter, retrospective analysis of the efficacy of ruxolitinib treatment in patients with MF in 15 Polish hematology centers. As responses to ruxolitinib occur within the first 6 months, we used this point to evaluate the efficacy of treatment. Symptoms response was defined as ≥50% reduction of the MF constitutional symptoms assessed by Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS). Spleen response was defined as ≥50% reduction of the difference between the spleen's baseline length and the upper limit norm measured by ultrasonography.Results320 MF patients were enrolled. At 6 months of therapy, the spleen response was detected in 140 (50%) patients, and symptoms response in 241 patients (76%). Multivariable analysis identified leukocytosis <25 G/L (OR 2.06, 95%CI: 1.12-3.88, P = .0200), and reticulin fibrosis MF 1 (OR 2.22, 95%CI: 1.11-4.46, P = .0249) contributed to better spleen response. The time interval between MF diagnosis and ruxolitinib administration shorter than 3 months, and platelets ≥150 G/L (OR 1.69, 95% CI 1.01-2.83, P = .0466) influenced symptoms response.ConclusionEstablishing predictive factors for ruxolitinib response is particularly important given the potential for new therapies in MF. In patients with a low likelihood of responding to ruxolitinib, using other JAK inhibitors or adding a drug with a different mechanism of action to ruxolitinib may be of clinical benefit.     

Phase 3 Trial Comparing Nanoparticle Albumin-Bound Paclitaxel With Docetaxel for Previously Treated Advanced NSCLC

IntroductionWe aimed to evaluate the efficacy and safety of nanoparticle albumin-bound (nab-) paclitaxel for previously treated patients with advanced NSCLC.MethodsIn this randomized, open-label, noninferiority phase 3 trial, we enrolled patients with advanced NSCLC previously treated with cytotoxic chemotherapy. Patients were randomly allocated (1:1) to receive docetaxel (60 mg/m²) on day 1 or nab-paclitaxel (100 mg/m²) on days 1, 8, and 15 of a 21-day cycle. The primary end point was overall survival (OS) analyzed on an intention-to-treat basis.ResultsBetween May 22, 2015, and March 12, 2018, a total of 503 patients were randomly allocated to the treatment. Median OS was 16.2 months (95% confidence interval [CI]: 14.4–19.0) for the 252 patients allocated to nab-paclitaxel and 13.6 months (95% CI: 10.9–16.5) for the 251 patients allocated to docetaxel (hazard ratio = 0.85, 95.2% CI: 0.68–1.07). Median progression-free survival was 4.2 months (95% CI: 3.9–5.0) for the nab-paclitaxel group versus 3.4 months (95% CI: 2.9–4.1) for the docetaxel group (hazard ratio = 0.76, 95% CI: 0.63–0.92, p = 0.0042). The objective response rate was 29.9% (95% CI: 24.0–36.2) for the nab-paclitaxel group and 15.4% (95% CI: 10.9–20.7) for the docetaxel group (p = 0.0002). Adverse events of grade greater than or equal to 3 included febrile neutropenia (5 of 245 patients [2%] in the nab-paclitaxel group versus 55 of 249 patients [22%] in the docetaxel group) and peripheral sensory neuropathy (24 [10%] versus 2 [1%], respectively).ConclusionsNab-paclitaxel was noninferior to docetaxel in terms of OS. It should, thus, be considered a standard treatment option for previously treated patients with advanced NSCLC.     

Different outcomes for relapsed versus refractory neuroblastoma after therapy with 131I-metaiodobenzylguanidine (131I-MIBG)

Background¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG) is a targeted radiopharmaceutical with significant activity in high-risk relapsed and chemotherapy-refractory neuroblastoma. Our primary aim was to determine if there are differences in response rates to ¹³¹I-MIBG between patients with relapsed and treatment-refractory neuroblastoma.MethodsThis was a retrospective cohort analysis of 218 patients with refractory or relapsed neuroblastoma treated with ¹³¹I-MIBG at UCSF between 1996 and 2014. Results were obtained by chart review and database abstraction. Baseline characteristics and response rates between relapsed patients and refractory patients were compared using Fisher exact and Wilcoxon rank sum tests, and differences in overall survival (OS) were compared using the log-rank test.ResultsThe response rate (complete and partial response) to ¹³¹I-MIBG-based therapies for all patients was 27%. There was no difference in response rates between relapsed and refractory patients. However, after ¹³¹I-MIBG, 24% of relapsed patients had progressive disease compared to only 9% of refractory patients, and 39% of relapsed patients had stable disease compared to 59% of refractory patients (p = 0.02). Among all patients, the 24-month OS was 47.0% (95% confidence interval (CI) 39.9–53.9%). The 24-month OS for refractory patients was significantly higher at 65.3% (95% CI 51.8–75.9%), compared to 38.7% (95% CI 30.4–46.8%) for relapsed patients (p < 0.001).ConclusionsAlthough there was no significant difference in overall response rates to ¹³¹I-MIBG between patients with relapsed versusrefractory neuroblastoma, patients with prior relapse had higher rates of progressive disease and had lower 2-year overall survival after ¹³¹I-MIBG compared to patients with refractory disease.