Randomised,double-blind trial of carboplatin and paclitaxel with daily oral cediranib or placebo in patients with advanced non-small cell lung cancer: NCIC Clinical Trials Group study BR29

IntroductionThis randomised double-blind placebo-controlled study evaluated the addition of cediranib, an inhibitor of vascular endothelial growth factor receptors 1–3, to standard carboplatin/paclitaxel chemotherapy in advanced non-small cell lung cancer.MethodsEligible patients received paclitaxel (200 mg/m²) and carboplatin (area under the concentration time curve 6) intravenously every 3 weeks. Daily oral cediranib/placebo 20 mg was commenced day 1 of cycle 1 and continued as monotherapy after completion of 4–6 cycles of chemotherapy. The primary end-point of the study was overall survival (OS). The trial would continue to full accrual if an interim analysis (IA) for progression-free survival (PFS), performed after 170 events of progression or death in the first 260 randomised patients, revealed a hazard ratio (HR) for PFS of ⩽0.70.ResultsThe trial was halted for futility at the IA (HR for PFS 0.89, 95% confidence interval [CI] 0.66–1.20, p = 0.45). A final analysis was performed on all 306 enrolled patients. The addition of cediranib increased response rate ([RR] 52% versus 34%, p = 0.001) but did not significantly improve PFS (HR 0.91, 95% CI 0.71–1.18, p = 0.49) or OS (HR 0.94, 95% CI 0.69–1.30, p = 0.72). Cediranib patients had more grade 3 hypertension, diarrhoea and anorexia.ConclusionsThe addition of cediranib 20 mg daily to carboplatin/paclitaxel chemotherapy increased RR and toxicity, but not survival.     

Prognostic impact of the time interval between surgery and chemotherapy in advanced ovarian cancer: Analysis of prospective randomised phase III trials

Background and AimsSurgery followed by platinum-taxane chemotherapy is the current standard approach to treat advanced ovarian cancer. The impact of the time interval between surgery and initiation of chemotherapy for clinical outcome has not been clarified yet.MethodsIndividual patient data analysis of 3326 patients from three prospective randomised phase III trials conducted between 1995 and 2002 to investigate platinum-taxane based chemotherapy regimens in advanced ovarian cancer. Time to chemotherapy (TTC) was analysed and correlated with outcome.ResultsMedian TTC was 19 days (range 1–56). The effect of TTC differed significantly for patients with or without residual disease for progression-free (PFS; interaction p = 0.004) and for overall survival (OS; interaction p = 0.028). A delayed start of chemotherapy was associated with earlier disease recurrence (HR 1.038, 95% CI 0.973; 1.106, p = 0.257 per week delay) and a significantly decreased OS (HR 1.087, 95% CI 1.005; 1.176 p = 0.038) in patients with no residual tumour after surgery. In contrast, in patients with residual disease, a longer TTC was significantly associated with later progression (HR 0.931, 95% CI 0.895; 0.969, p < 0.001) and no effect towards OS (HR 0.983, 95% CI 0.940; 1.028, p = 0.452).ConclusionsOur results provide evidence that early initiation of chemotherapy might result in slightly improved survival in patients with complete cytoreduction while patients with residual disease after surgery did not benefit from earlier chemotherapy. A prospective study randomising patients to different time intervals could clarify the definitive relevance of the time between surgery and chemotherapy.     

Plasma TIMP-1 levels and treatment outcome in patients treated with XELOX for metastatic colorectal cancer

BackgroundThe aim was to evaluate the association between plasma tissue inhibitor of metalloproteinase-1 (TIMP-1) and serum carcinoembryonic antigen (CEA) levels and outcome in patients with metastatic colorectal cancer (mCRC) receiving XELOX (combination chemotherapy with capecitabine and oxaliplatin) as first-line treatment.Patients and methodsOne hundred and twenty patients were included. Blood samples were collected before treatment and 3 weeks later before the next treatment cycle. Plasma TIMP-1 and serum CEA levels were correlated to treatment outcome.ResultsNo significant associations between baseline TIMP-1 or CEA levels and best response to treatment or progression-free survival (PFS) could be demonstrated. In contrast, high baseline plasma TIMP-1 levels were associated with poor overall survival (OS), P = 0.008, hazard ratio (HR) = 1.80 [95% confidence interval (CI): 1.17–2.78]. Furthermore, increase in TIMP-1 levels from baseline to immediately before the second cycle of chemotherapy had a significant negative effect on survival (P = 0.03, HR = 1.30, 95% CI: 1.02–1.65) while a decrease in TIMP-1 was significantly associated with a higher objective response rate (P = 0.03).ConclusionsBoth high baseline and subsequent increase in TIMP-1 levels were associated with shorter OS in patients with mCRC receiving XELOX as first-line treatment, whereas baseline TIMP-1 levels were not associated with response or PFS following XELOX treatment.     

Genetic polymorphisms of SLC28A3, SLC29A1 and RRM1 predict clinical outcome in patients with metastatic breast cancer receiving gemcitabine plus paclitaxel chemotherapy

BackgroundPaclitaxel and gemcitabine (PG) combination chemotherapy is effective as a maintenance chemotherapeutic regimen in metastatic breast cancer (MBC) patients because it increases progression-free survival (PFS), which increases overall survival (OS). The primary purpose of our study was to investigate the association between genetic polymorphisms in the genes involved in PG pathways and clinical outcomes in MBC patients treated with PG chemotherapy.MethodsA total of 324 MBC patients were enrolled in this prospective multicenter trial of PG as the first-line chemotherapy. Eighty-five of the 324 patients from two institutes were available for analysis of single nucleotide polymorphisms (SNPs). Germline DNA was extracted from peripheral blood mononuclear cells. Thirty-eight SNPs in 15 candidate genes selected from pathways that may influence the metabolism and transport of, or sensitivity, to PG were analysed.ResultsThe median PFS and OS of all 324 patients were 8.7 months (95% confidence interval [CI]: 7.5–9.6 months) and 26.9 months (95% CI: 23.6–30.1 months), respectively. An SNP in SLC28A3 (rs7867504, C/T) was associated with OS (CC or CT versus TT: 37 versus 21 months, p = 0.027, hazard ratio [HR] 2.6, 95% CI: 1.1–6.3). SLC29A1 GA haplotype had a significantly shorter OS (p = 0.030, HR 3.391, 95% CI: 1.13–10.19). RRM1 (ribonucleotide reductase large subunit M1) SNP (rs9937), and haplotypes ATAA and ATGA were significantly associated with neurotoxicity.ConclusionGenetic polymorphisms in SLC28A3, SLC29A1 and RRM1 can influence the clinical outcome of MBC patients treated with PG chemotherapy. Further studies on the functional mechanisms relating to these germline polymorphisms in these genes are warranted.     

Impact of primary tumour resection on survival of patients with colorectal cancer and synchronous metastases treated by chemotherapy: Results from the multicenter,randomised trial Fédération Francophone de Cancérologie Digestive 9601

ObjectiveTo assess the impact of primary tumour resection on overall survival (OS) of patients diagnosed with stage IV colorectal cancer (CRC).DesignAmong the 294 patients with non-resectable colorectal metastases enrolled in the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 phase III trial, which compared different first-line single-agent chemotherapy regimens, 216 patients (73%) presented with synchronous metastases at study entry and constituted the present study population. Potential baseline prognostic variables including prior primary tumour resection were assessed by univariate and multivariate Cox analyses. Progression-free survival (PFS) and OS curves were compared with the logrank test.ResultsAmong the 216 patients with stage IV CRC (median follow-up, 33 months), 156 patients (72%) had undergone resection of their primary tumour prior to study entry. The resection and non-resection groups did not differ for baseline characteristics except for primary tumour location (rectum, 14% versus 35%; p = 0.0006). In multivariate analysis, resection of the primary was the strongest independent prognostic factor for PFS (hazard ratio (HR), 0.5; 95% confidence interval [CI], 0.4–0.8; p = 0.0002) and OS (HR, 0.4; CI, 0.3–0.6; p < 0.0001). Both median PFS (5.1 [4.6–5.6] versus 2.9 [2.2–4.1] months; p = 0.001) and OS (16.3 [13.7–19.2] versus 9.6 [7.4–12.5]; p < 0.0001) were significantly higher in the resection group. These differences in patient survival were maintained after exclusion of patients with rectal primary (n = 43).ConclusionResection of the primary tumour may be associated with longer PFS and OS in patients with stage IV CRC starting first-line, single-agent chemotherapy.     

Systematic review and meta-analysis of randomised,phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer

BackgroundPrevious studies have demonstrated the efficacy and safety of bevacizumab in the treatment of non-small-cell lung cancer (NSCLC).MethodsSummary data from randomised trials comparing first-line bevacizumab plus platinum-based chemotherapy with chemotherapy alone for inoperable locally advanced, recurrent or metastatic NSCLC were meta-analysed. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and pooled odds ratio (OR) for adverse events were calculated. The chi-squared tests evaluated interactions between treatment effects, and prognostic factors and patient characteristics.ResultsData of 2194 patients (1313 bevacizumab; 881 controls) from four phase II and III trials: AVF-0757g, JO19907, ECOG 4599 and AVAiL, were analysed. Compared with chemotherapy alone, bevacizumab significantly prolonged OS (HR 0.90; 95% confidence interval [CI] 0.81, 0.99; P = 0.03), and PFS (0.72; 95% CI 0.66, 0.79; P < 0.001). Bevacizumab showed a significantly greater effect on OS in patients with adenocarcinoma versus other histologies (P = 0.02), and patients with body weight loss ≤5% versus >5% (P = 0.03). Bevacizumab significantly increased the risk of grade ≥3 proteinuria, hypertension, haemorrhagic events, neutropenia, and febrile neutropenia.ConclusionsBevacizumab significantly prolonged OS and PFS when added to first-line platinum-based chemotherapy in patients with advanced NSCLC; no unexpected toxicity was evident.     

Bevacizumab combined with chemotherapy for patients with advanced colorectal cancer: a systematic review

BackgroundFluoropyrimidine-based chemotherapy is considered standard treatment of advanced colorectal cancer. Recent studies indicate benefit to the addition of bevacizumab, a recombinant monoclonal antibody targeting vascular endothelial growth factor.MethodsMedline, EMBASE, Cochrane Library, and conference proceedings were searched to identify randomized trials in advanced colorectal cancer comparing chemotherapy plus bevacizumab with chemotherapy alone. A meta-analysis of published data was carried out.ResultsFive trials comparing chemotherapy plus bevacizumab with chemotherapy alone as first- or second-line treatment were identified. Our meta-analysis indicates an advantage in favor of the addition of bevacizumab to chemotherapy in terms of overall survival (OS) [hazard ratio (HR) 0.79; 95% confidence interval (CI) 0.69–0.90; P = 0.0005], progression-free survival (PFS) (HR 0.63; 95% CI 0.49–0.81, P = 0.0004), and response rate (RR 1.50; 95% CI 1.06–2.10, P = 0.02). The most commonly observed adverse effects related to bevacizumab included hypertension, proteinuria, bleeding, and thrombosis. Gastrointestinal perforation and poor wound healing were also observed; however, their incidence was rare.ConclusionsFor patients with advanced colorectal cancer receiving first- or second-line fluoropyrimidine-based chemotherapy, the addition of bevacizumab improves PFS and OS at the expense of increased incidence of toxicity. The magnitude of benefit may differ based on the chemotherapy regimen with which bevacizumab is partnered.     

Prognostic and predictive role of neutrophil/lymphocytes ratio in metastatic colorectal cancer: a retrospective analysis of the TRIBE study by GONO

BackgroundNeutrophil/lymphocyte ratio (NLR), defined as absolute neutrophils count divided by absolute lymphocytes count, has been reported as poor prognostic factor in several neoplastic diseases but only a few data are available about unresectable metastatic colorectal cancer (mCRC) patients (pts). The aim of our study was to evaluate the prognostic and predictive role of NLR in the TRIBE trial.Patients and methodsPts enrolled in TRIBE trial were included. TRIBE is a multicentre phase III trial randomizing unresectable and previously untreated mCRC pts to receive FOLFOXIRI or FOLFIRI plus bevacizumab. A cut-off value of 3 was adopted to discriminate pts with low (NLR < 3) versus high (NLR ≥ 3) NLR, as primary analysis. As secondary analysis, NLR was treated as an ordinal variable with three levels based on terciles distribution.ResultsNLR at baseline was available for 413 patients. After multiple imputation at univariate analysis, patients with high NLR had significantly shorter progression-free survival (PFS) [hazard ratio (HR) 1.27 (95% CI 1.05–1.55), P = 0.017] and overall survival (OS) [HR 1.56 (95% CI 1.25–1.95), P < 0.001] than patients with low NLR. In the multivariable model, NLR retained a significant association with OS [HR 1.44 (95% CI 1.14–1.82), P = 0.014] but not with PFS [HR 1.18 (95% CI 0.95–1.46), P = 0.375]. No interaction effect between treatment arm and NLR was evident in terms of PFS (P for interaction = 0.536) or OS (P for interaction = 0.831). Patients with low [HR 0.84 (95% CI 0.64–1.08)] and high [HR 0.73 (95% CI 0.54–0.97)] NLR achieved similar PFS benefit from the triplet and consistent results were obtained in terms of OS [HR 0.83 (95% CI 0.62–1.12) for low NLR; HR 0.82 (95% CI 0.59–1.12) for high NLR].ConclusionThis study confirmed the prognostic role of NLR in mCRC pts treated with bevacizumab plus chemotherapy in the first line, showing the worse prognosis of pts with high NLR. The advantage of the triplet is independent of NLR at baseline.     

Elevated LDH predicts poor outcome of recurrent germ cell tumours treated with dose dense chemotherapy

Aims of the studyPrognostic factors for recurrent germ cell tumours (GCTs) treated with dose dense salvage chemotherapy have not been identified. This study determines whether lactate dehydrogenase (LDH) or established prognostic models can predict the outcome of recurrent GCTs treated with dose dense cisplatin-based chemotherapy.Patients and methodsRetrospective analysis of 117 consecutive male patients with a first recurrence of a GCT treated with dose dense chemotherapy at a single cancer centre. Characteristics associated with progression-free survival (PFS) and overall survival (OS) were identified by univariate and multivariate analyses. Prognostic criteria published by the Medical Research Council (MRC) and the Memorial Sloan Kettering Cancer Centre (MSK) were also applied in an attempt to validate them and to compare their performance to that of LDH.ResultsRaised LDH was significantly associated with poor PFS (hazard ratio (HR) = 3.7; p < 0.001) and OS (HR = 3.4; p = 0.001). Further factors associated with poor PFS and OS, respectively, were failure to achieve a complete response or marker negative partial response for at least 6 months (HR = 2.1; p = 0.033) and seminoma histology (HR = 3.4; p = 0.003). The MRC prognostic model, but not the MSK model, identified groups of patients with statistically significant differences in PFS and OS but raised LDH predicted OS and PFS with a higher HR.ConclusionsRaised LDH is associated with a poor prognosis in recurrent GCTs and outperforms established prognostic models in this setting. LDH as a prognostic factor should be validated prospectively and should also be assessed in patients receiving conventional dose chemotherapy regimens.     

RAC1b overexpression correlates with poor prognosis in KRAS/BRAF WT metastatic colorectal cancer patients treated with first-line FOLFOX/XELOX chemotherapy

IntroductionChemotherapy is the principal treatment in metastatic colorectal cancer (mCRC) patients. RAC1b, a RAC1 spliced variant, is over-expressed in colorectal cancer (CRC), and impairs apoptosis by activation of nuclear-factor-KB. Since RAC1b has been associated with the BRAF^V600E mutation, associated with poor prognosis in CRC, we evaluated the role of RAC1b expression as a predictor of chemotherapy efficacy in mCRC.MethodsWe analysed KRAS and BRAF mutation, microsatellite instability and RAC1b expression in 157 mCRC patients treated with FOLFOX/XELOX in first-line therapy.ResultsKRAS mutations were detected in 46 patients (34%), 10 patients were BRAF mutant (7%) and 79 were WT for both, KRAS and BRAF (59%). RAC1b overexpression was found in 30 patients (19%). In the multivariate analysis, BRAF mutational status was a poor prognostic factor for overall survival (OS); hazard ratio (HR), 2.78 (95% confidence interval (CI), 1.35–5.72; p = 0.0057). RAC1b overexpression was a poor survival factor for OS (HR, 2.35; 95% CI, 1.2–4.59; p = 0.01) and progression-free survival (PFS) (HR, 2.4; 95% CI, 1.2–4.78; p = 0.01) in KRAS/BRAF WT mCRC patients.ConclusionsRAC1b overexpression constitutes a marker of poor prognosis in KRAS/BRAF WT mCRC patients treated with first-line FOLFOX/XELOX therapy.     

Biomarker assessment of the CBCSG006 trial: a randomized phase III trial of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer

BackgroundCBCSG006 trial reported the superior efficacy of cisplatin plus gemcitabine (GP) regimen than paclitaxel plus gemcitabine (GT) regimen as first-line treatment of metastatic triple-negative breast cancer (mTNBC). This study focused on the updated survival data and the explorations of potential biomarkers for efficacy.Patients and methodsGerm-line mutations of homologous recombination (HR) panel, BRCA1/2 included, were evaluated in 55.9% (132/236) patients. PD-L1 expression was evaluated in 48.3% (114/236) patients. A nonparametric sliding-window subpopulation treatment effect pattern plot (STEPP) methodology was used to analyze the absolute survival benefits. All statistical tests were two-sided.ResultsMedian progression-free survival (PFS) was 7.73 [95% confidence interval (CI) 6.46–9.00] months for GP arm and 6.07 (95% CI 5.32–6.83) months for GT arm (P = 0.005). No significant difference in overall survival (OS) was observed. There was significant interaction between HR status and treatment for PFS and status of HR deficient significantly correlated with higher objective response rate (ORR) and longer PFS in GP arm than in GT arm (71.9% versus 38.7%, P = 0.008; 10.37 versus 4.30 months, P = 0.011). There was no significant interaction between germ-line BRCA1/2 (gBRCA1/2) status and treatment for PFS. Patients with gBRCA1/2 mutation had numerically higher ORR and prolonged PFS in GP arm than in GT arm (83.3% versus 37.5%, P = 0.086; 8.90 versus 3.20 months, P = 0.459). There was no significant interaction between PD-L1 status and treatment for PFS, and no significant differences in ORR, PFS or OS between two arms regardless of PD-L1 status. In STEPP analysis, patients with lower composite risks had more absolute benefits in PFS than those with higher composite risks.ConclusionsGP regimen has superior efficacy than GT regimen as first-line chemotherapy for mTNBC patients. Germ-line mutations of BRCA1/2 and HR panel are possible biomarkers for better performance of cisplatin-based regimens. A composite risk model was developed to guide patient selection for GP treatment in TNBC patients.Trial registrationClinicalTrials.gov, NCT01287624.     

Long-term results of a randomised phase III trial of weekly versus three-weekly paclitaxel/platinum induction therapy followed by standard or extended three-weekly paclitaxel/platinum in European patients with advanced epithelial ovarian cancer

BackgroundWeekly paclitaxel/carboplatin might improve survival in platinum-resistant epithelial ovarian cancer (EOC). We compared efficacy of first-line weekly to three-weekly paclitaxel/cis- or carboplatin (PCw and PC3w) induction therapy, followed by either three or six PC3w cycles.Patients and methodsIn this multicentre, randomised phase III trial with 2×2 design, patients with FIGO stage IIb–IV EOC were randomised to six cycles PCw (paclitaxel 90 mg/m², cisplatin 70 mg/m² or carboplatin AUC 4) or three cycles PC3w (paclitaxel 175 mg/m², cisplatin 75 mg/m² or carboplatin AUC 6), followed by either three or six cycles PC3w. Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints were response rate (RR) and toxicity.ResultsOf 267 eligible patients, 133 received PCw and 134 PC3w. The first 105 patients received cisplatin, after protocol amendment the subsequent 162 patients received carboplatin. Weekly cisplatin was less well tolerated than weekly carboplatin. All PC3w cycles were well tolerated. At the end of all treatments, RR was 90.8% with no differences between the treatment arms. After a follow-up of median 10.3 years (range 7.1–14.8), median PFS was 18.5 (95% confidence interval (CI) 15.9–21.0) months for PCw and 16.4 (95% CI 13.5–19.2) months for PC3w (p = 0.78). Median OS was 44.8 (95% CI 33.1–56.5) months for PCw and 41.1 (95% CI 34.4–47.7) months for PC3w (p = 0.98).ConclusionsThere was no benefit in terms of OS, PFS or RR for a weekly regimen nor for extended chemotherapy as first-line treatment for EOC in European patients.     

Sequential therapy for the locally advanced larynx and hypopharynx cancer subgroup in TAX 324: survival,surgery, and organ preservation

BackgroundLocally advanced laryngeal and hypopharyngeal cancers (LHC) represent a group of cancers for which surgery, laryngectomy-free survival (LFS), overall survival (OS), and progression-free survival (PFS) are clinically meaningful end points.Patients and methodsThese outcomes were analyzed in the subgroup of assessable LHC patients enrolled in TAX 324, a phase III trial of sequential therapy comparing docetaxel plus cisplatin and fluorouracil (TPF) against cisplatin and fluorouracil (PF), followed by chemoradiotherapy.ResultsAmong 501 patients enrolled in TAX 324, 166 had LHC (TPF, n = 90; PF, n = 76). Patient characteristics were similar between subgroups. Median OS for TPF was 59 months [95% confidence interval (CI): 31–not reached] versus 24 months (95% CI: 13–42) for PF [hazard ratio (HR) for death: 0.62; 95% CI: 0.41–0.94; P = 0.024]. Median PFS for TPF was 21 months (95% CI: 12–59) versus 11 months (95% CI: 8–14) for PF (HR: 0.66; 95% CI: 0.45–0.97; P = 0.032). Among operable patients (TPF, n = 67; PF, n = 56), LFS was significantly greater with TPF (HR: 0.59; 95% CI: 0.37–0.95; P = 0.030). Three-year LFS with TPF was 52% versus 32% for PF. Fewer TPF patients had surgery (22% versus 42%; P = 0.030).ConclusionsIn locally advanced LHC, sequential therapy with induction TPF significantly improved survival and PFS versus PF. Among operable patients, TPF also significantly improved LFS and PFS. These results support the use of sequential TPF followed by carboplatin chemoradiotherapy as a treatment option for organ preservation or to improve survival in locally advanced LHC.     

Cisplatin and gemcitabine in patients with advanced biliary tract cancer (ABC) and persistent jaundice despite optimal stenting: Effective intervention in patients with luminal disease

IntroductionThe advanced biliary tract cancer (ABC)-02 study established cisplatin and gemcitabine (CisGem) as a reference 1^st-line regimen for patients with advanced/metastatic biliary tract cancer; patients with bilirubin ⩾1.5 × upper limit of normal (ULN) were excluded and there are few extant data for systemic treatment in the context of elevated bilirubin.MethodsPatients with ABC, receiving CisGem with a baseline bilirubin of ⩾1.5×ULN were eligible for this retrospective analysis; response, toxicity and survival data were collected.ResultsThirty-three patients of 545 screened; median age 59 years, range 23–79; 58% male, 58% with metastases (79% in the liver) of performance status (PS) 0 (33%), 1 (64%) or 2 (3%) were eligible. The median baseline bilirubin was 55 μmol/L (range 32–286); due to biliary tract obstruction (BTO, 76%) or liver metastases (LM, 24%). Toxicity was comparable to the ABC-02 study; bilirubin normalised in 64% during chemotherapy/follow-up. The median progression-free survival (PFS) was 6.9 months (95% confidence interval (CI): 4.4–9.0) and median overall survival (OS) 9.5 months (95% CI: 5.7–12.8). Patients with BTO had a longer PFS and OS than those with LM (7.0 versus 2.6 months; p = 0.1633 and 9.8 versus 4.4 months, hazard ratio (HR) 0.74; p = 0.465, respectively); not statistically significant (due to small sample size). Normalisation of bilirubin and completion of eight CisGem cycles were associated with longer OS (11.4 versus 2.9 months, HR 0.49; p = 0.08 and 15.2 versus 5.4 months, HR 0.12 p < 0.001, respectively). No difference in OS was shown between the bilirubin percentiles (for either PFS or OS).ConclusionFor PS 0-1 patients with ABC and high bilirubin due to luminal disease despite optimal stenting CisGem can be used safely with results similar to those in patients with normal bilirubin.     

Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer

BackgroundWe analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).Patients and methodsALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders.ResultsAmong 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4–5.6) versus 10.3 months (95% CI: 8.6–12.0), P < 0.001; OS 15.0 months (95% CI: 5.0–24.9) versus 50.0 months (95% CI: 22.9–77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3–4.1) versus 6.2 months (95% CI: 1.8–10.5), P = 0.021; OS 2.0 months (95% CI: 0.0–4.6) versus 9.0 months (95% CI: 6.1–11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9–7.2) versus 14.0 months (95% CI: 8.0–20.1), P < 0.001; OS 17.0 months (95% CI: 6.7–27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1–10.7) versus 9.9 months (95% CI: 6.4–13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001).ConclusionsIn ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.     

Early tumour shrinkage as a prognostic factor and surrogate end-point in colorectal cancer: A systematic review and pooled-analysis

PurposeEarly tumour shrinkage (ETS), defined as a reduction of at least 20% in tumour size at first reassessment, has been recently investigated retrospectively in first-line trials of metastatic colorectal cancer (CRC), and appears to be associated with better outcomes. We have performed a systematic review and meta-analysis of published trials to evaluate the prognostic value of ETS in CRC in terms of overall survival (OS) and progression-free survival (PFS).Material and methodsAn electronic search of the PubMed, SCOPUS, EMBASE, the Web of Science, and the Cochrane Central Register of Controlled Trial databases identified trials that compared outcomes of patients with or without ETS during first-line chemotherapy for metastatic CRC. The OS, reported as a hazard ratio (HR) with a 95% confidence interval (CI), was the primary outcome measure; the correlation coefficient (R) between ETS with median OS was also estimated.ResultsTwenty-one trials from 10 publications were analysed. Overall, patients with ETS were associated with a better OS (HR, 0.58; 95% CI, 0.53 to 0.64; P < 0.00001) and PFS (HR, 0.57; 95% CI, 0.47–0.69; P < 0.00001) compared with patients who were early non-responders. However, ETS was poorly correlated with OS in terms of surrogacy (R = 0.37; 95% CI - 0.31–0.78; P = 0.28).ConclusionsETS is a good prognostic factor but an inappropriate surrogate for predicting outcome in CRC patients. These findings support ETS as prognostic tool in ascertaining earlier non-responders; however, its role as a surrogate end-point deserves further evaluation.     

Prognostic role of pretreatment blood neutrophil-to-lymphocyte ratio in advanced cancer survivors: A systematic review and meta-analysis of 66 cohort studies

BackgroundNeutrophil-to-lymphocyte ratio (NLR) is crucial for the incidence and mortality of various tumors. However, little is known on NLR and its association with prognosis in advanced tumors. Here we performed a meta-analysis to establish the prognostic significance of pretreatment blood NLR for advanced tumors.MethodsA systematic literature search through April 2016 was performed to evaluate the association between pretreatment blood NLR and overall survival (OS) or progression-free survival (PFS) in patients with advanced tumors. Data were extracted from studies reporting hazard ratios (HRs) and 95% confidence interval (CI) and pooled using the Mantel–Haenszel random-effect model.ResultsSixty-six studies with a total of 24536 individuals were included in the meta-analysis. Pooled analyses revealed that elevated pretreatment NLR was associated with worse OS (HR 1.70, 95% CI 1.57–1.84, P < 0.001) and PFS (HR 1.61, 95% CI 1.42–1.82, P < 0.001) in advanced tumors. Subgroup analysis stratified by tumor type demonstrated that pancreatic cancer patients with high pretreatment NLR had the worst OS (HR 1.94, 95% CI 1.55–2.54, P < 0.001) and colorectal cancer with the worst PFS (HR 1.74, 95% CI 1.04–2.90, P < 0.001). When stratified by cut-off value for NLR, we found that cut-off value being five indicated the worst PFS (HR 2.23, 95% CI 1.54–3.23, P = 0.019).ConclusionsOverall, high pretreatment blood NLR could be an adverse prognostic indicator for advanced tumor. Large-scale prospective studies investigating its survival outcomes in specific cancer type are strongly advocated.     

Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: A meta-analysis

BackgroundWild type RAS (RAS-wt) status is predictive of the activities of the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab (C) and panitumumab (P). We examined the impact of C and P on progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) in advanced colorectal cancer (CRC) patients who have RAS-wt/BRAF-mutant (BRAF-mut) status.MethodsRandomised trials that compared C or P plus chemotherapy (or C or P monotherapy) with standard therapy or best supportive care (BSC) were included. We used published hazard ratios (HRs) if they were available, or we derived treatment estimates from other survival data. Pooled estimates of the treatment efficacy of anti-EGFR-based therapy with C or P for the RAS-wt/BRAF-mut subgroup were calculated with the random-effect inverse variance weighted method. All statistical tests were two-sided.ResultsNine phase III trials and one phase II trial (six first-line and two second-line trials, plus two trials involving chemorefractory patients), that included 463 RAS-wt/BRAF-mut CRC patients, were analysed. Overall, the addition of C or P treatment in the BRAF-mut subgroup did not significantly improve PFS (HR, 0.88; 95% confidence interval (CI), 0.67–1.14; p = 0.33), OS (HR, 0.91; 95% CI, 0.62–1.34; p = 0.63) and ORR (relative risk, 1.31; 95% CI 0.83–2.08, p = 0.25) compared with control regimens.ConclusionsC- or P-based therapy did not increase the benefit of standard therapy or the BSC in RAS-wt/BRAF-mut CRC patients. These findings support BRAF mutation assessment before initiation of treatment with anti-EGFR monoclonal antibodies.     

Prior long response to androgen deprivation predicts response to next-generation androgen receptor axis targeted drugs in castration resistant prostate cancer

BackgroundThere is an urgent need for qualified predictive biomarkers of sensitivity for the treatments used in patients with castration-resistant prostate cancer (CRPC). We attempted to identify ready-to-use clinical predictors of improved outcome in metastatic CRPC (mCRPC) patients treated with next generation androgen receptor (AR) axis targeted drugs.Patients and methodsWe reviewed a cohort of patients who received AR axis targeted drugs for CRPC at two major French cancer centres. The predictive role of several clinical, biological and radiological parameters on progression-free survival (PFS) was studied.ResultsThe study cohort consisted of 173 patients. Median duration of response to initial androgen deprivation therapy (ADT) (time to castration resistance, TTCRPC) was 17.8 months. The 50% prostate-specific antigen (PSA) response rate to AR axis targeted drugs was 16% (95% confidence interval (CI): 6–27) and 41% (95% CI: 30–47) in patients with TTCRPC of under and over 12 months respectively (p = 0.005). Median PFS was 2.8 months (95% CI: 2.1–3.9) and 5.8 (95% CI: 4.6–7.8; HR: 0.58, p = 0.002). In patients treated with post-docetaxel enzalutamide (n = 57), median PFS was 2.8 months and 8.6 months, (Hazard ratio (HR) = 3.1; 95% CI: 1.6–5.8, p = 0.0016) according to TTCRPC, whereas no difference was observed in placebo-treated patients (n = 27). The 50% PSA response rate to enzalutamide was 8% (95% CI: 0–38) and 58% (95% CI: 42–73) in patients with a TTCRPC of under and over 12 months respectively (p < 0.001).ConclusionThe previous duration of response to ADT is a predictor of sensitivity to next generation AR axis targeted drugs in patients with mCRPC.