Derived neutrophil lymphocyte ratio may predict benefit from cisplatin in the advanced biliary cancer: the ABC-02 and BT-22 studies

BackgroundThe superiority of cisplatin and gemcitabine (CisGem) chemotherapy over gemcitabine (Gem) alone in patients with advanced biliary tract cancer (ABC) has been demonstrated in two randomised trials; ABC02 and the Biliary Tract (BT) 22 study. We used a combined dataset from these two trials to investigate the derived neutrophil-to-lymphocyte ratio (dNLR), which is thought to be a prognostic factor associated with clinical outcomes in several solid tumours, including ABC.MethodsWhite blood cell (WBC) and absolute neutrophil count (ANC) were available for 379 of 410 patients from ABC-02 and all 83 patients in BT-22. The dNLR was calculated as ANC/(WBC-ANC), as previously specified. We examined the association between dNLR and overall survival (OS) and progression-free survival (PFS), as well as comparing the treatment effect in two patient groups defined by their dNLR level. A high dNLR was defined as ≥3.0, which was approximately the upper tertile value.ResultsA total of 462 individual patient records were analysed, 328 with baseline dNLR <3 and 134 with dNLR ≥3. There were 443 deaths in the cohort, and all surviving patients had a dNLR <3. There was strong evidence that dNLR was closely associated with both OS [hazard ratio (HR), 1.62; 95% confidence interval (CI) 1.32–2.01] and PFS (HR, 1.40; 95% CI 1.13–1.72). There was limited evidence (P = 0.10) of a differential effect of CisGem on OS between the two dNLR groups, but this was clearest in the ABC-02 dataset (P = 0.06). There was good evidence (P = 0.008) of an association between low baseline dNLR and long-term survival on a CisGem regimen. There was also good evidence of an association between ECOG performance status (split at 0 and 1 versus 2) on both OS (P < 0.001) and PFS (P = 0.01), but no evidence of a differential treatment effect, with both groups receiving benefit from the addition of cisplatin.ConclusionsThese data confirm that high dNLR is associated with worse OS and PFS, and suggests it may also be predictive of benefit for the addition of cisplatin to gemcitabine in European patients with ABC. Incorporating dNLR into the clinical context may better inform prognosis and chemotherapy decisions in ABC patients.     

Progression free survival of first line vascular endothelial growth factor-targeted therapy is an important prognostic parameter in patients with metastatic renal cell carcinoma

PurposeIntrinsic resistance in metastatic renal cell carcinoma (mRCC) was recently associated with poor overall survival (OS), suggesting that VEGF inhibitor sensitivity may represent a valuable prognostic marker. We explored the duration of progression free survival (PFS) in first-line treatment and other variables as prognostic markers in mRCC.MethodsMedical records from 119 mRCC patients receiving first line treatment with tyrosine kinase inhibitors (TKI) were retrieved retrospectively. Kaplan–Meier and log-rank analyses were employed on PFS and OS and multivariate Cox proportional hazard model analysed clinical parameters for their prognostic relevance.ResultsThe median PFS of first line treatment was 8.4 months (95% confidence interval 5.8–11) associated with a median OS of 28.2 months (95% CI 20.9–35.4). Second line therapy with another TKI or mTOR-inhibitor was applied to 81 patients (68%). PFS of any second line therapy was 5.1 and 3.7 months in first line treatment responders and non-responders (p = 0.3), respectively. Univariate analyses revealed bone metastases, prior cytokine treatment, Memorial Sloan Kettering cancer centre (MSKCC) score, objective response rate, Eastern Cooperative Oncology Group (ECOG) performance status, first line PFS with 6 months taken as cut-off parameter and second line treatment as prognostic variables. Multivariate analyses proved first line PFS above 6 months (95% CI 0.154–0.641; HR 0.314), second line treatment (95% CI 0.162–0.657; HR 0.326), MSKCC score (95% CI 1.07–3.392; HR 1.905) and objective response rate (95% CI 0.358–0.989; HR 0.595) to be independent prognostic markers.ConclusionsThe duration of first line PFS is an independent prognostic variable but not predictive for subsequent therapy.     

Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials

BackgroundTwo recent studies (ABC-02 [UK] and BT22 [Japan]) have demonstrated the superiority of cisplatin and gemcitabine (CisGem) chemotherapy over gemcitabine (Gem) alone for patients with pathologically proven advanced biliary tract cancer (BTC: cholangiocarcinoma, gallbladder and ampullary cancers). This pre-planned analysis evaluates the efficacy of CisGem with increased statistical power.Patients and methodsWe carried out a meta-analysis of individual patient-level data of these studies to establish the effect of CisGem versus Gem on progression-free survival (PFS), overall survival (OS) and carried out exploratory subgroup analyses.ResultsCisGem demonstrates a significant improvement in PFS [hazard ratio (HR) = 0.64, 95% confidence interval (CI) 0.53–0.76, P < 0.001] and OS (HR = 0.65, 95% CI 0.54–0.78, P < 0.001) over Gem. This effect is most marked among patients with good performance status (PS 0–1): HR for PFS is 0.61 (95% CI 0.51–0.74), P < 0.001 and OS HR = 0.64 (95% CI 0.53–0.77), P < 0.001. CisGem resulted in improved PFS and OS for intra- and extra-hepatic cholangiocarcinomas and gallbladder cancer. The treatment effect between UK and Japanese patients was consistent with respect to OS (HR = 0.65, 95% CI 0.53–0.79 and 0.65, 95% CI 0.42–1.03, respectively); with similar OS in the combination arms (median 11.7 and 11.1 months, respectively). Subgroups least likely to benefit included patients with ampullary tumours and poor performance status (PS2).ConclusionsCisGem is the standard of care for the first-line treatment of good-PS patients with advanced BTC regardless of ethnicity. Future studies should aim to enhance the effectiveness of this regimen in the first-line setting, establish the role of subsequent (second-line) therapy and assess the role of rationally developed molecular-targeted therapies.     

Prognostic factors in young ovarian cancer patients: An analysis of four prospective phase III intergroup trials of the AGO Study Group,GINECO and NSGO

ObjectivesWe evaluated in a large study meta-database of prospectively randomised phase III trials the prognostic factors for progression-free survival (PFS) and overall survival (OS) in patients < and >40 years of age with advanced epithelial ovarian cancer.MethodsA total of 5055 patients of the AGO, GINECO, NSGO intergroup studies AGO-OVAR 3, 5, 7 and 9 were merged to identify 294 patients <40 years and 4761 patients ≥40 years. We conducted survival analyses and Cox proportional hazard regression models and additionally analysed a very homogeneous subcohort of 405 patients with serous epithelial ovarian cancer, excellent performance status, who had received complete macroscopic upfront cytoreduction and ≥5 chemotherapy cycles.ResultsFor patients <40 years, the median PFS was 28.9 months and the median OS was 75.3 months, while the median PFS for patients ≥40 years was 18.1 months and the median OS was 45.7 months. Independent prognostic factors were similar in both age groups. In a multivariate analysis including prognostic factors potentially leading to confounding, young age appeared to improve PFS (hazard ratio [HR], 0.86; 95% confidence interval [CI]: 0.72–1.03) and OS (HR, 0.73; 95% CI: 0.59–0.91). The observed effect was even stronger in the subcohort of optimally treated patients with SEOC: PFS (HR, 0.34; 95% CI: 0.19–0.59) and OS (HR, 0.23; 95% CI: 0.09–0.56).DiscussionPrognostic factors were similar in both age groups. Young age appeared a strong independent protective prognostic factor for PFS and OS in the subcohort.     

Treatment outcomes of gemcitabine alone versus gemcitabine plus platinum for advanced biliary tract cancer: a Korean Cancer Study Group retrospective analysis

Purpose

ABC-02 trial of gemcitabine plus cisplatin combination showed prolongation of overall survival in biliary tract cancer (BTC) patients. In this multicenter retrospective study, we evaluated the treatment outcome of gemcitabine combined with platinum (GP) compared to that of gemcitabine (G) alone in Korean BTC patients.

Methods

One hundred and fifty-one patients with histologically confirmed biliary tract adenocarcinoma were enrolled at nine institutions between July 2003 and May 2011, including 100 treated with GP and 51 treated with G.

Results

With a median follow-up of 7.7 months (range 0.4–38.3 months), the median overall survival (OS) was 12.4 months [95 % confidence interval (CI) 9.4–15.6 months] of the G group, which was not significantly different for the median OS of 11.0 months (95 % CI 9.7–12.3 months) of the GP group (p = 0.599). The median progression-free survival (PFS) was 3.9 months (95 % CI 0.8–7.0 months) in the G group and 3.3 months (95 % CI 2.6–4.0 months) in the GP group (p = 0.504). Overall response rates (ORR) were 18.8 % in G group and 23.9 % in GP group (p = 0.485).

Conclusions

There was no significant difference in ORR, PFS, or OS for patients between the G group and the GP group, which was different from the ABC-02 trial. Therefore, gemcitabine monotherapy and GP combination are both effective regimens for Korean BTC patients.     

Value of KRAS as prognostic or predictive marker in NSCLC: results from the TAILOR trial

BackgroundThe prognostic and predictive role of KRAS mutations in advanced nonsmall-cell lung cancer (NSCLC) is still unclear. TAILOR prospectively assessed the prognostic and predictive value of KRAS mutations in NSCLC patients treated with erlotinib or docetaxel in second line.Patients and methodsNSCLC patients from 52 Italian hospitals were genotyped for KRAS and EGFR mutational status in two independent laboratories. Wild-type EGFR patients (N = 218) received first-line platinum-based chemotherapy and were randomly allocated at progression to erlotinib or docetaxel. Overall survival (OS) according to KRAS mutational status was the primary end point.ResultsKRAS mutations were present in 23% of TAILOR randomized cases. The presence of a KRAS mutation did not adversely affect progression-free (PFS) or overall (OS) survival [hazard ratio (HR) PFS = 1.01, 95% confidence interval (CI) 0.71–1.41, P = 0.977; OS = 1.24, 95% CI 0.87–1.77, P = 0.233], nor influenced treatment outcome (test for interaction: OS P = 0.965; PFS P = 0.417). Patients randomized to docetaxel treatment experienced longer survival independently from the KRAS mutational status of their tumors (HR: mutated KRAS 0.81, 95% CI 0.45–1.47; wild-type KRAS 0.79, 95% CI 0.57–1.10).ConclusionIn TAILOR, KRAS was neither prognostic nor predictive of benefit for either docetaxel or erlotinib. Docetaxel remains superior independently from KRAS status for second-line treatment in EGFR wild-type advanced NSCLC patients.Clinical trial registrationNCT00637910.     

Phase II randomised trial of autologous tumour lysate dendritic cell plus best supportive care compared with best supportive care in pre-treated advanced colorectal cancer patients

BackgroundAutologous tumour lysate dendritic cell vaccine (ADC) has T-cell stimulatory capacity and, therefore, potential antitumour activity. We designed a phase II randomised trial of ADC + best supportive care (BSC) (experimental arm [EA]) compared with BSC (control arm [CA]), in pre-treated metastatic colorectal cancer (mCRC) patients.Patients and methodsPatients with progressive mCRC, at least to two chemotherapy regimens and Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2, were randomised to EA versus CA. Stratification criteria: ECOG PS (0–1 versus 2) and lactate dehydrogenase (<Upper Limit of Normal [ULN] versus >ULN). EA was administered subcutaneously till progressive disease. Primary end-point was progression-free survival (PFS) at 4 months.ResultsFifty-two patients were included (28 EA/24 CA). An interim analysis recommended early termination for futility. No objective radiological response was observed in EA. Median PFS in EA was 2.7 months (95% confidence interval [CI], 2.3–3.2 months) versus 2.3 months (95% CI, 2.1–2.5 months) in CA (p = 0.628). Median overall survival (OS) was 6.2 months (95% CI, 4.4–7.9 months) in EA versus 4.7 months (95% CI, 2.3–7 months) in CA (p = 0.41). No ADC-related adverse events were reported. Immunization induces tumour-specific T-cell response in 21 of 25 (84%) patients. Responder patients have an OS of 7.3 months (95% CI, 5.2–9.4 months) versus 3.8 months (95% CI, 0.6–6.9 months) in non-responders; p = 0.026).ConclusionOur randomised clinical trial comparing ADC + BSC versus BSC in mCRC demonstrates that ADC generates a tumour-specific immune response but not benefit on PFS and OS. Our results do not support the use of ADC alone, in a phase III trial.     

Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study

BackgroundDespite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we carried out a meta-analysis using individual patient level trial data.MethodsIndividual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated.ResultsOS data were available for 912 patients. The median PFS was 3.3 months (95% CI 2.9–3.6) and 6-month PFS rate was 27% (95% CI 24–30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3 cm versus <3 cm) to be substantially associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH and elevated ALP were substantially associated with shorter PFS. The most substantial factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2 months (95% CI 9.5–11.0) and 1 year OS was 43% (95% CI 40–47). The most substantial prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS.ConclusionBenchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.     

Prognostic factors for progression-free and overall survival with sunitinib targeted therapy and with cytokine as first-line therapy in patients with metastatic renal cell carcinoma

BackgroundAnalysis of prognostic factors for progression-free survival (PFS) and overall survival (OS) was performed using final data from a randomized phase III trial of sunitinib versus interferon-α (IFN-α) as first-line metastatic renal cell carcinoma (RCC) therapy.DesignA multivariate Cox regression model analyzed baseline variables for prognostic significance. Each variable was investigated univariately and then multivariately using a stepwise algorithm.ResultsEach treatment arm comprised 375 patients. For sunitinib, multivariate analysis of PFS identified five independent predictors, including serum lactate dehydrogenase (LDH) level, presence of ≥2 metastatic sites, no prior nephrectomy, Eastern Cooperative Oncology Group (ECOG) performance status, and baseline platelet count, while multivariate analysis of OS identified serum LDH level, corrected serum calcium level, time from diagnosis to treatment, hemoglobin level, ECOG performance status, and presence of bone metastasis as predictors. For IFN-α, LDH level and presence of ≥2 metastatic sites were common predictors of PFS to those for sunitinib, as were all predictors of OS except ECOG status.ConclusionsThis analysis identified prognostic factors for PFS and OS with sunitinib as first-line metastatic RCC therapy and confirmed that the Memorial Sloan-Kettering Cancer Center model is applicable in the era of targeted therapy.     

Urinary N-telopeptide (uNTx) is an independent prognostic factor for overall survival in patients with bone metastases from castration-resistant prostate cancer

BackgroundIn patients with bone metastases from castration-resistant prostate cancer (CRPC) not pretreated with a bisphosphonate elevated N-telopeptide of type I collagen (uNTx), a marker of bone resorption, predicts skeletal-related events (SRE). The aim of this study was to assess the prognostic value of uNTx for overall survival (OS) and the incidence of SRE in patients with bone metastases from CRPC receiving zoledronic acid.MethodsFrom 2004 to 2007, 94 patients with bone metastases from CRPC receiving zoledronic acid for at least 2 months were screened for uNTx.ResultsMedian age was 66 years (range 46–88). Median serum prostate-specific antigen (PSA) was 66 ng/ml (0–3984) and median uNTx was 19 nmol/mM creatinine (3–489). During follow-up, 38 patients (40%) experienced an SRE. Median OS was 20 months [95% (CI) confidence interval 15–24). In the multivariate analysis, elevated uNTx [hazard ratio (HR) 2.2 (95% CI 1.2–4.0)], serum PSA [HR 2.8 (95% CI 1.6–5.1)], and ECOG performance status were the only independent prognostic factors for OS. Median OS was 12 months (10–16) and 25 months (21–34) in patients with uNTx ≥20 nmol/mM creatinine and in those with uNTx <20 nmol/mM creatinine, respectively.ConclusionAn elevated uNTx level is an independent prognostic factor for OS in patients with bone metastases from CRPC receiving a bisphosphonate.     

In real life,one-quarter of patients with hormone receptor-positive metastatic breast cancer receive chemotherapy as initial palliative therapy: a study of the Southeast Netherlands Breast Cancer Consortium

BackgroundThe objective of this study was to present initial systemic treatment choices and the outcome of hormone receptor-positive (HR+) metastatic breast cancer.Patients and methodsAll the 815 consecutive patients diagnosed with metastatic breast cancer in 2007–2009 in eight participating hospitals were identified. From the 611 patients with HR+ disease, a total of 520 patients with HER2-negative (HER2-) breast cancer were included. Initial palliative systemic treatment was registered. Progression-free survival (PFS) and overall survival (OS) per initial palliative systemic therapy were obtained using the Kaplan–Meier method and compared using the log-rank test.ResultsFrom the total of 520 patients with HR+/HER2- metastatic breast cancer, 482 patients (93%) received any palliative systemic therapy. Patients that received initial chemotherapy (n = 116) were significantly younger, had less comorbidity, had received more prior adjuvant systemic therapy and were less likely to have bone metastasis only compared with patients that received initial endocrine therapy (n = 366). Median PFS of initial palliative chemotherapy was 5.3 months [95% confidence interval (CI) 4.2–6.2] and of initial endocrine therapy 13.3 months (95% CI 11.3–15.5), with a median OS of 16.1 and 36.9 months, respectively. Initial chemotherapy was also associated with worse outcome in terms of PFS and OS after adjustment for prognostic factors.ConclusionsA high percentage of patients with HR+ disease received initial palliative chemotherapy, which was associated with worse outcome, even after adjustment of relevant prognostic factors.     

Progression-free survival at 24 months (PFS24) and subsequent outcome for patients with diffuse large B-cell lymphoma (DLBCL) enrolled on randomized clinical trials

BackgroundPatients with diffuse large B-cell lymphoma treated with first-line anthracycline-based immunochemotherapy and remaining in remission at 2 years have excellent outcomes. This study assessed overall survival (OS) stratified by progression-free survival (PFS) at 24 months (PFS24) using individual patient data from patients with DLBCL enrolled in multi-center, international randomized clinical trials as part of the Surrogate Endpoint for Aggressive Lymphoma (SEAL) Collaboration.Patients and methodsPFS24 was defined as being alive and PFS24 after study entry. OS from PFS24 was defined as time from identified PFS24 status until death due to any cause. OS was compared with each patient’s age-, sex-, and country-matched general population using expected survival and standardized mortality ratios (SMRs).ResultsA total of 5853 patients enrolled in trials in the SEAL database received rituximab as part of induction therapy and were included in this analysis. The median age was 62 years (range 18–92), and 56% were greater than 60 years of age. At a median follow-up of 4.4 years, 1337 patients (23%) had disease progression, 1489 (25%) had died, and 5101 had sufficient follow-up to evaluate PFS24. A total of 1423 assessable patients failed to achieve PFS24 with a median OS of 7.2 months (95% CI 6.8–8.1) after progression; 5-year OS after progression was 19% and SMR was 32.1 (95% CI 30.0–34.4). A total of 3678 patients achieved PFS24; SMR after achieving PFS24 was 1.22 (95% CI 1.09–1.37). The observed OS versus expected OS at 3, 5, and 7 years after achieving PFS24 was 93.1% versus 94.4%, 87.6% versus 89.5%, and 80.0% versus 83.7%, respectively.ConclusionPatients treated with rituximab containing anthracycline-based immunochemotherapy on clinical trials who are alive without progression at 24 months from the onset of initial therapy have excellent outcomes with survival that is marginally lower but clinically indistinguishable from the age-, sex-, and country-matched background population for 7 years after achieving PFS24.     

索拉非尼治疗进展期肝细胞癌的疗效及预后因素分析

  目的  评价索拉非尼治疗进展期肝细胞癌（HCC）的疗效及分析其预后影响因素。  方法  前瞻性分析2007年8月至2009年7月间110例接受索拉非治疗的进展期HCC患者,评价其疗效、不良反应,以总生存期和无肿瘤进展生存期为预后指标进行单因素和Cox比例风险模型多因素分析。  结果  110例患者随访中位时间9（2~18）个月,服用索拉非尼中位时间6.5（2~18）个月。14例（12.7%）获得完全缓解（CR）,16例（14.5%）部分缓解（PR）,40例（36.4%）病情稳定（SD）,总有效率为70例（63.6%）。中位生存期和无肿瘤进展生存期分别为10.5个月（95%CI:8.7~12.3）和5.0个月（95%CI:3.7~6.3）。多因素分析显示:联合局部治疗（肝动脉化疗栓塞或氩氦刀）、美国东部肿瘤协作组活动状态评分（Eastern Cooperative Oncology Group performance status score,ECOG PS）和Child-Pugh分级是影响无肿瘤进展生存时间的独立预后因素,而联合局部治疗、ECOG PS评分和AFP（alfa-fetopro? tein）水平是影响总生存期的独立预后因素。亚组分析显示:在肝癌进展组患者中继续服用索拉非尼其总生存期明显长于终止索拉非尼治疗者（11个月vs. 7.5个月,P < 0.001）。  结论  索拉非尼治疗进展期HCC,ECOG PS评分是影响生存期的一个重要因素,联合局部治疗有益于改善生存期。      

Circulating tumor cells predict progression-free and overall survival in Chinese patients with metastatic breast cancer,HER2-positive or triple-negative (CBCSG004): a multicenter,double-blind,prospective trial

BackgroundThe aim of this multicenter, double-blind, prospective study was to evaluate the potential utility of circulating tumor cell (CTC) measurements in predicting responses to anticancer therapies, including response to human epidermal growth factor receptor-2 (HER-2)-targeted agents, progression-free survival (PFS), and overall survival (OS) in Chinese women with metastatic breast cancer (MBC).Patients and methodsThree hundred MBC patients planned to complete three CTC blood draws and two imaging studies.ResultsA total of 294 of the 300 MBC patients enrolled from six leading Chinese cancer centers were assessable. In multivariate Cox regression analyses, the baseline CTC number remained an independent prognostic factor for PFS [hazard ratio (HR) = 1.93; 95% confidence interval (CI) = 1.39–2.69; P < 0.001) and OS (HR = 3.76; 95% CI = 2.35–6.01; P < 0.001). Similar results were observed for CTC counts at the first follow-up visit for both PFS (P = 0.049) and OS (P < 0.001).ConclusionsEnumeration of CTCs in Chinese MBC patients provides substantial prognostic information and is an independent factor associated with PFS and OS. Moreover, we demonstrated the prognostic value in the various disease subtypes, including HER-2-positive disease irrespective of therapy.     

Paclitaxel plus bevacizumab or paclitaxel as first-line treatment for HER2-negative metastatic breast cancer in a multicenter national observational study

BackgroundBevacizumab combined with paclitaxel as first-line chemotherapy for patients with HER2-negative metastatic breast cancer (MBC) has led to mixed results in randomized trials, with an improvement in progression-free survival (PFS) but no statistically significant overall survival (OS) benefit. Real-life data could help in assessing the value of this combination.Patients and methodsThis study aimed to describe the outcome following first-line paclitaxel with or without bevacizumab in the French Epidemiological Strategy and Medical Economics (ESME) database of MBC patients, established in 2014 by Unicancer. The primary and secondary end points were OS and PFS, respectively.ResultsFrom 2008 to 2013, 14 014 MBC patient files were identified, including 10 605 patients with a HER2-negative status. Of these, 3426 received paclitaxel and bevacizumab (2127) or paclitaxel (1299) as first-line chemotherapy. OS adjusted for major prognostic factors was significantly longer in the paclitaxel and bevacizumab group compared with paclitaxel [hazard ratio (HR) 0.672, 95% confidence interval (CI) 0.601–0.752; median survival time 27.7 versus 19.8 months]. Results were consistent in all supportive analyses (using a propensity score for adjustment and as a matching factor for nested case–control analyses) and sensitivity analyses. Similar results were observed for the adjusted PFS, favoring the combination (HR 0.739, 95% CI 0.672–0.813; 8.1 versus 6.4 months).ConclusionsIn this large-scale, real-life setting, patients with HER2-negative MBC who received paclitaxel plus bevacizumab as first-line chemotherapy had a significantly better OS and PFS than those receiving paclitaxel. Despite robust methodology, real-life data are exposed to important potential biases, and therefore, results need to be treated with caution. Our data cannot therefore support extension of current use of bevacizumab in MBC.     

First‐line treatment with FOLFOXIRI for advanced pancreatic cancer in clinical practice: Patients' outcome and analysis of prognostic factors

FOLFIRINOX is a standard first‐line treatment for advanced pancreatic cancer (aPC). The Gruppo Oncologico Nord Ovest (GONO) FOLFOXIRI regimen demonstrated efficacy in metastatic colorectal cancer. We aimed to evaluate activity and tolerability of FOLFOXIRI regimen in patients with aPC and to explore putative prognostic factors. One hundred thirty‐seven consecutive aPC patients were treated with FOLFOXIRI in our institution between 2008 and 2014. Clinical, laboratory and pathological data were collected and their association with activity, progression free survival (PFS) and overall survival (OS) was investigated. After a median follow up of 30 months, median PFS and OS were 8.0 months (95% CI 6.19–9.81) and 12 months (95% CI 9.75–14.25), respectively. Response rate was 38.6%, while disease‐control rate 72.2%. At multivariate analysis liver metastases (p = 0.019; Hazard Ratio, HR, 0.59, 95% Confidence Interval, CI, 0.380.96), Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1 (p = 0.001; HR 2.26, 95%CI 1.42–3.59) and neutrophil‐lymphocyte ratio (NLR)> 4 (p= 0.002; HR: 2.42; 95% CI 1.38–4.25) were associated with poorer OS. We categorized 119 pts with complete available data as good‐risk (0 factors, 38 pts), intermediate‐risk (1 factor, 49 pts) and poor‐risk (≥2 factors, 32 pts). Median OS for these three groups were 17.6, 11.1 and 7.4 months, respectively (p < 0.001). FOLFOXIRI is active and feasible in aPC. Prognosis of aPC pts treated with FOLFOXIRI is influenced by easily available factors: our analysis revealed ECOG PS, liver metastases and NLR as the most important predictors of survival. These factors could be helpful for treatment decision and clinical trial design.     

Prognostic value of baseline functional status measures and geriatric screening in vulnerable older patients with metastatic colorectal cancer receiving palliative chemotherapy – The randomized NORDIC9-study

IntroductionAppropriate patient selection based on functional status is crucial when considering older adults for palliative chemotherapy. This pre-planned analysis of the randomized NORDIC9-study explored the prognostic value of four functional status measures regarding progression-free survival (PFS) and overall survival (OS) in vulnerable older patients with metastatic colorectal cancer (mCRC) receiving first-line palliative chemotherapy.Materials and methodsPatients ≥70 years of age with mCRC not candidates for standard full-dose combination chemotherapy were randomized to receive full-dose S1 or reduced-dose S1 + oxaliplatin. At baseline, functional status was assessed using ECOG performance status (ECOG PS), frailty phenotype, Geriatric 8 (G8), and Vulnerable Elderly Survey-13 (VES-13). Multivariable regression models were applied and C-statistics were estimated.ResultsIn total, 160 patients with a median age of 78 years (IQR: 76–81) were included. While in univariate analyses, ECOG PS, frailty phenotype, and VES-13 were statistically significantly associated with differences in OS between subgroups, G8 was not (HR = 1.55, 95%CI: 0.99–2.41, p = 0.050). In multivariable analyses adjusted for age, sex, body mass index, and treatment allocation, we found significant differences between subgroups for all applied tools and with C-statistics in the moderate range for ECOG PS and VES-13.Concerning PFS, statistically significant differences were observed between subgroups of ECOG PS, G8, and VES-13 both in uni- and multivariable analyses, but not for frailty phenotype.DiscussionIn this Nordic cohort of vulnerable older patients with mCRC, baseline ECOG PS, frailty phenotype, G8, and VES-13 showed prognostic value regarding overall survival, and moderate predictive value of models based on ECOG PS and VES-13 was demonstrated.     

Gemcitabine–erlotinib versus gemcitabine–erlotinib–capecitabine in the first-line treatment of patients with metastatic pancreatic cancer: Efficacy and safety results of a phase IIb randomised study from the Spanish TTD Collaborative Group

BackgroundGemcitabine and erlotinib have shown a survival benefit in the first-line setting in metastatic pancreatic cancer (mPC). The aim of this study was to assess whether combining capecitabine (C) with gemcitabine + erlotinib (GE) was safe and effective versus GE in patients with mPC.Patients and methodsPreviously untreated mPC patients were randomised to receive G (1000 mg/m², days 1, 8, 15) + E (100 mg/day, days 1–28) + C (1660 mg/m², days 1–21) or GE, q4 weeks, until progression or unacceptable toxicity. Primary end-point: progression-free survival (PFS); secondary end-points: overall survival (OS), response rate, relationship of rash with PFS/OS and safety.Results120 patients were randomised, median age 63 years, ECOG status 0/1/2 33%/58%/8%; median follow-up 16.5 months. Median PFS in the gemcitabine–erlotinib–capecitabine (GEC) and GE arms was 4.3 and 3.8 months, respectively (hazard ratio [HR]: 0.88, 95% confidence interval [CI]: 0.58–1.31; p = 0.52). Median OS in the GEC and GE arms was 6.8 and 7.7 months, respectively (HR: 1.09, 95% CI: 0.72–1.63; p = 0.69). Grade 3/4 neutropenia (GEC 43% versus GE 15%; p = 0.0008) and mucositis (GEC 9% versus GE 0%; p = 0.03) were the only statistically significant differences in grade 3/4 adverse events. PFS and OS were significantly longer in patients with rash (grade ≥1) versus no rash (grade = 0): PFS 5.5 versus 2.0 months (HR = 0.39, 95% CI: 0.26–0.6; p < 0.0001) and OS: 9.5 versus 4.0 months (HR = 0.51, 95% CI: 0.33–0.77; p = 0.0014).ConclusionPFS with GEC was not significantly different to that with GE in patients with mPC. Skin rash strongly predicted erlotinib efficacy.The study was registered with ClinicalTrials.gov: NCT01303029.     

Peripheral T-cell lymphomas in a large US multicenter cohort: prognostication in the modern era including impact of frontline therapy

BackgroundOptimal frontline therapy for peripheral T-cell lymphoma (PTCL) in the modern era remains unclear.Patients and methodsWe examined patient characteristics, treatment, and outcomes among 341 newly diagnosed PTCL patients from 2000 to 2011. Outcome was compared with a matched cohort of diffuse large B-cell lymphoma (DLBCL) patients, and prognostic factors were assessed using univariate and multivariate analyses.ResultsPTCL subtypes included PTCL, not otherwise specified (PTCL-NOS) (31%), anaplastic large T-cell lymphoma (ALCL) (26%), angioimmunoblastic T-cell lymphoma (23%), NK/T-cell lymphoma (7%), acute T-cell leukemia/lymphoma (6%), and other (7%). Median age was 62 years (range 18-95 years), and 74% had stage III-IV disease. Twenty-three (7%) patients received only palliative care whereas 318 received chemotherapy: CHOP-like regimens (70%), hyperCVAD/MA (6%), or other (18%). Thirty-three patients (10%) underwent stem-cell transplantation (SCT) in first remission. The overall response rate was 73% (61% complete); 24% had primary refractory disease. With 39-month median follow-up, 3-year progression-free survival (PFS) and overall survival (OS) were 32% and 52%. PFS and OS for PTCL patients were significantly inferior to matched patients with DLBCL. On multivariate analysis, stage I–II disease was the only significant pretreatment prognostic factor [PFS: hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.34–0.85, P = 0.007; OS: HR 0.42, 95% CI 0.22–0.78, P = 0.006]. ALK positivity in ALCL was prognostic on univariate analysis, but lost significance on multivariate analysis. The most dominant prognostic factor was response to initial therapy (complete response versus other), including adjustment for stage and SCT [PFS: HR 0.19, 95% CI 0.14–0.28, P < 0.0001; OS: HR 0.26, 95% CI 0.17–0.40, P < 0.0001]. No overall survival difference was observed based on choice of upfront regimen or SCT in first remission.ConclusionsThis analysis identifies early-stage disease and initial treatment response as dominant prognostic factors in PTCL. No clear benefit was observed for patients undergoing consolidative SCT. Novel therapeutic approaches for PTCL are critically needed.     

Prognostic role of tumor PIK3CA mutation in colorectal cancer: a systematic review and meta-analysis

BackgroundSomatic mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT pathway play a vital role in carcinogenesis. Approximately 15%–20% of colorectal cancers (CRCs) harbor activating mutations in PIK3CA, making it one of the most frequently mutated genes in CRC. We thus carried out a systematic review and meta-analysis investigating the prognostic significance of PIK3CA mutations in CRC.Materials and methodsElectronic databases were searched from inception through May 2015. We extracted the study characteristics and prognostic data of each eligible study. The hazard ratio (HR) and 95% confidence interval (CI) were derived and pooled using the random-effects Mantel–Haenszel model.ResultsTwenty-eight studies enrolling 12 747 patients were eligible for inclusion. Data on overall survival (OS) and progression-free survival (PFS) were available from 19 and 10 studies, respectively. Comparing PIK3CA-mutated CRC patients with PIK3CA-wild-type CRC patients, the summary HRs for OS and PFS were 0.96 (95% CI 0.83–1.12) and 1.20 (95% CI 0.98–1.46), respectively. The trim-and-fill, Copas model and subgroup analyses stratified by the study characteristics confirmed the robustness of the results. Five studies reported the CRC prognosis for PIK3CA mutations in exons 9 and 20 separately; neither exon 9 mutation nor exon 20 mutation in PIK3CA was significantly associated with patient survival.ConclusionsOur findings suggest that PIK3CA mutation has the neutral prognostic effects on CRC OS and PFS. Evidence was accumulating for the establishment of CRC survival between PIK3CA mutations and patient-specific clinical or molecular profiles.