Survival benefit of statins in older patients with rectal cancer: A Swedish population-based cohort study

ObjectivesIncreasing evidence suggests that statins may have antitumor effects but their role in rectal cancer appears inconclusive. The aim of this study was to investigate whether statins may have an impact on survival of older and younger patients with rectal cancer.Materials and MethodsThis study included 238 patients ≥70 years and 227 patients <70 years old, from the Southeast Health Care Region of Sweden, who were diagnosed with rectal adenocarcinoma between 2004 and 2013.ResultsIn the older group (n = 238), statin use at the time of diagnosis was related to better cancer-specific survival (CSS) and overall survival (OS), compared to non-use (CSS: Hazard Ratio (HR), 0.37; 95% CI, 0.19–0.72; P = .003; OS: HR, 0.62; 95% CI, 0.39–0.96; P = .032). In the older group with stages I-III disease (n = 199), statin use was associated with better disease-free survival (DFS) compared to non use (HR, 0.18; 95% CI, 0.06–0.59; P = .005). The improvement of CSS, OS and DFS remained significant after adjusting for potential confounders. In the older group with stage III disease, statin users had better CSS and DFS compared to non-users (log rank P = .043; log-rank P = .028, respectively). In the older group with short course radiotherapy, statin use was related to better CSS (log-rank P = .032). No such association was present in the younger group.ConclusionStatin use was related to improved survival in older patients with rectal cancer.This observation is important given the low cost and safety of statins as a drug.     

Disease-free and overall survival at 3.5 years for neoadjuvant bevacizumab added to docetaxel followed by fluorouracil,epirubicin and cyclophosphamide,for women with HER2 negative early breast cancer: ARTemis Trial

BackgroundThe ARTemis trial previously reported that addition of neoadjuvant bevacizumab (Bev) to docetaxel (D) followed by fluorouracil, epirubicin and cyclophosphamide (D-FEC) in HER2 negative breast cancer improved the pathological complete response (pCR) rate. We present disease-free survival (DFS) and overall survival (OS) with central pathology review.Patients and methodsPatients were randomized to 3 cycles of D followed by 3 cycles of FEC (D-FEC), ±4 cycles of Bev (Bev + D-FEC). DFS and OS were analyzed by treatment and by central pathology reviewed pCR and Residual Cancer Burden (RCB) class.ResultsA total of 800 patients were randomized [median follow-up 3.5 years (IQR 3.2–4.4)]. DFS and OS were similar across treatment arms [DFS hazard ratio (HR)=1.18 (95% CI 0.89–1.57), P = 0.25; OS HR = 1.26 (95% CI 0.90–1.76), P = 0.19). Both local pathology report review and central histopathology review confirmed a significant improvement in DFS and OS for patients who achieved a pCR [DFS HR = 0.38 (95% CI 0.23–0.63), P < 0.001; OS HR = 0.43 (95% CI 0.24–0.75), P = 0.003]. However, significant heterogeneity was observed (P = 0.02); larger improvements in DFS were obtained with a pCR achieved with D-FEC than a pCR achieved with Bev + D-FEC. As RCB class increased, significantly worse DFS and OS was observed (P for trend <0.0001), which effect was most marked in the ER negative group.ConclusionsThe addition of short course neoadjuvant Bev to standard chemotherapy did not demonstrate a DFS or OS benefit. Achieving a pCR with D-FEC is associated with improved DFS and OS but not when pCR is achieved with Bev + D-FEC. At the present time therefore, Bev is not recommended in early breast cancer.ClinicalTrials.gov numberNCT01093235.     

The impact of age on outcome in phase III NRG Oncology/RTOG trials of radiotherapy (XRT) +/− systemic therapy in locally advanced head and neck cancer

PurposeTo examine the role age plays in the treatment and prognosis of locally advanced head and neck cancer (LAHNC) treated definitively with radiation alone or combined modality therapy.MethodsA retrospective analysis was performed of three NRG/RTOG trials examining either radiation alone or combined radiation and systemic therapy for LAHNC. The effect of age (≥70 yrs.) on cause-specific survival (CSS), overall survival (OS), and toxicity was evaluated.ResultsA total of 2688 patients were analyzed, of whom 309 patients (11.5%) were ≥ 70. For all studies combined, the hazard ratio (HR) for CSS for patients age ≥ 70 vs. those <70 was 1.33 (95%CI: 1.14–1.55, p < 0.001). For OS, the HR for patients age ≥ 70 vs. those <70 for all studies combined was 1.55 (95% CI 1.35–1.77, p < 0.001). After adjustment for all covariates, age ≥ 70 was associated with worse OS regardless of adjustment for smoking and p16 status. The survival difference was more pronounced in those receiving combined radiation and systemic therapy. Hematologic and renal toxicities were increased in combined modality trials in patients ≥70 years old.ConclusionsPatients age ≥ 70 with LAHNC were underrepresented in these clinical trials. Their CSS and OS proved inferior to patients <70 years old.     

Multivariate analysis of prognostic factors in primary squamous cell vulvar cancer: The role of perineural invasion in recurrence and survival

Objectiveto assess the prognostic role in recurrence and survival of perineural invasion (PNI) in vulvar squamous cell cancer (VSCC).MethodsPatients underwent primary surgery for VSCC from January 2009 to December 2016 served as the study cohort. We collected demographic, clinical, pathological characteristics and follow-up data, and we compared them among PNI-negative versus -positivepatients. We calculated disease-free survival (DFS) and overall survival (OS) using Kaplan-Meier and univariate log-rank test. We conducted a multivariate analysis with cox-proportional hazard models for DFS and OS, including age, tumor size, depth of invasion, free tumor margin <8 mm, high-grade histology, lymph vascular space invasion, PNI, extracapsular lymph nodal disease, lymph nodal ratio >0.2 and FIGO Stage 2009 (Early I-II versus Advanced III-IV).ResultsWe found 74 patients with a PNI prevalence of 31.1%. The 5-year DFS was favourable for PNI-negative patients (72% versus 18%; p = 0.00). The 5-year OS was 75% versus 35% in favor of PNI-negative patients (p = 0.00). The subgroup analysis conducted among stage confirmed a decreased DFS and OS in PNI-positive patients. Multivariate analysis showed that PNI (HR 2.74; CI95% 1.10–7.13; p = 0.03) and extracapsular lymph nodal disease (HR 13.54; CI95% 2.87–64.07; p = 0.01) are independent prognostic factors for earlier recurrence. OS was significantly reduced in case of PNI (HR 4.93; CI95% 1.33–18.35; p = 0.01) and extracapsular lymph nodal disease (HR 10.63; CI95% 1.65–68.57; p = 0.01).ConclusionsPNI is an independent prognostic factor for aggressive behavior and unfavorable course in VSCC and should be considered in adjuvant treatment planning.     

The good,the bad and the ugly: a tale of miR-101, miR-21 and miR-155 in pancreatic intraductal papillary mucinous neoplasms

BackgroundThis multicenter study evaluated three candidate microRNAs (miRNAs) (miR-21, miR-155 and miR-101) as potential biomarkers in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas.Patients and methodsmiRNA expression was quantified by quantitative RT-PCR in 86 laser-microdissected specimens, including 65 invasive IPMNs, 16 non-invasive IPMNs and 5 normal pancreatic ductal tissues. Univariate and multivariate analyses compared miRNAs and clinical parameters with overall (OS) and disease-free survival (DFS).ResultsmiR-21 and miR-155 were up-regulated in invasive IPMNs compared with non-invasive IPMNs, as well as in non-invasive IPMNs compared with normal tissues. Conversely, miR-101 levels were significantly higher in non-invasive IPMNs and normal tissues compared with invasive IPMNs. High levels of miR-21 were associated with worse OS [hazard ratio (HR) = 2.47, 95% confidence interval (CI) = 1.37–5.65, P = 0.0047]. Patients with high-miR-21 expression also had a shorter median DFS (10.9 versus 29.9 months, P = 0.01). Multivariate analysis confirmed miR-21 as independently prognostic for mortality and disease progression (death risk: HR = 3.3, 95% CI = 1.5–7.0, P = 0.02; progression risk: HR = 2.3, 95% CI = 1.2–4.8, P = 0.02), as well as positive lymph-node status (death risk: HR = 2.6, 95% CI = 1.1–6.3, P = 0.03; progression risk: HR = 2.2, 95% CI = 1.0–4.8, P = 0.04).ConclusionsmiR-21, miR-155 and miR-101 showed significant differences in invasive versus non-invasive IPMNs. miR-21 emerged as an independent prognostic biomarker in invasive IPMNs and should be validated in prospective studies.     

Improved outcomes in elderly patients with metastatic castration-resistant prostate cancer treated with the androgen receptor inhibitor enzalutamide: results from the phase III AFFIRM trial

BackgroundThe randomized, double-blind phase III AFFIRM trial demonstrated that enzalutamide, an oral androgen receptor inhibitor, significantly prolonged overall survival (OS) [median 18.4 versus 13.6 months (hazard ratio, HR) 0.63 (95% confidence interval, CI, 0.53–0.75); P < 0.001] compared with placebo in patients with metastatic castration-resistant prostate cancer who received prior docetaxel chemotherapy.Patients and methodsA post hoc analysis was carried out to assess the efficacy and safety of enzalutamide on outcomes in younger (<75 years) and elderly (≥75 years) patients in the AFFIRM population. Statistics are presented by age group (<75 years, ≥75 years) for efficacy outcomes of OS, radiographic progression-free survival (rPFS), time to prostate-specific antigen (PSA) progression, PSA response, and safety.ResultsOS was significantly improved with enzalutamide over placebo in patients <75 years [median not yet reached versus 13.6 months; HR 0.63 (95% CI 0.52–0.78), P < 0.001] and in patients ≥75 years [median 18.2 versus 13.3 months; HR 0.61 (95% CI 0.43–0.86), P = 0.004], respectively. rPFS was similarly improved in both the younger [HR 0.45 (95% CI 0.38–0.53), P < 0.001] and elderly patient cohorts [HR 0.27 (95% CI 0.20–0.37), P < 0.001] relative to placebo, as were time to PSA progression and PSA response. Adverse events (AEs) were similar between the two enzalutamide age groups, with the exception of an increase in patients ≥75 years in the rates of all grade peripheral edema (22.1% versus 12.5%), fatigue (39.7% versus 31.6%), and diarrhea (26.6% versus 19.6%). The overall grade ≥3 AE rates were low with no major difference in frequency or severity between age groups or treatment arms. Five patients were reported with seizure events; three patients <75 years and two patients ≥75 years.ConclusionsEnzalutamide significantly improves outcomes in both younger (<75 years) and elderly patients (≥75 years), with comparable safety and tolerability.     

Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12

These final results from ABCSG-12 confirm that twice-yearly ZOL safely enhances the efficacy of adjuvant endocrine therapy. Tamoxifen together with Goserelin for now remains the endocrine standard of care. In general, overall survival of more than 95% at 8 years' median follow-up supports the efficacy of endocrine-only regimens in this premenopausal patient population.BackgroundZoledronic acid (ZOL) plus adjuvant endocrine therapy significantly improved disease-free survival (DFS) at 48- and 62-month follow-up in the ABCSG-12 trial. We present efficacy results of a final additional analysis after 94.4 months.Patients and methodsPatients were premenopausal women who had undergone primary surgery for stage I/II estrogen-receptor-positive and/or progesterone-receptor-positive breast cancer with <10 positive lymph nodes, and were scheduled for standard goserelin therapy. All 1803 patients received goserelin (3.6 mg every 28 days) and were randomized to tamoxifen (20 mg/days) or anastrozole (1 mg/days), both with or without ZOL (4 mg every 6 months) for 3 years. The primary end point was DFS; recurrence-free survival and overall survival (OS) were secondary end points.ResultsAfter 94.4-month median follow-up (range, 0–114 months), relative risks of disease progression [hazard ratio (HR) = 0.77; 95% confidence interval (CI) 0.60–0.99; P = 0.042] and of death (HR = 0.66; 95% CI 0.43–1.02; P = 0.064) are still reduced by ZOL although no longer significant at the predefined significance level. Overall, 251 DFS events and 86 deaths were reported. Absolute risk reductions with ZOL were 3.4% for DFS and 2.2% for OS. There was no DFS difference between tamoxifen alone versus anastrozole alone, but there was a pronounced higher risk of death for anastrozole-treated patients (HR = 1.63; 95% CI 1.05–1.45; P = 0.030). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw.ConclusionThese final results from ABCSG 12 suggest that twice-yearly ZOL enhances the efficacy of adjuvant endocrine treatment, and this benefit is maintained long-term.ClinicalTrials.govNCT00295646 (http://www.clinicaltrials.gov/ct2/results?term=00295646).     

PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab

BackgroundThe predictive value of PIK3CA mutations in HER2 positive (HER2+) breast cancer treated with neoadjuvant anti-HER2 and chemotherapy has been reported, but the power for subgroup analyses was lacking.Patients and methodsWe combined individual patient data from five clinical trials evaluating PIK3CA mutations and associations with pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Patients received either trastuzumab (T), lapatinib (L) or the combination T/L in addition to a taxane-based chemotherapy. PIK3CA was genotyped in tumour biopsies taken before therapy.ResultsA total of 967 patients were included in this analysis; the median follow-up is 47 months. Overall, the pCR rate was significantly lower in the PIK3CA mutant compared with the wild-type group (16.2% versus 29.6%; P < 0.001). Within the hormone-receptor positive (HR+) subgroup, the PIK3CA mutant group had a pCR rate of only 7.6% compared with 24.2% in the wild-type group (P < 0.001). In contrast, in the HER2+/HR– group, there was no difference in pCR (27.2% versus 36.4%; P = 0.125) according to PIK3CA mutation status (interaction test P = 0.036). According to treatment arm, the pCR rate for mutant versus wild-type was 20.3% versus 27.1% for T (P = 0.343), 11.3% versus 16.9% for L (P = 0.369) and 16.7% versus 39.1% for T/L (P < 0.001). In the HR+ T/L group, the pCR rate was 5.5% versus 33.9% (interaction between HR and PIK3CA genotype P = 0.008). DFS and OS were not significantly different by mutation status, though the incidence rate of events was low. However, HR+/PIK3CA mutant patients seemed to have significantly worse DFS {hazard ratio (HR) 1.56 [95% confidence interval (CI) 1.00–2.45], P = 0.050; P_interaction = 0.021}. T/L tended to improve DFS compared with T in the wild-type cohort, especially in the HR– group [HR 0.72, 95% CI (0.41–1.25), P = 0.242].ConclusionOverall PIK3CA mutant/HER2+ tumours had significantly lower pCR rates compared with wild-type tumours, however mainly confined to the HR+/PIK3CA mutant population. No definite conclusions can be drawn regarding survival.     

Effects of CytoReductive surgery plus hyperthermic IntraPEritoneal chemotherapy (HIPEC) versus CytoReductive surgery for ovarian cancer patients: A systematic review and meta-analysis

BackgroundThe effects of Hyperthermic IntraPEritoneal Chemotherapy (HIPEC) and CytoReductive Surgery (CRS) for ovarian cancer patients remain controversial.MethodsA systematic review and meta-analysis was conducted using PubMed, Embase and Web of Science databases to investigate Overall Survival (OS), Disease Free Survival (DFS) and adverse effects between HIPEC and CRS group. Results: In our overall analysis (13 studies), patients in the HIPEC group exhibited a significantly improved OS (HR = 0.56, 95% CI = 0.41–0.76, P < 0.01) and DFS (HR = 0.61, 95% CI = 0.48–0.77, P < 0.01). Subgroup analysis revealed improved OS (HR = 0.57, 95% CI = 0.40–0.83, P = 0.04) and DFS (HR = 0.61, 95% CI = 0.47–0.80, P < 0.01) for primary ovarian cancer in favour of HIPEC group. However, recurrent ovarian cancer patients who received HIPEC exhibited only significantly improved OS (HR = 0.48, 95% CI = 0.24–0.96, P < 0.01) but not DFS (HR = 0.59, 95% CI = 0.33–1.08, P = 0.09). In addition, both significantly improved OS and DFS were also observed in patients who received HIPEC in the subgroups based on the following factors: studies published before 2015, studies with ≥100 total patients, a single drug used for HIPEC, 90-min HIPEC duration and a regimen of CRS plus HIPEC followed by chemotherapy. Moreover systematically reviewed toxicity, morbidity, mortality and long-term outcomes were tolerable after HIPEC.ConclusionsThe addition of HIPEC to CRS could significantly improve OS of ovarian cancer patients, albeit optimal drug regimen is not clear.     

Effect of Coexisting KRAS and TP53 Mutations in Patients Treated With Chemotherapy for Non–small-cell Lung Cancer

BackgroundKRAS and TP53 are common mutations in non–small-cell lung cancer (NSCLC). The Lung Adjuvant Cisplatin Evaluation Biological Program group found adjuvant chemotherapy to be deleterious in patients with coexisting KRAS/TP53 mutations.Patients and MethodsTo validate these results, patients with NSCLC tested for KRAS and TP53 mutations and receiving chemotherapy for any stage NSCLC were selected. Mutation status was analyzed using next generation sequencing (Illumina) or multiplex recurrent mutation detection (MassARRAY, Agena Biosciences) assays, and was correlated with clinical and demographic data. Disease-free (DFS) or progression-free survival (PFS) was the main endpoint, and overall survival (OS) was the secondary endpoint.ResultsAmong 218 patients, 28 had coexisting KRAS/TP53 mutations, 77 TP53, 37 KRAS, 76 had neither KRAS nor TP53 mutation (WT/WT). There was no DFS/PFS difference for the KRAS/TP53 group versus all others among 99 patients who received adjuvant chemotherapy (hazard ratio [HR], 1.22; 95% confidence interval [CI], 0.61-2.44; P = .57), 27 stage III patients who received chemo-radiation (HR, 0.87; 95% CI, 0.32-2.38; P = .8), and 63 patients who received palliative chemotherapy (HR, 0.68; 95% CI, 0.31-1.48; P = .33). OS was longer in the WT/WT group compared with any other group (KRAS: HR, 1.87; 95% CI, 1.02-3.43; P = .043; TP53: HR, 2.17; 95% CI, 1.3-3.61; P = .0028; KRAS/TP53: HR, 2.06; 95% CI, 1.09-3.88; P = .026). No OS difference was seen for KRAS/TP53 compared with the other groups (HR, 1.26; 95% CI, 0.75-2.13; P = .38).ConclusionsThere was no significant difference in DFS/PFS between the 4 groups. However, OS was longer for patients with TP53 and KRAS wild-type NSCLC who received chemotherapy for any stage compared with patients with KRAS, TP53 mutation, or double mutant tumors.     

Impact of premenopausal status at breast cancer diagnosis in women entered on the placebo-controlled NCIC CTG MA17 trial of extended adjuvant letrozole

BackgroundMA17 showed improved outcomes in postmenopausal women given extended letrozole (LET) after completing 5 years of adjuvant tamoxifen.Patients and methodsExploratory subgroup analyses of disease-free survival (DFS), distant DFS (DDFS), overall survival (OS), toxic effects and quality of life (QOL) in MA17 were performed based on menopausal status at breast cancer diagnosis.ResultsAt diagnosis, 877 women were premenopausal and 4289 were postmenopausal. Extended LET was significantly better than placebo (PLAC) in DFS for premenopausal [hazard ratio (HR) = 0.26, 95% confidence interval (CI) 0.13–0.55; P = 0.0003] and postmenopausal women (HR = 0.67; 95% CI 0.51–0.89; P = 0.006), with greater DFS benefit in those premenopausal (interaction P = 0.03). In adjusted post-unblinding analysis, those who switched from PLAC to LET improved DDFS in premenopausal (HR = 0.15; 95% CI 0.03–0.79; P = 0.02) and postmenopausal women (HR = 0.45; 95% CI 0.22–0.94; P = 0.03).ConclusionsExtended LET after 5 years of tamoxifen was effective in pre- and postmenopausal women at diagnosis, and significantly better in those premenopausal. Women premenopausal at diagnosis should be considered for extended adjuvant therapy with LET if menopausal after completing tamoxifen.     

A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802)

BackgroundThis multicenter adjuvant phase III trial evaluated the addition of irinotecan to LV5FU2 in colon cancer patients at high risk of relapse.Patients and methodsA total of 400 patients with histologically proven primary colon cancer with postoperative N1 detected by occlusion/perforation or N2 were randomised to: A—LV5FU2 [leucovorin 200 mg/m², 2-h infusion, 5-fluorouracil (5-FU) 400 mg/m² bolus, 600 mg/m² 22-h continuous infusion, days 1 and 2] or B—LV5FU2 + IRI (irinotecan 180 mg/m² 90-min infusion day 1 + LV5FU2) fortnightly for 12 cycles. Primary end point was disease-free survival (DFS).ResultsMedian follow-up was 63 months. Significantly more T4 tumours and 15 or more positive lymph nodes were observed in arm B. 5-FU relative dose intensity (RDI) was >0.80 for 94% and 77% in arms A and B, respectively (P < 0.001). Irinotecan RDI was >0.80 for 70% patients. There were more grades 3 and 4 neutropenia in arm B (4% versus 28%, P < 0.001). The 3-year DFS was 60% [95% confidence interval (CI) 53% to 66%] and 51% (95% CI 44% to 58) in arms A and B, respectively. No difference was observed [hazard ratio (HR) = 1.12, 95% CI 0.85–1.47, P = 0.42] even when adjusted for prognostic factors (adjusted HR = 0.98, 95% CI 0.74–1.31, P = 0.92). The 5-year overall survival (OS) was 67% (95% CI 59% to 73%) and 61% (95% CI 53% to 67%) in arms A and B, respectively.ConclusionAdjuvant LV5FU2 + IRI compared with LV5FU2 alone in patients at high risk of relapse showed no improvement in DFS and OS.     

Detection of circulating tumor cells for prediction of recurrence after adjuvant chemoradiation in locally advanced squamous cell carcinoma of the head and neck

BackgroundThe prognostic role of persistence of circulating tumor cells (CTC) after upfront tumor surgery for outcome of adjuvant (chemo)radiation in locally advanced squamous cell carcinoma of the head and neck (LASCCHN) was evaluated.Patients and methodsIn this prospective study, peripheral blood samples from 144 patients with LASCCHN presenting after tumor resection for adjuvant treatment were analyzed for CTC. Their detection was correlated with tumor site, clinical risk factors, disease-free (DFS) and overall survival (OS).ResultsCTC were detected in 42 of 144 patients (29%). CTC detection was higher in cases with nodal involvement and in carcinomas located at the tonsil or base of tongue but was not influenced by age, smoking history, T stage, extracapsular lymph node extension, surgical margins or the human papillomavirus status. Overall, the presence of CTC was not predictive for OS or DFS. However, while in oropharyngeal carcinomas (OPC, n = 63), the detection of CTC was associated per trend with improved DFS [CTC+ versus CTC- (% of patients without evidence of disease at 2 years): 100% versus 79%; log rank: P = 0.059]; the reverse was observed for carcinomas from other sites (non-OPC, n = 81; CTC+ versus CTC-: 29% versus 75%; P = 0.001). In multivariate analysis, CTC remained an independent prognostic marker for DFS [hazard ratio (HR) 4.3, 95% confidence interval (CI) 1.7–10.9, P = 0.002] and OS (HR 2.7, 95% CI 1.2–6.3, P = 0.016) in non-OPC.ConclusionsAssessment of CTC in non-OPC should prove useful for identification of patients who benefit from treatment intensification. The basis for the good prognostic value of CTC in OPC has to be elucidated in future studies.     

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.     

Does Gleason score at initial diagnosis predict efficacy of abiraterone acetate therapy in patients with metastatic castration-resistant prostate cancer? An analysis of abiraterone acetate phase III trials

BackgroundThe usefulness of Gleason score (<8 or ≥8) at initial diagnosis as a predictive marker of response to abiraterone acetate (AA) plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) was explored retrospectively.Patients and methodsInitial diagnosis Gleason score was obtained in 1048 of 1195 (COU-AA-301, post-docetaxel) and 996 of 1088 (COU-AA-302, chemotherapy-naïve) patients treated with AA 1 g plus prednisone 5 mg twice daily by mouth or placebo plus prednisone. Efficacy end points included radiographic progression-free survival (rPFS) and overall survival (OS). Distributions and medians were estimated by Kaplan–Meier method and hazard ratio (HR) and 95% confidence interval (CI) by Cox model.ResultsBaseline characteristics were similar across studies and treatment groups. Regardless of Gleason score, AA treatment significantly improved rPFS in post-docetaxel [Gleason score <8: median, 6.4 versus 5.5 months (HR = 0.70; 95% CI 0.56–0.86), P = 0.0009 and Gleason score ≥8: median, 5.6 versus 2.9 months (HR = 0.58; 95% CI 0.48–0.72), P < 0.0001] and chemotherapy-naïve patients [Gleason score <8: median, 16.5 versus 8.2 months (HR = 0.50; 95% CI 0.40–0.62), P < 0.0001 and Gleason score ≥8: median, 13.8 versus 8.2 months (HR = 0.61; 95% CI 0.49–0.76), P < 0.0001]. Clinical benefit of AA treatment was also observed for OS, prostate-specific antigen (PSA) response, objective response and time to PSA progression across studies and Gleason score subgroups.ConclusionOS and rPFS trends demonstrate AA treatment benefit in patients with pre- or post-chemotherapy mCRPC regardless of Gleason score at initial diagnosis. The initial diagnostic Gleason score in patients with mCRPC should not be considered in the decision to treat with AA, as tumour metastases may no longer reflect the histology at the time of diagnosis.Clinical trials numberCOU-AA-301 (NCT00638690); COU-AA-302 (NCT00887198).     

The elevated C-reactive protein level is associated with poor prognosis in prostate cancer patients treated with radiotherapy

BackgroundC-reactive protein (CRP) is a sensitive marker of inflammation that has been linked with prognosis in various solid tumours. In the present study, we analysed the prognostic relevance of elevated plasma CRP levels in prostate cancer patients treated with radiotherapy.MethodsA total of 261 prostate cancer patients treated with 3D-conformal radiotherapy were evaluated retrospectively. Cancer specific survival (CSS), overall survival (OS) and clinical disease-free survival (DFS) were assessed using Kaplan–Meier analysis. To evaluate the independent prognostic significance of CRP plasma levels, multivariate Cox regression models were applied.ResultsThe median follow-time was 80 months. Applying receiver operating characteristics (ROC) analysis, the optimal cut-off level for the plasma CRP was 8.6 mg l⁻¹. An elevated CRP level was associated with decreased CSS in univariate (hazard ratio (HR) 3.36, 95% confidence interval (CI) 1.42–7.91; p = 0.006) and multivariate analysis (HR 4.31, 95% CI 1.22–15.1; p = 0.023). Furthermore, a significant association with OS was detected in univariate (HR 2.69, 95% CI 1.57–4.59; p < 0.001) and multivariate analyses (HR 3.24, 95% CI 1.84–5.71, p < 0.001). Multivariate analysis also showed a significant association between plasma CRP and clinical DFS (HR 2.07, 95% CI 1.02–4.17; p = 0.043).ConclusionsIn the present study, an elevated plasma CRP (⩾8.6 mg l⁻¹) has been identified as a prognostic factor for poor CSS, OS and DFS in prostate cancer patients undergoing radiotherapy. The association between elevated CRP levels and poor prognosis was independent of other measures of prognosis such as tumour stage, Gleason grading and prostate specific antigen (PSA) level at diagnosis. If confirmed by additional studies, our findings may contribute to future individual risk assessment in prostate cancer patients.     

Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy

BackgroundThis multicenter randomized trial compared oral capecitabine with bolus i.v. 5-fluorouracil (5-FU)/folinic acid (FA) as adjuvant therapy for stage III colon cancer.Patients and methodsPatients were assigned to 24 weeks of capecitabine 1250 mg/m² twice daily on days 1–14 every 3 weeks or 5-FU/FA (Mayo Clinic regimen). The primary end point was disease-free survival (DFS).ResultsThe intent-to-treat population received capecitabine (n = 1004) or 5-FU/FA (n = 983). With a median follow-up of 6.9 years, capecitabine was at least equivalent to 5-FU/FA in terms of DFS [hazard ratio (HR) = 0.88; 95% confidence interval (CI) 0.77–1.01] and overall survival (OS) (HR = 0.86; 95% CI 0.74–1.01); the 95% CI upper limits were significantly less than the predefined noninferiority margins of 1.20 (P < 0.0001) and 1.14 (P < 0.001), respectively. This pattern was maintained in all subgroups, including patients aged ≥70 years. Preplanned multivariate analyses showed that capecitabine had statistically significant beneficial effects on DFS (P = 0.021) and OS (P = 0.020) versus 5-FU/FA. A post hoc analysis suggested that the occurrence of hand–foot syndrome may be associated with better outcomes in capecitabine recipients.ConclusionOral capecitabine is an effective alternative to bolus 5-FU/FA as adjuvant treatment of patients with stage III colon cancer with efficacy benefits maintained at 5 years and in older patients.     

Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer

BackgroundThe composition of gut microbiota affects antitumor immune responses, preclinical and clinical outcome following immune checkpoint inhibitors (ICI) in cancer. Antibiotics (ATB) alter gut microbiota diversity and composition leading to dysbiosis, which may affect effectiveness of ICI.Patients and methodsWe examined patients with advanced renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC) treated with anti-programmed cell death ligand-1 mAb monotherapy or combination at two academic institutions. Those receiving ATB within 30 days of beginning ICI were compared with those who did not. Objective response, progression-free survival (PFS) determined by RECIST1.1 and overall survival (OS) were assessed.ResultsSixteen of 121 (13%) RCC patients and 48 of 239 (20%) NSCLC patients received ATB. The most common ATB were β-lactam or quinolones for pneumonia or urinary tract infections. In RCC patients, ATB compared with no ATB was associated with increased risk of primary progressive disease (PD) (75% versus 22%, P < 0.01), shorter PFS [median 1.9 versus 7.4 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.4–6.9, P < 0.01], and shorter OS (median 17.3 versus 30.6 months, HR 3.5, 95% CI 1.1–10.8, P = 0.03). In NSCLC patients, ATB was associated with similar rates of primary PD (52% versus 43%, P = 0.26) but decreased PFS (median 1.9 versus 3.8 months, HR 1.5, 95% CI 1.0–2.2, P = 0.03) and OS (median 7.9 versus 24.6 months, HR 4.4, 95% CI 2.6–7.7, P < 0.01). In multivariate analyses, the impact of ATB remained significant for PFS in RCC and for OS in NSCLC.ConclusionATB were associated with reduced clinical benefit from ICI in RCC and NSCLC. Modulatation of ATB-related dysbiosis and gut microbiota composition may be a strategy to improve clinical outcomes with ICI.     

Randomized phase III trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA–N2 nonsmall-cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy

This prospective, randomized, phase III trial shows that prophylactic cranial irradiation prolongs disease-free survival, decreases the rate of cerebral metastases and does not affect quality-of-life for patients with fully resected postoperative pathologically confirmed stage IIIA-N2 non-small-cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy.BackgroundThis study compared prophylactic cranial irradiation (PCI) with observation in patients with resected stage IIIA–N2 non-small-cell lung cancer (NSCLC) and high risk of cerebral metastases after adjuvant chemotherapy.Patients and methodsIn this open-label, randomized, phase III trial, patients with fully resected postoperative pathologically confirmed stage IIIA–N2 NSCLC and high cerebral metastases risk without recurrence after postoperative adjuvant chemotherapy were randomly assigned to receive PCI (30 Gy in 10 fractions) or observation. The primary end point was disease-free survival (DFS). The secondary end points included the incidence of brain metastases, overall survival (OS), toxicity and quality of life.ResultsThis trial was terminated early after the random assignment of 156 patients (81 to PCI group and 75 to control group). The PCI group had significantly lengthened DFS compared with the control group, with a median DFS of 28.5 months versus 21.2 months [hazard ratio (HR), 0.67; 95% confidence interval (CI) 0.46–0.98;P = 0.037]. PCI was associated with a decrease in risk of brain metastases (the actuarial 5-year brain metastases rate, 20.3% versus 49.9%; HR, 0.28; 95% CI 0.14–0.57;P < 0.001). The median OS was 31.2 months in the PCI group and 27.4 months in the control group (HR, 0.81; 95% CI 0.56–1.16;P = 0.310). While main toxicities were headache, nausea/vomiting and fatigue in the PCI group, they were generally mild.ConclusionIn patients with fully resected postoperative pathologically confirmed stage IIIA–N2 NSCLC and high risk of cerebral metastases after adjuvant chemotherapy, PCI prolongs DFS and decreases the incidence of brain metastases.     

Prognostic significance of p53 expression in malignant bone tumors: a meta-analysis

Osteosarcoma and Ewing’s sarcoma are the two most common primary malignant bone tumors, and findings of prognostic factors are important for clinicians to decide treatment options. High p53 expression has been implicated in tumor development and progression, but studies investigating the prognostic role of p53 overexpression in malignant bone tumors report conflicting findings. We performed a meta-analysis to assess the relationship between p53 overexpression and the survival of malignant bone tumors. A meta-analysis of 13 studies with a total of 703 patients was carried out to evaluate the association between p53 overexpression and overall survival (OS) and disease-free survival (DFS) in patients with malignant bone tumors. The pooled hazard ratio (HR) with its 95 % confidence interval (CI) was used as the effect size estimate. There was no between-study heterogeneity in both OS studies (I ²?=?0.0 %) and DFS studies (I ²?=?0.0 %). Overall, high p53 expression predicted both poor OS (HR 2.13, 95 % CI 1.81–2.52, P?<?0.001) and poor DFS (HR 2.06, 95 % CI 1.58–2.69, P?<?0.001) in patients with malignant bone tumors. Subgroup analyses by tumor types suggested that p53 expression predicted poor OS in both osteosarcoma patients (HR 2.15, 95 % CI 1.78–2.60, I ²?=?15.2 %, P?<?0.001) and Ewing’s sarcoma patients (HR 2.09, 95 % CI 1.47–2.97, I ²?=?0.0 %, P?<?0.001). Besides, p53 expression also predicted poor DFS in both osteosarcoma patients (HR 2.38, 95 % CI 1.60–3.52, I ²?=?0.0 %, P?<?0.001) and Ewing’s sarcoma patients (HR 1.83, 95 % CI 1.28–2.63, I ²?=?0.0 %, P?=?0.001). Egger’s test also did not suggest evidence for publication bias in both OS studies (P?=?0.615) and DFS studies (P?=?0.258). High p53 expression indicates a poorer prognosis for patients with osteosarcoma and Ewing’s sarcoma.