Efficacy and safety of capecitabine plus cisplatin in Japanese patients with advanced or metastatic gastric cancer: subset analyses of the AVAGAST study and the ToGA study

Background

Capecitabine plus cisplatin (XP) is recognized as one of the global standard first-line chemotherapy regimens for patients with metastatic gastric cancer (mGC). Recent multinational phase III trials in mGC have been conducted with XP as the control arm, although no data on XP in Japanese patients with mGC have been published to date. The AVAGAST (XP ± bevacizumab in mGC) and ToGA (XP ± trastuzumab in human epidermal growth factor receptor 2 [HER2]-positive mGC) studies were the first two global studies including Japanese mGC patients. The aim of this analysis was to investigate the efficacy and safety of XP in Japanese mGC patients, using AVAGAST and ToGA subgroup data.

Methods

Efficacy and safety analyses were carried out in Japanese patients with mGC receiving XP alone, based on results from the AVAGAST and ToGA studies. There were differences in the target populations between the two studies; for example, the ToGA study limited patients to those with HER2-positive tumors; therefore, efficacy was evaluated separately.

Results

Ninety-four Japanese patients in the AVAGAST study and 50 in the ToGA study received XP alone. Median overall and progression-free survivals were 14.2 and 5.7 months, respectively, in the AVAGAST study, and 17.7 and 5.6 months, respectively, in the ToGA study. Overall response rates were 49.2 % in the AVAGAST and 58.5 % in the ToGA study. Adverse events were generally mild; the most common grade 3/4 events were neutropenia, anemia, anorexia, and nausea.

Conclusions

XP is effective and well tolerated in Japanese patients with mGC, and could be one of the standard regimens for the first-line treatment in this cohort.     

Rechallenge treatment with a platinum-based regimen in patients with sensitive relapsed small-cell lung cancer

Among patients with relapsed small-cell lung cancer (SCLC), those who relapse?>?90 days after first-line chemotherapy are classified sensitive relapse. Rechallenge with a first-line platinum-based regimen has been used in sensitive relapsed SCLC patients, but its importance is not known. We evaluated the outcome of rechallenge with platinum-based chemotherapy for sensitive relapse patients. We reviewed consecutive patients with sensitive relapsed SCLC who received second-line chemotherapy between January 1999 and December 2016. We evaluated the treatment outcomes of platinum-based rechallenge and non-rechallenge regimens for second-line chemotherapy in sensitive relapse patients. Of 245 patients, 81 sensitive relapse patients received second-line chemotherapy. Sixty-seven patients (82.7%) were treated with rechallenging platinum-based regimens (“rechallenge group”) and 14 patients (17.3%) were treated with other regimens (“non-rechallenge group”) as second-line chemotherapy. Median progression-free survival (PFS) was 5.1 months in the rechallenge group and 3.5 months in the non-rechallenge group, and median survival time was 10.8 and 8.2 months, respectively. There were no significant differences in PFS or overall survival (OS) between the two groups. Sub-analyses of patients who received chemotherapy alone as first-line treatment showed that the rechallenge group had longer PFS than that of the non-rechallenge group (median 5.4 vs. 3.6 months, p?=?0.0038), and the rechallenge group had a tendency to have longer OS than non-rechallenge group. These data suggest that rechallenge treatment with a platinum-based regimen could be second-line chemotherapy in patients with sensitive relapsed SCLC, especially those treated with chemotherapy alone as first-line therapy.     

Phase 2 study of eribulin mesylate as first-line therapy for locally recurrent or metastatic human epidermal growth factor receptor 2-negative breast cancer

Eribulin mesylate, a novel non-taxane microtubule dynamics inhibitor, is approved for treatment of metastatic breast cancer (MBC) in patients who have previously received at least 2 chemotherapeutic regimens for MBC that should have included an anthracycline and a taxane in the adjuvant or metastatic setting. This phase 2 study evaluated efficacy and safety of eribulin as first-line therapy for human epidermal growth factor receptor 2-negative (HER2-negative) MBC. Patients with measurable HER2-negative locally recurrent breast cancer or MBC with ≥12 months since prior neoadjuvant or adjuvant (neo/adjuvant) chemotherapy received eribulin mesylate 1.4 mg/m² IV on days 1 and 8 of each 3-week cycle. Endpoints included objective response rate (ORR) per RECIST v1.1 (primary), safety, progression-free survival (PFS), clinical benefit rate (ORR + stable disease ≥6 months; CBR), and duration of response (DOR). Fifty-six patients were enrolled and received eribulin; 38 (68 %) had prior neo/adjuvant therapy, including 33 who had anthracycline and/or taxane-containing chemotherapy; 41 (73 %) had estrogen receptor-positive disease, and 12 (21 %) had estrogen receptor-negative, progesterone receptor-negative, and HER2-negative (triple-negative) disease. Patients received a median of 7 cycles (range 1–43); 6 (11 %) received treatment for ≥12 months. ORR was 29 % (95 % CI 17.3–42.2), CBR was 52 %, and median DOR was 5.8 months. Median PFS was 6.8 months. Thirty-six patients (64 %) had grade 3/4 treatment-related adverse events; most common were neutropenia (50 %), leukopenia (21 %), and peripheral neuropathy (21 %). These results demonstrate that eribulin has substantial antitumor activity as first-line treatment for HER2-negative MBC with acceptable safety.     

Heterogeneity of first-line palliative systemic treatment in synchronous metastatic esophagogastric cancer patients: A real-world evidence study

The optimal first-line palliative systemic treatment strategy for metastatic esophagogastric cancer is not well defined. The aim of our study was to explore real-world use of first-line systemic treatment in esophagogastric cancer and assess the effect of treatment strategy on overall survival (OS), time to failure (TTF) of first-line treatment and toxicity. We selected synchronous metastatic esophagogastric cancer patients treated with systemic therapy (2010–2016) from the nationwide Netherlands Cancer Registry (n = 2,204). Systemic treatment strategies were divided into monotherapy, doublet and triplet chemotherapy, and trastuzumab-containing regimens. Data on OS were available for all patients, on TTF for patients diagnosed from 2010 to 2015 (n = 1,700), and on toxicity for patients diagnosed from 2010 to 2014 (n = 1,221). OS and TTF were analyzed using multivariable Cox regression, with adjustment for relevant tumor and patient characteristics. Up to 45 different systemic treatment regimens were found to be administered, with a median TTF of 4.6 and OS of 7.5 months. Most patients (45%) were treated with doublet chemotherapy; 34% received triplets, 10% monotherapy and 10% a trastuzumab-containing regimen. The highest median OS was found in patients receiving a trastuzumab-containing regimen (11.9 months). Triplet chemotherapy showed equal survival rates compared to doublets (OS: HR 0.92, 95%CI 0.83–1.02; TTF: HR 0.92, 95%CI 0.82–1.04) but significantly more grade 3–5 toxicity than doublets (33% vs. 21%, respectively). In conclusion, heterogeneity of first-line palliative systemic treatment in metastatic esophagogastric cancer patients is striking. Based on our data, doublet chemotherapy is the preferred treatment strategy because of similar survival and less toxicity compared to triplets.     

Oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX-4) as salvage chemotherapy in patients with pretreated colorectal cancer

BACKGROUND: There are a few clinical trials of combination chemotherapy of oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX-4) in Japan, and its efficacy and safety have not been confirmed yet, especially clinical experience in patients with prior chemotherapy. PURPOSE: To analyze the efficacy and safety of FOLFOX-4 in patients with colorectal cancer who received prior chemotherapy. PATIENTS AND METHODS: Twenty patients were treated with FOLFOX-4 beginning in April 2005. Three patients were entered into the safety study, and seventeen patients were treated on a reduced dose, because they had already received heavy doses of prior chemotherapy. RESULTS: Number of prior chemotherapy was 1 regimen in 7 patients, more than two regimens in 13 patients. The median course of FOLFOX-4 was 10 (4-12), which gave an overall response rate of 20.0% and a median time to progression of 5.0 months. The median survival time was 15.6 months from initiation of the FOLFOX-4, and 28.5 months from the first-line treatment. Grade 3/4 neutropenia was seen in 12 patients (60%), and neuropathy was observed in 11 patients (55%). No response was seen in irinotecan based regimens after FOLFOX-4. CONCLUSION: FOLFOX-4 in patients with pretreated colorectal cancer was effective, and contributed to prolonged life with the TTP of 5 months. However, hematological toxicity was high despite the reduced dose. Further extension of prolonged life is anticipated by administering incorporating molecular targeting agents.     

First-line bevacizumab in combination with weekly paclitaxel for metastatic breast cancer: efficacy and safety results from a large, open-label, single-arm Japanese study

Despite extensive evaluation of first-line bevacizumab-containing therapy in randomized trials in locally recurrent/metastatic breast cancer (LR/mBC), data from Japanese populations are limited. We conducted a phase II study exclusively in Japanese patients to evaluate bevacizumab combined with weekly paclitaxel. Patients with HER2-negative measurable LR/mBC who had received no prior chemotherapy for LR/mBC received bevacizumab 10 mg/kg, days 1 and 15, in combination with paclitaxel 90 mg/m(2), days 1, 8, and 15, repeated every 4 weeks, until disease progression, unacceptable toxicity, or patient/physician decision. Co-primary endpoints of this single-arm open-label phase II study were progression-free survival (PFS) and safety. A total of 120 patients (median age 55 years) received study therapy. At the time of data cut-off, the median duration of therapy was 11.1 months (range 0.5-24.7 months). Median PFS was 12.9 months (95% CI: 11.1-18.2) according to Independent Review Committee assessment and 14.9 months by investigator assessment. Median PFS was 9.6 months in the subgroup of 38 patients with triple-negative LR/mBC. The overall response rate was 74% (95% CI: 64.5-81.2%). Median overall survival (OS) was 35.8 months (95% CI: 26.4-not estimated) and the 1-year OS rate was 88.9% (95% CI: 83.2-94.6). The regimen was well tolerated and the safety profile was generally consistent with previous reports of bevacizumab-paclitaxel combination therapy. Grade 3 hypertension was reported in 17% of patients. Grade 4 hypertension, grade 3/4 proteinuria, and gastrointestinal perforation were absent. There were no new bevacizumab safety signals. In 50 patients (42%), treatment was continued for ≥ 1 year. Conclusion: The high activity of first-line bevacizumab in combination with weekly paclitaxel observed in our study confirms the results of the E2100 trial. Our results suggest that the activity and tolerability of first-line bevacizumab-containing regimens demonstrated in E2100 can be reproduced in Japanese populations.     

Associations between early tumor shrinkage and depth of response and clinical outcomes in patients treated with 1st-line chemotherapy for advanced gastric cancer

Background

Although early tumor shrinkage (ETS) predictions of the efficacy and depth of response (DpR) reflects clinical outcomes in chemotherapy with epidermal growth factor receptor inhibitor regimens to treat metastatic colorectal cancer, their value in assessing treatments for advanced gastric cancer (AGC) is unclear. Here we evaluated relationships between ETS and DpR and clinical outcomes in AGC patients treated with first-line chemotherapy.

Methods

We retrospectively enrolled 612 consecutive patients treated with first-line chemotherapy for AGC between January 2010 and June 2016. ETS and DpR were defined as changes from baseline in summed longest diameters in target lesions at 8 (±4) weeks for ETS and at the smallest observed volume for DpR.

Results

Eligible patients were sorted into HER2⁺ (n = 100) and HER2^? (n = 186) groups. Median follow-up was 14.8 months. The overall response rate and disease control rates were 64 and 87% in the HER2⁺ group and 53.2 and 86.0% in the HER2^? group. Respective median PFS and OS were HER2⁺: 7.9 and 20.8 months and HER2^?: 6.6 and 13.8 months. The respective ETS rate and median DpR were HER2⁺: 70 and 44% and HER2^?: 57.5 and 24%. Clinical outcomes and ETS/DpR were correlated, especially in the HER2⁺ group (OS: P < 0.0001; PFS: P < 0.0001). In multivariate analysis, ETS was an independent predictor for OS in the HER2⁺ group and for PFS in both groups.

Conclusion

These results indicate that ETS may be an early-on treatment predictor of the efficacy of HER2⁺ advanced gastric cancer treated with first-line chemotherapy that includes trastuzumab.

     

Trastuzumab combined with doublet or single-agent chemotherapy as first-line therapy for HER2-positive metastatic breast cancer

Purpose

To investigate the efficacy and safety of doublet versus single-agent chemotherapy (CT) plus trastuzumab (H) as first-line therapy for human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer (MBC).

Methods

We searched for randomized clinical trials (RCTs) that evaluated the treatment effects of single-agent or doublet CT+H as first-line therapies for HER2-positive MBC. The main outcomes measured for this study included the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). A meta-analysis and trial sequential analysis (TSA) were performed, and the study quality was evaluated using the GRADE framework. The PROSPERO registry number of our analysis is CRD42016043766.

Results

The results from four RCTs including 1044 participants were pooled. Moderate-quality evidence indicated that compared with single-agent CT+H, doublet CT+H correlated better with prolonged PFS (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.63–0.75, P < 0.0001) and OS (HR = 0.90, 95% CI 0.88–0.92, P < 0.0001). However, moderate-quality evidence revealed no significant difference between the two regimens regarding the ORR (relative risk [RR] = 1.07, 95% CI 0.98–1.17, P = 0.157), which was confirmed by TSA, indicating that the cumulative Z-curve entered the futility area. Moderate-quality evidence indicated that treatment-related grade 3 or 4 toxicities of thrombocytopenia (RR = 4.08, P = 0.000), nausea/vomiting (RR = 4.26, P = 0.002), diarrhea (RR = 2.81, P = 0.002), and stomatitis (RR = 5.02, P = 0.003) were observed more frequently with doublet CT+H than with single-agent CT+H.

Conclusions

Compared with single-agent CT, the combination of doublet CT with trastuzumab as first-line therapy for HER2-positive MBC is associated with longer PFS and OS, but more treatment-related grade 3 or 4 toxicities. Therefore, doublet CT appears to be an appropriate regimen for HER2-positive MBC with a good performance status.

     

First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup analyses of data from 2447 patients

BackgroundBevacizumab has consistently demonstrated improved progression-free survival (PFS) and response rate when combined with first-line chemotherapy for HER2-negative metastatic breast cancer (mBC). However, the lack of a significant overall survival (OS) difference continues to attract debate, and identification of patients deriving greatest benefit from bevacizumab remains elusive.Patients and methodsIndividual patient data from three randomised phase III trials in the first-line HER2-negative mBC setting were analysed, focusing specifically on efficacy in poor-prognosis patients.ResultsThe meta-analysis (n = 2447) demonstrated a PFS hazard ratio (HR) of 0.64 (95% confidence interval [CI] 0.57–0.71; median 9.2 months with bevacizumab versus 6.7 months with non-bevacizumab therapy) and response rate of 49% versus 32%, respectively. The OS HR was 0.97 (95% CI 0.86–1.08); median 26.7 versus 26.4 months, respectively. In patients with triple-negative mBC, the HRs for PFS and OS were 0.63 (95% CI 0.52–0.76) and 0.96 (95% CI 0.79–1.16), respectively. Median PFS was 8.1 months with bevacizumab versus 5.4 months with chemotherapy alone, median OS was 18.9 versus 17.5 months, respectively, and 1-year OS rates were 71% versus 65%.ConclusionsBevacizumab improves efficacy, including 1-year OS rates, both overall and in subgroups of poor-prognosis patients with limited treatment options.     

Elastography in the differential diagnosis of thyroid nodules in Hashimoto thyroiditis

In the present study, we aimed to evaluate the effectiveness of second-line gemcitabine-based chemotherapy regimens on overall survival (OS) in malignant pleural mesothelioma (MPM) patients receiving first-line pemetrexed-based regimens. A total of 73 patients with MPM from Akdeniz University, Acibadem Kayseri Hospital, Kayseri Training and Research Hospital, and Erciyes University were analyzed and evaluated retrospectively as two groups: second-line gemcitabine-based chemotherapy and no second-line chemotherapy. The median OS of patients who received second-line gemcitabine-based chemotherapy was 11.3 (5.1–17.5) months, while it was 9.9 (2.1–17.7) months in the patients who did not receive chemotherapy in the second-line setting (p = 0.056). When we evaluated the survival rate at the 6th, 12th, 18th, 24th, and 36th month, the OS rate of the 36th month was significantly higher in patients who received gemcitabine-based second-line chemotherapy (p = 0.041). When evaluating the OS from diagnosis to death, the median OS values were 20.8 (17.5–24.1) months for first-line pemetrexed-based regimens then second-line gemcitabine alone and 13.1 (9.0–17.1) months supportive care after first-line pemetrexed-based regimens (p = 0.005). According to our results, we may consider gemcitabine-based regimens as second-line chemotherapy after treatment with pemetrexed plus platinum in patients with MPM.     

Phase II study of gefitinib, fluorouracil, leucovorin, and oxaliplatin therapy in previously treated patients with metastatic colorectal cancer.

PURPOSE: To investigate the gefitinib, fluorouracil (FU), leucovorin, and oxaliplatin regimen (IFOX) in previously treated patients with metastatic colorectal cancer. PATIENTS AND METHODS: Eligible patients had stage IV colorectal adenocarcinoma and had demonstrated progression or intolerance to a prior chemotherapy regimen not including oxaliplatin. Each cycle consisted of 14 days. Cycle 1 consisted of oxaliplatin 85 mg/m2 intravenously (IV) during 2 hours on day 1, hours 0 to 2; leucovorin 200 mg/m2 IV on days 1 and 2, hours 0 to 2; FU 400 mg/m2 IV push on days 1 and 2; and FU 600 mg/m2 IV on days 1 and 2, hours 2 to 24 (FOLFOX-4). All subsequent cycles consisted of FOLFOX-4 with gefitinib at 500 mg/d administered orally throughout the 14-day cycle. RESULTS: Twenty-seven patients were enrolled onto the study. The median number of prior chemotherapy regimens was two, and 74% of all patients received prior irinotecan. Nine of the 27 patients (33%) and six of the 20 patients (30%) who had prior FU and irinotecan had a partial response by Response Evaluation Criteria in Solid Tumors Group criteria. Median overall survival was 12.0 months. Median event-free survival was 5.4 months. Grade 3 to 4 toxicities included neutropenia (48%), diarrhea (48%), nausea (22%), and vomiting (15%). CONCLUSION: IFOX is an active regimen in patients with previously treated metastatic colorectal adenocarcinoma, demonstrating higher response rates than those reported with FOLFOX-4 alone in a similar patient population.     

ACORN: Observational Study of Bevacizumab in Combination With First-Line Chemotherapy for Treatment of Metastatic Colorectal Cancer in the UK

IntroductionSurvival in metastatic colorectal cancer is worse than expected in the United Kingdom. Real-world data are needed to better understand UK-specific treatment practices that may explain this.Patients and MethodsThe Avastin ColORectal Non-interventional (ACORN) study is a multicenter, prospective, UK-based, observational, phase 4 study (ClinicalTrials.gov, NCT01506167) that recruited patients with metastatic colorectal cancer scheduled to receive bevacizumab in combination with first-line chemotherapy as part of routine clinical practice. Primary end points included progression-free survival, overall survival (OS), serious adverse events (AEs), and grade 3 to 5 bevacizumab-related AEs.ResultsA total of 714 patients were recruited between August 30, 2012, and February 4, 2014. Median follow-up was 16.4 months. Median first-line chemotherapy duration was 5.6 months, with capecitabine/oxaliplatin (265 [37.1%]) being the most common regimen. Median total chemotherapy duration was 8.1 months and did not vary by geographic location in the UK. Median progression-free survival (95% confidence interval) was 8.7 (8.2-9.1) months, and median OS was 17.8 (16.1-19.3) months. There was no significant difference in efficacy by chemotherapy regimen administered. Ninety-nine patients (13.9%) received bevacizumab after disease progression. The safety profile of bevacizumab was consistent with previous studies.ConclusionACORN provided evidence that there were no clear differences observed in outcomes between bevacizumab with capecitabine-based chemotherapy and fluorouracil-based regimens, and confirmed the safety profile of bevacizumab in a real-world UK-based population. The lower-than-expected OS is likely due to the short total chemotherapy duration, less frequent use of bevacizumab after disease progression, and higher rates of in-situ primary tumors.     

Comparing cytotoxic backbones for first‐line trastuzumab‐containing regimens in human epidermal growth factor receptor 2‐positive advanced oesophagogastric cancer: A meta‐analysis

According to the Trastuzumab for Gastric Cancer (ToGA) study, trastuzumab plus cisplatin and capecitabine/5‐fluorouracil (5‐FU) is standard first‐line treatment for human epidermal growth factor receptor 2 (HER2)‐positive advanced oesophagogastric cancer. We examined the relative efficacy and safety of alternative trastuzumab‐based cytotoxic backbone regimens compared to the standard ToGA regimen using meta‐analysis. We searched Medline, EMBASE, CENTRAL and ASCO and ESMO up to March 2017 for studies investigating alternative first‐line trastuzumab‐based regimens for HER2‐positive oesophagogastric cancer, defined as high protein expression IHC3+ or IHC2+ and gene amplification by in situ hybridisation. We compared primary outcome overall survival (OS) of alternative trastuzumab‐based regimens to the ToGA regimen. Hazard ratios (HRs) and 95% confidence intervals (95%CI) were calculated by extraction of the published Kaplan‐Meier curves. Incidence counts and toxicity sample‐sizes were extracted for adverse events and compared using single‐arm proportion meta‐analysis in R. Fifteen studies (N = 557 patients) were included. OS was significantly longer with regimen trastuzumab plus doublet oxaliplatin and capecitabine/5‐FU (median OS = 20.7 months) versus ToGA (16.0 months, HR = 0.75, 95% CI = 0.59–0.99) and was less toxic. Trastuzumab plus doublet cisplatin and S‐1 showed no OS difference versus ToGA, but showed a different toxicity profile, including less hand‐foot syndrome. Trastuzumab plus cisplatin or capecitabine as singlet backbone showed significantly worse survival and more toxicity versus ToGA regimen. Trastuzumab with triplet cytotoxic backbones or with bevacizumab and doublet cytotoxic backbone showed no survival benefit and more toxicity. In conclusion, trastuzumab plus doublet cytotoxic backbone containing oxaliplatin is preferable over the ToGA regimen with cisplatin. S‐1 can substitute capecitabine or 5‐FU when specific toxicities are encountered.     

Multicenter retrospective study of 132 patients with unresectable small bowel adenocarcinoma treated with chemotherapy

Background. No standard chemotherapy regimen has been established for unresectable or recurrent small bowel adenocarcinoma (SBA). Methods. Clinical courses of 132 patients with unresectable or recurrent SBA who received chemotherapy at 41 institutions in Japan were reviewed retrospectively. Patients were classified into five groups according to first-line chemotherapy regimens: fluoropyrimidine monotherapy (group A), fluoropyrimidine-cisplatin (group B), fluoropyrimidine-oxaliplatin (group C), fluoropyrimidine-irinotecan (group D), and other regimens (group E). Results. The number of patients in each group was as follows: groups A, 60 patients; group B, 17 patients; group C, 22 patients; group D, 11 patients; and group E, 22 patients. Median progression-free survival (PFS) times were as follows: group A, 5.4 months; group B, 3.8 months; group C, 8.2 months; group D, 5.6 months; and group E, 3.4 months. Median overall survival (OS) times were as follows: group A, 13.9 months; group B, 12.6 months; group C, 22.2 months; group D, 9.4 months; and group D, 8.1 months. Patients in group C achieved significantly longer PFS times and substantially (but not significantly) longer OS times than patients in group A. After adjusting for clinical background characteristics, fluoropyrimidine-oxaliplatin therapy was a significant positive prognostic factor for PFS and OS times. Conclusion. The results suggest that fluoropyrimidine-oxaliplatin combination therapy is the most promising first-line chemotherapy regimen for unresectable or recurrent SBA.     

晚期胆系恶性肿瘤化疗方案的回顾性研究

  目的  回顾性分析浙江大学医学院附属第一医院收治的91例晚期胆系恶性肿瘤患者的化疗疗效及影响因素。  方法  收集浙江大学医学院附属第一医院2010年1月至2015年4月治疗的91例晚期胆系恶性肿瘤患者临床资料,分析患者的基础特征、治疗方案及疗效。  结果  91例患者中男性56例,女性35例,中位年龄为57岁。共90例患者接受了一线化疗并且可以评价疗效,69例患者接受了GP方案,21例患者接受了其他方案,二者疾病控制率（disease control rate,DCR）为68.1% vs. 52.4%;中位无进展生存期（median progression free survival,mPFS）为5.10个月vs. 2.50个月（P=0.025）;中位总生存期（median overall survival,mOS）为13.00个月vs. 7.20个月。43例患者接受了二线化疗并且可以评价疗效,31例患者接受了S-1为基础的化疗方案,12例患者接受了非S-1为基础的化疗方案,DCR、mPFS、mOS差异均无统计学意义。4例患者接受了含贝伐珠单抗的二线治疗方案,其mPFS及mOS较其他方案均延长,但差异无统计学意义。血液学毒性为一线GP方案最常见的不良反应。S-1为基础的化疗方案不良反应较少。  结论  对晚期胆系肿瘤患者来说,GP方案是有效的一线治疗方案,S-1作为二线治疗药物疗效尚可,贝伐珠单抗的治疗效果亟需进一步试验证实。      

Comparative Analysis of the Efficacy and Safety of Oxaliplatin Plus 5-Fluorouracil/Leucovorin (Modified FOLFOX6) with Advanced Gastric Cancer Patients having a Good or Poor Performance Status

Background: Combination chemotherapy of 5 fluorouracil (5-FU) and leucovorin (LV) with oxaliplatin,mainly FOLFOX regimens, has shown considerable antitumor activity and a tolerable toxicity profile in gastriccancer. The goal of this study was to retrospectively compare the efficacy and toxicity of modified FOLFOX-6(mFOLFOX6) regimen in advanced gastric cancer (AGC) patients with good and poor performance status (PS).Materials and Methods: AGC patients receiving the mFOLFOX6 regimen including oxaliplatin 85 mg/m2, bolusof 5-FU 400 mg/m2 and LV 400 mg/m2 on the first day, followed by 2400mg/m2 of 5- FU as a continious infusionover 46 hour for first-line treatment were eligible for the study. Results: A total 58 patients with a median age of59.5 (32-81) were included. The median follow up of the study was 9.2 months. Thirty patients (51.7%) with anECOG PS 0-1 were assigned to the good PS arm, while 28 patients (48.3%) with ECOG PS 2 were in the poor PSarm. Overall response rates were 36.6 and 28.8%, respectively (p=0.91). Median PFS was 6.7 and 6.3 months ingood PS and poor PS arms (p=0.50) and median OS was 9.6 and 10.4 months (p=0.55). As compared with goodPS arm, poor PS arm was associated with more grade 3-4 neutropenia and anemia. Dose reduction and dosedelays were also significantly higher. Conclusions: In this study, mFOLFOX6 was similarly effective in botharms. Although hematologic toxicity was significantly higher in patients with poor PS, it remained manageable.Our results suggest that this regimen may be an effective treatment option for AGC patients with poor PS.     

ERCC1 and histopathology in advanced NSCLC patients randomized in a large multicenter phase III trial

BackgroundCustomized chemotherapy is likely to improve outcome in patients with advanced non-small-cell lung cancer (NSCLC). Excision repair cross-complementation group 1 (ERCC1) is a promising biomarker; however, current evidence is inadequate. Impact of ERCC1 status was evaluated among patients participating in a large randomized chemotherapy trial.Patients and methodsFour hundred and forty-three patients with advanced NSCLC were enrolled in a phase III trial and were randomly allocated to triplet chemotherapy or standard doublet regimen. Immunohistochemical evaluation for ERCC1 status was mainly carried out on bioptic material.ResultsTwo hundred and sixty-four (59.5%) patients had representative tissue samples for ERCC1 evaluation. Median overall survival (OS) in the ERCC1-negative and ERCC1-positive population was 11.8 and 9.8 months, respectively (P = 0.028). The median OS among patients with adenocarcinomas (n = 122) was 15.2 and 8.3 months, respectively (P = 0.007). Interaction analysis between ERCC1-negative status and adenocarcinomas yielded a hazard ratio of 0.64 for death (P = 0.002).ConclusionsClinically applicable evaluation of ERCC1 status predicted cisplatin sensitivity in the largest randomized patient population with advanced NSCLC reported to date. The predictive value can be ascribed to the adenocarcinomas emphasizing the relevance of ERCC1 expression in this subgroup.     

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.     

A phase II study of bevacizumab in combination with vinorelbine and trastuzumab in HER2-positive metastatic breast cancer

We aimed to evaluate the efficacy and feasibility of combining trastuzumab/vinorelbine with bevacizumab in patients with first-or second-line HER2-positive, metastatic breast cancer (MBC). Eligible patients had HER2-positive measureable MBC, with no more than one prior line of chemotherapy, and were treated with trastuzumab (4 mg/kg × 2 mg/kg weekly thereafter), vinorelbine (25 mg/m² weekly), and bevacizumab (10 mg/kg every 2 weeks). Co-primary endpoints were (a) the proportion of patients alive and progression-free at 1 year and (b) safety profile/feasibility. Feasibility was defined as a rate of grade 3/4 non-hematologic toxicity attributable to protocol-based therapy <20 %. Twenty-nine patients were enrolled (n = 22 first-line, n = 7 second-line). Median age was 48 years (range 37–68). The median number of cycles received was 8 (1–23) and median duration on treatment was 7.4 months (range 1–22). The study was closed early due to higher-than-expected rates of grade 3/4 non-hematologic toxicities, with 50 events in 20 patients. A total of six patients (21 %) were taken off study for treatment-related toxicity. Most common treatment-related toxicities included fatigue (n = 7), febrile neutropenia (n = 4), and headache (n = 3). At 1 year, 8/22 first-line (36 %) and 2/7 second-line (29 %) patients were alive and progression-free. Median PFS was 9.9 months and 7.8 months in the first- and second-line cohorts, respectively. Objective responses were observed in 16/22 (73 %) and 5/7 (71 %) patients in the first- and second-line settings. Although the combination of vinorelbine, trastuzumab, and bevacizumab showed notable activity in HER2-positive MBC, the proportion of first-line patients alive and progression-free at 1 year was deemed unlikely to reach the pre-defined threshold for declaring success. Additionally, unacceptable toxicity was observed, at rates greater than previously reported with vinorelbine/trastuzumab or vinorelbine/bevacizumab doublet combinations.     

Gemcitabine in patients with ovarian cancer

Standard first-line treatment of ovarian cancer (OC) consists of platinum-taxane combined chemotherapy. However, this regimen only cures about 25% of women with OC. Phase II studies have shown that platinum-gemcitabine doublet and platinum-taxane-gemcitabine triplet regimens are active first-line chemotherapy in advanced OC, with overall response rates (ORR) above 55%. Several phase III studies of gemcitabine-based doublet and triplet chemotherapy in OC are currently underway. Preliminary data show that these regimens are well-tolerated, with manageable haematological toxicity, and the efficacy results are eagerly awaited. Gemcitabine is also active as second-line monotherapy in women with recurrent OC, and studies combining gemcitabine with paclitaxel, docetaxel, liposomal doxorubicin or topotecan resulted in higher ORR than gemcitabine alone. Gemcitabine-cisplatin and gemcitabine-carboplatin are active in women with platinum-resistant recurrent OC suggesting in vivo synergy between these two classes of drug. These studies show that gemcitabine-based chemotherapy may have an important role as second-line treatment in women with platinum-resistant OC. Gemcitabine combinations are also highly recommended as they avoid the problems of neurotoxicity and alopecia seen with other regimens. In order to respect the quality of life of women with recurrent OC, assessment of prognostic factors is recommended so that the most appropriate chemotherapy can be administered.