Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer

BackgroundThe randomised phase III TANIA trial demonstrated that continuing bevacizumab with second-line chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC) after progression on first-line bevacizumab-containing therapy significantly improved progression-free survival (PFS) compared with chemotherapy alone [hazard ratio (HR) = 0.75, 95% confidence interval (CI) 0.61–0.93]. We report final results from the TANIA trial, including overall survival (OS) and health-related quality of life (HRQoL).Patients and methodsPatients with HER2-negative LR/mBC that had progressed on or after first-line bevacizumab plus chemotherapy were randomised to receive standard second-line chemotherapy either alone or with bevacizumab. At second progression, patients initially randomised to bevacizumab continued bevacizumab with their third-line chemotherapy, but those randomised to chemotherapy alone were not allowed to cross over to receive third-line bevacizumab. The primary end point was second-line PFS; secondary end points included third-line PFS, combined second- and third-line PFS, OS, HRQoL and safety.ResultsOf the 494 patients randomised, 483 received second-line therapy; 234 patients (47% of the randomised population) continued to third-line study treatment. The median duration of follow-up at the final analysis was 32.1 months in the chemotherapy-alone arm and 30.9 months in the bevacizumab plus chemotherapy arm. There was no statistically significant difference between treatment arms in third-line PFS (HR = 0.79, 95% CI 0.59–1.06), combined second- and third-line PFS (HR = 0.85, 95% CI 0.68–1.05) or OS (HR = 0.96, 95% CI 0.76–1.21). Third-line safety results showed increased incidences of proteinuria and hypertension with bevacizumab, consistent with safety results for the second-line treatment phase. No differences in HRQoL were detected.ConclusionsIn this trial, continuing bevacizumab beyond first and second progression of LR/mBC improved second-line PFS, but no improvement in longer term efficacy was observed. The second-line PFS benefit appears to be achieved without detrimentally affecting quality of life.ClinicalTrials.govNCT01250379.     

Successful treatment using apatinib with or without docetaxel in heavily pretreated advanced non-squamous non-small cell lung cancer: A case report and literature review

Although targeted therapy directed toward driver mutations has produced a significant efficacy benefit for patients with non-small cell lung cancer (NSCLC), many patients do not possess mutations associated with the approved targeted drugs. Angiogenic agents play an important role in the therapeutic strategy for advanced NSCLC. Apatinib is a novel tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2. A phase II clinical trial demonstrated the survival benefit of apatinib monotherapy in advanced NSCLC. Moreover, addition of anti-angiogenic agents to chemotherapy showed robust efficacy in advanced NSCLC, regardless of tumor histology. Here, we present the case of a heavily pretreated lung adenocarcinoma patient who was treated with apatinib and apatinib continuation plus docetaxel re-challenge. He was negative for several driver genes, including EGFR, ALK, KRAS, ROS1, HER2, RET and BRAF. The previous treatment included platinum-based doublets, pemetrexed monotherapy, docetaxel plus bevacizumab, gefitinib monotherapy, nab-paclitaxel monotherapy, irinotecan plus oxaliplatin and radiotherapy. He obtained a partial response after both apatinib monotherapy and apatinib plus docetaxel treatment, with progression-free survival durations of 5 months and 6 months, respectively. This case indicated that apatinib monotherapy or apatinib plus docetaxel might be regarded as a therapeutic option for heavily pretreated patients with advanced non-squamous NSCLC.     

Irinotecan monotherapy as third-line treatment for advanced gastric cancer refractory to fluoropyrimidines,platinum, and taxanes

Background

Because standard chemotherapy for advanced gastric cancer consists of oral fluoropyrimidines plus platinum as first-line therapy, with paclitaxel plus ramucirumab as the second line, irinotecan is usually positioned as third-line chemotherapy in clinical practice in Japan.

Methods

A retrospective evaluation was conducted to determine the efficacy and safety of irinotecan as third-line chemotherapy for advanced gastric cancer in patients refractory or intolerant to fluoropyrimidines, platinum, and taxanes.

Results

Between February 2008 and December 2013, 52 patients received third-line irinotecan monotherapy. Among the 32 patients with measurable lesions, 1 patient achieved a confirmed partial response and 6 patients had stable disease. The overall response rate was 3% and the disease control rate was 22%. Median progression-free survival was 2.3 months [95% confidence interval (CI), 1.8–2.8] and median overall survival was 4.0 months (95% CI, 2.6–5.3). The most common adverse events of grade 3 severity or higher were neutropenia (27%), febrile neutropenia (12%), anorexia (12%), and diarrhea (6%). Although no treatment-related deaths occurred, 2 patients (4%) died of disease progression within 30 days after the last administration of irinotecan.

Conclusion

Irinotecan monotherapy appears to be tolerated but was shown to have modest activity as third-line chemotherapy for advanced gastric cancer.

     

Role of chemotherapy for patients with recurrent platinum-resistant advanced epithelial ovarian cancer: A cost-effectiveness analysis

BACKGROUND: Current chemotherapy in platinum-resistant ovarian cancer patients has demonstrated minimal to no improvements in survival. Despite the lack of benefit, significant resources are utilized with such therapies. Therefore, the objective in the current study was to assess the cost-effectiveness of salvage chemotherapy for patients with platinum-resistant epithelial ovarian cancer (EOC). METHODS: A decision analysis model evaluated a hypothetical cohort of 4000 platinum-resistant patients with recurrent EOC. Several chemotherapy strategies were analyzed: 1) best supportive care (BSC); 2) second-line chemotherapy-monotherapy; 3) second-line chemotherapy-combination therapy; 4) third-line chemotherapy after disease progression on second-line monotherapy; and 5) third-line chemotherapy after disease progression on second-line combination therapy. Sensitivity analyses were performed on all pertinent uncertainties. RESULTS: Using costs alone, BSC was the only definitive cost-effective treatment for platinum-resistant recurrent ovarian cancer patients, and second-line monotherapy was a reasonable cost-effective strategy with an incremental cost-effectiveness ratio (ICER) of 64,104 dollars. The cost-effectiveness ranged from 4,065 dollars per month of overall survival (OS) for BSC to 12,927 dollars for third-line previous combination therapy. Compared with BSC, second-line monotherapy gained an additional 3 months of OS, with a cost-effectiveness of 4,703 dollars per month of OS. Second-line combination therapy and third-line therapies exhibited unfavorable ICER. CONCLUSIONS: The current decision analysis was intended to be thought-provoking and bring awareness to the high costs of subsequent chemotherapy with limited effectiveness in patients with recurrent platinum-resistant EOC. Although actual patients may receive multiple lines of chemotherapy, from the perspective of costs alone this model using a hypothetical cohort demonstrated that best supportive care was the only cost-effective strategy, with second-line monotherapy appearing to be a reasonable cost-effective strategy given current chemotherapeutic options.     

A Bayesian network meta-analysis on second-line systemic therapy in advanced gastric cancer

Background

It is unclear which regimen is the most efficacious among the available therapies for advanced gastric cancer in the second-line setting. We performed a network meta-analysis to determine their relative benefits.

Methods

We conducted a systematic review of randomized controlled trials (RCTs) through the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases and American Society of Clinical Oncology abstracts up to June 2014 to identify phase III RCTs on advanced gastric cancer in the second-line setting. Overall survival (OS) data were the primary outcome of interest. Hazard ratios (HRs) were extracted from the publications on the basis of reported values or were extracted from survival curves by established methods. A Bayesian network meta-analysis was performed with WinBUGS to compare all regimens simultaneously.

Results

Eight RCTs (2439 patients) were identified and contained extractable data for quantitative analysis. Network meta-analysis showed that paclitaxel plus ramucirumab was superior to single-agent ramucirumab [OS HR 0.51, 95 % credible region (CR) 0.30–0.86], paclitaxel (OS HR 0.81, 95 % CR 0.68–0.96), docetaxel (OS HR 0.56, 95 % CR 0.33–0.94), and irinotecan (OS HR 0.71, 95 % CR 0.52–0.99). Paclitaxel plus ramucirumab also had an 89 % probability of being the best regimen among all these regimens. Single-agent ramucirumab, paclitaxel, docetaxel, and irinotecan were comparable to each other with respect to OS and were superior to best supportive care.

Conclusions

This is the first network meta-analysis to compare all second-line regimens reported in phase III gastric cancer trials. The results suggest the paclitaxel plus ramucirumab combination is the most effective therapy and should be the reference regimen for future comparative trials.

     

Second-line chemotherapy for patients with advanced gastric cancer

The first choice for treating patients with metastatic gastric cancer is chemotherapy, and combination therapy with fluorouracil, platinum, and trastuzumab has been established as the standard first-line chemotherapy. For further improvement of treatment outcomes, it is important to develop second- and third-line chemotherapy. In the first decade of this century, irinotecan and taxanes, cytotoxic agents, and various molecular targeted agents began to be developed as second-line therapy. Treatment with paclitaxcel weekly in combination with ramucirumab targeting vascular endothelial growth factor receptor 2 has become the first choice for second-line therapy. Immune checkpoint inhibitors are now being developed, and the current treatment strategies for advanced gastric cancer may undergo major changes in the future. This review summarizes the transitions and future prospects of clinical developments for second-line therapy in patients with advanced gastric cancer.     

Irinotecan combined with 5-fluorouracil and leucovorin third-line chemotherapy after failure of fluoropyrimidine, platinum, and taxane in gastric cancer: treatment outcomes and a prognostic model to predict survival

Background

The aim of this study was to evaluate the activity and safety of the combination chemotherapy of 5-fluorouracil (5-FU), leucovorin, and irinotecan (FOLFIRI regimen) after failure of fluoropyrimidine, platinum, and taxane in gastric cancer (GC) and to evaluate the prognostic factors for survival.

Methods

Patients received biweekly FOLFIRI chemotherapy as third-line treatment. The FOLFIRI-1 consisted of irinotecan (180 mg/m² in a 2-h infusion) on day 1, and then leucovorin (200 mg/m² in a 2-h infusion) and 5-FU (a 400 mg/m² bolus, followed by 600 mg/m² in a 22-h continuous infusion) on days 1 and 2. FOLFIRI-2 consisted of irinotecan (180 mg/m² in a 2-h infusion) on day 1, and then leucovorin (400 mg/m² in a 2-h infusion) and 5-FU (a 400 mg/m² bolus, followed by 2400 mg/m² in a 46-h continuous infusion) on day 1.

Results

A total of 158 patients were included. The overall response rate was 9.6 % in patients with measurable lesions. The median progression-free survival (PFS) and overall survival (OS) were 2.1 months [95 % confidence interval (CI), 1.7–2.5] and 5.6 months (95 % CI, 4.7–6.5), respectively. The major grade 3/4 toxicity was myelosuppression (36.7 %). Good performance status (PS), fewer metastatic sites, and longer duration from the first-line to third-line chemotherapy were independent prognostic factors affecting both PFS and OS.

Conclusions

The FOLFIRI regimen showed antitumor activity and tolerable toxicity profiles against advanced GC in the third-line setting. Patients with good PS, fewer metastatic sites and longer previous treatment duration might have the maximal benefit from third-line chemotherapy.     

Efficacy of third-line pemetrexed monotherapy versus pemetrexed combination with bevacizumab in patients with advanced EGFR mutation-positive lung adenocarcinoma

Objective

The purposes of this study were to observe the effects of different treatment strategies, including third-line pemetrexed alone versus its combination with bevacizumab, in patients with advanced epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma, and to analyze the effects of the different medication orders of first- and second-line drugs on third-line efficacy.

Patients and methods

One hundred and sixteen cases of patients with EGFR-positive lung adenocarcinoma who had received third-line pemetrexed alone or in combination with bevacizumab between March 2010 and March 2014 at Guangzhou Institute of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University were analyzed retrospectively. Additionally, all the patients were treated with first-line gemcitabine and cisplatin (GP) chemotherapy and second-line EGFR tyrosine kinase inhibitor (TKI) or with first-line EGFR-TKI and second-line GP chemotherapy.

Results

The median survival of 61 cases with third-line pemetrexed monotherapy was 36.22 months, the median survival time of 55 cases with third-line pemetrexed plus bevacizumab was 38.76 months, and there was a significant difference in survival time between the two groups (P=0.04). Subgroup analysis revealed that among the 55 cases with third-line bevacizumab plus pemetrexed treatment, the median survival of 29 patients with first-line GP and second-line EGFR-TKI was 42.80 months, while the median survival of 26 patients with first-line EGFR-TKI and second-line GP was only 34.46 months; additionally, there was a significant difference in the survival time between the two subgroups (P=0.001). Among 61 cases with third-line pemetrexed treatment, the median survival of 34 patients with first-line GP and second-line EGFR-TKI was 38.72 months, while the median survival of 27 patients with first-line EGFR-TKI and second-line GP was only 32.94 months; the survival time of the two subgroups was significantly different (P=0.001).

Conclusions

Regardless of the order of the first- and second-line chemotherapy and TKI therapy, the pemetrexed plus bevacizumab regimen was superior to the pemetrexed monotherapy as the third-line therapy in patients with advanced EGFR-positive lung adenocarcinoma. However, this strategy is worth further investigation in prospective studies.     

Phase II study of paclitaxel associated with lipid core nanoparticles (LDE) as third-line treatment of patients with epithelial ovarian carcinoma

Ovarian cancer is often diagnosed at advanced stages, when poorly responsive to standard treatment. First-line treatment consists in schemes including cytoreductive surgery followed by adjuvant chemotherapy schemes with platinum and taxane derivatives. Second-line regimens are based on gemcitabine and liposomal doxorubicin. Third line is often not worthwhile because of the high toxicity with poor response to treatment. Previously, we showed that paclitaxel (PTX) carried in non-protein lipid core nanoparticles (LDE) resembling the chemical structure of LDL has remarkably reduced toxicity. Here, the hypothesis was tested whether PTX-LDE could safely benefit patients in third-line treatment setting. Fourteen women unresponsive to second-line chemotherapy for ovarian cancer, aged 61 ± 10 years, clinical stage IV and TqNqM1, were included. PTX-LDE was administered at 175 mg/m², 3/3 week dose. Patients were submitted to clinical examinations before each chemotherapy cycle. Serum biochemistry and imaging examinations to monitor disease progression were performed. In total, 74 cycles of chemotherapy were done and, in all cycles, clinical or laboratorial toxicities were not observed. Median progression-free survival (PFS) was 3.0 months (95% CI 2.0–3.9). In four patients, PFS was >6 months and in 2 > 1 year. The unpreceded, striking absence of toxicity and consistently long PFS, compared to previous results, indicate that at least 4 among 14 patients had tumor arrest by the treatment and clear benefit of PTX-LDE at third-line setting. The absence of observable toxicity allows dose escalating to improve response to treatment, as perspective to be tested in the ensuing studies.     

A retrospective analysis of ramucirumab monotherapy in previously treated Japanese patients with advanced or metastatic gastric adenocarcinoma

Background

The REGARD trial demonstrated that ramucirumab monotherapy improved both overall survival (OS) and progression-free survival (PFS) compared with best supportive care plus placebo as second-line treatment for patients with advanced gastric cancer. However, the efficacy and safety of ramucirumab monotherapy for previously treated Japanese patients with advanced gastric cancer remains unknown.

Methods

Previously treated Japanese patients with advanced gastric cancer who received ramucirumab monotherapy between June 2015 and March 2016 at the Cancer Institute Hospital were enrolled in the study. OS, PFS, best overall response, and safety profiles were retrospectively evaluated.

Results

Nineteen patients were enrolled in this study. Ramucirumab monotherapy was generally administered as third-line therapy. After a median follow-up period of 7.4 months, the median PFS was 2.1 months (95% CI 1.0–3.5), and median OS was 12.9 months (95% CI 2.3, not reached). In 13 patients who had measurable lesions on radiologic examination, partial response was observed in one patient (7.7%) and stable disease was observed in five patients (38.5%). A total of 12 patients (63.2%) had adverse events (AEs). Common AEs included hypertension (8 patients, 42.1%), fatigue (6 patients, 31.6%), and bleeding (5 patients, 26.3%). Grade 3 AEs included gastrointestinal bleeding and aspiration pneumonia (1 patient each, 5.3%).

Conclusions

Our data suggest that ramucirumab monotherapy in Japanese patients with previously treated advanced gastric cancer has comparable efficacy and safety profiles as reported in the REGARD trial.

     

Second-line treatments for advanced gastric cancer: Interpreting outcomes by network meta-analysis

AIM: To study the effectiveness of second-line treatments for advancer gastric cancer by application of Bayesian network meta-analysis.METHODS: Our search covered the literature up to February 2015. The following 6 treatments were evaluated: (1) irinotecan (camptothecins); (2) paclitaxel (taxanes class); (3) docetaxel (taxanes); (4) everolimus (mammalian target of rapamycin inhibitors); (5) ramucirumab (vascular endothelial growth factor receptor 2 inhibitors); (6) ramucirumab + paclitaxel. Our methodology was based on standard models of Bayesian network meta-analysis. The reference treatment was best supportive care (BSC). The end-point was overall survival. Median survival was the outcome measure along with 95% credible intervals.RESULTS: Our search identified a total of 7 randomized controlled trials. These trials included 2298 patients (in 15 treatment arms) in whom a total of 6 active treatments were evaluated as well as BSC. There were 21 head-to-head comparisons (6 direct, 15 indirect). The difference in survival between each of two active treatments (paclitaxel and ramucirumab + paclitaxel) vs BSC was statistically significant, while the other 4 showed no statistical difference. In the 6 head-to-head comparisons between active treatments, no significant survival difference was demonstrated.CONCLUSION: Our results indicate that both paclitaxel monotherapy and ramucirumab + paclitaxel determine a significant prolongation in survival as compared with BSC.     

跨线曲妥珠单抗联合不同化疗方案治疗HER2阳性晚期乳腺癌的临床研究

目的 观察跨线曲妥珠单抗联合不同化疗方案治疗人表皮生因子受体2（human epidermal growth factor receptor 2, HER2）阳性晚期乳腺癌的疗效、不良反应和生存期。方法 收集2009年1月至2014年6月间应用跨线曲妥珠单抗（H）联合不同化疗方案治疗HER2阳性的晚期乳腺癌患者71例,均完成一线H治疗,30例患者疾病进展后继续二线H治疗,19例患者疾病再次进展后继续三线H治疗,主要观察疗效、不良反应、生存情况及预后分析。结果 一、二、三线治疗中,曲妥珠单抗联合紫杉类方案和联合非紫杉类方案相比在有效率（RR）和临床获益率（clinical benefit rate, CBR）方面差异均无统计学意义（P＞0.05）。一、二、三线治疗的中位无进展生存时间（PFS）和中位总生存时间（OS）分别为14、9、4月和26、39、53月,总的中位PFS为11月,总的中位OS为36月。一线治疗的PFS较二、三线治疗明显延长（P=0.000）,曲妥珠单抗持续应用至三线的中位OS较仅一线治疗的有延长（P=0.008）。全组患者的1、2、3年生存率分别为88%、66%、39%。71例患者中14例出现了17次心脏相关事件,1例患者因左心室射血分数（LVEF）下降至48%停止曲妥珠单抗治疗,无治疗相关性死亡发生。在OS的Log rank单因素分析中,术后淋巴结转移的个数、有无脑转移、治疗线数、一线治疗的PFS时间与OS有关（P=0.026, P=0.042, P=0.028, P=0.005）。在OS的多因素Cox比例风险模型分析中,治疗线数、有无脑转移、DFS和一线PFS时间为对OS有影响的独立因素（P=0.004,P=0.021, P=0.018, P=0.000）。结论 在HER-2阳性晚期乳腺癌治疗中,疾病进展后跨线曲妥珠单抗联合化疗的疗效优于未继续使用曲妥珠单抗的方案,曲妥珠单抗的跨线使用可以使患者持续获益,跨线曲妥珠单抗联合化疗的方案疗效确切,不良反应可以耐受,值得进一步研究。     

Docetaxel Plus RAmucirumab With Primary Prophylactic Pegylated Granulocyte-ColONy Stimulating Factor Support for Elderly Patients With Advanced Non–small-cell Lung Cancer: A Multicenter Prospective Single Arm Phase II Trial: DRAGON Study (WJOG9416L)

We exhibit our ongoing multicenter, prospective, single-arm, phase II trial of docetaxel plus ramucirumab with primary prophylactic pegylated-granulocyte-colony stimulating factor (PEG-G-CSF) support for chemotherapy-naive elderly patients with advanced non–small-cell lung cancer (NSCLC) (University Hospital Medical Information Network database: UMIN000030598). Docetaxel monotherapy is the Japanese standard of care for chemotherapy-naive elderly patients with advanced NSCLC. Docetaxel plus ramucirumab showed superior survival benefit over docetaxel monotherapy in the second-line setting for NSCLC. A Japanese phase II study comparing docetaxel plus ramucirumab and docetaxel monotherapy in the second-line setting showed febrile neutropenia (FN) incidence of approximately one-third in the docetaxel plus ramucirumab arm. Docetaxel plus ramucirumab could be a promising candidate for elderly patients with NSCLC, but such high FN incidence is a clinically critical concern. To overcome this problem, we adopt a routine primary prophylactic PEG-G-CSF with docetaxel plus ramucirumab therapy. We hypothesize that primary prophylactic PEG-G-CSF reduces FN and maximizes the efficacy of docetaxel plus ramucirumab in Japanese elderly patients with NSCLC. Intravenous docetaxel (60 mg/m², day 1) plus ramucirumab (10 mg/kg, day 1) with subcutaneous PEG-G-CSF (3.6 mg, day 2) every 3 weeks is administered until progression. The primary endpoint is overall response rate (ORR). We decided the threshold ORR to be 20%, and the expected ORR 35%. Taking statistical points (α/β errors: 0.05/0.80) and ineligible patients into account, the sample size was set at 65. When the study results are promising, we will conduct a phase III trial to compare docetaxel plus ramucirumab with PEG-G-CSF support versus docetaxel monotherapy for chemotherapy-naive elderly patients with NSCLC.     

Clinical evidence for second- and third-line treatment options in advanced non-small cell lung cancer

In the U.S. and Europe, the current options for the second- and third-line treatment of advanced non-small cell lung cancer (NSCLC) are cytotoxic drugs and targeted agents. Docetaxel was the first drug approved for second-line treatment after two phase III trials demonstrated its superiority over best supportive care (BSC) alone and single-agent chemotherapy. Pemetrexed was also registered for use as second-line therapy after it was demonstrated to have activity comparable with, and a more favorable toxicity profile than, docetaxel. Erlotinib, an epidermal growth factor receptor inhibitor, is the only biological agent to have been approved in the U.S. and Europe for lung cancer treatment after a study showed its superiority over BSC in recurrent (second-/third-line) NSCLC patients. This review focuses on these drugs, dealing with the results supporting the choice among docetaxel, pemetrexed, and erlotinib in second- and/or third-line treatment.     

Present status and prospects for chemotherapy for advanced or recurrent gastric cancer in our hospital

Since S-1 was approved in 1999, the response rate and the disease control rate of the chemotherapy for advanced or recurrent gastric cancer have improved. It is important to perform chemotherapy using key drugs and to plan the chemotherapy for each case. Of the 32 patients in our hospital, the median survival time (MST) was 21 months for chemotherapy in advanced or recurrent gastric cancer during 2003-2006. MST for patients who had up to second- or third-line treatment was longer than for patients with up to first-line treatment. In addition, it there was no difference in prognosis for patients using CPT-11 or taxane at second-line after using S-1 at first-line treatment. The first-line chemotherapy for advanced or recurrent gastric cancer should be decided by the disease condition of each patient and the characteristics of each anti-cancer drug. In addition, the prognosis of patients will improve if second- or third-line chemotherapy can be performed.     

阿帕替尼用于一线治疗进展后晚期非鳞非小细胞肺癌的疗效和生存分析

背景与目的 晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的二线、三线化疗有效率较低,靶向药物的应用为部分患者带来生存获益.阿帕替尼是一种新型小分子抗血管生成药物,在多种恶性肿瘤治疗中展现出令人满意的抗癌活性.本研究旨在评价阿帕替尼用于一线治疗进展后晚期非鳞NSCLC的安全性和疗效.方法 回顾性分析128例晚期非鳞NSCLC不同治疗组患者的疗效和生存情况,用Kaplan-Meier法和Cox模型进行分析.结果 以单纯化疗组为对照,阿帕替尼单药组、单纯化疗组和阿帕替尼联合化疗组的中位无进展生存期(progression free survival,PFS)分别为3.0个月(P=0.381)、3.7个月和6.0个月(P<0.001),中位总生存期(overall survival,OS)分别为6.0个月(P=0.494)、6.5个月和9.0个月(P=0.001).3级-4级不良反应发生率分别为18.5%、15.8%和16.0%(P=0.947).治疗方案(P=0.018)及体能状态(performance status,PS)(P<0.001)是PFS的独立影响因素,吸烟史(P=0.014)、治疗方案(P=0.002)和PS(P<0.001)是OS的独立影响因素.结论 阿帕替尼安全性高,肺癌一线治疗失败后,二线或三线化疗联合阿帕替尼,与单纯化疗相比,患者有PFS和OS获益,阿帕替尼单药与单纯化疗组间PFS和OS无明显差异;无吸烟史、PS 0分-1分和联合治疗的患者预后更好.     

Salvage S-1 monotherapy in metastatic colorectal cancer patients who failed irinotecan-based or oxaliplatin-based chemotherapy

The purpose of the study was to evaluate the efficacy and tolerability of S-1 monotherapy in metastatic colorectal cancer (CRC) patients who have failed the standard oxaliplatin-based or irinotecan-based chemotherapy. From 2007 to 2010, metastatic CRC patients who received S-1 monotherapy as salvage treatment were identified from tumor registry at Samsung Medical Center. All patients received ≥ second-line treatment for CRC. S-1 was administered orally from day 1 to day 14, every 3 weeks. The dose of S-1 for each patient was determined according to body surface area (BSA) as follows: for BSA < 1.25 m², 80 mg/day; for 1.25 m² < BSA < 1.5 m², 100 mg/day; and for BSA > 1.5 m², 120 mg/day divided by 2 doses. The median age of the 19 patients was 59 years (range: 33–77). Fourteen (73.7%) of 19 patients received S-1 monotherapy as third-line treatment after failing oxaliplatin-based or irinotecan-based chemotherapy. Previous regimens prior to S-1 therapy were as follows: FOLFOX, XELOX, FOLFIRI, XELOX + avastin, and cetuximab + irinotecan. The median number of administered S-1 courses given in the entire studied population was 3 cycles (1–10 cycles). Three patients had confirmed partial response (PR) after 3 cycles of S-1 treatment. After a follow-up duration of 22.3 months (range: 6.7–32.6 months), median time to progression (TTP) was 2.1 (95% CI, 1.8–4.2) months. Median overall survival was 11.3 months (95% CI, 8.8–16.8) from the time of S-1 chemotherapy administration. Two patients had grade 1 hand-foot syndrome (HFS) after first and 2nd cycles of treatments, respectively, but treatments were continued without developing further adverse events. The salvage S-1 monotherapy in metastatic colorectal cancer patients who failed irinotecan-based or oxaliplatin-based chemotherapy was moderately effective and well tolerated.

     

Outcomes of multiple salvage chemotherapy for advanced gastric cancer: implications for clinical practice and trial design

Purpose

We analyzed the natural history of advanced gastric cancer with sequential salvage chemotherapy following first-line treatment.

Methods

We studied 532 patients with unresectable gastric adenocarcinoma who were treated at Yonsei Cancer Center (2000–2008). The patients were managed with multiple sequential salvage chemotherapy as allowed by performance status and toxicity profiles. The tumor response was assessed every two cycles.

Results

Four hundred sixty patients received palliative chemotherapy and 72 received supportive care only. The median overall survival was 12.0 months for all patients, 12.1 months for the chemotherapy group, and 2.5 months for the supportive care group (P < 0.001). In the chemotherapy group, 87% received first-line chemotherapy, 47% second-line, 23% third-line, 9% fourth-line, and 3% fifth-line. Response rates were 24.8, 12.6, 10.9, 2.6, and 0% and disease control rates were 76.3, 60.1, 54.2, 54.2, and 53.3% for first- to fifth-line treatment, respectively. The median progression-free survival was 5.5, 3.4, 2.5, 1.9, and 2.0 months and overall survival was 12.1, 7.9, 5.5, 5.0, and 6.8 months. Performance status and metastatic pattern were consistent prognostic factors throughout salvage treatment.

Conclusions

Clinical trials may be feasible in second- or third-line salvage chemotherapy for gastric cancer. Future clinical trials in these settings should take into account the low response rate, short progression-free survival, and the prognostic factors for optimal trial design.     

Aflibercept Plus FOLFIRI vs. Placebo Plus FOLFIRI in Second-Line Metastatic Colorectal Cancer: a Post Hoc Analysis of Survival from the Phase III VELOUR Study Subsequent to Exclusion of Patients who had Recurrence During or Within 6 Months of Completing Adjuvant Oxaliplatin-Based Therapy

The aim of this post hoc analysis of the VELOUR study (ClinicalTrials.gov NCT00561470) was to investigate the treatment effect of adding aflibercept to second-line infusional 5-fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) in patients with metastatic colorectal cancer (mCRC) who had failed any prior oxaliplatin-containing regimen. Adjuvant rapid relapsers (ARR), who were enrolled directly following relapse during or within 6 months of completion of oxaliplatin-containing adjuvant chemotherapy (N?=?124, including 17 patients who also received bevacizumab as part of their adjuvant therapy), were excluded from the original VELOUR intention-to-treat (ITT) population (N?=?1226). After exclusion of the ARR, overall survival (OS) in the ITT minus ARR (ITT-ARR) population (N?=?1102) was longer in the aflibercept plus FOLFIRI arm than in the placebo plus FOLFIRI arm [hazard ratio (HR) 0.78, 95 % confidence interval (CI) 0.68–0.90; median survival difference 1.87 months]. In the subgroup of patients assigned to the prior bevacizumab stratum at randomization, OS was numerically longer in the aflibercept plus FOLFIRI arm than in the placebo plus FOLFIRI arm (HR 0.81; 95 % CI 0.63–1.04; median survival difference 2.14 months). Comparison of the post hoc analysis results with the primary analysis from VELOUR suggests that the inclusion of the directly enrolled ARR may have understated the aflibercept treatment benefit for both bevacizumab-pretreated and bevacizumab-naïve patients in the strictly second-line setting although no definitive conclusion may be inferred. The benefit associated with the addition of aflibercept to second-line FOLFIRI in patients with mCRC was observed whatever the timing of first-line disease progression. There were no unexpected safety concerns.

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Efficacy and tolerability of ramucirumab monotherapy or in combination with paclitaxel in gastric cancer patients from the Expanded Access Program Cohort by the Korean Cancer Study Group (KCSG)

Background

Ramucirumab improves survival in gastric cancer patients. The efficacy and safety of ramucirumab outside of a clinical trial were evaluated using an expanded access program (EAP).

Methods

Advanced gastric cancer patients treated with ramucirumab in combination with paclitaxel or with ramucirumab monotherapy in a Korean EAP were evaluated. Baseline characteristics were assessed for progression-free survival (PFS) and overall survival (OS), and adverse events were evaluated according to the treatment regimen.

Results

Of 265 patients, 228 received ramucirumab plus paclitaxel, and 37 received ramucirumab monotherapy. Grade 3 or 4 neutropenia was more common with ramucirumab plus paclitaxel than with ramucirumab monotherapy (46.7 vs. 8.1%). Gastrointestinal (GI) perforation developed in seven patients (3.1%) in the ramucirumab plus paclitaxel group. The overall response and disease control rates were 16.6 and 66.3% in the ramucirumab plus paclitaxel group, and 5.4 and 37.8% in the ramucirumab monotherapy group, respectively. PFS and OS were 3.8 and 8.6 months in the ramucirumab plus paclitaxel group, and 1.8 and 6.4 months in the ramucirumab monotherapy group, respectively. In multivariate analysis, alkaline phosphatase, albumin, and neutrophil-to-lymphocyte ratio (NLR) were the independent prognostic factors for PFS, while albumin, NLR, number of metastatic sites, and large amount of ascites were independent prognostic factors for OS.

Conclusion

In the Korean EAP cohort, ramucirumab showed similar efficacy to the results of the previous trials for gastric cancer. However, the level of GI perforation was slightly increased in the ramucirumab plus paclitaxel group.