Salvage chemotherapy with the combination of oxaliplatin,leucovorin, and 5-fluorouracil in advanced gastric cancer refractory or intolerant to fluoropyrimidines,platinum, taxanes,and irinotecan

Background

Although nivolumab showed survival benefit in patients with advanced gastric cancer (AGC) progressing after standard chemotherapy, there is a lack of data regarding oxaliplatin-based chemotherapy in this clinical setting.

Methods

We retrospectively evaluated the efficacy and safety of oxaliplatin with l-leucovorin and bolus/continuous infusion of 5-fluorouracil as salvage treatment in patients with AGC refractory or intolerant to fluoropyrimidines, cisplatin, taxanes, and irinotecan.

Results

Overall, 50 patients treated between December 2009 and December 2013 were included in this analysis. The overall response rate (ORR) was 21.2% among 33 patients with measurable disease. The median time to treatment failure (TTF) and overall survival (OS) were 2.4 and 4.2 months. In multivariate analysis, factors associated with OS included poor performance status [hazard ratio (HR) 3.20; 95% confidence interval (CI) 1.55–6.60], shorter time from the start of first-line therapy (HR 2.20; 95% CI 1.18–4.12), and higher neutrophil/lymphocyte ratio value (HR 4.87; 95% CI 2.32–10.25). In patients (n?=?35) with at most one risk factor, the ORR, median TTF, and OS were 26.1%, 3.6, and 6.7 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (30%), anemia (22%), febrile neutropenia (8%), and peripheral neuropathy (8%). Initial and subsequent dose reduction was performed in 18 (36%) and 23 (46%) patients. There was one treatment-related death caused by septic infection.

Conclusions

Salvage chemotherapy with the combination of oxaliplatin, leucovorin, and 5-fluorouracil has a potential activity and is tolerable for heavily treated AGC with appropriate dose modification and patient selection.

     

A phase II study of combination therapy with oral S-1 and cisplatin in elderly patients with advanced gastric cancer

Background

A combination of S-1 and cisplatin is recognized as one of the standard first-line chemotherapy regimens for patients with advanced gastric cancer. However, demographic analyses of pivotal phase III studies have showed that only a minority of treated patients were aged 76 years or older. The purpose of this phase II study was to evaluate the safety and efficacy of combination therapy with S-1 and cisplatin in elderly patients with chemotherapy-naive advanced gastric cancer.

Methods

Patients aged 76 years or older received S-1 40 mg/m² orally twice daily for 21 days and cisplatin 60 mg/m² intravenously infused at day 8 of each 35-day cycle. Dose modification was performed according to creatinine clearance. The primary endpoint was overall survival (OS). Secondary endpoints included response rate, progression-free survival (PFS), time to treatment failure (TTF), and adverse events.

Results

A total of 40 patients were enrolled. Median OS was 12.3 months, PFS was 7.8 months, and TTF was 4.3 months. The response rate was 54%. The most common grade 3–4 adverse events were anorexia (25%), neutropenia (23%), hyponatremia (20%), anemia (18%), and febrile neutropenia (8%). No treatment-related death occurred.

Conclusions

Combination chemotherapy with S-1 and cisplatin is an effective and well-tolerated regimen for elderly patients with advanced gastric cancer when the dose is adjusted according to renal function.

     

Phase II study of oxaliplatin,irinotecan and S-1 therapy in patients with advanced gastric cancer: the Korean Cancer Study Group ST14-11

Background

Doublet chemotherapy of platinum and 5-fluorouracil is a standard first-line treatment for patients with unresectable gastric cancer. Although the addition of taxane or irinotecan to this regimen has yielded promising efficacy, its use has been limited due to severe toxicities. To overcome this limitation, we evaluated the efficacy and safety of the combination of irinotecan, oxaliplatin, and S-1 (OIS) for the treatment of advanced gastric cancer.

Methods

Chemotherapy-naïve patients with pathologically proven advanced gastric adenocarcinoma were assessed for eligibility. Irinotecan (135 mg/m²) and oxaliplatin (65 mg/m²) were administered intravenously on day 1, and S-1 (80 mg/m²/day) was administered orally on days 1–7 of every 2-week cycle.

Results

Forty-four patients (median age 57 years) were enrolled and all but one patient had a good performance status (ECOG 0 or 1). A total of 529 cycles were administered, with a median of 9.5 (range 1–31) cycles per patient. The overall response rate was 61.4% (95% confidence interval [CI] 46.6–74.3). The median progression-free survival and overall survival were 10.8 months (95% CI 7.6–14.0) and 15.4 months (95% CI 12.6–18.2), respectively. Major toxicities included grade 3/4 neutropenia (38.6%), febrile neutropenia (13.6%), abdominal pain (9.1%), and diarrhea (9.1%).

Conclusion

These data suggest that the OIS regimen is effective and relatively well tolerated in patients with advanced gastric cancer. Given that all the patients treated, but one, had a good performance status, these results must be confirmed in a patient population more representative of regular clinical practice.

Trial Registration

ClinicalTrials.gov Identifier: NCT02527785.

     

Phase II study of S-1 plus oxaliplatin 130 mg/m<Superscript>2</Superscript> in Japanese patients with advanced gastric cancer

Purpose

Although oxaliplatin 130 mg/m² every 3 weeks was approved for advanced gastric cancer in Japan, data regarding S-1 plus oxaliplatin 130 mg/m² (SOX130) are limited in Japanese patients with advanced gastric cancer. We investigated the feasibility and safety of SOX130 in Japanese patients with advanced gastric cancer.

Methods

Patients with unresectable or recurrent gastric adenocarcinoma, no previous chemotherapy, and Eastern Cooperative Oncology Group Performance Status of 0–1 were treated with SOX130. The primary endpoint was the 3-cycle completion rate, defined as the proportion of patients who completed the first three cycles with ≥?80% relative dose intensity of oxaliplatin.

Results

Twenty-five patients were enrolled from April 2015 to 2016. The 3-cycle completion rate was 72.0% (90% confidence interval: 53.8–86.1), which was higher than the predetermined threshold rate of 50%. With the median number of cycles being 6 (range, 1–19+), grade 3 or 4 adverse events occurred in 10 patients (40%). Major grade 3 adverse events were anorexia (24%), thrombocytopenia (16%), and neutropenia (12%). No febrile neutropenia or treatment-related deaths occurred. Among 12 patients with measurable lesions, the overall response rate was 58.3%. Median progression-free and overall survival were 5.7 months (95% confidence interval 2.9–8.5) and 13.1 months (95% confidence interval 7.4–19.0), respectively.

Conclusion

Results indicated that SOX130 was feasible in Japanese patients with advanced gastric cancer.

     

A phase II trial of capecitabine plus cisplatin (XP) for patients with advanced gastric cancer with early relapse after S-1 adjuvant therapy: XParTS-I trial

Backgrounds

In Japan, standard regimens for advanced gastric cancer (AGC) include S-1 chemotherapy. The standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine alone is platinum-based chemotherapy, while the standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine plus platinum is second-line chemotherapy. To evaluate the efficacy and safety of capecitabine plus cisplatin (XP) treatment for AGC patients who relapse within 6 months after S-1-based therapy, we conducted a multicenter phase II trial (NCT01412294).

Methods

HER2-negative gastric cancer patients treated with adjuvant chemotherapy including S-1 for more than 12 weeks and relapsed within 6 months were treated with capecitabine 1000 mg/m² bid for 14 days plus cisplatin 80 mg/m² on day 1 of a 3-week cycle. The primary endpoint was PFS; secondary endpoints were OS, time to treatment failure, overall response rate (ORR) and safety.

Results

Forty patients (median age 64) were enrolled; of those, 37 (92.5%) received adjuvant S-1 monotherapy. Median PFS was 4.4 months (95% CI 3.6–5.1), which was longer than the 2-month protocol-specified threshold (p < 0.001). Median OS was 13.7 months (95% CI 9.0–17.7) and ORR was 8/30 (26.7%) (95% CI 14.2–44.4). Most common grade ≥ 3 adverse events were neutropenia (23%), anemia (18%), elevated serum creatinine (18%), fatigue (13%), diarrhea (7.5%), and anorexia (7.5%).

Conclusions

XP was safe and effective in patients with early relapse after S-1 adjuvant chemotherapy for curatively resected gastric cancers. XP may be a good option for the treatment of patients after early failure after adjuvant S-1.

Trial registration

NCT01412294.

     

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.

     

Salvage treatment with irinotecan/cisplatin versus pemetrexed/cisplatin in patients with non-small cell lung cancer pre-treated with a non-platinum-based regimen in the first-line setting: a randomized phase II study of the Hellenic Oncology Research Group (HORG)

Background

Platinum-based chemotherapy is the standard front-line treatment for patients with advanced non-small cell lung cancer (NSCLC). However, non-platinum combinations of third-generation chemotherapeutic agents are considered an alternative therapeutic option for patients who cannot tolerate the toxic effects of platinum compounds. In this study, the efficacy and toxicity of the combination of irinotecan plus cisplatin (IC) was compared to pemetrexed plus cisplatin (PC) regimen, in platinum-naïve patients with advanced NSCLC, who had been previously treated with the combination of a taxane plus gemcitabine.

Patients and methods

A total of 124 patients with locally advanced or metastatic NSCLC were randomly assigned to either irinotecan 110 mg/m² on day 1 and 100 mg/m² on day 8 plus cisplatin 80 mg/m² on day 8 every 3 weeks (IC arm) or pemetrexed 500 mg/m² plus cisplatin 80 mg/m² on day 1 every 3 weeks (PC arm). The primary endpoint of the study was the overall response rate (ORR).

Results

The ORR and median progression-free survival (PFS) in the IC arm were 18 % and 3.3 months, respectively, while in the PC arm were 19 % and 4.2 months (p = ns). Median overall survival (OS) was significantly higher in patients with PC (6.9 vs. 10.9; p = 0.013). PC regimen had a better toxicity profile compared to IC, with a statistically significant lower incidence of grade 3/4 neutropenia (3 vs. 31 %; p = 0.0001) and diarrhea (1.6 vs. 14.7 %, p = 0.018).

Conclusions

In patients with advanced NSCLC pretreated with docetaxel/gemcitabine, the combination of pemetrexed/cisplatin is associated with increased OS and is better tolerated than the combination of irinotecan/cisplatin and should be considered as a valid therapeutic option for platinum-naive, previously treated patients.

ClinicalTrials.gov Identifier

NCT00614965.

     

Phase II study of docetaxel,cisplatin, and concurrent radiation followed by platinum-based adjuvant chemotherapy for technically unresectable,locally advanced head and neck squamous cell carcinoma

Background

Phase I study of weekly administration of low-dose docetaxel/cisplatin concurrent with conventionally fractionated radiotherapy for locally advanced head and neck squamous cell carcinoma suggested the recommended dose of docetaxel at 10 mg/m² and cisplatin at 20 mg/m². Phase II study of the concurrent chemoradiotherapy for technically resectable disease showed satisfactory results.

Methods

This phase II study was designed to address efficacy and safety when patients with technically unresectable disease were treated with concurrent chemoradiotherapy, followed by two cycles of moderate-dose platinum-based adjuvant chemotherapy: docetaxel, cisplatin, and fluorouracil (modified TPF). Modified TPF was replaced with docetaxel/carboplatin when renal impairment became evident. Surgical salvage was considered when residual or recurrent locoregional disease was technically resectable and free of distant metastasis.

Results

Of 33 enrolled patients, 31 were analyzable: 24 (78 %) and 18 (58 %) patients completed chemoradiotherapy and adjuvant chemotherapy, respectively; 15 (48 %) patients completed study treatment per protocol, and overall complete response rate was 45 %. Seven patients underwent surgical salvage, which was successful in 4 patients. At a median follow-up of 60.8 months for surviving patients, median progression-free survival and median overall survival were 16.2 and 39.9 months, respectively. Grade 3 or 4 toxicity included mucositis (77 %) and dysphagia (45 %) during the chemoradiotherapy period and neutropenia (100 %) and febrile neutropenia (35 %) during the adjuvant period. No patient died of toxicity.

Conclusion

The tested regimen seems effective, although there is room for improvement in adjuvant chemotherapy because of the high toxicity and low compliance of modified TPF.

     

Fortgeschrittenes Magenkarzinom

Background

Systemic chemotherapy has become established as the standard treatment for advanced incurable gastric cancer. In the metastatic setting, systemic chemotherapy can prolong the survival time, improve symptom control and help to maintain a better quality of life.

Material and methods

Testing the human epidermal growth factor receptor 2 (HER2) expression status of the primary tumor and/or metastases is warranted before initiation of first-line treatment.

Results

In cases of HER2 overexpression or amplified tumors, trastuzumab in combination with cisplatin and 5?fluorouracil (5-FU) or capecitabine are the standard forms of treatment. Tumors that are HER2 negative or weakly positive are treated with a platinum-fluoropyrimidine combination as doublet or as a triplet with docetaxel in younger patients who can tolerate more intensive treatment. Taxane derivatives, such as docetaxel and paclitaxel as well as irinotecan are accepted treatment options for patients who show progress during or after first-line chemotherapy. The anti-vascular endothelial growth factor receptor 2 (anti-VEGFR2) antibody ramucirumab demonstrated efficacy with prolongation of survival both as monotherapy and in combination with paclitaxel.

Objective

This review article outlines the indications and clinical data for pharmaceutical treatment of advanced gastric cancer.

     

Incidence of and risk factors for preoperative deep venous thrombosis in patients undergoing gastric cancer surgery

Background

Pulmonary thromboembolism (PE) is one of the life-threatening complications of gastric cancer surgery. D-dimer assay is a safe and rapid tool to exclude the presence of deep venous thrombosis (DVT). In July 2012, we started preoperative DVT screening of patients scheduled for gastric cancer surgery using a combination of D-dimer measurements and lower extremity venous ultrasonography to prevent PE.

Methods

Between July 2012 and August 2015, 976 consecutive patients underwent gastric cancer surgery with preoperative D-dimer screening. Lower extremity venous ultrasonography was performed in patients with a positive D-dimer assay result (greater than 1.0 μg/ml). The incidence of and risk factors for preoperative DVT and the incidence of PE were examined in patients undergoing gastric cancer surgery.

Results

Of the 976 patients, 176 (18.0%) showed positive D-dimer assay results, and in 13 (1.3%) DVT was diagnosed by lower extremity ultrasonography. Our analysis identified neoadjuvant chemotherapy as a risk factor for preoperative detection of DVT in patients undergoing gastric cancer surgery (P = 0.021). The incidence of PE was 0.1% (1/976).

Conclusion

Preoperative gastric cancer patients receiving neoadjuvant chemotherapy seem to be at higher risk for the development of DVT.

     

Nomograms predicting survival of patients with unresectable or metastatic gastric cancer who receive combination cytotoxic chemotherapy as first-line treatment

Background

Some clinicopathological variables are known to influence the survival of patients with advanced gastric cancer. A comprehensive model based on these factors is needed for prediction of an individual’s survival and appropriate patient counseling.

Methods

A nomogram for predicting 1-year survival in patients with advanced gastric cancer in the palliative chemotherapy setting was developed using clinicopathological data from 949 patients with unresectable or metastatic gastric cancer who had received first-line doublet cytotoxic chemotherapy from 2001 to 2006 at the National Cancer Center, Korea (Baseline Nomogram). For 836 patients whose initial response to chemotherapy is known, another nomogram (ChemoResponse-based Nomogram) was constructed using the response to chemotherapy as additional variable. Nomogram performance in terms of discrimination and calibration ability was evaluated using the C statistic and Hosmer–Lemeshow-type χ ² statistics.

Results

Two different nomograms were developed and subjected to internal validation. The baseline nomogram incorporated 13 baseline clinicopathological variables, whereas the chemoresponse-based nomogram was composed of 11 variables including initial response to chemotherapy. Internal validation revealed good performance of the two nomograms in discrimination: C statistics = 0.656 (95% confidence interval, 0.628–0.673) for the baseline and 0.718 (95% confidence interval, 0.694–0.741) for the chemoresponse-based nomogram, which showed significantly better discrimination performance than the baseline nomogram (Z statistics = 3.74, p < 0.01).

Conclusion

This study suggests that individual 1-year survival probability of patients receiving first-line doublet cytotoxic chemotherapy for advanced gastric cancer can be reliably predicted by a nomogram-based method incorporating clinicopathological variables and initial response to chemotherapy.

     

Efficacy and cost-effectiveness of second-line chemotherapy in elderly patients with advanced gastric cancer

Purpose

Second-line chemotherapy has been shown to benefit patients with advanced gastric cancer (AGC), extending the overall survival (OS) and progression-free survival (PFS). This study aimed to assess the efficacy and cost-effectiveness of second-line treatment for elderly patients with AGC.

Methods

Medical records and follow-up information of elderly patients (≥70 years) with AGC who received second-line chemotherapy were collected. A Markov model comprising three health states PFS, progressive disease and death was developed to simulate the process of AGC. Cost was calculated from the perspective of Chinese society. Sensitivity analyses were applied to explore the impact of essential variables.

Results

Forty-three elderly patients with AGC receiving second-line chemotherapy were included in our study. The median OS was 6.0 months (95% confidence interval (CI) 3.90–8.10) and PFS was 3.1 months (95% CI 1.38–4.82). No treatment-related death occurred. The most frequently drug-related grade 3/4 AEs were diarrhea (2.3%), leukopenia (16.3%) and nausea (7.0%). The incremental cost-effective ratio was $18,223.75/QALY for second-line chemotherapy versus BSC, which was below the threshold of 3× the per capita GDP of China, $23,970.00.

Conclusion

Second-line chemotherapy was an optimal strategy for elderly AGC patients in China from the efficacy and cost-effectiveness perspective.

     

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.

     

BAK is a predictive and prognostic biomarker for the therapeutic effect of docetaxel treatment in patients with advanced gastric cancer

Background

Preoperative chemotherapy is a promising strategy for downstaging advanced gastric cancer before radical resection, although severe adverse events can occur and clinical outcomes are often unsatisfactory. To identify predictive biomarkers of drug sensitivity, we used a well-designed functional apoptosis assay and assessed the correlations between chemosensitivity and clinical outcomes.

Methods

Drug sensitivity to docetaxel, cisplatin, and 5-fluorouracil was examined in 11 gastric cancer cell lines. BCL2-homology domain 3 (BH3) profiling was performed and assessed for correlations with drug sensitivity. Immunohistochemical staining of clinical gastric cancer specimens was performed before preoperative chemotherapy, and correlations with histopathological responses and clinical outcomes were assessed.

Results

BIM (BCL2L11)-BH3 profiling results correlated with docetaxel sensitivity and BAK protein expression, whose knockdown caused docetaxel resistance. The BAK expression indexes of 69 gastric cancer specimens before preoperative chemotherapy (including docetaxel treatment) were determined by multiplying numerical values describing the degrees of BAK positivity and staining intensity observed. Patients whose specimens showed good chemotherapeutic histopathological responses had higher BAK indexes than those with poor responses. Patients with BAK index values ≥3 showed improved progression-free survival (HR, 2.664; 95 % CI, 1.352–5.248; P = 0.005) and overall survival (HR, 3.390; 95 % CI, 1.549–7.422; P = 0.002).

Conclusions

BH3 profiling clearly showed that BIM expression, which depends on BAK expression, correlated with docetaxel sensitivity. BAK expression in gastric cancer is thus predictive of chemotherapeutic responses to docetaxel and clinical prognosis in patients treated with preoperative chemotherapy.

     

Cost-effectiveness analysis of sensitive relapsed small-cell lung cancer based on JCOG0605 trial

Purpose

Since combined strategy with cisplatin, etoposide, and irinotecan has shown the superiority to topotecan alone as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer, this study aimed to compare these two treatments based on JCOG0605 trail from Chinese cost-effectiveness perspective.

Methods

Basic medical information was derived from a multicenter, open-label, randomized phase III trial (JCOG0605). A Markov model including three health states: progression-free state, progressive disease (PD), and death, was developed to simulate the process of sensitive relapsed small-cell lung cancer. Cost was calculated from the perspective of Chinese society. Sensitivity analyses were applied to explore the impact of essential variables.

Results

Treatment with combination chemotherapy was estimated to increase costs by $6947.32 compared with topotecan alone, with a gain of 0.26 quality-adjusted life years (QALYs). Thus, the incremental cost-effective ratio was $26720.46/QALY for combination treatment versus monotherapy, which was beyond the threshold of 3 × the per capita GDP of China, $24423.00. The costs of PD state were the most influential factors to the model.

Conclusion

The combination chemotherapy with cisplatin, etoposide, and irinotecan was not a cost-effectiveness choice for patients with sensitive relapsed SCLC in China from the cost-effectiveness perspective.

     

First-line bolus 5-fluorouracil plus leucovorin for peritoneally disseminated gastric cancer with massive ascites or inadequate oral intake

Background

There are few chemotherapeutic options for advanced gastric cancer with severe disseminated peritoneal metastases, which are usually accompanied by ascites. Bolus 5-fluorouracil (5-FU) plus leucovorin therapy has been widely used against gastrointestinal malignancies, with resulting mild toxicities.

Methods

We retrospectively analyzed the efficacy and safety of first-line chemotherapy with bolus 5-FU plus l-leucovorin in 30 advanced gastric cancer patients who had massive ascites and/or inadequate oral intake. This therapy consisted of 5-FU (600 mg/m² IV bolus) plus l-leucovorin (250 mg/m² 2-h IV infusion) administered on a 6 weeks on/2 weeks off schedule.

Results

Among all the patients, 26 (87%) were unable to eat and 12 (40%) had massive ascites. Major grade 3 or 4 adverse events were neutropenia (17%), nausea (7%), fatigue (7%), and diarrhea (3%); no treatment-related deaths were observed. The median progression-free survival and overall survival (OS) were 2.4 months [95% confidence interval (CI), 0.6–4.1] and 6.0 months (95% CI, 2.1–9.9), respectively. Objective improvement in oral intake was seen in 7 patients (27%). Improvement in ascites occurred in 9 (39%) of 23 patients. In multivariate analyses, the presence of both massive ascites and inadequate oral intake was significantly associated with worse OS (hazard ratio, 5.25; 95% CI, 1.61–17.1). The median OS for patients (n = 22) without this factor was 7.2 months (95% CI, 4.2–10.3).

Conclusion

Our study suggests that bolus 5-FU plus l-leucovorin therapy is feasible and has clinical activity as palliative therapy in patients with severe peritoneal metastases from gastric cancer.

     

An application study of low-dose computed tomography perfusion imaging for evaluation of the efficacy of neoadjuvant chemotherapy for advanced gastric adenocarcinoma

Background

This study used low-dose computed tomography (CT) perfusion imaging technology to evaluate the efficacy of neoadjuvant chemotherapy in patients with advanced gastric adenocarcinoma and to determine whether any of the perfusion parameters could predict tumor response to chemotherapy.

Methods

Forty patients with gastric adenocarcinoma (T3-4NxM0) received three cycles of neoadjuvant chemotherapy and low-dose spiral CT perfusion imaging prior to and after the first and third series of chemotherapy. We calculated tissue blood flow (BF) and blood volume (BV) using commercial software. One-way analysis of variance (ANOVA) was used to detect any significant variation of the tested parameters between different times of scanning. Spearman's test was used to evaluate the correlation among perfusion parameters, tumor size and pathological efficacy grade, and clinical response after chemotherapy, respectively. A receiver-operating characteristic analysis was used to determine the optimal diagnostic cutoff value for changes in perfusion parameters and tumor size.

Results

One-way ANOVA showed significant differences in BF and BV values between those before and after chemotherapy (p < 0.01). The BF, BV and size reduction rate after three series of chemotherapy were significantly correlated with pathological efficacy grade. BF and BV values after the first and third series of chemotherapy were also significantly correlated with clinical response (p < 0.01, respectively). The diagnostic sensitivity and specificity of the BV reduction rate were higher than those of size reduction rate.

Conclusions

Low-dose CT perfusion imaging is a valuable tool that permits microcirculation evaluation and therefore can evaluate the efficacy of neoadjuvant chemotherapy in patients with advanced gastric adenocarcinoma.

     

A phase II study of paclitaxel by weekly 1-h infusion for advanced or recurrent esophageal cancer in patients who had previously received platinum-based chemotherapy

Purpose

To evaluate the efficacy and safety of weekly paclitaxel (Taxol^®) in patients with advanced or recurrent esophageal cancer.

Methods

Fifty-three patients with recurrent or advanced esophageal cancer who had previously received platinum-based chemotherapy were treated with paclitaxel 100 mg/m² once weekly by 1-h infusion on days 1, 8, 15, 22, 29, and 36 of a 49-day cycle. Fifty-two patients were evaluable for efficacy and 53 for safety. Forty-one (77%) patients had recurrent, and 12 (23%) had advanced disease. Most patients (52/53) had squamous cell carcinoma, and one had adenocarcinoma.

Results

A median of 2 cycles was delivered (range 1–8). The overall response rate was 44.2% (23/52; 95% confidence interval (CI) 30.5, 58.7%), with 4 patients (7.7%) achieving complete response. The median duration of response was 4.8 months, and median overall survival was 10.4 months. The most common Grade 3 or 4 adverse events were neutropenia (52.8%), leukopenia (45.3%), anorexia (9.4%), and fatigue (9.4%). Adverse events resulted in treatment discontinuation in 34.0% of patients and dose reductions in 43.4%. There were no treatment-related deaths.

Conclusions

Weekly paclitaxel demonstrated efficacy and manageable toxicity in patients with advanced or recurrent esophageal cancer and may be a treatment option for this population.

     

Effects of neutropenia and histological responses in esophageal squamous cell carcinoma with neo-adjuvant chemotherapy

Background

Neo-adjuvant chemotherapy (NAC) followed by radical esophagectomy has been shown to prolong survival in patients with locally advanced esophageal squamous cell carcinoma (ESCC). However, neutropenia, one of the major adverse events due to NAC, influences the therapeutic course. The aim of this study is to clarify the relationship between neutropenia and therapeutic response in ESCC with NAC.

Methods

A total of 117 patients with clinical stage II/III ESCC who had undergone NAC followed by radical esophagectomy were retrospectively analyzed in terms of the relationship between neutropenia and clinicopathological features or outcomes.

Results

Neutropenia was the major adverse event observed in 56 % (66/117) and grade 3/4 neutropenia occurred in 29 % of patients. Grade 3/4 neutropenia correlated with a high histological response (Grade 1b–3) (p < 0.01). Correlative analysis identified grade 3/4 neutropenia and poor differentiation as independent predictors of a high histological response (odds ratio 5.13 and 3.25, p < 0.01 and p = 0.01, respectively). Survival analysis showed that patients with a high histological response had significantly longer survival than those with a low histological response (Grade 0–1a) (p = 0.03), whereas no significant differences were found for survival according to the grade of neutropenia (p = 0.45). In a subgroup analysis according to histological response, grade 3/4 neutropenia correlated with worse survival in patients with a low histological response (p = 0.05).

Conclusion

Severe neutropenia due to NAC correlates with a high histological response in ESCC. However, severe neutropenia may also result in a worse prognosis for patients with a low histological response.

     

Ramucirumab for the treatment of metastatic gastric or gastroesophageal junction adenocarcinoma following disease progression on first-line platinum- or fluoropyrimidine-containing combination therapy in Japanese patients: a phase 2, open-label study

Background

Ramucirumab, a monoclonal antibody vascular endothelial growth factor receptor-2 antagonist, given as monotherapy improved survival in a global phase 3 study (REGARD) of patients with gastric cancer. However, REGARD did not include Japanese patients. This study evaluated the efficacy and safety of ramucirumab monotherapy in Japanese patients with advanced gastric cancer.

Methods

This multicenter, open-label, nonrandomized phase 2 study (Clinicaltrials.gov: NCT01983878) was performed at 16 Japanese sites. Patients with advanced gastric or gastroesophageal junction cancer after disease progression following first-line chemotherapy received intravenous ramucirumab 8 mg/kg every 2 weeks. Primary efficacy outcome: 12-week progression-free survival rate (PFS).

Results

Thirty-six patients were enrolled. The 12-week PFS rate was 23.8% [90% confidence interval (CI) 12.4–37.2); the primary outcome was not met as the lower limit of the CI was outside the threshold of 16%. Median PFS was 6.6 weeks (90% CI 6.1–7.1). No patients achieved an objective response, and 11 (31%) patients achieved disease control. Median overall survival was 8.6 months (90% CI 5.7–10.7). The most frequent treatment-emergent adverse events (TEAEs) were diarrhea (9/36; 25%) and decreased appetite (8/36; 22%). Three patients reported Grade ≥ 3 ileus; all other Grade ≥ 3 TEAEs were reported by ≤ 2 patients. The most frequent adverse events of special interest (AESIs) were hypertension (10/36; 28%), bleeding/hemorrhage (7/36; 19%), and proteinuria (7/36; 19%). All Grade ≥ 3 AESIs were reported by ≤ 2 patients.

Conclusions

These findings suggest that ramucirumab monotherapy has clinical activity and a manageable safety profile in Japanese patients with gastric cancer after disease progression following first-line chemotherapy.