|Year : 2013 | Volume
| Issue : 7 | Page : 153-157
A phase II study of triweekly paclitaxel and capecitabine combination therapy in patients with fluoropyrimidine-platinum-resistant metastatic gastric adenocarcinoma
Xiao-tian Zhang1, Jian Li1, Yu Bai2, Yu-ping Chu3, Jie Li1, Yan Li1, Ji-fang Gong1, Lin Shen1
1 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China
2 Department of Medical Oncology, Peking University, First Hospital, Beijing, China
3 Department of Medical Oncology, Beijing Chao yang Hospital, Capital Medical University, Beijing, China
|Date of Web Publication||30-Nov-2013|
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing 100 142
Source of Support: None, Conflict of Interest: None
Background: Although randomized trials have shown a survival benefit of second-line chemotherapy (SLC) in metastatic gastric adenocarcinoma (MGA), no standard regimen has yet been established. Paclitaxel acts synergistically with capecitabine. In this phase II study, we evaluated the efficacy and safety of paclitaxel/capecitabine (PX) as an SLC regimen for patients with fluoropyrimidine-resistant MGA.
Materials and Methods: Patients were eligible if the tumor progressed to fluoropyrimidine-based regimens or relapsed within 6 months after completion of therapy with adjuvant fluoropyrimidines. Treatment consisted of paclitaxel (80 mg/m 2 , days 1 and 8) and capecitabine (1000 mg/m 2 , bid, days 1-14), called PX, every 3 weeks. The primary endpoint was the objective response rate (ORR). Thirty-five patients were required according to the statistical design, and PX combination would be rejected if fewer than five patients responded.
Results: From November 2004 to May 2007, 36 eligible patients were enrolled. Among them, 35 (97.2%) had previously received platinum/fluoropyrimidine as first-line therapy. Response was assessed in 35 patients; 10 partial responses were obtained, resulting in an ORR of 28.5%. The median progression-free survival was 5.0 months, and the median overall survival was 11.1 months. The most frequent grade 3/4 toxicity was neutropenia, observed in 11.1% of the patients.
Conclusions: PX regimen was clearly demonstrated to be active and safe for fluoropyrimidine-platinum-resistant MGA, and further evaluation in future phase III trials is warranted.
Keywords: Capecitabine, fluoropyrimidine-platinum resistant, metastatic gastric adenocarcinoma, paclitaxel, second-line chemotherapy
|How to cite this article:|
Zhang Xt, Li J, Bai Y, Chu Yp, Li J, Li Y, Gong Jf, Shen L. A phase II study of triweekly paclitaxel and capecitabine combination therapy in patients with fluoropyrimidine-platinum-resistant metastatic gastric adenocarcinoma. J Can Res Ther 2013;9, Suppl S2:153-7
|How to cite this URL:|
Zhang Xt, Li J, Bai Y, Chu Yp, Li J, Li Y, Gong Jf, Shen L. A phase II study of triweekly paclitaxel and capecitabine combination therapy in patients with fluoropyrimidine-platinum-resistant metastatic gastric adenocarcinoma. J Can Res Ther [serial online] 2013 [cited 2019 Aug 24];9:153-7. Available from: http://www.cancerjournal.net/text.asp?2013/9/7/151/122512
| > Introduction|| |
Gastric cancer is the fourth most frequent malignant disease and the second most common cause of cancer-related deaths in the world.  It is also the second most frequent malignancy in China.  As resection is curative in only about 30% of patients,  systemic chemotherapy is proved to be effective and safe in a large majority of patients who experience a relapse after radical surgery or are diagnosed with metastatic disease initially (REAL-2, ML 17032, V325). ,,
However, no standard regimens for the first-line chemotherapy have been set up on a global scale. In most Asian countries, a combination of fluoropyrimidine and platinum is now regarded as the standard treatment, but European or American countries favor triplet regimens in clinical practice. ,, Moreover, attitudes toward second- or third-line chemotherapy differ between Asian and western countries. Subsequent use of second-line chemotherapy (SLC) differed between European and Japanese studies, with the ration of 14% in REAL-2 study  and 75% in SPIRITS study.  Also, in AVAGAST study, patients with at least one post-study therapy formed 67% in Asian countries and only 24% in European or Pan-American countries.  Besides progression-free survival (PFS), post progression survival (PPS) is also correlated with overall survival (OS) in first-line chemotherapy for metastatic gastric adenocarcinoma (MGA). 
Recently, the results of four randomized controlled trials (RCTs), published in full articles , or abstracts, , showed OS benefit from treatment including irinotecan or taxanes compared with best supportive care (BSC) alone in patients in whom one or two prior treatments failed. However, several problems remain unsettled in routine clinical practice. Compared with monotherapy, could doublet regimens bring even much more survival benefit? For patients with poor performance status after progression of first-line therapy, how to balance the antitumor efficacy and quality of life? What would be the role of new agents in second-line settings?
Paclitaxel, widely administrated in China, acts in a synergistic way with capecitabine by further up-regulating thymidine phosphorylase (TP) in tumor tissue and shows synergy with capecitabine in tumor xenograft models.  Based on our previously reported retrospective study in which paclitaxel combined with capecitabine (PX) was offered as second- or third-line therapy in MGA,  we launched a multicenter phase II study in 2003 to prospectively evaluate the efficacy and safety of PX as SLC. When designing this trial, there was neither the evidence to support the role of SLC nor the recommended SLC regimens in MGA.
| > Materials and Methods|| |
were eligible if they were 18-75 years old with a histologically confirmed gastric or esophagogastric junction (EGJ) adenocarcinoma. Patients were required to have had evidence of tumor progression despite prior treatment with fluoropyrimidine-based regimens and at least one measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.0) criteria. Previous neo-adjuvant or adjuvant treatment for gastric cancer was permissive, but the relapse had to occur within 6 months after completion of therapy containing (neo-) adjuvant fluoropyrimidines. Patients were required to have Karnofsky performance status (KPS) ≥60 with a life expectancy of at least 2 months. No prior radiotherapy was permitted except for radiotherapy at non-target lesion which had been completed more than 4 weeks. Adequate organ function was required. Patients were considered ineligible if they satisfied any of the following criteria: Brain metastasis, previous paclitaxel administration in first-line systemic therapy or adjuvant chemotherapy, surgery (excluding diagnostic biopsy) within 4 weeks prior to study entry, uncontrolled cardiac disease within the last 6 months, known allergy to any study treatment, inability to take oral medication, pregnancy or lactation period, intake of any investigational agent within the past 28 days, other previous malignancy within 5 years except for non-melanoma skin cancer or in situ cervix carcinoma, pre-existing neuropathy >grade 1, and legal incapacity.
Baseline evaluation included medical history, physical examination, concomitant medication, and laboratory assessments (hematology and clinical chemistry). For females of childbearing potential, a negative pregnancy test was also required. Patients underwent a baseline ECG and computed tomography (CT) scan or magnetic resonance imaging (MRI) scans of abdomen and pelvis. Chest radiography was accepted if no metastatic lesions were suspected.
Patients received paclitaxel 80 mg/m 2 on days 1 and 8, capecitabine (Xeloda; Roche) 1000 mg/m 2 orally twice a day on days 1-14 (PX regimen), standard anti-allergic pre-medication, and delayed emesis prophylaxis. Treatment was repeated every 21 days, with a maximum of six cycles.
Evaluation of study and dose modification
Routine evaluation of patients was carried out on a weekly basis during therapy. These evaluations included a physical examination, vital signs, KPS, laboratory hematologic and serum chemistry assessments, and the recording of adverse events (AE).
Evaluation of tumor response was based on CT or MRI. Patients are assessable for response if they had received at least one course of therapy. In addition, those patients developing rapid tumor progression, or who died of progressive disease (PD), before response evaluation, were also considered assessable for response. The tumor was evaluated every 6 weeks during the treatment and at least every 12 weeks during the follow-up. RECIST 1.0 criteria were used to assess the type of response. Confirmatory scans were obtained at least 4 weeks after initial documentation of objective complete or partial response (CR or PR).
National Cancer Institute Common Adverse Event Criteria, version 3.0 were used to assess toxicity. PX dose reduction was planned in the event of severe hematologic and/or non-hematologic toxic effects. For grade 3/4 toxic effects including hand-foot syndrome (HFS), there was 25% paclitaxel and/or capecitabine dose reduction. Unless severe adverse events (SAE) occurred, concurrent dose reduction of both agents was not allowed. In cases of insufficient hematologic function (neutrophil count <1500/mm 3 and platelet count <100,000/mm 3 ), chemotherapy was delayed for up to 21 days. If no recovery occurred at this point, the treatment was discontinued.
This was an open-label, non-randomized phase II trial. The primary objective of the study was to determine the objective response rate (ORR, CR + PR), In our previous retrospective study, the ORR of 25.0% was reported for PX regimen as SLC in MGA;  however, another ORR of paclitaxel monotherapy was reported to be 9.8%.  Patients were accrued with an assumption of P0 = 0.1 (the level of no interest), P1 = 0.3 (the target activity level of interest), and both type I and type II errors of 0.1. The combination would be rejected if fewer than five patients responded among the total 35 evaluable patients.
The secondary objectives were evaluation of PFS, disease control rate (DCR, ORR + SD), OS, and safety. The percentages of ORR and DCR are reported with the corresponding 2-sided extract 95% confidence intervals. PFS or OS curves were generated using the Kaplan-Meier method and compared by the log-rank test. Exact 95% CIs were provided for proportions. Safety variables including AE, SAE, and drug dose exposure were analyzed by descriptive method.
| > Results|| |
From November 2004 to May 2007, 36 patients were enrolled at three participating institutions. Patient characteristics are presented in [Table 1]. As fluoropyrimidine-platinum was the most widely accepted first-line therapy, in fact, 35 of the 36 patients were refractory to platinum/fluoropyrimidines rather than fluoropyrimidines alone.
Altogether, 36 patients received therapy, 35 patients received at lease one course of therapy, and the tumor response was assessed in 35 cases. Drug exposure and relative dose intensity are outlined in [Table 2].
In accordance with the requirement of the study design, 2 of the first 10 patients achieved PR; therefore, the study was warranted to continue to the second stage. Response was assessed in 35 patients, with the results being 10 PR, 15 stable disease (SD), and 10 PD. In response-evaluable patients, ORR was 28.5% and DCR was 71.4%. Up to the last follow-up date of June 2009 with a median follow-up of 16.6 months, 3 patients were lost during follow-up and 33 patients died; the median OS was 11.1 months (95% CI 7.3-14.9 months). Progression of disease was observed in all cases and the median PFS (mPFS) was 5.0 months (95% CI 3.5-6.5 months) [Figure 1] and [Table 3].
|Figure 1: Kaplan– Meier curves of (a) median PFS and (b) median OS (a) mPFS 5.0 months; (b) mOS 11.1 months|
Click here to view
At the time of this analysis, treatment had been discontinued in all patients. Thirty patients discontinued therapy for PD, 1 for AE, and 5 on personal willingness. After progression, 16 patients accepted BSC alone; the other 20 patients received at least one subsequent treatment, including chemotherapy, radiotherapy, and hepatic arterial infusion.
Toxicity was assessed in all 36 enrolled patients [Table 4]. The most frequent chemotherapy-related toxicity included grade 3/4 neutropenia (11.1%), but only one patient developed febrile neutropenia with grade 1. Grade 3/4 nausea/vomiting and HFS occurred in 5.6% of the patients. One patient developed SAE of allergy at the first administration of paclitaxel; paclitaxel was then discontinued. Also, the patient recovered with no sequelae after the necessary medication, but later withdrew the informed consent.
| > Discussion|| |
Many patients with MGA are refractory to first-line chemotherapy or experience disease progression after certain time of disease control. Owing to the availability of new agents with well-controlled toxicity, physicians, especially in Asian countries, have been offering second- or third-line chemotherapy despite lack of evidence in the refractory settings. Recently, four randomized trials have demonstrated the improvement of OS with second- or third-line chemotherapy over BSC. The Korean trial by Kang et al.  is the largest completed randomized trial involving 202 patients, with SLC regimen of irinotecan or docetaxel. The trial by Thuss-Patience et al.  in Europe was prematurely closed with only 40 patients due to poor accrual, with SLC regimen of irinotecan monotherapy. A trial by Cook et al.  that enrolled 168 European patients was presented in the form of an abstract this year, with SLC regimen of irinotecan as well. A meta-analysis by Kim et al. further demonstrated evidence to support SLC in MGA. 
However, despite all these data, no standard regimen has been established worldwide. In Japan and China, paclitaxel has been used more frequently than docetaxel as the SLC.  A trial by Ueda et al., presented as an abstract in 2012, recruiting 223 Japanese patients aimed to compare irinotecan with weekly paclitaxel (wPTX). In this trial, the median OS was 8.4 months for irinotecan and 9.5 months for wPTX, and the median PFS (mPFS) was 2.3 months for irinotecan and 3.6 months for wPTX. The ORR was 13.6% for irinotecan and 20.9% for wPTX. Although the superiority was not supported by statistical analysis, wPTX tended to be more active and showed better toxicity profile on both hematologic or non-hematologic toxicities.
Paclitaxel might be a better choice than irinotecan as an SLC agent. First, pharmacokinetics data show high concentration of paclitaxel in ascites and peritoneal cavity, up to 40% of plasma concentration, lasting for at least 12 h.  Since local recurrence and peritoneal dissemination are the most frequent patterns of relapse after radical surgery,  paclitaxel might be more promising in the control of peritoneal lesions. Secondly, deterioration of nutrition status or quality of life caused by paclitaxel is less than that caused by irinotecan, which shows high frequency of grade 3/4 neutropenia, diarrhea, and fatigue. So patients are more likely to complete the whole treatment schedule.
Consistent with Japanese data, , our retrospective study evaluating paclitaxel-based doublet or triplet as SLC in MGA showed ORR of 25%, median time to progression (TTP) of 4.5 months, and mOS of 8.8 months. PX subgroup showed optimal disease control compared with paclitaxel/5 FU, possibly due to synergism of paclitaxel and capecitabine. To further evaluate the role of PX as SLC in MGA, we carried out the present trial. From the above results, the present phase II study of PX as SLC in treating refractory MGA is judged to be positive on the basis of the decision rule defined in the protocol. Our data are comparative with historical reports, with an ORR of 16-30% and a PFS of 2.6-6.4 months. However, OS reached 11.1 months compared to 5.2-10.0 months in other trials. , This may due to the subsequent third-line therapy or other treatment modalities including radiotherapy or radiofrequency under indication. Since 97.2% of the patients were resistant to fluoropyrimidine/platinum as the first-line therapy, it is reasonable to consider a so-called "sequential therapy" for MGA, namely, platinum/fluoropyrimidine as the first line and PX as SLC, which might be most beneficial in long-term control of MGA and is worthy of further evaluation in large-scale phase III trial.
The toxicity of the PX regimen can be considered well tolerable and manageable. Hematologic toxicity was within the expected range, including grade 3/4 neutropenia, observed in four patients (11.1%) and grade 1 febrile neutropenia in only one patient.
In conclusion, the efficacy and safety of PX regimen as SLC in MGA was successfully demonstrated in this present phase II study and warrants further evaluation in future phase III trials.
| > Acknowledgments|| |
First of all, we thank all the patients who agreed to participate in this trial. We thank all the institutions that participated in the study.
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[Table 1], [Table 2], [Table 3], [Table 4]