Original Article
A phase II study of triweekly paclitaxel and capecitabine combination therapy in patients with fluoropyrimidineplatinum-resistant metastatic gastric adenocarcinoma ABSTRACT 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/m2, days 1 and 8) and capecitabine (1000 mg/m2, 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. KEY WORDS: Capecitabine, fluoropyrimidine-platinum resistant, metastatic gastric adenocarcinoma, paclitaxel, second-line chemotherapy
INTRODUCTION Gastric cancer is the fourth most frequent malignant disease and the second most common cause of cancer-related deaths in the world.[1] It is also the second most frequent malignancy in China.[2] As resection is curative in only about 30% of patients,[3] 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).[4-6] 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.[4-6] 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[4] and 75% in SPIRITS study.[7] 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.[8] 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).[9]
Xiao-tian Zhang, Jian Li, Yu Bai1, Yu-ping Chu2, Jie Li, Yan Li, Ji-fang Gong, Lin Shen Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, 1 Department of Medical Oncology, Peking University, First Hospital, 2 Department of Medical Oncology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China For correspondence: Prof. Lin Shen, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing 100 142, China. E-mail: lin100@ medmail.com.cn Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.122512 PMID: *** Quick Response Code:
Recently, the results of four randomized controlled trials (RCTs), published in full articles [10,11] or abstracts,[12,13] showed OS benefit from treatment
Journal of Cancer Research and Therapeutics - Supplement 3 - 2013 - Volume 9
S151
Zhang, et al.: Paclitaxel and capecitabine combination therapy
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.[14] Based on our previously reported retrospective study in which paclitaxel combined with capecitabine (PX) was offered as second- or third-line therapy in MGA,[15] 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 Patient eligibility Patients 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. Treatment plan Baseline evaluation included medical history, physical examination, concomitant medication, and laboratory assessments (hematology and clinical chemistry). For females S152
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/m2 on days 1 and 8, capecitabine (Xeloda; Roche) 1000 mg/m2 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
A phase II study of triweekly paclitaxel and capecitabine combination therapy in patients with fluoropyrimidineplatinum-resistant metastatic gastric adenocarcinoma ABSTRACT 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/m2, days 1 and 8) and capecitabine (1000 mg/m2, 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. KEY WORDS: Capecitabine, fluoropyrimidine-platinum resistant, metastatic gastric adenocarcinoma, paclitaxel, second-line chemotherapy
INTRODUCTION Gastric cancer is the fourth most frequent malignant disease and the second most common cause of cancer-related deaths in the world.[1] It is also the second most frequent malignancy in China.[2] As resection is curative in only about 30% of patients,[3] 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).[4-6] 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.[4-6] 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[4] and 75% in SPIRITS study.[7] 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.[8] 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).[9]
Xiao-tian Zhang, Jian Li, Yu Bai1, Yu-ping Chu2, Jie Li, Yan Li, Ji-fang Gong, Lin Shen Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, 1 Department of Medical Oncology, Peking University, First Hospital, 2 Department of Medical Oncology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China For correspondence: Prof. Lin Shen, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing 100 142, China. E-mail: lin100@ medmail.com.cn Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.122512 PMID: *** Quick Response Code:
Recently, the results of four randomized controlled trials (RCTs), published in full articles [10,11] or abstracts,[12,13] showed OS benefit from treatment
Journal of Cancer Research and Therapeutics - Supplement 3 - 2013 - Volume 9
S151
Zhang, et al.: Paclitaxel and capecitabine combination therapy
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.[14] Based on our previously reported retrospective study in which paclitaxel combined with capecitabine (PX) was offered as second- or third-line therapy in MGA,[15] 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 Patient eligibility Patients 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. Treatment plan Baseline evaluation included medical history, physical examination, concomitant medication, and laboratory assessments (hematology and clinical chemistry). For females S152
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/m2 on days 1 and 8, capecitabine (Xeloda; Roche) 1000 mg/m2 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
