Int J Clin Exp Med 2015;8(10):18620-18628 www.ijcem.com /ISSN:1940-5901/IJCEM0014195
Original Article Efficacy of paclitaxel-based doublet regimens combining with intraperitoneal chemotherapy for advanced gastric cancer with peritoneal metastasis Yu Chen1,2*, Wei-Feng Tang4*, Jing Lin1, Yi Shi2,5, Xiao-Jie Wang1, Qiang Chen3,6, Zeng-Qing Guo1,2,3 Department of Medical Oncology, Fujian Provincial Cancer Hospital, Fujian Medical University Teaching Hospital, Fuzhou, Fujian Province, People’s Republic of China; 2Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian Province, People’s Republic of China; 3Fujian Provincial Key Laboratory of Tumor Biotherapy, Fuzhou, Fujian Province, People’s Republic of China; 4Department of Cardiothoracic Surgery, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, People’s Republic of China; 5Department of Molecular Pathology, Fujian Provincial Cancer Hospital, Fujian Medical University Teaching Hospital, Fuzhou, Fujian Province, People’s Republic of China; 6The Union Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China. *Equal contributors. 1
Received August 9, 2015; Accepted October 5, 2015; Epub October 15, 2015; Published October 30, 2015 Abstract: We aim to evaluate the efficacy and safety of paclitaxel-based doublet intravenous chemotherapy (IVC) with and without intraperitoneal chemotherapy (IPC) as the first-line treatment in advanced gastric cancer (AGC) with peritoneal metastasis (PM). 173 AGC patients with peritoneal metastasis were enrolled. All patients received paclitaxel-based doublet systemic chemotherapy Among them, 117 patients received IVC+IPC and 56 patients received IVC alone. The median OS of patients in the IP+ group was longer than the IP- group, however, there was no statistical difference between the two groups (11.1 months vs. 10.1 months, P = 0.072). In the multivariate analysis, the ECOG PS and IVC±IPC were independent prognostic factors for PFS and OS. There were no significant differences in the incidence of grade 3 and 4 toxicity between the IP+(DDP), IP+(FUDR) and IP- groups. Paclitaxel-based doublet regimens combining with IPC is effective, feasible and tolerated in AGC patients with PM. Keywords: Advanced gastric cancer, peritoneal metastasis, intraperitoneal chemotherapy, intravenous chemotherapy, paclitaxel
Introduction Gastric cancer is the fourth most common malignant disease worldwide and the second most common cause of death from cancer [1, 2]. About 1 million new cases of gastric cancer were diagnosed in 2008, 74% of which were in Asia (47% in China) [3]. The peritoneal cavity is also a frequent site for metastatic disease after resection, particularly in patients with serosa-infiltrating tumours [4]. Peritoneal metastasis (PM) is the most frequent and most life-threatening modality of disease progression in patients with gastric cancer. Patients with gastric cancer and peritoneal carcinomatosis, have a poor prognosis, with a median survival without treatment of 3.1 months [5].
For many years 5-fluorouracil (5-FU)-based or cisplatin-based regimens were the most common treatments for advanced gastric cancer (AGC) used worldwide [6-8]. In some recently reported clinical trials, the third generation platinum compound, oxaliplatin, proved to be equal to, if not better than, cisplatin with regard to efficacy. Moreover, oxaliplatin was associated with slightly reduced toxicity and better tolerability compared to cisplatin [9-11]. To develop a more active and efficacious chemotherapy regimen, docetaxel, another cytotoxic agent against AGC, has been added to a doublet combination with 5-FU plus cisplatin. The global V325 phase 3 study showed the superiority of docetaxel plus cisplatin and fluorouracil (DCF regimen) over CF in terms of objective response rate, time to progression, and overall survival. However, the high toxicity profile, in particular
Therapy for advanced gastric cancer with peritoneal metastasis Table 1. Patient characteristics Characteristics
IP+ group IP- group N = 117 N = 56 Sex Male 76 36 Female 41 20 Age (years) 3 months, 10) All patients non-randomly received one of the systemic chemotherapy regimens, including PF, PO, for at least four cycles, and patients received intraperitoneal perfusion chemotherapy, including cisplatin (CDDP) or 5-fluoro-2’-deoxyuridine5’-phosphate (FUDR), were given at least four cycles. Treatment The PF regimen consisted of a 3-hour infusion of paclitaxel (135 mg/m2) followed by leucovorin (400 mg/m2), administered simultaneously over a 2-hour infusion period. Subsequently, a 46-hour infusion of 5-florouracil (2400 mg/m2) was administered using an ambulatory pump. The PO regimen consisted of a 3-hour infusion of paclitaxel (135 mg/m2) followed oxaliplatin (85 mg/m2). A total dose of 1,000 mg FUDR or 60 mg CDDP in 1.5 liters of normal saline was introduced into the peritoneal cavity with a catheter placed at the lower right or lower left abdominal wall. The catheter and drains were clamped for 24 h and no effort was made to drain the intraperitoneal solution unless it was necessary for patient comfort and the next IP infusion [20]. The treatment course was repeated every two weeks until observation of unacceptable toxicity, disease progression, or patient choice. All patients received a standard supportive regi-
Int J Clin Exp Med 2015;8(10):18620-18628
Therapy for advanced gastric cancer with peritoneal metastasis
Figure 1. A. Kaplan-Meier curves for progression-free survival (PFS) and overall survival (OS) in 173 patients. B. PFS and OS in the patients who received intravenous chemotherapy with and without intraperitoneal chemotherapy.
men including oral corticosteroids, antihistamines, and antiemetics. With the eventual failure of this combination chemotherapy, secondline chemotherapy was recommended to all patients if their performance status was preserved. Evaluation of toxicity and efficacy A complete blood cell count and measurements of liver and renal function were assessed at least once a week during the treatment. Nonhematological toxicities were also verified at least once a week by patient interview and 18622
physical examination. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 3.0 [21]. During the treatment, patients were evaluated with abdominal computed tomography (CT) scans and assessed for an objective response in measurable lesions every 1-2 months according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria [22]. Progression-Free-Survival (PFS) was measured from the day of initial treatment to the first evidence of progression or death. Overall Survival (OS) was defined from the date of initial treatment to death from any cause. Int J Clin Exp Med 2015;8(10):18620-18628
Therapy for advanced gastric cancer with peritoneal metastasis Table 2. Univariate analysis of factors associated with survival of 173 advanced gastric cancer patients with peritoneal metastasis Variable Sex Age (years) Histological grade ECOG PS Regimens of IVC IVC±IPC Regimens of IPC
Male Female
Original Article Efficacy of paclitaxel-based doublet regimens combining with intraperitoneal chemotherapy for advanced gastric cancer with peritoneal metastasis Yu Chen1,2*, Wei-Feng Tang4*, Jing Lin1, Yi Shi2,5, Xiao-Jie Wang1, Qiang Chen3,6, Zeng-Qing Guo1,2,3 Department of Medical Oncology, Fujian Provincial Cancer Hospital, Fujian Medical University Teaching Hospital, Fuzhou, Fujian Province, People’s Republic of China; 2Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian Province, People’s Republic of China; 3Fujian Provincial Key Laboratory of Tumor Biotherapy, Fuzhou, Fujian Province, People’s Republic of China; 4Department of Cardiothoracic Surgery, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, People’s Republic of China; 5Department of Molecular Pathology, Fujian Provincial Cancer Hospital, Fujian Medical University Teaching Hospital, Fuzhou, Fujian Province, People’s Republic of China; 6The Union Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China. *Equal contributors. 1
Received August 9, 2015; Accepted October 5, 2015; Epub October 15, 2015; Published October 30, 2015 Abstract: We aim to evaluate the efficacy and safety of paclitaxel-based doublet intravenous chemotherapy (IVC) with and without intraperitoneal chemotherapy (IPC) as the first-line treatment in advanced gastric cancer (AGC) with peritoneal metastasis (PM). 173 AGC patients with peritoneal metastasis were enrolled. All patients received paclitaxel-based doublet systemic chemotherapy Among them, 117 patients received IVC+IPC and 56 patients received IVC alone. The median OS of patients in the IP+ group was longer than the IP- group, however, there was no statistical difference between the two groups (11.1 months vs. 10.1 months, P = 0.072). In the multivariate analysis, the ECOG PS and IVC±IPC were independent prognostic factors for PFS and OS. There were no significant differences in the incidence of grade 3 and 4 toxicity between the IP+(DDP), IP+(FUDR) and IP- groups. Paclitaxel-based doublet regimens combining with IPC is effective, feasible and tolerated in AGC patients with PM. Keywords: Advanced gastric cancer, peritoneal metastasis, intraperitoneal chemotherapy, intravenous chemotherapy, paclitaxel
Introduction Gastric cancer is the fourth most common malignant disease worldwide and the second most common cause of death from cancer [1, 2]. About 1 million new cases of gastric cancer were diagnosed in 2008, 74% of which were in Asia (47% in China) [3]. The peritoneal cavity is also a frequent site for metastatic disease after resection, particularly in patients with serosa-infiltrating tumours [4]. Peritoneal metastasis (PM) is the most frequent and most life-threatening modality of disease progression in patients with gastric cancer. Patients with gastric cancer and peritoneal carcinomatosis, have a poor prognosis, with a median survival without treatment of 3.1 months [5].
For many years 5-fluorouracil (5-FU)-based or cisplatin-based regimens were the most common treatments for advanced gastric cancer (AGC) used worldwide [6-8]. In some recently reported clinical trials, the third generation platinum compound, oxaliplatin, proved to be equal to, if not better than, cisplatin with regard to efficacy. Moreover, oxaliplatin was associated with slightly reduced toxicity and better tolerability compared to cisplatin [9-11]. To develop a more active and efficacious chemotherapy regimen, docetaxel, another cytotoxic agent against AGC, has been added to a doublet combination with 5-FU plus cisplatin. The global V325 phase 3 study showed the superiority of docetaxel plus cisplatin and fluorouracil (DCF regimen) over CF in terms of objective response rate, time to progression, and overall survival. However, the high toxicity profile, in particular
Therapy for advanced gastric cancer with peritoneal metastasis Table 1. Patient characteristics Characteristics
IP+ group IP- group N = 117 N = 56 Sex Male 76 36 Female 41 20 Age (years) 3 months, 10) All patients non-randomly received one of the systemic chemotherapy regimens, including PF, PO, for at least four cycles, and patients received intraperitoneal perfusion chemotherapy, including cisplatin (CDDP) or 5-fluoro-2’-deoxyuridine5’-phosphate (FUDR), were given at least four cycles. Treatment The PF regimen consisted of a 3-hour infusion of paclitaxel (135 mg/m2) followed by leucovorin (400 mg/m2), administered simultaneously over a 2-hour infusion period. Subsequently, a 46-hour infusion of 5-florouracil (2400 mg/m2) was administered using an ambulatory pump. The PO regimen consisted of a 3-hour infusion of paclitaxel (135 mg/m2) followed oxaliplatin (85 mg/m2). A total dose of 1,000 mg FUDR or 60 mg CDDP in 1.5 liters of normal saline was introduced into the peritoneal cavity with a catheter placed at the lower right or lower left abdominal wall. The catheter and drains were clamped for 24 h and no effort was made to drain the intraperitoneal solution unless it was necessary for patient comfort and the next IP infusion [20]. The treatment course was repeated every two weeks until observation of unacceptable toxicity, disease progression, or patient choice. All patients received a standard supportive regi-
Int J Clin Exp Med 2015;8(10):18620-18628
Therapy for advanced gastric cancer with peritoneal metastasis
Figure 1. A. Kaplan-Meier curves for progression-free survival (PFS) and overall survival (OS) in 173 patients. B. PFS and OS in the patients who received intravenous chemotherapy with and without intraperitoneal chemotherapy.
men including oral corticosteroids, antihistamines, and antiemetics. With the eventual failure of this combination chemotherapy, secondline chemotherapy was recommended to all patients if their performance status was preserved. Evaluation of toxicity and efficacy A complete blood cell count and measurements of liver and renal function were assessed at least once a week during the treatment. Nonhematological toxicities were also verified at least once a week by patient interview and 18622
physical examination. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 3.0 [21]. During the treatment, patients were evaluated with abdominal computed tomography (CT) scans and assessed for an objective response in measurable lesions every 1-2 months according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria [22]. Progression-Free-Survival (PFS) was measured from the day of initial treatment to the first evidence of progression or death. Overall Survival (OS) was defined from the date of initial treatment to death from any cause. Int J Clin Exp Med 2015;8(10):18620-18628
Therapy for advanced gastric cancer with peritoneal metastasis Table 2. Univariate analysis of factors associated with survival of 173 advanced gastric cancer patients with peritoneal metastasis Variable Sex Age (years) Histological grade ECOG PS Regimens of IVC IVC±IPC Regimens of IPC
Male Female
