Combination chemotherapy with S-1 plus CPT-11 for patients with advanced or recurrent colorectal cancer

Various kinds of combination chemotherapies with 5-FU as a base agent have been performed for patients with advanced or recurrent colorectal cancer. S-1 was a newly developed 5-FU derivative and was orally administered. One of the combination therapies with S-1 plus irinotecan (CPT-11) has also been expected to have a better therapeutic value. Recently this combination therapy has been undertaken by our department, and its clinical use and toxicities are described in this article.     

First-line chemotherapy with irinotecan plus capecitabine for advanced colorectal cancer

OBJECTIVE: The aim of this study was to evaluate efficacy and safety of the combination chemotherapy with irinotecan plus capecitabine in patients with advanced colorectal adenocarcinoma. METHODS: Patients with histologically proven advanced colorectal adenocarcinoma received a first-line chemotherapy with irinotecan 240 mg/m2 on day 1 and capecitabine 2,000 mg/m2/day as an intermittent regimen of 2 weeks of treatment followed by a 1-week rest. Treatment was repeated every 3 weeks. RESULTS: Thirty-nine patients were registered, and 36 were assessable for responses. Sixteen objective responses (44%) were observed with a median response duration of 6.9 months. Stable disease was documented in 14 cases (39%). The median time to progression was 6.7 months. The median overall survival was not reached at the time of analysis, and the 1-year survival rate was 67%. Two patients died: 1 due to sepsis not complicating myelosuppression, and 1 patient, known as a hepatitis B virus carrier prior to chemotherapy, died of hepatic failure, the cause of which was not clinically verified. Frequently encountered therapy-related events were leukopenia and gastrointestinal side effects including diarrhea. Severe hand-and-foot syndrome was observed in only 1 patient. CONCLUSIONS: The combination chemotherapy of irinotecan and capecitabine is an active and tolerable regimen for advanced colorectal adenocarcinoma, but the observed deaths suggest a future randomized trial that requires a cautious patient selection.     

Combination chemotherapy for advanced colorectal cancer. A pilot study

Twenty-three patients with advanced colorectal carcinoma, mostly with liver and lung metastases and measurable disease, were treated with mitomycin-C 20 mg/m2 I.V. and vincristine 1.2 mg/m2 I.V. every 6 weeks, and cisplatinum 50 mg/m2 I.V. and 5-fluorouracil 1,000 mg/m2/24 hours I.V. continuous infusion for 96 hours every 3 weeks based upon the hypothesis that cisplatinum may potentiate the antitumor activity of antimetabolites and alkylating agents. Five patients had received prior chemotherapy and six had received prior radiotherapy, with one of these patients receiving both. One complete and 10 partial responses were observed, with an overall response rate of 48% (90% confidence interval 30-70%). The toxicity was manageable. A possible potentiating effect of cisplatinum is suggested in this first attempt in the treatment of colorectal cancer, and warrants further exploration.     

Phase II study of combined chemotherapy with irinotecan and S-1 (IRIS) plus bevacizumab in patients with inoperable recurrent or advanced colorectal cancer

Abstract Background. In Japan, a study comparing the effectiveness and safety of irinotecan plus S-1 (IRIS) with those of a combination of 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) as second-line treatment in patients with advanced or recurrent colorectal cancer demonstrated that IRIS was non-inferior to FOLFIRI. We previously reported that IRIS is also effective as first-line treatment. Patients and methods. Eligibility criteria included inoperable recurrent colorectal cancer with a confirmed diagnosis of adenocarcinoma, age ≥20 years, and no history of prior chemotherapy. S-1 (40-60 mg twice daily) was given orally on Days 1 to 14, and irinotecan (100 mg/m(2)) and bevacizumab (5 mg/kg) were given intravenously on Days 1 and 15 of a 28-day cycle. The primary endpoint was safety. The secondary endpoints included overall response (OR), progression-free survival (PFS), and overall survival (OS). Results. A total of 52 eligible patients were enrolled from October 2007 through March 2009. In safety analysis, the incidences of grade 3 or 4 adverse reactions were as follows: neutropenia, 27%; hypertension, 21%; and diarrhea, 17%. The overall response rate was 57.7%. Median progression-free survival was 16.7 months. Conclusion. IRIS plus bevacizumab is a well-tolerated, highly effective chemotherapeutic regimen that is easy to administer.     

健择联合卡铂治疗晚期肺癌

目的研究健择联合卡铂治疗晚期肺癌的疗效及毒性反应.方法经病理组织学或细胞学证实的58例的晚期肺癌患者给予健择1000 mg/m2静脉滴注,第1、8天;卡铂第1天以AUC=5计算所得的剂量,静脉滴注,21天为1周期.结果可评价疗效58例,CR 1例,PR29例,SD 21例,PD 7例,RR为51.7%.毒副作用主要为白细胞及血小板减少,但均可耐受,胃肠道反应及肾毒性轻.结论健择联合卡铂治疗晚期肺癌疗效确切,毒副作用可以耐受.     

Phase I study of combination chemotherapy using irinotecan hydrochloride and nedaplatin for advanced or recurrent cervical cancer

OBJECTIVE: We performed a phase I clinical study to evaluate combination chemotherapy with irinotecan hydrochloride (CPT-11) and nedaplatin (CPT-11/nedaplatin) for cervical cancer. METHODS: This study included patients with primary or recurrent cervical cancer. The regimen for CPT-11/nedaplatin therapy consisted of CPT-11 administered 3 times over 2 weeks (days 1, 8 and 15) and nedaplatin infused intravenously as a single dose (day 1). This course was repeated at 4-week intervals. The step 1 doses of the two agents were 50 mg/m(2), respectively. Dose escalation was performed in tandem. Plasma CPT-11, SN-38, total platinum, and filterable platinum levels were measured. RESULTS: In step 3 (CPT-11, 60 mg/m(2); nedaplatin, 60 mg/m(2)), dose-limiting toxicity was observed in 2 of 3 patients. The step 3 doses were regarded as the maximum tolerated doses. The incidences of grade 3/4 adverse events in the first courses (n = 12) [and all courses (n = 45)] were: leukopenia 33% (22%), neutropenia 42% (31%), anemia 17% (20%), nausea 8% (7%), and diarrhea 8% (7%). Following CPT-11 administration, the mean areas under the curve (AUC; ng.h/ml) of SN-38 were 0.11 at 50 mg/m(2) and 0.17 at 60 mg/m(2). Following nedaplatin administration, the mean AUCs (microg x h/ml) of filterable platinum were 6.0 at 50 mg/m(2), and 6.0 at 60 mg/m(2). The response rate was 50% (2 complete responses and 2 partial responses). CONCLUSION: The recommended doses of CPT-11 and nedaplatin for a phase II clinical study were established as 50 and 60 mg/m(2), respectively.     

Preliminary study of fortnightly irinotecan hydrochloride plus cisplatin therapy in patients with advanced gastric and colorectal cancer

PURPOSE: Irinotecan hydrochloride shows a strong activity against gastric cancer and colorectal cancer, while combined therapy with irinotecan and cisplatin is useful for gastric cancer. However, myelosuppression and diarrhea are still dose-limiting factors. To reduce such toxicities to enable therapy to be performed on an outpatient basis, we tested the effect of divided administration of cisplatin. METHODS: Irinotecan (60 mg/m2) plus cisplatin (30 mg/m2) were administered on days 1 and 15 every 4 weeks to 13 patients with advanced gastric cancer and 13 with advanced colorectal cancer. Treatment was continued if a leukocyte count > or = 3000/mm3, a platelet count > or = 100,000/mm3, and grade 0 diarrhea were confirmed. Doses were reduced if grade 3-4 hematological toxicity and grade 2 or higher nonhematological toxicity occurred. RESULTS: The major toxicity was leukopenia (neutropenia), but grade 3-4 nonhematological toxicity was not observed. The response rate was 41.7% for gastric cancer (5/12 evaluable patients) and 36.7% for colorectal cancer (4/11 evaluable patients). The median survival time was 313 days (range 29-920 days) for gastric cancer patients and 490 days (range 83-1184 + days) for colorectal cancer patients. CONCLUSION: Fortnightly administration of irinotecan and cisplatin (with a divided cisplatin dose) seems to be a useful regimen for gastrointestinal cancer. It reduces toxicity while maintaining a good antitumor effect.     

Phase II study of irinotecan as first-line chemotherapy for patients with advanced colorectal carcinoma

BACKGROUND: The objective of this multicenter, open-labeled, Phase II study performed in Spain was to assess the efficacy and safety of irinotecan (CPT-11) as first-line chemotherapy for patients suffering from advanced colorectal carcinoma (CRC). METHODS: Patients with histologically proven CRC and at least one bidimensionally measurable lesion, ages 18-70 years, with a performance status < or = 2, normal analytical values, and no prior chemotherapy or only adjuvant chemotherapy completed before study entry were selected. The treatment schedule was CPT-11 350 mg/m(2) intravenously administered once every 3 weeks. Both tumor response and toxicity were assessed using the World Health Organization and National Cancer Institute common toxicity criteria. Changes in performance status, weight, and symptoms also were measured. RESULTS: Sixty-five patients (44 chemotherapy-na?ve patients and 21 patients who completed prior adjuvant treatment) were enrolled. Of these, 24.7% of patients responded to the treatment, and 41.5% of patients had stable disease. Patients who had not received prior adjuvant chemotherapy had a lower rate of progression on therapy (27.3%) compared with those who had received prior adjuvant chemotherapy (42.9%). The median survival was 19.9 months (range, 0.3-29.3 months). No significant differences were found in the median survival between chemotherapy-na?ve patients and patients who had received previous chemotherapy. Grade 3-4 diarrhea and neutropenia were the most frequent severe toxic events, which were observed in 23.1% and 30.8% of patients and in 5.9% and 10.9% of the cycles, respectively. CONCLUSIONS: The current antitumor efficacy results show that 350 mg/m(2) of CPT-11 administered every 3 weeks is an active and feasible first-line chemotherapy regimen for patients with CRC. Finally, the overall safety data confirmed that CPT-11 is a well tolerated treatment.     

Retrospective study of irinotecan plus fluorouracil and l-leucovorin chemotherapy for advanced and metastatic colorectal cancer

Ten cases of advanced and metastatic colorectal cancer treated with irinotecan plus fluorouracil and l-leucovorin systemic chemotherapy (CPT-11/5-FU/l-LV) were investigated. The 10 patients consisted of 7 males and 3 females with a mean age of 64.3 years. We diagnosed adenocarcinoma of the colon in 2 patients and of the rectum in 8 patients. Five patients had liver and lung metastases, 1 had lymph node metastases, 1 had bone marrow metastases and 3 had recurrence in a pelvic lesion. All patients underwent 3-week chemotherapy regimen (CPT-11 50 mg/m2/week + 5-FU 400 mg/m2/week + l-LV 20 mg/m2/week). Five patients received this regimen as a first-line chemotherapy and the other patients as a second-line chemotherapy after 5-FU/l-LV chemotherapy. The effect was CR or PR in all patients receiving the regimen as a first-line chemotherapy. The progression free survival time was 6.8 months and mean survival time was 10.0 months in the first-line patients. Otherwise, all second-line patients had PD. The suppression of white blood cells (grade 1 or 2) was seen in 4 patients. All patients were able to receive the systemic chemotherapy in the outpatient setting. CPT-11/5-FU/l-LV chemotherapy appears to be an effective first-line chemotherapy for advanced and metastatic colorectal cancer.     

Combination chemotherapy with irinotecan and cisplatin in pretreated patients with unresectable or recurrent gastric cancer

Background The combination of irinotecan (CPT-11) and cisplatin (CDDP) is an active regimen for metastatic gastric cancer in the first-line setting. The objective of this retrospective study was to clarify its efficacy and safety in patients with prior chemotherapy for advanced or recurrent gastric cancer. Methods Patients in the study fulfilled the following selection criteria: (1) histologically proven gastric cancer with metastatic lesions; (2) performance status of 2 or less; (3) age of 75 years or younger; (4) at least one prior chemotherapy regimen without CPT-11 or CDDP; (5) adequate bone marrow, liver, and kidney function; (6) normal cardiac function; (7) no other severe medical conditions; (8) no other active malignancy; and (9) the provision of written informed consent. The treatment consisted of CPT-11 (70 mg/m²) on day 1 and day 15 and CDDP (80 mg/m²) on day 1; repeated every 4 weeks. Results Thirty-two patients were recruited, and 28 were assessable for clinical response. There were eight partial responses, resulting in a response rate of 28%. Median time to progression was 104 days (range, 24–863 days) and median overall survival time was 283 days from the initiation of this therapy. The incidences of grade 4 neutropenia, grade 3 or higher infection, and diarrhea were 69%, 9%, and 3%, respectively. Other adverse reactions were mild. No treatment-related deaths occurred. Conclusion A combination of CPT-11 and CDDP may be active and feasible for gastric cancer patients with prior chemotherapy. Further studies with larger numbers of patients are needed to clarify this regimen's significance in the second-line setting.     

A retrospective study of irinotecan plus fluorouracil and l-leucovorin chemotherapy for advanced and metastatic colorectal cancer

We have treated 14 advanced and metastatic colorectal cancers with irinotecan (CPT-11) plus fluorouracil (5-FU) and l-leucovorin (l-LV) combination chemotherapy. The 14 patients consisted of 8 males and 6 females with a mean age of 65 years. We diagnosed adenocarcinoma of the colon in 10 patients and of the rectum in 4 patients. Four patients had liver metastases, five had lung metastases, and one had both, while one had lung and lymph node metastases, two had lymph node metastases and one had a local recurrence. The chemotherapy consisted of CPT-11 100 mg/m(2) div, as a 150-minute infusion, simultaneously l-LV 10 mg/m(2) div, as a 30-minute infusion, followed by 5-FU 500 mg/m(2) iv, as a bolus injection. This treatment was administered weekly for 2 weeks followed by a 2-week rest period and repeated every 4 weeks. All patients received this regimen as first-line chemotherapy. All patients were evaluated for efficacy 1 CR, 2 PR, 9 SD, and 2 PD. The overall response rate was 21.4% with a median time to progression of 8.1 months and a median survival time of 18.6 months. Grade 3 nausea, diarrhea and the suppression of white blood cells were seen in 3 patients, respectively. All other adverse reactions were mild (grade 1 or 2). Except for one patient,residual patients were able to receive the systemic chemotherapy on schedule. CPT-11/5-FU/l-LV combination chemotherapy appears to be effective first-line chemotherapy for advanced and metastatic colorectal cancer.     

Retrospective study on utility of irinotecan hydrochloride in patients with advanced and recurrent breast cancer

Irinotecan hydrochloride has been administered to patients with breast cancer resistant to anthracyclines and/or taxanes in our department. A retrospective analysis of the efficacy and toxicity of irinotecan therapy was conducted to clarify its clinical usefulness. A total of 35 consecutive patients with advanced or recurrent breast cancer were treated with irinotecan between June 1996 and March 2002. The patients ranged in age from 37 to 66 years old (median, 52). The most frequent metastatic lesion was in the liver. The number of previous chemotherapy was 2 to 7 regimens (median, 3). Ninety-one percent and 97% of the tumors were anthracycline- and taxane-resistant, respectively. The weekly dose of irinotecan was 40-160 mg/body (median, 100), and the total dose was 40-6, 110 mg/body (median, 840). An objective response rate of 6% and a clinical benefit rate of 23% were obtained. The median time-to-progression and overall survival were 3 months and 8 months, respectively. Severe toxicity (grade 3 or 4) was observed in 34% of the patients for a decrease in the white blood count, in 26% for neutropenia, in 17% for nausea/vomiting and in 6% for diarrhea. Although this study suggests that irinotecan is a clinically useful treatment of anthracycline- and/or taxane-resistant breast cancer, its anti-tumor effect was not satisfactory. The activity of first-line irinotecan therapy or the combined use of irinotecan with other agents should be investigated in clinical studies.     

Combination chemotherapy using cyclophosphamide, adriamycin, and cisplatin in recurrent or advanced endometrial cancer--a preliminary report

Four patients with recurrent or advanced endometrial cancer have undergone combination chemotherapy with Cyclophosphamide, Adriamycin and Cisplatin (CAP). All drugs were administered by I.V. on day 1 in the following doses: Cyclophosphamide 500 mg/m2, Adriamycin 50 mg/m2 and Cisplatin 50 mg/m2. The treatment was repeated every 4 weeks and continued as long as there was disease progression. Two complete clinical responses and two partial responses were achieved. Based on these good results, we have initiated post-operative prophylactic chemotherapy using CAP in high risk patients. Adverse effects including myelo-suppression, nausea, and vomiting, and alopecia were seen in almost all patients. In no case, however, did any patient experience life-threatening toxicity. Based on our experience, CAP therapy appears tolerable when used per our schedule.     

Weekly paclitaxel infusion in patients with recurrent ovarian cancer--a pilot study

This preliminary study was performed to evaluate the safety and efficacy of weekly paclitaxel administration by 1-hour infusion. A total of 7 patients with recurrent ovarian cancer were treated with weekly paclitaxel (TXL). TXL was given at a dose of 70 mg/m2 in 1-hour infusions every week for at least 20 consecutive weeks unless lesions became progressive. Premedication was administered 30 min before TXL infusion. The 7 patients received a total 110 cycles of therapy. Hypersensitivity reactions were not observed. Grade 3 or 4 neutropenia occurred in only 0.9% of the cycles. Neurotoxicity was commonly observed, but that of grade 3 or greater severity was not recorded. No other severe non-hematologic toxicities were observed. Partial responses were seen in three of 7 patients. Weekly 1-hour TXL is considered to be safe and effective as a salvage therapy in patients with recurrent ovarian cancer.     

Fucoidan reduces the toxicities of chemotherapy for patients with unresectable advanced or recurrent colorectal cancer

Combination chemotherapy with oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX) or irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) has become a standard regimen for advanced or recurrent colorectal cancer. Numerous studies have reported that long-term use of FOLFOX or FOLFIRI leads to better survival for these patients. Thus, control of the toxicity of these drugs may be crucial to prolonging survival. Fucoidan is one of the major sulfated polysaccharides of brown seaweeds and exhibits a wide range of biological activities. In the present study, we analyzed the effect of fucoidan on suppressing the toxicity of anti-cancer drugs. A total of 20 patients with unresectable advanced or recurrent colorectal cancer scheduled to undergo treatment with FOLFOX or FOLFIRI were randomly allocated into a fucoidan treatment group (n=10) and a control group without fucoidan treatment (n=10). Results showed that fucoidan regulated the occurrence of fatigue during chemotherapy. Chemotherapy with fucoidan was continued for a longer period than chemotherapy without fucoidan. Additionally, the survival of patients with fucoidan treatment was longer than that of patients without fucoidan, although the difference was not significant. Thus, fucoidan may enable the continuous administration of chemotherapeutic drugs for patients with unresectable advanced or recurrent colorectal cancer, and as a result, the prognosis of such patients is prolonged.     

A phase II study of irinotecan plus cisplatin for patients with advanced stage IIIB or IV NSCLC previously treated with nonplatinum-based chemotherapy

BACKGROUND: Irinotecan (1) and cisplatin (P) are active chemotherapy agents with clinical synergy in non-small-cell lung cancer (NSCLC). We evaluated the efficacy of IP regimen as a salvage treatment of patients with NSCLC that progressed after nonplatinum-containing regimen(s). METHODS: Eligibility required histologically confirmed NSCLC, bidimensionally measurable disease, ECOG PS 0-2, and progressive disease after nonplatinum-based chemotherapy. Treatment consisted of I (65 mg/m2) and P (30 mg/m2) i.v. on Days 1 and 8 of a 21-day cycle, for a maximum of 6 cycles. An informed consent was obtained from all patients. RESULTS: Between August 2002 and May 2004, 32 patients with median age of 56 years (range, 42-74) were enrolled. Twenty-four (75%) patients were men, and 28 (88%) had ECOG PS 0 or 1. Twenty-five patients had adenocarcinoma and 6 had squamous-cell carcinoma. All patients were evaluated for response and toxicity, and the response rate was 40.6%. After a median follow-up of 18.5 months, the median survival time was found to be 9.3 months, with a 1-year survival rate of 43.8%. Toxicities were moderate and manageable, with 47% G3 and 9% G4 neutropenia, 19% G3 diarrhea, and 22% G3 asthenia. There was no G4 nonhematologic toxicity. CONCLUSIONS: The irinotecan and cisplatin combination is an active and well-tolerated regimen for the patients with advanced NSCLC that progressed after nonplatinum-containing regimen(s).     

Combination chemotherapy with carboplatin and bleomycin for advanced and recurrent head and neck cancer: a phase II study

Carboplatin is a platinum analogue with activity reported in head and neck cancer. We conducted a phase II trial with 14 patients who had recurrent head and neck cancer. They were treated with carboplatin 300 mg/m2 intravenously (I.V.) and bleomycin 30 units I.V. every 4 weeks. No responses were observed in this group of patients. Dose intensity of carboplatin administration may be an important determinant of response.     

Phase II study of weekly carboplatin and irinotecan as first-line chemotherapy for patients with advanced non-small cell lung cancer

Purpose

Platinum-based doublet chemotherapy has a major role in the treatment of patients with advanced non-small cell lung cancer (NSCLC). The weekly fractionated administration of cisplatin for patients with NSCLC has been shown to be active. Irinotecan and carboplatin are effective against NSCLC and demonstrated synergism with non-cross-resistance in preclinical studies. We conducted a phase II study of weekly combination of carboplatin and irinotecan as first-line chemotherapy for patients with advanced NSCLC.

Methods

From March 2009 to November 2011, 24 patients who were diagnosed with inoperable or metastatic NSCLC were enrolled. Treatment consisted of carboplatin at an AUC 2.5 mg/mL/min over 30-min intravenous infusion and irinotecan 65 mg/m² over 90-min intravenous infusion on day 1 and day 8, respectively. The treatment was repeated every 3 weeks.

Results

One patient (4.2 %) achieved complete response, and seven (29.2 %) showed partial response. Overall response rate was 33.3 %, with median response duration of 4.55 months. Nine patients had stable disease, and disease control rate was 70.8 %. With median follow-up of 12.8 months, median progression-free survival was 4.5 months (95 % CI 1.8–7.2), and median overall survival was 15.5 months (95 % CI 6.9–24.1). Major toxicity was myelosuppression. Grade 3–4 neutropenia and thrombocytopenia occurred in 50 and 20.8 % of patients, respectively. Two patients experienced febrile neutropenia. Non-hematologic toxicities were generally mild. One patient suffered grade 4 diarrhea, and one treatment-related death due to pneumonia was occurred.

Conclusion

The weekly combination of carboplatin and irinotecan showed favorable activity and manageable toxicity profiles in chemo-naïve patients with advanced NSCLC. Our results suggest that this regimen can be a reasonable chemotherapeutic option for patients with advanced NSCLC.     

A phase II study of irinotecan and docetaxel combination chemotherapy for patients with previously treated metastatic or recurrent advanced gastric cancer

Purpose  Irinotecan (I) and docetaxel (D), each of which has a unique mechanism of action, were recently introduced in the treatment of patients with advanced gastric cancer (AGC). We have evaluated the efficacy and safety of the ID combination for AGC patients after failure of fluoropyrimidine- or platinum-based chemotherapy. Materials and methods  Patients with relapsed or progressive AGC after prior fluoropyrimidine- or platinum-based chemotherapy were treated with I (160 mg/m², 90 min) followed by D (65 mg/m², 1 h) every 3 weeks. Because of the unacceptable toxicity among the first ten patients, the doses were reduced for I (120 mg/m²) and D (50 mg/m²) every 3 weeks. Results  Forty-nine patients, of median age 53 years (range, 27–68 years), were treated with 170 cycles of chemotherapy (median, 2 cycles; range, 1–12 cycles). Three patients achieved complete response and seven achieved partial response, resulting in an overall response rate (ORR) of 20.4% [95% confidence interval (CI), 9.1–31.7%], with a median duration of 7.1 months (range: 2.1–69.1 months). ORR was 60% (95% CI, 29.6–90.3%) for the higher dose and 10.3% (95% CI, 0.7–19.8%) for the lower dose. Median time to progression for all patients was 2.7 months (95% CI, 1.7–3.8 months) and the median overall survival was 8.9 months (95% CI, 6.6–11.3 months). Grade 3/4 toxicities included neutropenia (90%), febrile neutropenia (50%), asthenia (40%), and diarrhea (10%) with the higher dose and neutropenia (71%), febrile neutropenia (11%), diarrhea (24%), and asthenia (24%) with the lower dose. There were two possible treatment-related deaths. Conclusion  The combination of irinotecan and docetaxel, once every three weeks shows anti-tumor activity but is not feasible as a second-line treatment for AGC patients after failure of fluoropyrimidine- or platinum-based chemotherapy due to the high rate of toxicities. S. J. Sym and H. M. Chang have contributed equally to this article.