A phase II study of combination chemotherapy with gemcitabine, 5-fluorouracil, and cisplatin for advanced pancreatic cancer]

BACKGROUND/AIMS: Gemcitabine has been the standard regimen for advanced pancreatic cancer, but the effect on the response rate and survival is still disappointing, leading to many trials of combination chemotherapy. 5-FU and cisplatin were combined with gemcitabine in this trial, as they are synergistic with gemcitabine and each other as well. This study was aimed to assess the effectiveness and safety of combination chemotherapy with gemcitabine, 5-FU, and cisplatin for advanced pancreatic cancer. METHODS: Patients with advanced pancreatic cancer were entered into this study. Gemcitabine at a dose of 800 mg/m2 on day 1 and 8, 5-FU 1,000 mg/m2/day from day 1 to 3 for 72 hours, and cisplatin 60 mg/m2 on day 2, 24 hours after the start of gemcitabine were administered every 3 weeks. RESULTS: From December 2001 to January 2004, twenty patients were enrolled in this study. Among 17 of these patients assessable, 3 patients had a partial remission with the response rate of 23.6% (95% confidence interval, 6.2-41.0%). The median time to disease progression was 230 days and median duration of survival was 322 days. Among total of 91 cycles, leukopenia, neutropenia, and thrombocytopenia of grade 3 or 4 occurred in 12 cycles (13.2%), 12 cycles (13.2%), and 23 cycles (24.4%), respectively. Grade 3 or 4 mucositis developed at 2 cycles (2.2%), and nausea and vomiting were encountered in 3 cycles (3.3%). CONCLUSIONS: Combination chemotherapy with gemcitabine, 5-FU, and cisplatin for advanced pancreatic cancer is active and well-tolerated, warranting a phase III study.     

A combination immunochemotherapy of 5-fluorouracil, cisplatin, leucovorin, and OK-432 for advanced and recurrent gastric carcinoma

BACKGROUND/AIMS: Based on theories of biochemical modulation and immunotherapy, a novel regimen consisting of 5-fluorouracil, cisplatin, leucovorin, and OK-432 (FLPO therapy) was devised for the treatment of patients with advanced and recurrent gastric carcinoma. METHODOLOGY: The 14-day combination therapy consisted of continuous infusion of 5-fluorouracil (250 mg/m2/day), a bolus injection of 10 mg cisplatin and 30 mg leucovorin every other day, and a subcutaneous injection or per oral administration of OK-432 (3KE or 5KE) every other day. Thirty patients completed 59 courses of treatment consisting of 2 weeks of therapy followed by at least 2 weeks rest. RESULTS: The overall response rate was 40%, with 1 complete response and 11 partial responses observed. All twelve patients responded after 1 course of treatment. The response rate differed depending upon tumor location, 22.2% at the primary site, 60.0% in the lymph nodes, 45.5% with peritoneal dissemination, 44.4% with liver metastases, 50.0% in the lung, and 100.0% with skin metastases. The most frequently observed toxicity was stomatitis (53.3%). The overall incidence of toxicities of grade 3 or greater was 6.6%, including diarrhea (3.3%) and stomatitis (3.3%). One patient required treatment interruption because of the grade 3 toxicity of diarrhea. The median survival time was 198 days overall, 242 days for responders and 125 days for non-responders. CONCLUSIONS: FLPO therapy seemed to be an effective regimen for the treatment of advanced and recurrent gastric carcinoma.     

5-氟尿嘧啶节律性化疗对晚期胃癌患者的临床疗效观察

目的观察5-氟尿嘧啶节律性化疗对晚期胃癌患者的临床疗效。方法选择我院24例晚期胃癌患者,使用5-氟尿嘧啶500 mg静脉持续泵入12 h d1-21,4周1个疗程,3～9个疗程后,对接受至少3个疗程的患者进行疗效评价。结果 24例患者随访8～24个月,3例部分缓解(12.5%),9例病情稳定(37.5%),无1例患者完全缓解,12例患者病情进展(50.0%),疾病控制率为50.0%。治疗有效患者的中位疾病进展时间(TTP)为3.2个月。结论 5-氟尿嘧啶节律性化疗可以有效控制老年晚期胃癌患者的病情进展,不良反应少且轻。     

Non-platinum-based chemotherapy for treatment of advanced gastric cancer:5-fluorouracil,taxanes,and irinotecan

Despite numerous advances in treatment options,advanced gastric cancer(AGC)remains a major public health issue and the leading cause of cancer-related deaths.Cisplatin is one of the most effective broadspectrum anticancer drugs for AGC and a doublet combination regimen of either cisplatin-based or 5-fluorouracil(5FU)-based chemotherapy is generally used for treatment of patients with AGC.However,there is still no consensus on the best regimen for treating AGC.Recently,various new chemotherapeutic agents,including oral 5FU,taxanes,and irinotecan,have been identified as improving the outcomes for AGC when used as a single agent or in combination with nonplatinum chemotherapy.Nonetheless,it is still unclear whether non-platinum-based chemotherapy is a viable treatment option for patients with AGC.Accordingly,this review focuses on the efficacy and tolerability of non-platinum-based chemotherapy for patients with AGC.     

Systemic chemotherapy using cisplatin plus 5-fluorouracil for inoperable gallbladder cancer

We report a case of advanced gallbladder cancer in a 37-year-old man who presented in June 1993 with malignant obstructive jaundice. After percutaneous transhepatic biliary drainage and several diagnostic imaging examinations, the patient underwent laparotomy under a diagnosis of extremely advanced gallbladder cancer involving the confluence of the hepatic ducts. The tumor, however, was judged to be unresectable because of its massive spread into the liver along Glisson's sheath, and because of histologically proven peritoneal dissemination. After exploratory laparotomy, one course of anticancer chemotherapy (cisplatin, 100 mg/body IV, on day 1, and 5-fluorouracil, 1000 mg/body, on days 1–5, by continuous infusion) was administered and the completely obstructed hepatic duct was dramatically re-canalized. Four courses of chemotherapy were administered over a 16-month period until jaundice recurred. For these 16 months, the patient's quality of life was well maintained without biliary drainage. He died of increased peritoneal dissemination approximately 2 years after the first course of anticancer chemotherapy.     

Treatment of advanced neuroendocrine tumours using combination chemotherapy with lomustine and 5-fluorouracil

OBJECTIVE: Combination chemotherapy with the two agents streptozotocin (SZT), which is a nitrosurea, and 5-fluorouracil (5-FU), an alkylating agent, has a long-established role in the treatment of neuroendocrine tumours; however, it is often accompanied by considerable toxicity, and it has not been assessed in a comparative manner with other current chemotherapy regimens. In order to assess the therapeutic response and adverse effects using an alternative nitrosurea, lomustine (CCNU), which has a different side-effect profile, in combination with 5-FU, we have reviewed all patients with neuroendocrine tumours who received this form of treatment in our department. DESIGN: Retrospective analysis of the case notes of patients with metastatic neuroendocrine tumours who received treatment with the combination of CCNU and 5-FU, and who were followed up according to a defined protocol in a given time frame. PATIENTS: Thirty-one patients with metastatic neuroendocrine tumours (18 with carcinoid tumours, five islet-cell tumours, five chromaffin-cell tumours and three medullary carcinoma of the thyroid) treated with the combination of CCNU and 5-FU, and when necessary additional therapy, over a 22-year period, were included in this analysis. MEASUREMENTS: The symptomatic, hormonal and tumoural responses before and after chemotherapy with the combination of CCNU and 5-FU over a median follow-up duration of 25 months (range 9-348 months) were recorded. Of the 31 patients (16 males; median age 52 years, range 20-86 years), eight (four males; median age 61 years, range 30-74 years) were treated with the combination of CCNU and 5-FU alone (Group 1), whereas the other 23 patients (12 males; median age 47 years, range 20-86 years) received additional therapy with other chemotherapeutic regimens, somatostatin analogues, alpha-interferon or radiolabelled meta-iodobenzylguanidine (131I-MIBG) therapy (Group 2). RESULTS: A total of 121 therapeutic cycles was administered (mean 3.9, range 1-14 cycles). None of the patients obtained a complete tumour response. A partial tumour response (not a complete but a 50% or greater reduction of all measurable tumour) was seen in six out of the 29 patients (21%) (four out of eight in Group 1 and two out of 21 in Group 2, respectively). There was no tumour progression in eight out of the 29 patients (27.5%) (one out of eight in Group 1 and seven out of 21 in Group 2, respectively). The median survival over the period of the study was 48 months (95% confidence interval, CI, 22-74 months). The overall 5-year survival rate was 42% (95% CI, 17-67%) for all patients and 50% (95% CI, 18-83%) for the carcinoid group alone, according to Kaplan-Meier analysis. A complete or partial symptomatic response was obtained in 12 out of 27 (44%) patients who presented with symptoms (four out of eight in Group 1 and eight out 19 in Group 2, respectively) and a complete or partial hormonal response in eight out of 19 patients (42.1%) who presented with hormonally active disease (two out of four in Group 1 and six out of 15 in Group 2, respectively). Nine out of the 15 (60%) patients with carcinoid tumours who presented with symptoms obtained a symptomatic response, five out of 10 patients (50%) a hormonal response, and four out of 16 (25%) patients a partial tumoural response, respectively. The combination of CCNU and 5-FU was safe and well tolerated. Serious side-effects necessitating the termination of CCNU and 5-FU were seen only in two patients, and mainly consisted of reversible bone marrow suppression. No chemotherapy-related death was recorded. CONCLUSIONS: Chemotherapy with CCNU and 5-FU, either alone or in combination with other therapeutic modalities, produces considerable symptomatic and hormonal improvement and moderate tumour regression/stabilization according to currently accepted WHO criteria, particularly in patients with metastatic gastroenteropancreatic neuroendocrine tumours with minimal adverse effects. However, long-term survival was still relatively poor. It may therefore be a valuable additional therapl was still relatively poor. It may therefore be a valuable additional therapeutic option, particularly for well-differentiated carcinoid and islet-cell tumours, but mainly reserved for when there is no response or progression of the disease after currently available first-line treatment with somatostatin analogues or radiopharmaceuticals.     

A new combination chemotherapy with cis-diammine-glycolatoplatinum (Nedaplatin) and 5-fluorouracil for advanced esophageal cancers

OBJECTIVE: The efficacy of a new chemotherapeutic combination consisting of Cis-diammineglycolatoplatinum (Nedaplatin), a derivative of cisplatin (CDDP), and 5-fluorouracil (5FU) was evaluated in patients with advanced esophageal carcinomas. METHODS: Nedaplatin was administered at a dose of 80 or 100 mg/m2 with 500 ml of saline by slow drip infusion for 120 minutes on day 1. 5FU at a dose of 350 or 500 mg/m2 was mixed with 1,000 ml of saline and administered by continuous infusion for 24 hours on days 1 to 5. PATIENTS OR MATERIALS: This combination chemotherapy was tried in 17 patients with metastatic, recurrent, or bulky unresectable esophageal cancers. Of these, 15 evaluable patients received at least two courses of chemotherapy. RESULTS: The response rates in assessable and all patients were 60% and 52.9%, respectively. Cases with lymph node and liver metastases, as well as primary lesions, showed excellent response to the therapy with positive response rates of 54.5% (6/11), 100% (5/5) and 58.4% (7/12), respectively. The median response duration was 7 (range 3 to 37+) months for patients who achieved a partial response. Adverse drug reactions were limited to three cases of grade 3 toxicity, including allergy, and decreased hemoglobin and platelets, which were well tolerated by the patients. CONCLUSION: The present study thus indicated the combination chemotherapy of Nedaplatin and 5FU to be safe and efficacious for advanced esophageal cancer. Further investigations are clearly warranted.     

Prediction of nephrotoxicity induced by cisplatin combination chemotherapy in gastric cancer patients

AIM:To evaluate the treatment options for nephrotoxicity due to cisplatin combination chemotherapy.METHODS:We retrospectively reviewed patients who had received cisplatin combination chemotherapy for gastric cancer between January 2002 and December 2008.We investigated patients who had shown acute renal failure(ARF),and examined their clinical characteristics,laboratory data,use of preventive measures,treatment cycles,the amount of cisplatin administered,recovery period,subsequent treatments,and renal statu...     

Neoadjuvant chemotherapy with a combination of irinotecan and cisplatin in advanced gastric cancer--a case report

We report a case of advanced gastric carcinoma successfully treated with a combination of irinotecan and cisplatin as neoadjuvant chemotherapy. The patient, a 78-year-old man, had type 2 gastric cancer, which had metastasized to the paraaortic lymph nodes. He was treated with irinotecan, 70 mg on day 1 and day 15, and cisplatin, 80 mg on day 1. The course was repeated every 4 weeks. Two courses of treatment resulted in a marked reduction of both the primary tumor and lymph nodes. Subsequently, the patient underwent curative surgery consisting of total gastrectomy, splenectomy, and D3 lymph node dissection. No surgical complications were observed. On microscopic examination, only a few tumor cells were detected in the granulation tissues of the resected stomach and in the lymph nodes. This would be the first case to demonstrate the effectiveness and the safety of irinotecan and cisplatin used in the neoadjuvant setting for treatment of advanced gastric carcinoma.     

Less cytotoxicity to combination therapy of 5—fluorouracil and cisplatin than5—fluorouracil alone in human colon cancer cell lines

AIM：Our previous studies showed increased sensitivity to 5-FU in colon cancer cell lines with microsatellite instability,and considered that mutations of TGFβ-RⅡ,IGFⅡR,RIZgene might enhance the potentials of cell growth and proliferation,which increased the sensitivity to 5-FU.Here we compared the distribution of cell cycle and P53 status between two human colon cancer cell lines with P53status between two human colon cancer cell lines with different sensitivity to5-FU.Because mechanistic differences exist between 5-FUand CDDP,we also analyzed the efficacy of CDDPand combination therapy on two human colon cancer cell lines.METHODS:We compared the sensitivity to CDDP of these two cell lines by MTT assay,Distributon of cell cycle under treatment of5-FU,cddp alone or both was analyzed by Flow Cytometry,and expression of P53was detected by immunocytochemical staining.RESULTS:SW480 cells were more sensitive to CDDP than LoVo cells at the concentrations above 16μmol/l(Ratio of absorption is 0.64and0.79at16μmol/l.respectively;P<0.010,Efficacy of combination therapy was conversely lower than that of single-therapy of 5-FU(Ratio of absorption in LoVo+5-FU,SW480+5-FU,LoVo+5-FU+CDDPand SW480+5-FU+CDDPis0.53,0.54,0.72,0.78,respectively;P<0.01).LoVo cells were negative whereas wsw480 cells positive inP53expression,5-FU induced G1-phase arrest in both cell lines,butLoVo cells peaked 24hours earlier than SW480cells,and 48hours earlier for an apparent hypodiploidDNA.However,CDDP showedthe contrary,inducingS-phase arrest,andSW480cells peaking 36hours earlier,Both cell lines showed hypodipliod nuclei 48hours after CDDP treatment.Percentage of cells in G1-phase and 5-phase dominated alternatively under conbination therapy in both cell lines.CONCLUSION:There results suggest that colon cancer cells with microsatellite instability are mor sensitive to 5-FU,whereas more resistant to CDDP.Combination therapy of5-FU and CDDPshows fewer efficacies than5-FU single-therapy,although it can render a cell cycle arrest.P53may be involoved in the shift of G1-phase to S-phase,but inessentially.     

Randomized trial of 5-fluorouracil, leucovorin and cisplatin in advanced pancreatic cancer.

BACKGROUND/AIMS: Phase II trials of combined 5 fluorouracil, leucovorin and cisplatin have demonstrated an 18-28% response rate in advanced pancreatic carcinomas. We investigated the effect of this chemotherapy regime on patients' survival. METHODOLOGY: Patients included gave informed consent. They had an advanced and proven pancreatic adenocarcinoma. The trial was multicentric, prospective and randomized. It compared a 5-day course of leucovorin (200 mg/m2/day), 5-fluorouracil (375 mg/m2/day) and cisplatin (15 mg/m2/day) repeated every 21 days (23 patients) with a control group (22 patients). The main end points were survival time (Kaplan-Meier and log-rank methods) a[not readable: see text]side effects of chemotherapy. RESULTS: Association of leucovorin, 5-fluorouracil and cisplatin failed to demonstrate any advantage of this regimen compared with supported care alone. Median survival times were 8.6 months (SD +/- 1.8) and 7.0 months (SD +/- 0.6), respectively. The modulation of 5-fluorouracil by leucovorin and cisplatin was well tolerated with moderate toxic effects. CONCLUSIONS: This multicentric trial failed to demonstrate any advantage of the evaluated chemotherapy regime in the palliative treatment of cancer of the exocrine pancreas. Other trials including gemcitabine and/or radiotherapy are needed in advanced pancreatic adenocarcinoma.     

吉西他滨联合顺铂治疗老年晚期非小细胞肺癌的临床疗效

目的评价吉西他滨联合顺铂（GP方案）治疗老年晚期非小细胞肺癌的临床疗效与毒副反应。方法对30例经病理和（或）细胞确诊的老年晚期非小细胞肺癌患者,采用吉西他滨联合顺铂化疗。吉西他滨1000mg／m^2,静脉点滴,第1,8天各静滴1次;顺铂25mgc／m^2,静脉点滴,第1,2,3天各静滴1次,每28d为一个周期,化疗中记录毒副反应。2个周期为1个疗程。疗程结束后,评定疗效与毒副反应。结果全组完全缓解（CR）0例,部分缓解11例（11／30）,总有效率36．67％。最常见的毒副反应为白细胞减少和血小板减少。结论吉西他滨联合顺铂方案治疗老年晚期非小细胞肺癌患者临床疗效较好,毒副反应可耐受,值得推广应用。     

Pilot trial of prolonged continuous-infusion 5-fluorouracil and weekly cisplatin in advanced colorectal cancer

Thirty-five patients with previously untreated, advanced, measurable metastatic colorectal carcinoma were treated with a 12-week course of continuous 5-fluorouracil (5-FU) and weekly cisplatin. Twenty of 32 evaluable patients responded (five complete and 15 partial responses), for an overall response rate of 63% (90% confidence limits, 43%-75%). Toxicity was generally mild and reversible and included mucositis (40%), painful erythema of the palmar and plantar skin (30%), diarrhea (21%), nausea and vomiting (15%), and leukopenia (6%). One patient died of sepsis secondary to mucositis and myelosuppression. This program is a well-tolerated outpatient regimen for metastatic colorectal carcinoma. The response rate is higher than expected for 5-FU and cisplatin and suggests clinical therapeutic synergism at this dose rate and schedule.     

多烯紫杉醇联合顺铂腹腔化疗治疗进展期胃癌45例

目的:探讨多烯紫杉醇及顺铂联合腹腔化疗治疗进展期胃癌的疗效.方法:对45例进展期胃癌患者进行多烯紫杉醇及顺铂联合腹腔化疗,比较腹腔化疗前后两组肿瘤体积大小、血常规、肝肾功的变化,观察腹腔化疗术后的不良反应,并对所有患者进行随访观察其生存时间.结果:腹腔化疗后胃癌体积明显缩小(72.4±22.4 cm3vs 7.23±2.4 cm3,t=2.946,P<0.01),患者中位生存期为14.0±1.4 mo,对癌性腹水近期有效率为59%.腹腔化疗对患者血常规、肝肾功能中部分指标有一定影响,主要不良反应为脱发、口腔炎、便秘及血尿.结论:多烯紫杉醇及顺铂联合腹腔化疗治疗胃癌疗效好,能明显缩小肿瘤体积,延长患者生存期,减少癌性腹水,且操作方便,不良反应少.     

Combination chemotherapy comprising 5-fluorouracil,leucovorin, etoposide,and cis-diamminedichloroplatinum for the treatment of advanced gastric cancer

PURPOSE: The FLEP regimen (5-FU, LV, ETP, and CDDP) has been recommended as a combination chemotherapy to control advanced and recurrent gastric cancer. We performed a phase II study of this regimen in 49 patients with advanced gastric cancer. METHODS: The treatment regimen consisted of: 5-FU at 370 mg/m(2) (days 1-5, i.v. 24 h); LV at a dose of 30 mg (days 1-5, i.v. bolus); and ETP and CDDP each at 70 mg/m(2) (days 7 and 21, i.a. 2 h), which was repeated every five weeks. RESULTS: The overall response rate was 40.8% (20/49 patients) and the median survival time was 12.6 months (range 1.1-41.8). The adverse events were Grade 3/4 leukocytopenia (16.3%), Grade 3/4 thrombocytopenia (8.2%), Grade 3 nausea and/or vomiting (4.1%), and Grade 3 stomatitis (2.0%). CONCLUSIONS: Based on the encouraging response rate and prognosis, we recommend applying the FLEP regimen to patients with primary advanced gastric cancer.     

Sequential chemotherapy with methotrexate and 5-fluorouracil for chemotherapy-naive advanced gastric cancer with disseminated intravascular coagulation at initial diagnosis

Purpose  

Advanced gastric cancer (AGC) rarely presents with disseminated intravascular coagulation (DIC) at the time of diagnosis before treatment with no current standard chemotherapy (CTx) regimen. However the prognosis is extremely poor without CTx. We investigated the effectiveness of sequential CTx with methotrexate and 5-fluorouracil (MF) in chemotherapy-naive AGC patients with DIC.     

Re-evaluation of antitumor effects of combination chemotherapy with interferon-α and 5-fluorouracil for advanced hepatocellular carcinoma

AIM: To evaluate the efficacy of combination chemotherapy with interferon-alpha (IFNalpha) and 5-fluorouracil (5-FU) in patients with advanced hepatocellular carcinoma (HCC). METHODS: Twenty-eight HCC patients in advanced stage were enrolled in the study. They were treated with IFNalpha/5-FU combination chemotherapy. One cycle of therapy lasted for 4 wk. IFNalpha (3 x 10(6) units) was subcutaneously injected thrice weekly on days 1, 3, and 5 for 3 wk, and 5-FU (500 mg/d) was administered via the proper hepatic artery for 5 consecutive days per week for 3 wk. No drugs were administered during the 4(th) wk. The effect of combination chemotherapy was evaluated in each patient after every cycle based on the reduction of tumor volume. RESULTS: After the 1(st) cycle of therapy, 16 patients showed a partial response (PR, 57.1%) but none showed a complete response (CR, 0%). At the end of therapy, the number of patients who showed a CR, PR, or no response (NR) was 1, 10, and 17, respectively. The response rate for therapy (CR+PR) was 21.5%. Biochemical tests before therapy were compared between responsive (CR+PR) and non-responsive (NR) patients, but no significant differences were found for any of the parameters examined, indicating that no reasonable predictors could be identified in our analysis. CONCLUSION: Attempts should be made to discriminate between responders and non-responders by evaluating tumor size after the first cycle of IFNalpha/5-FU combination chemotherapy. For non-responders, therapy should not proceed to the next cycle, and instead, different combination of anticancer drugs should be explored.     

Efficacy and safety of docetaxel/cisplatin/5-fluorouracil preoperative combination chemotherapy in esophageal cancer patients with extended lymph node metastases

Aim

We retrospectively investigated the efficacy and safety of combination chemotherapy with 5-fluorouracil (5-FU) and cisplatin plus docetaxel (DCF) as preoperative chemotherapy.

Methods

One hundred and seven patients were diagnosed with esophageal cancer of clinical stage II and III (except T4) from March 2007 to June 2009. Among these, five patients who had extensive locoregional lymph node metastases underwent preoperative DCF chemotherapy.

Results

Median age of the five patients was 59 (51–67) years, and all were men with clinical stage III esophageal cancer. The best overall responses were 80% with partial response (PR) and 20% with stable disease (SD). Histological response of grade 1b and more was also 80%. The hematologic toxicities included grade 3 leucopenia in 80% of patients; grade 3 or 4 neutropenia was observed in all patients. Febrile neutropenia occurred in 20% of patients. Nonhematologic toxicities included grade 3 anorexia in 80% of patients. The operations were not postponed due to any adverse events. Postoperative complications included pneumonia, pneumothorax, and cervical lymphatic leakage (one case each). No chemotherapy-related postoperative complications were observed. Median follow-up of surviving patients was 51.5 (33.9–56.4) months. Disease-free survival times were 12.1, 30.9, 48.0, 49.0, and 54.0 months, respectively. Overall survival times were 28.9, 33.9, 51.0, 52.1, and 56.4 months, respectively.

Conclusions

The response rate of preoperative DCF was 80%, and toxicities were tolerated with support therapies such as granulocyte colony-stimulating factor (G-CSF) and dexamethasone. We therefore concluded that this preoperative treatment might be a promising strategy for patients who have extensive regional lymph node metastases.