A combination chemotherapy of 5-fluorouracil and cisplatin against advanced gastric cancer

BACKGROUND/AIMS: This study was designed to clarify the effects of treatment and toxicity between 5-fluorouracil (5-FU) plus bolus infusion of Cisplatin (CDDP) and 5-FU plus continuous infusion of low-dose CDDP in advanced gastric cancer. METHODOLOGY: Seventy-three patients with advanced gastric cancer were enrolled in this study to compare the antitumor effect and toxicity between the bolus infusion of CDDP and the continuous infusion of low-dose CDDP in combination with the continuous infusion of 5-FU. Sixty-five eligible patients were divided into two groups: group A: curative resection cases; and, group B: non-curative, recurrent or inoperable cases. Patients were classified into two arms in each group. One arm of treatment regimen is 5-FU and bolus infusion of CDDP (A-1, B-1) and the other arm is 5-FU and continuous infusion of low-dose CDDP (A-2, B-2). RESULTS: Response rates were 9.1% and 38.5% in arm B-1 and arm B-2, respectively, although the difference between the two was not at a significant level. Frequently observed toxicities during the treatment were gastrointestinal symptoms such as nausea, vomiting, and anorexia. The incidence of side effects in arm A-2 and arm B-2 was almost the same as that in arm A-1 and arm B-1. CONCLUSIONS: These results revealed that there was no advantage of low-dose continuous infusion of CDDP with 5-FU in terms of response rate and clinical toxicity in our present study.     

A phase II study of docetaxel-irinotecan combination in advanced pancreatic cancer

BACKGROUND/AIMS: Chemotherapy provides dismal results in advanced pancreatic cancer patients, even when new compounds, such as gemcitabine, are used. Phase I studies of single-drug therapy with docetaxel or irinotecan suggested a response rate of about 15% in these patients. We report here a phase II study of docetaxel-irinotecan combination in advanced pancreatic cancer patients. METHODOLOGY: Docetaxel 60 mg/m2 was given in combination with irinotecan 250 mg/m2 every 3 weeks. Prednisolone premedication and anti-HT3 drugs were systematically administered. Hematopoietic growth factors were given in case of febrile neutropenia or grade 4 neutropenia at the previous cycle. Endpoints were response rate, progression-free survival, and tolerance. RESULTS: Twenty-seven patients were enrolled, of whom 25 had metastatic disease. We observed 3 partial responses and 11 stabilizations. The median progression-free survival was 4.3 months. Myelosuppression was the main toxicity with 18% of patients experiencing a grade 3-4 event. One patient died of neglected febrile neutropenia. Gastrointestinal toxicity was well controlled. Other toxicities were mild. CONCLUSIONS: This combination has acceptable tolerance and, despite an 11% response rate, some partial responses and prolonged stabilizations were observed. The treatment induced clinical benefit in 33% of the patients. Further trials should focus on docetaxel or irinotecan, possibly used in combination with more conventional strategies (gemcitabine).     

Phase II study of leucovorin, 5-fluorouracil and gemcitabine for locally advanced and metastatic pancreatic cancer (FOLFUGEM 2)

AIM: FOLFUGEM 1 (leucovorin 400 mg/m2 combined with 5-flurorouracil (FU) bolus 400 mg/m2 then 5-FU 2-3 g/m2/46 hours and gemcitabine 1000 mg/m2 in 30 min) in patients with locally-advanced and metastatic pancreatic adenocarcinoma appeared to be toxic (neutropenia and alopecia). The aims of this phase II multicentric study were to evaluate the response rate, clinical benefit and tolerance of a new scheme of combined leucovorin, 5-FU and gemcitabine (FOLFUGEM 2). PATIENTS AND METHODS: FOLFUGEM 2 associated leucovorin 400 mg/m2 in 2 hours followed by 5-FU 1000 mg/m2 in 22 hours, then gemcitabine 800 mg/m2 (10 mg/m2/min) with cycles every 14 days. Gemcitabine dose could be increased (1000 then 1250 mg/m2) when NCI/CTC toxicity was < or = grade 2. RESULTS: Fifty-eight patients were included (locally-advanced tumor: N = 13 and metastatic: N = 45). Among the 39 patients with measurable disease, 11 had partial response (28.2%, 95% confidence interval: 14-42%) and 11 had stable disease (28.2%). On an intent-to-treat analysis, the objective response rate was 19% (95% confidence interval: 9-29%). Clinical benefit rate was 46%. Median progression-free survival and median overall survival were 3.1 and 7.2 months, respectively. There were 13% grade 3-4 neutropenia and 36% complete alopecia. CONCLUSION: FOLFUGEM 2 schema has an antitumoral effect in advanced pancreatic cancer and has an acceptable toxicity which appears to be less than that of FOLFUGEM 1.     

老年晚期胰腺癌患者对吉西他滨联合顺铂化疗耐受性分析

目的 探讨老年晚期胰腺癌患者对吉西他滨联合顺铂化疗的耐受性.方法 对2004年1月至2009年1月收治的34例老年(>70岁)晚期胰腺癌患者的临床资料进行回顾性分析.结果 34例患者均行吉西他滨联合顺铂化疗,其中6例获得部分缓解(partial remission,PR),16例疾病稳定(stable disease,SD),临床获益率64.7%.18例患者治疗后镇痛药物用量减少≥50%,疼痛强度VAS评分下降35%以上;22例患者体力状况明显提高,体重增加≥7%.恶心、呕吐发生率为38.2%(13/34),4例巩膜皮肤黄染加重,肝功能异常,化疗2个周期中断治疗.Ⅲ～Ⅳ度骨髓抑制的发生率为34.6%,白细胞、血红蛋白、血小板均有不同程度的下降.血小板减少率28.3%(12/34),应用G-CSF治疗后血常规可恢复正常.无外周神经毒性发生,无化疗相关死亡.结论 老年胰腺癌,行为状态良好者可耐受吉西他滨联合顺铂方案化疗.     

Clinical efficacy of intra-arterial pharmacokinetic chemotherapy with 5-fluorouracil, CDDP, gemcitabine, and angiotensin-II in patients with advanced pancreatic cancer

BACKGROUND/AIMS: To deliver anticancer drugs more selectively into cancer tissues and to improve survival time, we have developed a new method of intra-arterial chemotherapy for unresectable pancreatic cancer. METHODOLOGY: From April 2002 to June 2006, twenty patients with pancreatic cancer with liver metastases were given intra-arterial infusions consisting of gemcitabine, 5-FU, and cisplatin mixed with angiotensin-II with the intent of increasing the blood flow into the tumor tissue but decreasing that to the non-tumor tissues. Simultaneously, tegafur/uracil was administered. A tumor marker and computed tomography (CT) findings were used to evaluate the efficacy of this chemotherapy. RESULTS: The median survival was 365 days, and 6-months and 1-year survival rates were 80.0% and 44.7%, respectively. In 12 of 20 cases, the tumor marker level was decreased after this chemotherapy. In 10 of 20 cases, computed tomography showed a decrease in the tumor size. In 6 patients, back pain was the chief complaint and was reduced to a self-controlled level in 20 patients. No major complications were encountered. CONCLUSIONS: Compared with the previously reported data in traditional chemotherapies, our method of intra-arterial chemotherapy appears to be quite useful not only for prolonging patient survival but also for improving the quality of life. Intra-arterial regional chemotherapy including changes in distribution of blood flow induced by angiotensin-II appears to be an effective palliative treatment for advanced pancreatic cancer.     

A phase II study of gemcitabine plus nab-paclitaxel as first-line therapy for locally advanced pancreatic cancer

Gemcitabine plus nab-paclitaxel (GnP) is widely used in clinical practice, despite a lack of prospective data to validate its efficacy in locally advanced pancreatic cancer (LAPC). We conducted a phase II study of GnP for LAPC to assess its efficacy and safety.We performed a single-arm, single-institution study with GnP in 24 patients with LAPC. The treatment protocol included successive administration of gemcitabine (1000 mg/m²) and nab-paclitaxel (125 mg/m²). The primary endpoint was the tumor overall response rate (ORR), and secondary endpoints were overall survival (OS), progression-free survival (PFS), and adverse events (AEs).The median PFS was 11.0 months, median OS was 21.2 months, ORR was 62.5%, and 37.5% of the patients had stable disease. Four (16.7%) of the patients were converted to surgical resection; 3 of these achieved R0 resection. Grade 3 to 4 AEs included hematological (neutropenia, 64%; thrombocytopenia, 12%), nonhematological (cholangitis, 16%), and sensory neuropathy (4%). These AEs were manageable and tolerable.The GnP treatment in patients with LAPC showed favorable tumor shrinkage, good toxicity profile, and enabled conversion to surgical resection in a subset of patients; therefore, GnP is an option for first-line chemotherapy in patients with LAPC.     

A phase II study of weekly 24-h infusion of high-dose 5-fluorouracil in advanced pancreatic cancer.

No single agent or combination chemotherapy protocol, with the exception of gemcitabine, has so far proven superior to standard bolus 5-fluorouracil regimes for the treatment of advanced pancreatic cancer. The present phase II trial was designed to study whether the effectivity of 5-fluorouracil can be improved with a weekly high-dose 5-fluorouracil schedule. 26 patients with cytologically or histologically verified, metastasized (n = 21) or locally advanced (n = 5) previously untreated adenocarcinoma of the pancreas were included in this study. Treatment consisted of weekly applications of 2,600 mg/m2 5-fluorouracil as 24-h infusion on days 1, 8, 15, 22, 29, 36. Treatment was repeated at day 50 and was continued until disease progression. Primary endpoints of the study were response rates and toxicity, secondary endpoints were survival and clinical benefit in terms of performance status, body weight and analgesia consumption. Toxicity of the regimen was mild with only four instances of grade-3 toxicity. Response rates were 8% (95% CI = 1.2-13.7) with two partial remissions. Improvement of at least one parameter of clinical benefit for > or = four weeks was observed for 11.5% of the study patients. The most prominent effect was a transient stabilization of objective tumor measurements (48% [95% CI = 27.8-68.7]) and individual parameters of clinical benefit (50-75%). Median survival was 248 days (95% CI = 164-459) for all patients included in the study. The present study indicates that the high-dose 5-fluorouracil regimen shows weak activity in advanced pancreatic cancer which seems comparable to gemcitabine.     

A phase II study of gemcitabine and cisplatin in patients with advanced hepatocellular carcinoma.

The primary objective of this study was to determine the response rates of a combination of gemcitabine and cisplatin in unresectable hepatocellular carcinoma (HCC) in Indian patients. The secondary objectives were to evaluate the toxicity, time to progressive disease and overall survival for this combination. Chemonaive patients with histopathologically proven, bidimensionally measurable, stage Ill or IV unresectable HCC were enrolled into this study. All the patients were required to have a Zubrod's performance status not greater than 2, should not have undergone prior radiotherapy and were required to have adequate major organ function. Patients received gemcitabine (1250 mg/m2 intravenously over 30 to 60 min) on days 1 and 8, and cisplatin (70 mg/m2 intravenously over 2 hours) on day land every 21 days. Response assessment was done by a Computed Tomography scan after every two cycles of chemotherapy. From May to December 1999, 30 patients were enrolled in the study; they were all eligible for efficacy and toxicity analysis. Six (20%) patients achieved a partial response and 13 (43%) patients demonstrated stable disease with 11 (37%) patients showing disease progression. The median time to progression was 18 weeks (range 1 to 74 weeks) and the median duration of response was 13 weeks (range 4 to 68 weeks). The 1-year survival rate was 27% and the median overall survival was 21 weeks (95% CI: 17 to 43 weeks). WHO grade 3 and 4 anemia was seen in 11 (37%) and 2 (7%) patients, respectively. Four (13%) patients each experienced grade 3 and 4 neutropenia and grade 3 and 4 thrombocytopenia was seen in 2 (7%) patients each. Major, non-hematologic toxicities were grade 4 elevated bilirubin levels and grade 3 oral toxicity, in 1 patient (3%) each. This regimen was well tolerated and did show activity in Indian patients with advanced unresectable HCC. There is a need to further evaluate this combination in order to define its role in the treatment of HCC.     

A phase II study of sequential methotrexate and 5-fluorouracil in metastatic pancreatic cancer

BACKGROUND/AIMS: Sequential administration with methotrexate and 5-fluorouracil (sequential MTX/5-FU) has synergistic cytotoxic activity for several malignant diseases, but its activity in pancreatic cancer has not been fully evaluated. The aim of this study was to evaluate the antitumor activity and toxicity of sequential MTX/5-FU in metastatic pancreatic cancer. METHODOLOGY: All patients were required to have a pathologic diagnosis of pancreatic adenocarcinoma with measurable metastatic lesions, and no prior chemotherapy. Sequential MTX/5-FU was administered weekly as followed; MTX 100 mg/m2 intravenous bolus infusion was given, followed 3 h later by 5-fluorouracil 600 mg/m2 intravenous infusion over 30 min. RESULTS: Thirty-one patients were enrolled and assessable for response and toxicity. There were no complete responses, 4 partial responses, 10 no change and 17 progressive disease. The response rate was 12.9% (95% confidence interval: 1.1-24.7%) and the duration of response was 7.1 months (range: 5.5-9.1 months). The median survival was 4.0 months. Chemotherapy was well tolerated, although grade 3-4 toxicities such as neutropenia and diarrhea were seen infrequently. CONCLUSIONS: The sequential MTX/5-FU had marginal antitumor activity with mild toxicity against metastatic pancreatic cancer.     

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.     

Gemcitabine and protracted 5-FU for advanced pancreatic cancer. A phase II study

BACKGROUND/AIMS: Although chemotherapy in advanced pancreatic cancer procures dismal results, both 5-fluorouracil and gemcitabine have shown a modest activity. We report a phase II study of gemcitabine combined with protracted 5-fluorouracil. METHODOLOGY: Gemcitabine was given at 1000 mg/m2/week intravenously, in combination with concomitant 5-fluorouracil 200 mg/m2/day as a protracted venous infusion, both 3 out of 4 weeks in patients with locally advanced or metastatic pancreatic adenocarcinoma. Twenty-nine patients were enrolled, among whom 27 were metastatic. Response rate, overall and progression-free survival were endpoints, as well as tolerance and clinical benefit. RESULTS: We observed 3 (10%) partial responses, and 12 (42%) stabilizations within which the median disease control was 5.6 months. The median progression-free and overall survivals were 2.8 and 4 months, respectively. A clinical benefit was observed in 39% of patients. Myelosuppression was the main toxicity, but no grade 4 was observed. Other toxicities were mild. CONCLUSIONS: This combination chemotherapy was well tolerated in advanced pancreatic cancer patients.     

Hypofractionated radiotherapy with concurrent 5-fluorouracil radiosensitisation for recurrent or locally advanced colorectal cancer A phase II study

In a pilot study we treated 19 patients suffering from recurrent or locally advanced inoperable colorectal cancer, with concurrent hypofractionated radiotherapy (4 – 5 Gy/fraction, 2 fractions per week) and 5-Fluorouracil bolus, 1 hour before RT at doses of 300 mg/m². For 16 patients treated with radical intent the Normalised Total Dose for α/β = 10 Gy ranged between 56 – 74 Gy (median 62 Gy). The schedule used was very well tolerated. Moderate grade II haematological toxicity was observed in 11% of cases and diarrhoea grade II/III resulting in 2 – 4 weeks treatment delay was observed in 26% of cases. One case with bowel perforation and one with painful subcutaneous fibrosis was observed during 12 – 27 months of follow-up. Out of 16 patients treated with radical intent 4 (25%) showed complete response and the overall response rate was 56% (9/16). The one year symptom free survival was obtained in 11/16 (69%) radically treated patients. It is concluded that hypofractionated radiochemotherapy with 5-Fluorouracil for recurrent or locally advanced colorectal cancer is an effective regimen and has acceptable acute and late toxicity. Further investigation is required.

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Résumé. Dans un projet pilote, nous avons traité 19 patients souffrant d'un cancer colo-rectal récidivant ou localement avancé inopérable par l'administration simultanée d'une radiothérapie hypofractionnée (4 – 5 Gy/fraction à raison de 2 fractions par semaine) et bolus de 5-Fluorouracil à la dose de 300 mg/m² une heure avant la radiothérapie. Chez 16 patients traités dans un but radical, la dose totale normalisée a été de 56 – 74 Gy (moyenne 62 Gy). Le schéma utilisé a été particulièrement bien toléré. Une toxicité hématologique modérée de grade II a été observée chez 11% des patients et une diarrhée de grade II/III entra?nant un délai dans le traitement de 2 à 4 semaines a été observée chez 26% des patients. Une perforation intestinale et une fibrose sous-cutanée douloureuse ont été observées au cours de la période postopératoire de 12 à 27 mois. Quatre des 16 patients traités à des fins curatives (25%) ont montré une résponse complète et une réponse globale a été observée chez 56% des patients (9/16). Une survie sans sympt?mes à un an a été obtenue chez 11 des 16 patients (69%). On conclut que l'assocation de 5-Fluorouracil et d'une radiothérapie hypofractionnée constitue un schéma thérapeutique effectif en cas de cancer colorectal récidivant ou localement avancé avec une toxicité aigu? et tardive acceptable. Des investigations complémentaires sont nécessaires.

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Accepted: 20 June 1996     

Phase II study of gemcitabine and cisplatin in advanced biliary tract cancer

BACKGROUND: The aim of this phase II study was to determine the efficacy of gemcitabine plus cisplatin chemotherapy in patients with advanced biliary tract cancer. METHODS: Eligibility criteria included histologically confirmed adenocarcinoma with measurable tumor in the biliary tract that was unresectable and either locally advanced or metastatic. Patients received a combination of gemcitabine (1000 mg/m(2) intravenously [IV] on days 1, 8, and 15) and cisplatin (75 mg/m(2) IV on day 1). Cycles were repeated every 28 days. Objective tumor response rates and toxicities were evaluated according to World Health Organization criteria. RESULTS: Twenty-seven patients were enrolled in the study and a total of 120 cycles of chemotherapy were administrated. Objective partial response was observed in nine (33.3%) patients, while stable disease was found in seven (25.9%) patients. The median survival time was 10.0 months and the 1-year survival rate was 36%. Median time to disease progression was 5.6 months. The most common grade 3-4 toxicities were leukopenia (25.9%), anemia (29.6%), thrombocytopenia (22.2%), and vomiting (18.5%). Only one patient was hospitalized for chemotherapy-related complications. CONCLUSION: Gemcitabine and cisplatin combination chemotherapy is an effective, safe, and well-tolerated regimen for the treatment of advanced biliary tract cancer.     

5-fluorouracil continuous infusion combined with cisplatin for advanced pancreatic cancer: a Japanese Cooperative Study

BACKGROUND/AIMS: The prognosis of patients with advanced pancreatic cancer is extremely poor. To improve their prognosis, providing effective chemotherapy is necessary. The aim of this study was to evaluate the anti-tumor activity and toxicity of combined chemotherapy (FP therapy) using 5-fluorouracil and cisplatin in Japanese chemo-naive patients with advanced pancreatic cancer. METHODOLOGY: Thirty-seven previously untreated patients with histologically proven pancreatic adenocarcinoma were treated with FP therapy. 5-fluorouracil was administered at 500 mg/m2/day by continuous intravenous infusion for 5 days and cisplatin was administered at 80 mg/m2 intravenously on the 1st day. Therapy was repeated every 4 weeks until there was evidence of disease progression or unacceptable toxicity. RESULTS: Three patients achieved partial responses, whereas none exhibited a complete response. The overall response rate was 8% (95% confidence interval, 2-22%) and the response durations were 6, 9 and 12 months, respectively. The median survival time of patients was 5 months. Toxicities were generally mild and acceptable, although nausea/vomiting was the most commonly observed toxicity. CONCLUSIONS: FP therapy on this schedule had limited anti-tumor activity for pancreatic cancer, indicating that, practically, it should not be performed in Japanese patients with advanced pancreatic cancer.     

A phase II study of weekly high-dose 5-fluorouracil and leucovorin plus biweekly alternating doxorubicin and cisplatin for advanced gastric carcinoma

On the basis of recent clinical data suggesting that high-dose continuous 5-fluorouracil (5-FU) is able to overcome resistance to 5-FU bolus application in gastric carcinoma, a phase II study was performed to evaluate the activity and toxicity of weekly high-dose 5-FU and leucovorin plus biweekly alternating doxorubicin and cisplatin as the first-line treatment in patients with advanced gastric carcinoma. Between October 1995 and September 1997, 24 consecutive patients with locally advanced (n = 4) or metastatic (n = 20) gastric carcinomas were treated with a combination of 500 mg/m² leucovorin as a 2-h infusion, followed by 2.0 g/m² 5-FU as a 24-h continuous infusion once weekly for 6 weeks, plus 20 mg/m² doxorubicin as a bolus application and 50 mg/m² cisplatin as a 1-h infusion, week 1, 3 and 5 (FLAP regimen). Response, toxicity and survival data were evaluated. A total of 20 patients were evaluable for response and 24 for toxicity. Objective responses were observed in 11 patients (55%) with no complete remission. Four patients (20%) showed stabilization and 5 patients (25%) experienced progressive disease. The median time to disease progression was 8 months and the overall duration of survival was 14 months. Myelosuppression was significant. In 2 patients, grade 4 WHO thrombocytopenia and leukopenia/anaemia respectively were registered, but there were no treatment-related deaths. We conclude that the weekly alternating FLAP regimen is effective in advanced gastric carcinoma with tolerable toxicity. However, significant myelotoxicity and frequent hospitalization suggest that FLAP should not be preferred to other regimens used in metastatic disease. Currently we intend to establish this regimen in the neoadjuvant setting in patients with primary unresectable localized gastric carcinomas. Received: 15 January 1998 / Accepted: 28 January 1998