Dihydropyrimidine dehydrogenase inactivation and 5-fluorouracil pharmacokinetics: allometric scaling of animal data,pharmacokinetics and toxicodynamics of 5-fluorouracil in humans

 The pharmacokinetics of 5-fluorouracil (5-FU) in different animal species treated with the dihy-dropyrimidine dehydrogenase (DPD) inactivator, 5-ethynyluracil (776C85) were related through allometric scaling. Estimates of 5-FU dose in combination with 776C85 were determined from pharmacokinetic and toxicodynamic analysis. Method: The pharmacokinetics of 5-FU in the DPD-deficient state were obtained from mice, rats and dogs treated with 776C85 followed by 5-FU. The pharmacokinetics of 5-FU in humans were then estimated using interspecies allometric scaling. Data related to the clinical toxicity for 5-FU were obtained from the literature. The predicted pharmacokinetics of 5-FU and the clinical toxicity data were then used to estimate the appropriate dose of 5-FU in combination with 776C85 in clinical trials. Results: The allometric equation relating total body clearance (CL) of 5-FU to the body weight (B) (CL=0.47B^0.74) indicates that clearance increased disproportionately with body weight. In contrast, the apparent volume of distribution (V_c) increased proportionately with body weight (V_c=0.58 B^0.99). Based on allometric analysis, the estimated clearance of 5-FU (10.9 l/h) in humans with DPD deficiency was comparable to the observed values in humans lacking DPD activity due to genetic predisposition (10.1 l/h), or treatment with 776C85 (7.0 l/h) or (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVdUrd, 6.6 l/h). The maximum tolerated dose (MTD) of 5-FU in combination with 776C85 was predicted from literature data relating toxicity and plasma 5-FU area under the concentration-time curve (AUC). Based on allometric analysis, the estimated values for the MTD in humans treated with 776C85 and receiving 5-FU as a single i.v. bolus dose, and 5-day and 12-day continuous infusions were about 110, 50 and 30 mg/m² of 5-FU, respectively. Discussion: The pharmacokinetics of 5-FU in the DPD-deficient state in humans can be predicted from animal data. A much smaller dose of 5-FU is needed in patients treated with 776C85. Received: 6 October 1995/Accepted: 28 May 1996     

In-vitro effect of a combination of 5-fluorouracil (5-FU) and cisplatin (CDDP) on human gastric cancer cell lines: timing of cisplatin treatment

Abstract. Background: To date, we have few effective chemotherapeutic agents against advanced and recurrent gastric cancer. 5-Fluorouracil (5-FU) and cisplatin (CDDP) are the most widely used drugs, and their combination has demonstrated favorable outcomes. However, the method (especially the timing) of CDDP administration is not well established. Methods: We examined the in-vitro effect of a combination of 5-FU and CDDP on four human gastric cancer cell lines: MKN-1, MKN-28, MKN-45, and MKN-74. The cell lines were exposed to 50% of the inhibitory concentrations of 5-FU and CDDP for 72 h and 8 h, respectively. CDDP was applied before, simultaneously with, and after the start of treatment with 5-FU. Results: When CDDP was applied after 5-FU, the cytotoxic activity against MKN-28, MKN-45, and MKN-74 was significantly potentiated. Against MKN-1, the earlier the initiation of CDDP treatment, the stronger was the cytotoxic effect. Conclusion: Our results suggest that the cytotoxicity of a combination of 5-FU and CDDP against human gastric cancer cells is both cell-line- and schedule-dependent and is especially affected by the timing of the CDDP treatment. Received: August 22, 2001 / Accepted: December 7, 2001     

Pharmacokinetics of intrapericardial administration of 5-fluorouracil

A 30-year-old patient with metastatic breast adenocarcinoma was diagnosed as having a malignant pericardial effusion. Methods: The patient was treated with two courses of 200 mg 5-fluorouracil (5-FU) followed by 20 mg cisplatin 5 h later directly infused into the pericardial space through a catheter. The drug levels of the 5-FU were monitored during the second treatment. The half-life of 5-FU in the pericardial space was 168.6 min with a concentration of 0.113 mg/ml still detected at 5 h. The area under the curve (AUC) was estimated to be 4.739 mg h/ml. The plasma concentrations of 5-FU ranged from 0.022 to 0.04 mg/ml throughout the infusion. Results: There was no significant change in the patient's blood counts or chemistry profile. She did not experience any side effects during the treatment. A pericardial window was performed 2 days later when balloon pericardiectomy was unsuccessful. The patient eventually succumbed to her disease 4 months later, but without evidence of pericardial effusion. Conclusions: We conclude that pericardial infusion of 5-FU allowed a high concentration of 5-FU to be achieved within the pericardial sac with a greatly increased half-life over that of systemic 5-FU treatment (168 min vs 6–20 min), and with little systemic toxicity. Received: 12 September 1996 / Accepted: 12 December 1996     

Sequential methotrexate and 5-fluorouracil therapy for gastric cancer patients with bone metastasis

Background. Patients with bone metastasis of gastric cancer occasionally experience disseminated intravascular coagulation (DIC), with a very poor prognosis. Methods. We treated 18 gastric cancer patients with bone metastasis with sequential methotrexate and 5-fluorouracil (sequential MTX/5-FU therapy). The treatment schedule comprised weekly administration of methotrexate (MTX; 100 mg/m², i.v. bolus) followed by 5-fluorouracil (5-FU; 600 mg/m², i.v. bolus) after an interval of 3 h. Calcium leucovorin (10 mg/m², p.o. or i.v.) was administered six times, every 6 h starting 24 h after the administration of MTX. Results. In 11 patients with measurable metastatic lesions, the response rate was 64% (7/11). Nine patients (50%) had DIC before the initiation of chemotherapy, and 8 of them (89%) recovered from it. Two of these 9 patients (22%) survived for more than 1 year. The median survival times for all patients and for the 9 with DIC were 186 and 113 days, respectively. Grade 4 leukopenia was observed in 3 patients (17%). No treatment-related deaths occurred. Conclusion. Sequential MTX/5-FU therapy may have palliative potential and may be a feasible treatment for gastric cancer patients with bone metastasis with or without DIC. Received: December 10, 1999 / Accepted: January 28, 2000     

Opiate effects on 5-fluorouracil disposition in mice

 Purpose: This study was performed to investigate the effects of morphine on the disposition of 5-fluorouracil (5-FU). Methods: Mice were injected subcutaneously (s.c.) with saline or morphine, 20 mg/kg. 5-FU was administered intravenously (i.v.) 30 min later as a single bolus or by constant infusion. Blood samples were obtained by orbital sinus puncture. Urine samples were obtained from the bladder after ligation of the external urethra. 5-FU concentrations in plasma and urine were determined by HPLC. Results: Morphine markedly elevated plasma levels of 5-FU given at doses of 100 to 860 mg/kg. The plasma clearance rate of a bolus dose of 100 mg/kg 5-FU was significantly reduced from 54 to 28 ml/min per kg and the elimination half-life was increased from 6.9 to 12.2 min by prior administration of morphine. When 5-FU was infused at 0.5 mg/kg per min, morphine reduced its plasma clearance rate from 145 to 94 ml/min per kg. Mice made tolerant by prior morphine administration required higher doses of this opiate to raise 5-FU levels as well as to cause analgesia. The effects of morphine on 5-FU disposition were antagonized by naltrexone. Excretion of 5-FU in urine was not affected by morphine treatment. Conclusions: The plasma clearance rate of 5-FU in mice is significantly reduced by concomitant use of morphine. This effect of morphine is due to reduced hepatic elimination of 5-FU rather than to a decrease in its renal excretion. Received: 22 December 1995 / Accepted: 25 May 1996     

Comparison of 5-fluorouracil anabolite levels after intravenous bolus and continuous infusion

The levels of 5-fluorouracil (5FU) and its anabolites in the serum, bile, pancreatic juice, liver, pancreas, and skeletal muscle of dogs were compared after single bolus administration and after continuous infusion. Six dogs had a bolus of 5FU (15 mg/kg) and were studied for 120 min. Five dogs had a continuous infusion of 5FU (30 mg/kg) and were studied for 24 h. After the bolus infusion, serum 5FU levels were initially high and then declined, whereas anabolite levels gradually increased over 45 min. Within 2 h, anabolite levels exceeded 5FU levels in tissues but were undetectable in bile and pancreatic juice. During the continuous infusion, anabolite levels in serum increased more rapidly than 5FU levels and remained significantly higher for 24 h. Anabolite levels also exceeded 5FU levels in bile, pancreatic juice, pancreas, and muscle but not in the liver. Continuous infusion of 5FU produced higher levels of the anabolites than did bolus infusion and maintained constant levels throughout the infusion period.     

Phase II study of the combination of carboplatin and 5-fluorouracil in metastatic nasopharyngeal carcinoma

 A carboplatin and 5-fluorouracil (CF) chemotherapy protocol was designed to evaluate tumor response and toxicity in patients with metastatic nasopharyngeal carcinoma (NPC). Patients with metastatic NPC were treated with a maximum of eight courses of CF. Carboplatin was given at 300 mg/m² by intravenous bolus on day 1 and 5-fluorouracil at 1 g/m² per day by continuous infusion on days 1 – 3; cycles were repeated once every 3 weeks. A total of 42 patients were evaluable for response and toxicity. They received a median of 6 courses (range 2 – 8) of chemotherapy. The overall response rate was 38% (16/42), comprising 7 complete responses (CR, 17%) and 9 partial responses (PR, 21%). The median survival was 12.1 months (range 6 – 54.2 months). The treatment was well tolerated. Toxicity was mainly bone marrow suppression. There were four episodes of neutropenic fever, but no renal toxicity or treatment-related death was documented. The combination of carboplatin given at a fixed dose of 300 mg/m² for 1 day and 5-fluorouracil given at 1 g/m² per day for 3 days produced an objective response rate of 38% and tolerable side effects. Received: 21 October 1995 / Recepted: 1 March 1996     

Phase II trial of biweekly paclitaxel plus infusional 5-fluorouracil and leucovorin in patients with advanced or recurrent inoperable gastric cancer

Purpose  To investigate the efficacy and safety of combination chemotherapy with biweekly paclitaxel plus infusional 5-fluorouracil and leucovorin in the treatment of patients with advanced or metastatic gastric cancer. Patients and methods  Chemonaive patients with histologically confirmed advanced or recurrent inoperable gastric cancer were enrolled in the present study. Treatment consisted of paclitaxel (75 mg/m²) and leucovorin (40 mg/m²) as a 2-h intravenous infusion, followed by 5-fluorouracil (2,400 mg/m²) as a 46-h continuous infusion. Cycles were repeated every 2 weeks. Results  Thirty patients were enrolled in this study. There were 12 partial responses, giving an overall response rate of 40.0%. At a median follow-up of 10.6 months, the median time to progression and median overall survival were 3.9 and 8.8 months, respectively. The most common hematological toxicity was grade 1–2 anemia, which was seen in 83.3% of patients. No grade 4 leukopenia, thrombocytopenia, or anemia was noted. The most common non-hematological toxicity was anorexia, which was seen in 70% of patients, although grade 3 anorexia was noted in only 10% of cases. There was no severe treatment-related morbidity or death. Conclusion  Combination chemotherapy consisting of biweekly paclitaxel plus infusional 5-fluorouracil and leucovorin was effective and well tolerated in patients with advanced gastric cancers.     

Peripheral blood mononuclear cell dihydropyrimidine dehydrogenase activity in volunteers with and without diabetes mellitus

 It has been reported that cancer patients with diabetes mellitus receiving a continuous infusion of 5-fluorouracil (5-FU) have more toxicity and higher plasma 5-FU levels than patients without diabetes mellitus. Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-FU. DPD activity in peripheral blood mononuclear cells has been reported to correlate inversely with 5-FU plasma levels in patients. We therefore undertook a study to compare the activity of DPD in peripheral blood mononuclear cells of human subjects with and without diabetes mellitus. The study groups comprised 43 volunteers with and 39 without diabetes mellitus, and peripheral blood mononuclear cell DPD activity was assayed on samples obtained between 8 a.m. and 11 a.m. DPD activity was not decreased in diabetic subjects. There was no relationship between DPD activity and gender, body mass index, or race. There was a modest correlation between DPD activity and age (r=0.19, P=0.08). We conclude that increases in 5-FU-related toxicities in diabetics must be related to factors other than peripheral blood mononuclear cell DPD activity. Received: 24 March 1995/Accepted: 21 July 1995     

Thymidylate synthase inhibition by an oral regimen consisting of tegafur-uracil (UFT) and low-dose leucovorin for patients with gastric cancer

 Purpose: 5-Fluorouracil (5-FU) remains a standard therapy for patients with advanced gastric cancer. There has been no study using an oral regimen with a combination of tegafur, a masked compound of 5-FU, and leucovorin in gastric cancer. The purpose of this study was to determine whether orally administered low-dose leucovorin enhances thymidylate synthase (TS) inhibition when added to tegafur-uracil (UFT) in patients with gastric cancer. Methods: A group of 26 patients with resectable gastric cancer were assigned to one of two regimens: UFT alone or UFT plus leucovorin. UFT, equivalent to 400 mg/day tegafur, with or without 30 mg/day leucovorin, was administered orally in divided daily doses every 12 h for 3 consecutive days prior to surgery. Tumor specimens were taken immediately following gastrectomy, and the TS inhibition rate (TSIR) was determined using a ligand-binding assay. Results: The TSIR was significantly higher in the UFT plus leucovorin group than in the UFT alone group (P<0.01). The TSIR in the patients treated with UFT alone ranged between 14% and 50%, while six of the eight patients treated with UFT plus leucovorin had a TSIR of 55% or higher. The remaining two patients in the group treated with UFT plus leucovorin, with a TSIR of 31% and 44%, had undifferentiated tumors. Conclusion: Our results suggest that orally administered low-dose leucovorin can add to the efficacy of UFT in patients with gastric cancer, and provide preliminary data for a randomized clinical trial. Received: 27 June 1995/Accepted: 6 December 1995     

氟尿嘧啶/亚叶酸钙+紫杉醇联合化疗双周方案治疗晚期胃癌

背景与目的：近来有临床研究显示紫杉醇(paclitaxel,PTX)可用于治疗胃癌,与5．氟尿嘧啶(5-fluorouracil,5-FU)联合治疗晚期胃癌疗效显著,不良反应轻。本研究观察5-Fu／亚叶酸钙(1eueovorin,CF) PTX联合化疗双周方案治疗晚期胃癌的临床疗效和不良反应。方法：采用高剂量5-FU／CF PTX深静脉输注方案(CF 200mg／m^2,静滴2小时,第1天;5-FU 500mg／m^2,静脉推注,第1天;5-FU 1500mg／m^2,静滴46小时;PTX90mg／m^2,静脉输注3小时,第1天),化疗方案以每两周为1周期,重复4周期后评定疗效。结果：全组20例均可评价疗效,总有效率为65．0％(13／20),其中完全缓解(CR)率为10.0％(2／20),部分缓解率为55．0％(11／20)。无治疗相关死亡,主要不良反应为口腔炎、手足综合征和脱发。结论：5-FU／CF PTX联合化疗双周方案治疗晚期胃癌缓解率较高、不良反应可耐受,是治疗晚期胃癌安全有效的化疗方案。     

Bioavailability of subcutaneous 5-fluorouracil: a case report

 The optimal schedule for the administration of 5-fluorouracil (5-FU) in the management of advanced colorectal cancer remains to be determined. It has been suggested that this drug may be given by the subcutaneous route and that following a short infusion the bioavailability is similar to that observed after intravenous administration. We report the results we obtained in a patient treated with an intravenous bolus of 5-FU followed by a 22-h subcutaneous infusion. In this patient the bioavailability of 5-FU given by subcutaneous infusion was 0.94. The steady-state plasma levels of 5-FU reached during subcutaneous infusion were comparable with those achieved during intravenous infusion. Following four cycles of subcutaneous therapy, painless blistering was noted at the infusion sites, which healed following the cessation of subcutaneous therapy. Further studies are required to evaluate this route of therapy as an alternative to protracted intravenous therapy. The main dose-limiting side effect appears to be local skin toxicity. Received: 27 August 1995 / Accepted: 16 November 1995     

Extensive liver metastasis of gastric cancer effectively treated by hepatic arterial infusion of 5-fluorouracil/cisplatin

Most gastric cancer patients with jaundice caused by extensive liver metastasis show no tumor shrinkage response to systemic chemotherapy, while often showing severe adverse reactions. Their prognosis is very poor. We experienced two patients for whom hepatic arterial infusion (HAI) of 5-fluorouracil (5-FU) and cisplatin through an implantable port was effective for treating extensive liver metastasis. One patient had jaundice (serum bilirubin level before HAI therapy, 12.4 mg/dl) caused by metachronous liver metastasis, and prior systemic chemotherapy with 5-FU and irinotecan had not been effective. The other patient had gastric cancer with synchronous liver metastasis and also exhibited jaundice (serum bilirubin level before HAI therapy, 11.8 mg/dl). Both patients were treated with HAI of cisplatin, 20 mg/m ² for 30 min on day 1, and continuous intraarterial infusion of 5-FU, 300 mg/m ² , from day 1 to day 4 every week. Their metastatic liver tumors were significantly reduced in volume and the jaundice disappeared. They survived for 30 and 27 weeks, respectively. A pharmacokinetic study conducted during the period of partial remission revealed that the extraction ratios of 5-FU and cisplatin in the liver were 0.89 and 0.024, respectively, suggesting a favorable first-pass effect of 5-FU. Although our findings here suggest that the successful local control of liver metastasis could improve the deteriorated condition and prolong the survival in some patients with far advanced cancer, it is essential to pay much attention to possible adverse effects during the treatment. Received: April 17, 2000 / Accepted: July 12, 2000     

5-Fluorouracil and low-dose leucovorin in metastatic colorectal cancer: a pilot study

 A total of 56 consecutive patients with metastatic colorectal cancer received treatment with 5-fluorouracil (5-FU) given at 425 mg/m² by rapid intravenous infusion, immediately preceded by leucovorin (LV) given at 20 mg/m², with cycles being repeated every 4 weeks. Of 48 evaluable patients undergoing this treatment, a tumor response was observed in 16 (33%); a complete response, in 2 (4%); and a partial response, in 14 (29%). The median survival was 8.5 months for all patients and 16.5 months for responders. An improvement in symptoms was seen in 9 (26%) of 34 symptomatic patients. In all 15 (27%) of 44 evaluable patients showed an improvement in performance status. The most significant toxicity attributable to the treatment was mucositis of grade 3 or 4, seen in 27% of the patients. Altogether, 2 patients (3.5%) were hospitalized for treatment-related toxicity. We conclude that the combination of 5-FU and low-dose LV is active in advanced colorectal cancer and is associated with acceptable toxicity. Received: 9 May 1994/Accepted: 15 July 1994     

Phase II multicenter trial of docetaxel, epirubicin, and 5-fluorouracil (DEF) in the treatment of advanced gastric cancer: a novel, safe, and active regimen

Background This study evaluated the efficacy and safety of docetaxel, epirubicin, and 5-fluorouracil (5-FU) [DEF] as treatment for locally advanced unresectable or metastatic gastric cancer. Methods Thirty-seven patients participated in the study (median age, 56 years; range, 22–73 years); Eastern Cooperative Oncology Group performance status [PS], 0–2). Docetaxel 75 mg/m² IV (day 1), 5-FU 500 mg/m² IV (days 1–3), and epirubicin 50 mg/m² IV (day 1) were administered every 3 weeks for six cycles. Results In total, 20/37 patients (54%) completed six treatment cycles. Thirteen patients (35%; 95% confidence intervals [CI], 20% to 51%) had an objective response; 1 patient (3%) achieved a complete response and 12 patients (32%) achieved partial responses. Stable disease was observed in 7 patients (19%) and progressive disease in 5 patients (14%). Twelve patients (32%) were unevaluable. Clinical benefit (based on PS, weight gain, and analgesic consumption) was observed in 11 patients (30%). Median follow-up was 41 months (range, 26–53 months), median time to progression was 6.6 months (range, 0.5–29.2 months), median overall survival was 10.7 months (range, 7.0–14.6 months), and 1-year survival was 40%. The regimen was well tolerated. Grade 3–4 febrile neutropenia occurred in 8 patients (22%; 6% of cycles) and grade 3–4 neutropenia in 1 patient (1% of cycles). The most frequent grade 3–4 toxicities were alopecia (11% of cycles), diarrhea (4% of cycles) and vomiting (2% of cycles); grade 1–2 asthenia and fatigue occurred in 43% of cycles. Conclusion DEF is effective in the treatment of advanced gastric cancer, and has a good safety profile. Presented at: 2002 ASCO Meeting (Poster Section): Proc Am Soc Clin Oncol 2002;21:163a and 2002 ESMO Meeting (Poster Section): Ann Oncol 2002;13(Suppl 5):192     

多西紫杉醇联合氟尿嘧啶及顺铂治疗晚期胃癌

 目的 观察国产多西紫杉醇（TAT）联合亚叶酸钙／5-氟尿嘧啶（CF／5Fu）及顺铂（DDP）治疗晚期胃癌的临床疗效与不良反应。方法 41例晚期胃癌患者接受TAT与CF／5-Fu及DDP联合化疗：TAT75mg／m2，静滴1h，d1；CF100mg，静滴2h，d1-5；5-Fu500mg／m2，22h微泵持续静滴，d1-5；DDP25mg／m2，静滴，d，1-3。28天为一个周期。治疗2个周期后评价疗效和不良反应。结果 41例患者均可评价疗效。完全缓解2例，部分缓解23例，有效率61．0％。中位疾病进展时间7．5个月，中位生存期10．6个月，1年生存率41．5％。主要不良反应为骨髓抑制，脱发和周围神经炎。结论 国产多西紫杉醇联合亚叶酸钙／5-氟尿嘧啶及顺铂治疗晚期胃癌缓解率高，毒副反应可以耐受。     

FOLFOX4方案治疗晚期胃癌的临床观察

目的:观察FOLFOX4方案治疗国人晚期胃癌的近期疗效和毒副反应。方法:28例晚期胃癌患者,先给予FOLFOX4方案,即:奥沙利铂(L-OHP)85mg/m2静脉点滴2h,d1;亚叶酸钙(CF)200mg/m2静脉点滴,2h,d1、d2;随后氟尿嘧啶(5-FU)400mg/m2静脉推注,d1、d2,5-FU600mg/m2微泵持续静脉滴注22h,d1、d2。2周重复。4个周期后以WHO评价标准评价疗效和毒性。结果:全组28例均可评价,其中完全缓解(CR)2例,部分缓解(PR)14例,稳定(SD)7例,进展(PD)5例,总有效率(CR PR)57.1%。中位肿瘤进展时间(TTP)5.5个月,中位生存时间(MST)为9个月。毒副反应主要是骨髓抑制,白细胞降低发生率达82.1%,其次为胃肠道反应,恶心呕吐发生率78.6%,口腔粘膜炎为21.4%,腹泻35.7%,无Ⅲ/Ⅳ度胃肠道反应;周围神经毒性发生率为46.4%。结论:FOLFOX4方案治疗国人晚期胃癌的近期疗效较好,毒副反应可以耐受,值得进一步研究应用。     

Phase I dose-escalating study of 24-h continuous infusion of 5-fluorouracil in combination with weekly docetaxel and cisplatin in patients with advanced gastric cancer

Purpose

To determine the maximum-tolerated dose (MTD) of a 24-h continuous infusion of 5-fluorouracil (5-FU) when administered in combination with a fixed weekly dose of docetaxel and cisplatin in patients with advanced gastric cancer.

Methods

Patients with advanced gastric adenocarcinoma (n = 21) received a weekly regimen of docetaxel, cisplatin and 5-FU (DCF) for 3 consecutive weeks every 4 weeks. The doses of docetaxel and cisplatin were fixed at 33.3 and 30 mg/m², respectively. The dose of 5-FU was increased from a starting dose of 1,000 mg/m² to the MTD.

Results

A total of 53 cycles of chemotherapy were administered (median = 3 cycles/patient). The MTD of 5-FU was 1,750 mg/m². All 21 patients were assessed for toxicity and 19 patients (90%) were evaluated for response. Both grade 3–4 hematologic and non-hematologic toxicities occurred in less than 10% of patients and there were no treatment-related deaths. Among the 19 patients, we observed 1 complete and 4 partial responses for an overall response rate of 26% (95% CI: 6–46%). This rate increased to 39% (95% CI: 12–66%) in 13 chemotherapy-naïve patients.

Conclusions

A consecutive weekly DCF regimen at 4-week intervals appears feasible for advanced gastric cancer with a favorable toxicity profile. The recommended doses are 33.3 mg/m² of docetaxel, 30 mg/m² of cisplatin and 1,500 mg/m² of a 24-h continuous intravenous infusion of 5-FU. The response of this weekly regimen in our study was favorable and deserved further investigation in a phase II trial.     

Tumor size and origin determine the antitumor activity of cisplatin or 5-fluorouracil and its modulation by leucovorin in murine colon carcinomas

 5-Fluorouracil (FUra) is one of the few effective agents in the treatment of patients with colorectal cancer. Its effects on the target enzyme thymidylate synthase (TS) can be modulated by leucovorin (LV) or cisplatin (CDDP). Tumor size and differentiation of tumor characteristics can influence therapeutic efficacy. We therefore studied the relationship between tumor size (cutoff point 200 mm³) and the antitumor activity of FUra and its modulation by LV in murine Colon 26 and Colon 38 tumors. The doubling time of tumors measuring >200 mm³ was about 160% longer. The antitumor effect of FUra in these large tumors was decreased and could not be modulated by LV. In addition, three subtypes of Colon 26 (Colon 26-A, Colon 26-B, and Colon 26-10) were identified and characterized for tumor-induced weight loss, TS activity, response to chemotherapy, and histological features. Mice bearing Colon 38 and Colon 26-10 did not lose weight as a result of tumor growth. Colon 26-A caused a weight loss of up to 19%, whereas mice with Colon 26-B tumors remained within 10% of their initial weight and tolerated at least 2.5 times more tumor load than did mice bearing Colon 26-A, which induces cachexia. Among untreated tumors, TS catalytic activity was highest in Colon 26-B (5536 pmol mg protein^-1 h^-1) and lowest in Colon 38 (799 pmol mg protein^-1 h^-1); Colon 26-A and Colon 26-10 had intermediate activities (about 2500 pmol mg protein^-1 h^-1). 5-Fluoro-2′-deoxyuridine monophosphate (FdUMP) binding was comparable in the three Colon 26 subtypes but was lower in Colon 38. The antitumor activity of FUra could be modulated by LV in Colon 38, Colon 26-10, and Colon 26-A but could not in Colon 26-B, with complete responses (CR) being obtained in Colon 26-10 and Colon 38. The latter two were highly sensitive to CDDP, followed by Colon 26-A and Colon 26-B (CRs: 50%, 40%, 25%, and 0, respectively). Furthermore, necrosis was noted in Colon 26-B and Colon 38 but not in Colon 26-A. In conclusion, (1) the antitumor activity of FUra in large tumors is decreased and cannot be modulated by LV and (2) characteristics and sensitivity to chemotherapeutics can vary substantially in closely related tumors of the same origin. Received: 12 August 1995 / Accepted: 20 March 1996     

Gemcitabine (GEM) plus oxaliplatin, folinic acid, and 5-fluorouracil (FOLFOX-4) in patients with advanced gastric cancer

Background and aims: oxaliplatin in combination with folinic acid (FA) and infusional 5-fluorouracil (5-FU) has shown significant anti-tumor activity in gastric cancer patients (FOLFOX). Previous studies have shown that gemcitabine (GEM), a new fluorinated anti-metabolite, enhances the individual anti-tumor activity of either 5-FU or oxaliplatin. We have therefore designed a multi-center phase II trial in order to test a novel GEM + FOLFOX-4 regimen in patients with metastatic gastric cancer. Methods: we enrolled 36 patients, 28 males and 8 females, with an average age of 64.4 years (range 37–78), who received bi-weekly treatment with GEM (1,000 mg/m² on day 1), levo-FA (100 mg/m² on days 1 and 2), a 5-FU (400 mg/m²) bolus injection followed by 22-h continuous infusion (800 mg/m²) on days 1 and 2, and oxaliplatin 85 mg/m² in a 4–6 h intravenous (i.v.) infusion before the second FUFA administration on day 2. Results: the most frequent side effect was grade 1–2 hematological toxicity and late sensorial neurotoxicity. Two patients developed hypersensitivity to oxaliplatin while another developed an aseptic eosinophilic pneumonitis. Two patients refused to continue the treatment after two cycles of chemotherapy and were lost at the follow-up. Among the remaining 34 patients four achieved a complete response, 15 a partial response, 12 had a stable disease and three progressed. Conclusions: these results may grant the rationale to evaluate this multi-drug combination in randomized phase III trials in advanced gastric cancer.