Pharmaco-dynamic study of methotrexate (MTX) during intraperitoneal MTX/5-FU sequential therapy after gastric surgery

A pharmaco dynamic study of Methotrexate (MTX) during intraperitoneal MTX/5-FU sequential therapy was carried out after gastric surgery. A comparative study of the route of MTX administration and its dose was also done. 1) Comparative study of the serum concentration of MTX between i.p. and i.v. administration revealed a similar MTX concentration except immediately after administration. 2) A comparative study of the serum concentration of MTX administered i.p. between patients with and without malignant ascites was conducted. Immediate elevation of the serum concentration of MTX was observed in patients without malignant ascites. On the other hand, the MTX concentration was slowly elevated and washed out in patients with malignant ascites. 3) The MTX concentration in the intraperitoneal fluid was compared between patient with and without malignant ascites. In patients without malignant ascites, MTX disappeared quickly from the intraperitoneal fluid. However, the MTX concentration lasted long in the malignant ascites cases. These results were similar with a low-dose MTX (30 mg/body) or moderate dose (100 mg/body). MTX/5-FU sequential i.p. therapy can thus be an effective treatment for patients after gastric surgery, though clearance of MTX was slow in cases with malignant ascites.     

Biliary and pancreatic excretion of methotrexate (MTX) and 5-FU on the MTX/5-FU sequential therapy

On the postoperative adjuvant MTX/5-FU sequential therapy, biliary and pancreatic excretion of both drugs was studied through the hepatic and pancreatic drainages in pancreatoduodenectomized patients. MTX: 100 mg/m2 of bolus injection and 5-FU: 800 mg/m2 of sequential one hour drip infusion were used in this series. Biliary excretion of MTX was reached peak concentration at 90 min, its mean value being 5 fold of serum concentration. During the observation period of 4.5 hours, the recovery of MTX in bile was calculated as 3-12% which presumed to be more because of still continuing biliary excretion on the terminal observation. Pancreatic excretion of MTX was minimal and not so as to have further clinical meaning. Though the serum concentration of 5-FU was raised up with its infusion, biliary and pancreatic outputs of 5-FU were small, each value showing one third compared with at a single shot of the same doses. From the obtained mode and time lag of concentration curves of both drugs, the rationale of per oral and earlier administration of Leucovorin was discussed as a possible way of removal of MTX from intestine.     

Therapeutic effect of sequential doses of methotrexate (MTX) and 5-fluorouracil (5-FU) in advanced gastric cancer: comparison of intermediate-dose MTX with high-dose MTX

Twenty-one patients were treated with sequential doses of MTX and 5-FU so as to be classified by MTX dosage into an intermediate MTX-dose group and a high MTX-dose group. In the intermediate-dose MTX group, the drug was given at a dosage of 100 mg/m2 intravenously (i.v.) and followed 1 hour later by 5-FU at 800 mg/m2 i.v. (dripping for 1 hour); the drugs were recycled every 1 week. In the high-dose MTX group, the drug was administered at a dose of 1.5 g/m2 i.v. (dripping for 2 hours) and followed 1 hour later by 5-FU at 1.5 g/m2 i.v. (dripping for 2 hours); the drugs were recycled every 2-3 weeks. Average MTX concentrations in serum at the start of 5-FU administration were 1.69 X 10(-5) and 1.33 X 10(-4) mol/l/h in the intermediate and high-dose MTX groups, respectively. Six (50%) of 12 patients adequately treated with intermediate-dose MTX had a partial response (PR), and one (14.3%) of 7 evaluable patients treated with high-dose MTX had a PR. Major toxicity included diarrhea (33.3%) in the intermediate-dose MTX group and hair loss (71.4%) in the high-dose MTX group. Hematological toxicity was mild in MTX group: six (50%) of 12 patients had a granulocyte count nadir less than 1,000/microliters and one (8.3%) of 12 patients had a platelet count nadir less than 10(5)/microliters in the intermediate-dose MTX group. Five (71.4%) of 7 patients had a granulocyte nadir less than 1,000/microliters and two (28.6%) of 7 patients had a platelet count nadir less than 10(5)/microliters in the high-dose MTX group.     

A case of advanced gastric cancer with DIC treated by sequential MTX and 5-FU

A 75-year-old man was admitted to our hospital complaining of gastric fatigue. Endoscope and CT scan revealed type 3 gastric cancer with paraaortic lymph nodal metastasis. Histological examination of the endoscopic biopsy revealed poorly differentiated adenocarcinoma. A blood examination and bone marrow biopsy revealed DIC causing bone marrow carcinosis. Chemotherapy with sequential therapy consisting of MTX and 5-FU was performed. Stretch of the fold and flatness of the ulcer were obtained against the gastric primary lesion observed endoscopically. Complete response was obtained against the lymph node around the abdominal aorta. Reduction of low back pain and DIC were observed. He was thus able to be discharged and sequential therapy was performed again over 2 months in outpatient care.     

Combined 5-fluorouracil (5-FU) and radiation therapy following resection of locally advanced gastric carcinoma

Twenty-five patients with locally advanced but resectable adenocarcinoma of the stomach were given concomitant postoperative radiotherapy to the tumor bed and chemotherapy with 5-Fluorouracil (5-FU). Twenty-two of the patients had regional lymph node involvement and seven had residual tumor in the surgical margins. Radiotherapy was delivered to a total dose of 5,000 rads in 7 weeks with a two-week split. 5-FU was given daily the first 3 days of each treatment period and was then continued weekly for a minimum of 1 year. At a median follow-up time of 19 months, 11 patients have relapsed, two locally and nine distally, and all have died. Thirteen patients remain alive, all but one disease-free, for a median of 21 months from diagnosis. One additional patient died of unrelated causes, free of tumor. The actuarial median survival for the whole group stands at 33 months with a projected 5-year survival of 40%. Treatment has been well tolerated.     

Efficacy of sequential methotrexate and 5-fluorouracil (MTX/5FU) in improving oral intake in patients with advanced gastric cancer with severe peritoneal dissemination

Background

Although peritoneal dissemination of gastric cancer is common and often causes deterioration of the patient’s condition and quality of life (QOL), these patients are usually excluded from clinical trials. We retrospectively investigated the clinical benefit and toxicity of sequential methotrexate and 5-fluorouracil (MTX/5FU) therapy for patients with peritoneal dissemination.

Methods

The subjects were 31 patients with severe peritoneal dissemination of gastric cancer who were treated with MTX/5FU. The treatment schedule comprised weekly administration of MTX (100 mg/m²) followed by 5FU (600 mg/m²). Leucovorin (10 mg/m²) was administered six times, every 6 h, starting 24 h after MTX administration.

Results

The median survival time was 255 days, and the median progression-free survival was 127 days. Of the 21 patients with measurable lesions, 4 (19%) patients achieved a partial response. Ascites volume decreased markedly in 14 (54%) of the 26 patients with ascites. Seventeen patients had adequate oral intake, but the other 14 patients had required nutritional support before treatment. The median dripinfusion free survival was 100 days in the former 17 patients, and oral intake improved in 3 (21%) of the latter 14 patients. Grade 3 or 4 neutropenia was observed in 26% of the patients and anemia was observed in 45%. The grade 3 nonhematological toxicities were vomiting (6%) and fatigue (10%). Early death, within 30 days of the last administration of MTX/5FU, occurred due to disease progression in 2 patients, but there were no treatment-related deaths.

Conclusion

MTX/5FU chemotherapy may be effective in treating peritoneal dissemination of gastric cancer and might improve the patient’s condition in terms of reducing ascites and improving oral intake.     

Cyclophosphamide plus 5-FU versus 5-FU alone in advanced gastric carcinoma

30 patients with advanced metastatic gastric adenocarcinoma, having a measurable indicator lesion, were randomized (1:2) to receive (intravenously) either weekly 5-fluorouracil alone (15 mg/kg) or combination treatment with cyclophosphamide (20 mg/kg) given on day 1 and 5-FU (15 mg/kg) given weekly on weeks 2-5, beginning on day 8. The combination cycle was repeated at 6-week intervals. Although the toxic effects of therapy were similar in both arms, the addition of cyclophosphamide to the single-agent 5-FU regimen did not increase either the frequency of objective response (5-FU 18%, combination 16%) or improve the median survival of patients with advanced measurable gastric carcinoma (5-FU 4.4 months, combination 5.2 months). Patients with pretreatment weight loss greater than 10% had significantly (p less than 0.05) shorter median survival (2.8 versus 5.6 months) compared to patients without weight loss.     

Phase II study of Adriamycin with sequential methotrexate and 5-fluorouracil (AMF) in gastric carcinoma

Summary The purpose of this study was to evaluate the response rate, methotrexate plasma levels, and toxicity of a three-drug regimen in patients with gastric carcinoma. A total of 37 patients with advanced measurable adenocarcinoma of the stomach were treated with Adriamycin, methotrexate, and 5-fluorouracil (AMF). Adriamycin and methotrexate were given as i.v. infusions on day 1; 24 h following methotrexate administration, patients received an i.v. infusion of 5-fluorouracil concomitantly with oral leukovorin factor (given over 48 h). Methotrexate levels were monitored regularly in all patients, and courses were repeated every 3 weeks. The median dose levels per course were 50 mg/m² (range, 40–60 mg/m²) for Adriamycin, 1,000 mg/m² (range, 650–1,250 mg/m²) for 5-fluorouracil, and 500 mg/m² (range, 160–625 mg/m²) for methotrexate. Of 36 evaluable patients, 8 (22%) achieved an objective response, including 1 complete remission. Stable disease was noted in 11 patients and a minor tumor regression occurred in 1. The median survival duration of all patients was 6 months (range, 2–31 + months). AMF was well tolerated; toxicities were mild to moderate, most frequently involving nausea and vomiting, mucositis, and neutropenia with or without fever. There was no death directly attributable to chemotherapy. Although the AMF regimen used a well-documented preclinical concept of synergism between methotrexate and 5-fluorouracil, response and survival results suggest a modest activity of this combination in patients with gastric cancer. Better preclinical models are necessary for the development of effective combination chemotherapy.     

Phase II study of sequential high-dose methotrexate (MTX) and 5-fluorouracil (F) alternated with epirubicin (E) and cisplatin (P) [FEMTX-P] in advanced gastric cancer

BACKGROUND:: FAMTX (5-fluorouracil, adriamycin, methotrexate) is one of themost effective drug combinations in gastric cancer. Therefore,modifications of FAMTX appear of interest and the FEMTX-P regimentwas conceived. PATIENTS AND METHODS:: Fifty patients with unresectable locally advanced and/or metastaticgastric carcinoma were treated with methotrexate 1500 mg/m²i.v. and 5-fluorouracil 1500 mg/m² i.v. on day 1; leucovorinrescue 15 mg/m² orally every 6 hours for 8 doses on days 2 and3; epirubicin 60 mg/ m² i.v. and cisplatin 50 mg/m² i.v. onday 15, q 4 weeks. RESULTS:: Of forty-seven patients evaluable for response, five (11%) achievedcomplete responses and seventeen (36%) partial responses (totalresponse rate 47%). The median duration of response was 8+ months(range: 5–25+ months). Four of 14 patients with locallyadvanced disease were successfully downstaged and subsequentlyresected. The median duration of survival of all patients was10 months (range: 1–25+ months). Leukopenia grade 4 occurredin 18% of patients and thrombocytopenia grade 4 and mucositisgrade 4 in 4% and 2%, respectively. Treatment postponement forhematologic toxicity was necessary in 54% of patients. CONCLUSIONS:: The FEMTX-P regimen is an active regimen in advanced gastriccarcinoma, with acceptable toxicity. chemotherapy, FEMTX-P, gastric cancer     

Continuous venous infusion of 5-fluorouracil (5-FU) under total parenteral nutrition (TPN) in advanced gastric cancer

Continuous venous infusion of 5-FU was investigated in patients with advanced gastric cancer under TPN. In preliminary research Yoshida Sarcoma-bearing rats were continuously infused with 5-FU at a dose of 20 mg/kg/day under TPN. The 5-FU level in the tumor was 2-5 times higher than that in the kidney, stomach, intestine and liver, and 40-50 times higher than that in serum. Advanced gastric cancer patients were continuously infused with 5-FU at a dose of 500 mg/day under TPN. Serum 5-FU level was constantly maintained at 0.05 mcg/ml during the infusion period. The effects of 5-FU continuously infused with other anticancer agents and TPN were satisfactory with regard to anticancer response and general condition. In conclusion, in advanced cancer, 5-FU is recommended for use in continuous infusion at a dose of 500 mg/day under TPN.     

Continuous 5-fluorouracil infusion in advanced gastric carcinoma

Fourteen patients with advanced gastric adenocarcinoma were treated with continuous 5-fluorouracil (5-FU) infusion, 300 mg/m2/day, through an indwelling central venous catheter; 13 were evaluable for response. The results were as follows; Partial remission was seen in 4 of 13 patients (31%), stable disease in 5 of 13 patients (38%), and progressive disease in 4 of 13 patients (31%). The median duration of response was 19 weeks (range, 10-41), and the median survival for all patients from initiation of infusion was 27 weeks (range, 9-54). Treatment interruption and/or dosage attenuation for toxicity was necessary in 7 of 14 patients (50%); however, myelosuppression, alopecia, and nausea and vomiting were not observed. 5-FU infusion is well-tolerated, palliative therapy for patients with advanced gastric carcinoma and may warrant further investigation in combination with other chemotherapeutic drugs.     

Postoperative immunochemotherapy (BCG + 5-FU) in advanced gastric cancer

Three hundred and twenty-two patients with locally advanced (stages III and IVA) and disseminated (stage IVB) gastric cancer were included in a randomized trial to assess the effect of immunochemotherapy (BCG and 5-fluorouracil,5-FU). The survival of patients receiving chemoimmunotherapy was compared to chemotherapy (5-FU) or no further treatment (control) groups. Patients with stage III underwent radical surgery (subtotal or total resection), stage IVA palliative resection, while explorative laparotomy or bypass was performed in stage IVB. Patients with stage III and IVA receiving immunochemotherapy had significantly (p less than 0.05) prolonged survival in comparison to chemotherapy or control groups. Prolongation of survival was more pronounced in patients with diffuse type carcinoma than in patients with intestinal type of tumour according to Lauren's classification. The survival of patients receiving chemotherapy was somewhat shorter than that of the control group, but the differences were not statistically significant. There was no effect of either immunochemotherapy or chemotherapy in patients with stage IVB. No serious side effects of immunochemotherapy were noted. These results indicate that immunochemotherapy may be a safe form of adjuvant treatment in patients with operable gastric cancer.     

Sequential MTX and 5-FU therapy of gastric cancer with systemic bone metastasis and disseminated intravascular coagulation]

Sequential therapy consisting of methotrexate (MTX) and 5-FU was performed together with the administration of heparin and FOY in 10 cases of gastric cancer with disseminated intravascular coagulation (DIC) causing systemic bone metastasis. The ages of the subjects ranged from 29 to 65 years (median: 49 years) with systemic bone metastasis and bone marrow carcinosis observed in all cases. Histological types consisted of 6 cases of poorly differentiated adenocarcinoma, 2 cases of signet-ring cell carcinoma, and one case each of mucocellular and tubular adenocarcinoma. Therapy consisted of intravenous injection of 30 mg-100 mg/m2 (one case, 20 mg) of MTX followed three hours later by intravenous injection of 600 mg/m2 of 5-FU weekly. Determination of DIC was made in accordance with the DIC diagnostic standards of the Ministry of Health and Welfare, and determination of tumor effectiveness was based on gastric cancer handling codes. Results: PR was observed in 3 cases. Diffuse metastasis observed in the entire lung field disappeared in one case, while remarkable improvement was observed in systemic bone metastasis in scintigram findings for the other 2 cases. All 3 cases were able to be discharged. Reduction of DIC score and absence of pain were observed in 8 cases. Based on the above, aggressive implementation of this treatment method is suggested.     

Combination therapy with 5-FU, etoposide and CDDP (FEP regimen) in advanced primary and recurrent gastric cancer]

Surgery is still the treatment of choice in gastric cancer. However, despite the availability of extended surgical procedures, the majority of patients with stage IV gastric cancer have a poor prognosis. Therefore, other treatment modalities, especially systemic chemotherapy, have been investigated intensively. The recent successes achieved with combination chemotherapy regimens, such as EAP, strongly indicated that gastric cancer is chemosensitive. We also treated previously untreated patients with advanced and recurrent gastric cancer. Chemotherapy of CDDP 30 mg/m2 was given intravenously (i.v.) on day 1; etoposide 70 mg/m2 (i.v.) on days 2 to 4; and 5-FU 500 mg/m2 (i.v.) on days 2 to 5. The courses were repeated every 3 weeks. FEP induced an overall response rate of 25%, including 25% PR (primary tumor) and 25% PR (liver-metastasis). The median survival rate for all patients was 7.3 months and partial responses were seen in three patients with a median response duration of 13.1 months. In 2 patients with PR of primary tumor, one patient underwent a second-look operation and one patient refused an operation. Therefore, ten of 12 patients entered have died, and 2 patients remain alive. We concluded that FEP regimen can be useful in the treatment of advanced and recurrent gastric cancer. Moreover, the preoperative use of effective regimens seems to improve prognosis.     

周剂量多西他赛联合顺铂、5-FU治疗晚期胃癌临床研究

背景与目的:大多数胃癌患者确诊时已处于晚期,并伴有相临脏器、淋巴结的广泛侵袭或远处转移.近年来,多西他赛作为一种新的紫杉类药物已通过大量的临床研究证实其可观的疗效,因此我们旨在对比观察多西他赛联合顺铂、5-FU每周方案与三周方案治疗晚期胃癌临床疗效及毒副反应.方法:80例晚期胃癌被分为两组,每周方案组(A组40例):多西他赛25 mg/m2静滴,第1,8,15天,顺铂25 mg/m2静滴,第1～3天,5-FU 500 mg/m2静滴,第1～5天,每4周重复.三周方案组(B组40例):多西他赛75 mg/m2静滴,第1天,顺铂25 mg/m2静滴,第1～3天,5-FU 500 mg/m2静滴,第1～5天,每3周重复.治疗2个周期评价疗效,每周期评价毒性.结果:两组共80例,均无化疗相关性死亡,A组总有效率42.4%,B组总有效率45.0%,两组中性粒细胞Ⅲ/Ⅳ度减少分别为32.5%和77.5%;非血液学毒性主要是Ⅲ/Ⅳ度疲劳乏力,两组分别为22.5%和42.5%.结论:多西他赛联合顺铂、5-FU治疗晚期胃癌每周与三周治疗相比,疗效相似,但每周治疗血液学毒性反应与疲劳乏力感明显下降,耐受性好.     

120-hour 5-fluorouracil (5-FU) continuous infusion (CI) plus BCNU in advanced colorectal cancer

Seventy-five previously untreated patients with measurable advanced colorectal cancer were treated with 5 fluorouracil 1,000 mg/m2 as a 24-hour intravenous (i.v.) continuous infusion during days 1-5 and 28-32 every cycle, plus 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 200 mg/m2 i.v. bolus on day 1, all given every 8 weeks up to 6 cycles. Median Karnofsky performance status (KPS) was 100. Sites of disease at entry were mainly the abdomen (45%) and liver (33%). All patients were evaluable for response and survival. There were two complete responses and seven partial responses (PR) for an overall response rate of 12% (95% confidence limits: 5-20%). Four out of 25 patients with liver metastases alone had PR. Stabilization was seen in 40 patients (53%). Median time to progression was 9.3 months and overall median survival was 12.5 months, whereas median survival for patients with liver metastases alone was 16 months. Toxicity was mild except for 8% with WHO grade 4 mucositis. Only KPS had statistical significance in the multivariate analysis of prognostic factors. It is concluded that this regimen is relatively active and well tolerated in patients with advanced colorectal cancer.     

5-FU/l-LV therapy is useful for hemodialysis patients with advanced gastric cancer

A 71-year-old man receiving maintenance dialysis because of diabetic nephropathy presented with hematemesis at another hospital in January 2008. A gastrointestinal endoscopy demonstrated a II a-like lesion in the angle of the stomach, and he was admitted to our hospital. A diagnosis of gastric adenocarcinoma (cT2N2M0, Stage IIIA) was made. An operation could not be performed because of the high risk, so combination chemotherapy with 5-FU and l-LV was initiated. After 3 courses of treatment, the size of the primary tumor was markedly reduced. After 6 courses, the primary lesion had changed to a scar, and an endoscopic biopsy revealed no cancer cells. His performance status did not deteriorate, and no serious adverse events occurred during the course of treatment. Chemotherapy was continued because the overall response was SD. 5-FU/l-LV therapy should be considered as a safe and useful treatment for a hemodialysis patient with advanced gastric cancer.     

Treatment of unresectable pancreatic carcinoma using irradiation with concurrent intravenous 5-FU infusion therapy

Ten patients with unresectable carcinoma of the pancreas who had only bypass surgery to relieve biliary obstruction were treated with radiation therapy to the pancreas and liver with concurrent 5-fluorouracil (5-FU) intravenous infusion therapy. Treatment regimen was three cycles of chemoradiotherapy with a two week rest period between cycles. 5-FU (1,000 mg/m2 per day) was administered by continuous infusion for the first five days of each cycle. In the first cycle radiotherapy was given to the pancreas to 2,000 cGy/10 fractions using 6 to 10 mV x-rays. In the second cycle 2,400 cGy/160 rads/fraction radiation was delivered to the pancreas and whole liver. In the third cycle, 1,600 cGy/160 rads/fraction to a total dose of 6,000 rads, was administered to the pancreatic tumor. All ten patients completed the treatments without interruption. No major side effects were noticed during the course of treatment. Survival ranged from 9 to 16 months and median survival was 11 months. Symptomatic relief was obtained in all 10 patients. One patient who lived for 16 months developed duodenal stenosis and underwent gastrojejunostomy.     

Sequential therapy with methotrexate and 5-fluorouracil in the treatment of advanced colorectal carcinoma

Twenty-nine patients with advanced colorectal carcinoma were entered in this study to evaluate the efficacy and toxicity of a sequential chemotherapeutic schedule with methotrexate (MTX), 200 mg/m2 intravenously (IV) (push injection) and 5-fluorouracil (5-FU), 1,200 mg/m2 in continuous IV infusion, using a 20-hour time interval. All patients received calcium leucovorin (LV), 25 mg, intramuscularly (IM) every six hours for eight doses beginning 24 hours after methotrexate administration. Courses were administered every 15 days. Of the 24 patients evaluable for response, 11 (46%) had major objective regressions (one complete remission [CR] and ten partial remissions [PR]). The survival rate of patients who responded to treatment was 60% at 16 months, whereas patients with no change and those in whom the disease progressed had a median survival of 9 months and 3 months, respectively. The median duration of response has not yet been reached in patients who presented objective tumor regression, and was 7.5 months in those with no change. Significant differences were found between objective regression and no change (P less than .0005) and between no change and tumor progression (P less than .05). All patients were evaluable for toxicity. There were three toxic-related deaths (10%) because of severe myelosuppresion, sepsis, and hemorrhage. These promising results, despite important toxicity, reveal the synergism between the two chemotherapeutic agents and also indicate that the response rate achieved could be a consequence of the 20-hour interval and high dose of 5-FU. Further studies are necessary to determine the optimal time interval and the adequate 5-FU dose.