Treatment of peritoneal dissemination of gastric cancer with sequential methotrexate and 5-fluorouracil

Background. Pretreatment with methotrexate (MTX) followed by 5-fluorouracil (5-FU) (sequential MTX and 5-FU), exerts biochemical modulation in which the antitumor effect of 5-FU is enhanced by the preceding MTX. Since the early 1980s, the sequential MTX/5-FU regimen has been employed clinically for gastric cancer in Japan, with high response rates for undifferentiated type gastric carcinoma. Methods. Peritoneal dissemination is more frequent in undifferentiated type carcinoma, we therefore employed sequential MTX and 5-FU for the treatment of 39 gastric cancer patients with peritoneal dissemination. We also investigated MTX levels in blood and ascitic fluid during the treatment. Results. Partial response (PR) was achieved in 6 of 26 patients (23%) who had evaluable lesions. PR lesions included abdominal wall tumors, primary gastric foci, inguinal lymph node, and rectal stenosis. Ascites was eliminated in 50% of the patients, and pleural effusion disappeared in 2 patients. Conclusions. In our study, sequential MTX and 5-FU had low toxicity and was beneficial for advanced gastric cancer patients with peritoneal dissemination. Further investigation of this treatment as induction and postoperative adjuvant chemotherapy for Borrmann type 4 gastric cancer seems warranted. Received for publication on Feb. 8, 1999; published on March 15, 1999     

Phase II trial of bimonthly leucovorin, 5-fluorouracil and gemcitabine for advanced pancreatic adenocarcinoma (FOLFUGEM)

Background:Gemcitabine alone or 5-fluorouracil (5-FU) according to several schedules are used for palliation of metastatic and locally advanced (LA) pancreatic adenocarcinoma. This study was designed to test the efficacy of the leucovorin–5-FU and gemcitabine combination. Patients and methods:This phase II trial combined a simplified bimonthly LV5FU2 with gemcitabine: leucovorin 400 mg/m² in a two-hour infusion, followed by 5-fluorouracil 400 mg/m² bolus and 2 or 3 g/m² continuous infusion over 46 hours; gemcitabine 1 g/m² was infused over 30 min on day 3 after 5-FU. Treatment was repeated every two weeks. Gemcitabine dose could be increased (250 mg/m² every two cycles up to 1500 mg/m²) in the absence of NCI-CTC toxicity >2. Results:Among the 62 patients included in this study, 22 had LA and 40 had metastatic disease. Objective response rate for the 54 patients with measurable disease was 25.9% (95% confidence interval (CI): 14%–37.8%) and 22.6% (95% CI: 12%–33.2%) in the intent-to-treat population; the clinical benefit rate for the 59 assessable patients was 49.2%. Median progression-free survival and median overall survival were 4.8 and 9 months, respectively, with 32.3% of patients alive at 1 year. The most frequent toxicity (grade 3–4) was neutropenia (56.5%) usually asymptomatic (1.1% febrile neutropenia), but requiring decreases of 5-FU and gemcitabine doses. Unexpected complete alopecia occurred in 97% of patients. Conclusions:Palliative effects, response rate and survival observed in this multicenter study seem to be superior to those obtained with gemcitabine or 5-FU alone, despite a limiting hematological toxicity.     

Low-dose trimetrexate glucuronate and protracted 5-fluorouracil infusion in previously untreated patients with advanced pancreatic cancer.

BACKGROUND: 5-Fluorouracil (5-FU)-based regimens have not been shown to prolong survival or provide clinical benefit in patients with advanced pancreatic cancer. The purpose of this study was to determine the tolerability of protracted venous infusion (PVI) of 5-FU, modulated by a low dose of the synthetic antifolate trimetrexate, in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Twenty-three chemotherapy-na?ve patients were evaluated. Patients were enrolled in four consecutive cohorts in which the weekly dose of trimetrexate was escalated in 10 mg/m2 increments, from 20 to 50 mg/m2. PVI 5-FU was administered at a fixed dose of 225 mg/m2/day. Treatment was administered for 6 successive weeks, every 8 weeks. RESULTS: Twenty-two patients were assessable. The maximum tolerated dose of trimetrexate was 40 mg/m2. The most common grade 3 and 4 toxicity was diarrhea. There were no treatment-related deaths. Preliminary analysis of activity revealed a response rate of 9%, with 41% of the patients having stable disease for a median duration of 3.8 months. The median survival for the entire group was 6.9 months (range 1-29 months). A clinical benefit response was experienced by 27.2% of patients. CONCLUSIONS: Low-dose trimetrexate can be safely administered in combination with PVI 5-FU. This treatment is well tolerated and is associated with palliative activity in advanced pancreatic cancer.     

High- versus low-dose levo-leucovorin as a modulator of 5-fluorouracil in advanced colorectal cancer: A 'GISCAD' phase III study

Background: Although leucovorin (LV) + 5-fluorouracil (5-FU) isconsidered the treatment of choice for advanced colorectal cancer in mostcountries, the optimal schedule of this combination has not yet beenestablished. Low-dose LV appears to be as active as high-dose LV in thedaily-times-five regimen, but no randomized study of the levorotatorystereoisomer (6S-LV) given at two different dose levels has been published.Patients and methods: Between November 1991 and June 1994, 422patients (all with measurable disease previously untreated with chemotherapy)were randomized to 6S-LV (100 mg/sqm/i.v.) + 5-FU (370 mg/sqm/15 min i.v.infusion), both administered for 5 days every 28 days (arm A), or to 6S-LV (10mg/sqm/i.v.) + 5-FU (doses as above), also given for 5 days every 28 days (armB). The primary endpoint of the study was the comparison of response rates(WHO criteria); the secondary endpoint was the assessment of survival andtolerability. No evaluation of the quality of life or the symptomatic effectof treatment was planned.Results: The response rate was 9.3% in arm A (95% CI:5.4–13.1), with 2 CR and 18 PR, and 10.7% in arm B (95%CI: 6.5–14.9), with 3 CR + 19 PR, without any significant difference(P = 0.78). The median time to progression was eight months in bothgroups and overall survival was 11 months, with no difference betweentreatments. Toxicity mainly consisted of gastrointestinal side effects(mucositis and diarrhoea), which were rarely severe (grade 3–4:5%–10% of patients) and similar in the two groups.Conclusions: In this large-scale multicentre trial, the low and highdoses of 6S-LV appeared to be equivalent in terms of the biochemicalmodulation of 5-FU in advanced colorectal cancer although, for several reasons(including the timing and the strict criteria of response evaluation, the highnumber of patients with unfavourable prognostic factors, themulti-institutional nature of the study, the dose and modality of 5-FUadministration), the response rate was lower than that reported in some of theother published studies. Given the considerable difference in economic costbetween the two dosages, the use of high-dose 6S-LV in the daily-times-fiveregimen is not recommended in clinical practice.     

Phase II study of a triplet regimen in advanced colorectal cancer using methotrexate, oxaliplatin and 5-fluorouracil

Building upon the concept of schedule-specific biochemical modulation of 5-fluorouracil (FU), which alternates bolus and continuous infusion (CI) FU, we have incorporated oxaliplatin (l-OHP) following the bolus part of the regimen to explore the activity of this new combination. Patients with advanced, untreated, measurable colorectal cancer received sequential methotrexate (MTX) (days 1 and 15)-->l-OHP+FU (days 2 and 16) (200, 85 and 600 mg m(-2), respectively) followed by 3 weeks of CI FU (200 mg m(-2) day(-1)) given from day 29 to 50, modulated by weekly leucovorin (LV) (20 mg m(-2)). After 1 week of rest, the second cycle was started. The treatment was continued until progression or patient's refusal. According to the intention-to-treat analysis on all 46 patients accrued, the response rate was 42% (95% CL=28-55%), with three complete responses and 16 partial responses. The median overall survival was 15.9 months and the median progression-free survival 6.9 months. Toxicity was very mild, with the bolus part of the regimen more toxic than the infusional part (24 vs 7% of grade III-IV, respectively). This new combination of MTX -->l-OHP-FU followed by FU CI is well tolerated, feasible and produces activity results similar to other more simple, but more toxic, regimens. Pros and cons of the different fluoropyrimidines-l-OHP combinations are discussed.     

5-fluorouracil modulated by leucovorin, methotrexate and mitomycin: highly effective, low-cost chemotherapy for advanced colorectal cancer

We have reported that an alternating regimen of bolus and continuous infusion 5-fluorouracil (FU) was superior to bolus FU in terms of response rate and progression-free survival in advanced colorectal cancer. Biochemical modulation was an essential part of this regimen and it was selective for the schedule of FU administration: bolus FU was in fact modulated by methotrexate (MTX) while continuous infusion FU was potentiated by 6-s-leucovorin (LV). Considering the low cost and the favourable report on the activity of mitomycin C (mito) added to CI FU, we have incorporated this agent in the infusional part of our treatment programme. 105 patients with untreated, advanced, measurable colorectal cancer were accrued from 13 Italian centres and treated with the following regimen. 2 biweekly cycles of FU bolus (600 mg/m(2)), modulated by MTX (24 h earlier, 200 mg/m(2)) were alternated with a 3-week continuous infusion of FU (200 mg/m(2)daily), modulated by LV (20 mg/m(2)weekly bolus). Mito, 7 mg/m(2), was given on the first day of the infusional period. After a 1 week rest, the whole cycle (8 weeks) was repeated, if indicated. 5 complete and 34 partial responses were obtained (response rate, 37% on the intention to treat basis; 95% confidence limits, 28-46%). After a median follow-up time of 26 months, 37 patients are still alive. The median progression-free survival is 7.7 months with an overall survival of 18.8 months and a 2-year survival rate of 30%. The regimen was very well tolerated with fewer than 13% of patients experiencing WHO grade III-IV toxicity. These results are consistent with those obtained by our group in 3 previous trials of schedule specific biochemical modulation of FU. They also indicate a highly active, little toxic, inexpensive regimen of old drugs to be used (a) as an alternative to the more expensive combinations including CPT-11 or oxaliplatin or (b) as the basis for combination programmes with these agents.     

Treatment of advanced pancreatic cancer with epirubicin, 5-fluorouracil and l-leucovorin: A phase II study

Background: Preclinical data suggest that the levorotatory isomer ofleucovorin (l-LV) can augment the cytotoxic effects of 5-fluorouracil (5-FU)more effectively than racemic LV. A phase II study was initiated to evaluatethe effect of a combination of the pure L-isomer of LV and 5-FU along withepirubicin in patients with advanced pancreatic cancer.Patients and methods: Twenty-eight consecutive, previously untreatedpatients with measurable metastatic adenocarcinoma of the pancreas wereenrolled in this study. Treatment consisted of epirubicin 50 mg/m² onday 1 and 5-FU 400 mg/m² plus l-LV 100 mg/m²both administered on days 1 to 5. Treatment cycles were repeated every fourweeks for a total of six months unless progressive disease was documentedearlier. The study endpoints were survival, toxicity, objective response aswell as palliative beneficial effects of the regimen in terms of performancestatus, body weight and pain.Results: Six patients had a partialresponse (21%; 95% CI, 8% to 44%) and 10(36%) stable disease (35%), while the remaining 12 patients(43%) progressed during treatment. The median time to treatmentfailure was 2.9 months (range 1.2–13.7 months), and the mediansurvival time was six months (range, 1.8–19 months), with threepatients (11%) being alive after one year. Beneficial palliativeeffects in terms of performance status, body weight and/or pain were seen in12 of 28 patients (43%): an improvement in performance status wasrecorded in four patients, pain was attenuated and/or analgetic consumptionreduced by 50% in eight patients, and five patients had weightgain of >5% of their pretreatment body weight.Treatment-associated side effects were generally mild to moderate. Severeadverse reactions included (asymptomatic) granulocytopenia in five,mucositis and/or diarrhea WHO grade 3 in four patients.Conclusion: Our data suggest that epirubicin plus 5-FU andl-LV is a tolerable regimen that has some positive effects in the treatmentof pancreatic cancer. Since this regimen, however, is unlikely to offer anymajor therapeutic advantage compared to monochemotherapy or othercombination regimens, the search for novel and more effective cytotoxicagents must continue.     

Treatment of unresectable, locally advanced pancreatic adenocarcinoma with combined radiochemotherapy with 5-fluorouracil, leucovorin and cisplatin

Although clinical response to primary chemotherapy in stage II and III breast cancer is associated with a survival advantage, it is the degree of pathological response in the breast and ipsilateral axilla that best identifies patients with a good long-term outcome. A mathematical model of the initial response of 39 locally advanced tumours to anthracycline-based primary chemotherapy has been previously shown to predict subsequent clinical tumour size. This model allows for the possibility of primary resistant disease, the presence of which should therefore be associated with a worse outcome. This study reports the application of this model to an additional five patients with locally advanced breast cancer, as well as to 63 patients with operable breast cancer, and confirms the biological reality of the model parameters for these 100 breast cancers treated with primary anthracycline-based chemotherapy. The tumours that responded to chemotherapy had higher cell-kill (P < 0.0005), lower resistance (P < 0.0001) and slower tumour regrowth (P < 0.002). Furthermore, ER-negative tumours had higher cell-kill (P < 0.05), as compared with ER-positive tumours. All patients with a pathological complete response had zero resistance according to the model. Furthermore, the long-term implication of chemo-resistant disease was demonstrated by survival analysis of these two groups of patients. At a median follow-up of 3.7 years, there was a statistically significantly worse survival for the 37 patients with locally advanced breast cancer identified by the model to have more than 8% primary resistant tumour (P < 0.003). The specificity of this putative prognostic indicator was confirmed in the 63 patients presenting with operable disease where, at a median follow-up of 7.7 years, those women with a resistant fraction of greater than 8% had a significantly worse survival (P < 0.05). Application of this model to patients treated with neoadjuvant chemotherapy may allow earlier identification of clinically significant resistance and permit intervention with alternative non-cross-resistant therapies such as taxoids.     

Schedule specific biochemical modulation of 5-fluorouracil in advanced colorectal cancer: A randomized study

Background:We have recently suggested that bolus 5-fluorouracil(5-FU) may work via a RNA directed mechanism while continuous infusion 5-FUmay kill cells via a thymidylate synthase related pathway. It may thus bepossible to selectively modulate each schedule biochemically. We have comparedan alternating regimen of bolus and continuous infusion 5-FU, selectivelymodulated for the schedule of administration, with modulated bolus 5-FU inadvanced colorectal cancer patients. Patients and methods:Two hundred fourteen patients from nineteenItalian centers were randomized to the control arm consisting of biweeklycycles of MTX, 200 mg/m² on day 1, followed by bolus 5-FU 600mg/m² on day 2 and 6-S-leucovorin rescue, or to the experimentalarm consisting of two biweekly cycles of the same regimen as in the controlarm alternated to three weeks of continuous infusion 5-FU (200mg/m² day) + weekly bolus 6-S-leucovorin, 20 mg/m². Results:Nine CR and twenty-seven PR were obtained on one hundredeleven evaluable patients treated in experimental arm (RR = 32%,95% confidence interval (95% CI): 24%–42%),while two CR and eleven PR were observed among one hunderd three evaluablepatients in control arm (RR = 13%, 95% CI:7%–21%). WHO grade 3–4 toxicity occurred in13% of cycles of experimental arm and in 8% of cycles in controlarm. The PFS was significantly longer in experimental arm (6.2 vs. 4.3 months,odds ratio 0.66, P = 0.003), while the overall survival was similarin both arms (14.8 months in experimental arm vs. 14.1 months in control arm);quality of life was similar as well. Eighty percent of patients receivingsecond-line chemotherapy in control arm were treated with continuous infusion5-FU. Conclusions:Alternating, schedule-specific biochemical modulationof FU is more active than MTX 5-FU as first-line treatment of advancedcolorectal cancer. However, the overall survival was similar suggesting thatalternating bolus and infusional 5-FU upfront may be as effective as givingthem in sequence as first- and second-line treatment.     

Adjuvant sequential methotrexate --> 5-fluorouracil vs 5-fluorouracil plus leucovorin in radically resected stage III and high-risk stage II colon cancer

The aim of the study was to determine whether modulation of 5-fluorouracil (FU) by methotrexate (MTX) improves survival compared to FU+6-s-leucovorin (LV) following potentially curative resection of stage II and III colon cancer. Within 8 weeks from surgery, 1945 patients with stage III (44%) or high-risk stage II (55%) colon cancer were randomly assigned to receive either 6 monthly cycles of FU 370 mg m(-2) i.v. bolus preceded by LV 100 mg m(-2) i.v. bolus on days 1-5, or 6 monthly cycles of sequential MTX 200 mg m(-2) i.v. days 1 and 15 and FU 600 mg m(-2) i.v. on days 2 and 16 followed by LV rescue (15 mg given p.o. q 6 h x 6 doses). Levamisole 50 mg p.o. t.i.d. on days 1-3, every 14 days for 6 months, was planned to be given in both arms. After a median follow-up of 4.2 years, 568 patients have relapsed and 403 have died. Survival was similar with MTX --> FU and FU+LV (77 vs 77% at 5 years; P = 0.90), as were 5-year disease-free survivals (67 vs 63%; P = 0.44). Efficacy results were similar for both stage III and II patients. There were two toxic deaths, two in the MTX --> FU arm (0.2%) and zero in the control arm. We conclude that biochemical modulation of FU with LV or with MTX produces similar results in the adjuvant setting of colon cancer.     

A phase II study of mitomycin C, cisplatin and protracted infusional 5-fluorouracil in advanced pancreatic carcinoma: efficacy and low toxicity.

BACKGROUND: The effective treatment of unresectable pancreatic carcinoma represents a formidable challenge. There is a need to develop systemic therapies which combine efficacy with acceptable toxicity. The current 'gold standard' gemcitabine gives an objective response rate of the order of 20% and median survival up to 6 months. Here we have evaluated the efficacy and toxicity of mitomycin C, cisplatin and protracted infusional 5-fluorouracil (MCF). PATIENTS AND METHODS: Forty-five patients with locally advanced (13 patients) or metastatic (32 patients) pancreatic carcinoma were treated with mitomycin C 7 mg/m(2) 6 weekly, cisplatin 60 mg/m(2) 3 weekly and protracted venous infusion 5-FU 300 mg/m(2)/day. Patients were evaluated for response after three cycles and received six cycles in total in the absence of progressive disease or poor tolerance. Median age was 62 (45-75) years; 41 patients were World Health Organization performance status 0-1. RESULTS: Treatment was well tolerated with 36 (84%) patients completing three or more cycles. Grade 3 or 4 toxicities were uncommon: anaemia in three patients (7%), mucositis in two (5%), nausea and vomiting in three (7%) and diarrhoea in one (1%). An objective response was seen in 21 (46%) patients. There was one complete response. The median survival overall was 7.1 months and 10.5 months in responders. The median duration of response was 4.3 months. One-year survival was 29%, 2-year survival was 18%. CONCLUSIONS: MCF combines efficacy with low toxicity in the treatment of advanced pancreatic carcinoma. The efficacy is at least comparable and may be superior to single-agent gemcitabine and MCF may therefore provide a cost-effective alternative.     

Phase II study of cisplatin, gemcitabine and 5-fluorouracil in advanced pancreatic cancer.

BACKGROUND: The aim of this study was to determine the activity of the combination of cisplatin, gemcitabine and 5-fluorouracil (5-FU) as therapy for metastatic or locally advanced inoperable pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients with histologically proven advanced or metastatic pancreatic adenocarcinoma received first-line chemotherapy comprising cisplatin (20 mg/m2 on days 1, 8, 15, 22, 29 and 36), gemcitabine (1000 mg/m2 on days 1, 8, 29 and 36) and 5-FU (200 mg/m2 as continuous infusion on days 1-42) every 56 days. RESULTS: A total of 34 patients were studied. Eighty courses were administered (median two courses per patient). Among 32 patients evaluable for response, two patients had a complete response and four a partial response for an overall response rate of 19% (95% confidence interval 7% to 36%). Thirteen patients had stable disease (40%) and 13 progressed. Median progression-free survival was 4.7 months, median survival 9.0 months and 26% of patients achieved 1-year survival. Ten of 25 patients (40%) with pain at presentation had a sustained reduction of analgesic consumption. The principal grade 3/4 toxicities were neutropenia, thrombocytopenia, anaemia and mucositis, occurring in 24%, 21%, 9% and 3% of patients. CONCLUSION: This schedule seems well tolerated and active in pancreatic cancer and worthwhile of further evaluation.     

5-Methyltetrahydrofolate for biochemical modulation of fluorouracil (FU) in patients with advanced colorectal cancer: A randomized phase I--II study of two different FU administration schedules

Background: To determine the maximum tolerable dose (MTD) and therapeutic activity of MTHF-modulated FU using two different administration schedules of the antimetabolite (bolus vs. two-hour infusion), the present randomized study using a 'pick-the-winner' design was undertaken in patients with advanced colorectal cancer.Patients and methods: Eighty-two patients with previously untreated advanced measurable colorectal cancer were randomly assigned to treatment with MTHF (100 mg/m2 days 1–5 i.v. bolus) plus FU (400 mg/m2 days 1–5) given either as i.v. bolus injection or as a two-hour infusion every four weeks. In the absence of dose-limiting toxicity (DLT, defined as WHO grade 3 hematotoxicity and/or WHO grade 2 nonhematologic side effects) and evidence of progressive disease, the FU dose was escalated by 50 mg/m2/day during each subsequent cycle until the individual maximum tolerable dose (MTD) was reached.Results: Forty patients were randomized to the FU bolus arm and 42 patients to the FU two-hour infusion arm. The median MTD was 475 mg/m2/day (95% CI: 450–500) in the FU bolus arm with stomatitis ± diarrhea being the most common DLT. Gastrointestinal side effects were also dose-limiting in the two-hour infusion arm; however, the median MTD was 600 mg/m2/day (95% CI: 568–632). Myelosuppression was more pronounced in the FU bolus arm than in the two-hour infusion arm. The overall response rates were 27.5% (95% CI: 15–44%; 1 CR and 10 PR) for patients treated in the bolus arm and 14.5% (95% CI: 5–28%; 1 CR and 5 PR) for those treated in the two-hour infusion arm. Analogous to recorded response, median time to progression (8.5 vs. 6.25) and overall survival time (14.0 vs. 11.0) tended to be superior in the FU bolus arm.Conclusions: The observed differences in tolerable drug dose and toxicity between the two treatment arms might be explained by the administration schedule-dependent clinical pharmacokinetics of FU and/or the difference in extent of biochemical modulation of the antimetabolite through MTHF. The fact that the two regimens were not equitoxic probably also helps to explain the favourable response activity noted in the MTHF/FU bolus arm. Whether MTHF is as effective as leucovorin for biochemical modulation of FU remains to be determined in a randomized trial, for which we would recommend its combined use with bolus FU ('winner arm') using a starting dose of 400 mg/m2/day ×5.     

Intermittent low-dose cisplatin infusion as a possible modulator of 5-fluorouracil

Background This study was designed to determine whether 5-fluorouracil combined with intermittent low-dose cisplatin (cis-diaminedichloroplatinum, CDDP), a 5-fluorouracil modulator, would be an effective antitumor regimen. Methods Sarcoma 180 tumor (mouse sarcoma) was implanted in mice, and intravenous CDDP injections (0.5 mg/kg) were given at intervals of 12 hours. Tumors were removed on days 1, 3, and 5 of treatment for quantification of the tumor tetrahydrofolate and blood platinum levels. One group of mice was treated with a combination of CDDP and 5-fluorouracil (10 mg/kg), and another group was treated with 5-fluorouracil alone. Tumor thymidylate synthetase levels and tumor weights were compared between these 2 groups. Results Blood total platinum levels rose as the number of doses increased, while the tumor tetrahydrofolate levels did not change. Neither the levels of thymidylate synthetase, nor tumor reduction, differed between the CDDP/5-fluorouracil and the 5-fluorouracil treatment groups. Conclusion No significant effect of intermittent low-dose CDDP therapy was seen on folic acid or thymidylate synthetase levels, or on tumor growth. The results of this study do not endorse the efficacy of intermittent low-dose CDDP as a modulator of 5-fluorouracil.     

吉西他滨加低剂量5-氟尿嘧啶持续静脉输注治疗晚期原发性肝癌

目的:评价吉西他滨加低剂量5-氟尿嘧啶(5-Fu)持续静脉输注治疗晚期原发性肝癌(PHC)患者的疗效、临床受益反应(clinicalbenefit response,CBR)以及不良反应。方法:l5例晚期PHC患者,采用吉西他滨800-1000mg/m2,静滴,d1,8,5-Fu250mg/(m2.day)经锁骨下静脉持续输注12天,21天为一周期。结果:15例患者中,13例可以评价疗效,其中2例PR,6例SD,5例PD。患者的肿瘤进展时间(TTP)为1-6.2个月,中位TTP3.2个月。CBR率为60%(9/15)。主要毒副反应为骨髓抑制,Ⅲ度-Ⅳ度贫血3例(20%),Ⅲ度粒细胞减少和血小板减少各2例(13.3%)和1例(6.7%)。消化道反应较轻,Ⅲ度腹泻和口腔粘膜炎各1例(6.7%)。结论:吉西他滨加低剂量5-Fu持续静脉输注治疗晚期原发性肝癌有一定的疗效,CBR率较高,毒副反应可以耐受,在晚期PHC尚无特别有效治疗措施的情况下,值得临床试用。     

Integrated analysis of overall survival in two randomised studies comparing 5-fluorouracil/leucovorin with or without trimetrexate in advanced colorectal cancer.

BACKGROUND: Two randomised studies were performed with trimetrexate (TMTX) as a biochemical modulator of 5-fluorouracil (5-FU)/leucovorin (LV) in advanced colorectal cancer (ACC), one in Europe and one in the United States. Both studies were similarly designed to detect a statistically significant difference in progression-free survival (PFS). Overall survival (OS), however, was later adopted as the primary outcome measure for approvability of agents for first-line treatment of ACC. Therefore, an integrated analysis of survival data from the European and USA trials was performed to detect a clinically relevant difference in survival. PATIENTS AND METHODS: The experimental arm was identical in both studies and consisted of TMTX 110 mg/m2 intravenously (i.v.) followed 24 h later by i.v. LV 200 mg/m2/5-FU 500 mg/m2 plus oral LV rescue. The 5-FU dose in the control arm was 600 mg/m2 in the European study and 500 mg/m2 in the USA study, and the USA study was placebo-controlled. Treatment was given weekly for 6 weeks every 8 weeks. RESULTS: A total of 746 patients were analysed. Median OS was 13.0 months for 5-FU/LV and 14.6 months for TMTX/5-FU/LV (P = 0.15; Wilcoxon). Median PFS was 4.4 months and 5.4 months, respectively (P = 0.07; Wilcoxon). CONCLUSIONS: The addition of TMTX to a weekly regimen of 5-FU/LV does not improve the outcome for patients with ACC.     

Gemcitabine combined with continuous infusion 5-fluorouracil in advanced and symptomatic pancreatic cancer: a clinical benefit-oriented phase II study

Gemcitabine and 5-fluorouracil are the only two compounds with reproducible activity against advanced pancreatic cancer (APC). We have evaluated a novel combination of gemcitabine and 5-fluorouracil on the clinical benefit response (CBR) end point. Eleven consecutive patients with symptomatic APC were entered in a two-stage phase II trial. Gemcitabine was administered by intravenous (i.v.) bolus injection at the dose of 1,000 mg m(-2) on days 1, 8, 15 and 5-fluorouracil 500 mg m(-2) was given by continuous i.v. infusion on days 1-5. Treatment was repeated every 28 days. A CBR was achieved in 7/11 patients. The mean time to loss of CBR was 26.5 weeks (range 14-18, median 22). Toxicity was mild and no APC patient experienced WHO grade 3 toxicity. The gemcitabine/5-fluorouracil combination is well tolerated and produces a symptomatic relief in the majority of APC patients.     

A phase II study of Tomudex alternated with methotrexate, 5-fluorouracil, leucovorin in first-line chemotherapy of metastatic colorectal cancer

Purpose: This multicenter phase II study was designed to assess the efficacy of the alternating schedule of tomudex with methotrexate (MTX)/5-fluorouracil (5-FU)/leucovorin (LV) in first-line chemotherapy for metastatic colorectal cancer.Patients and methods: Patients with histologically proven metastatic colorectal cancer and at least one bidimensionally measurable lesion, aged 18–70, with performance status 2, normal baseline biological values, and no prior chemotherapy, were selected. Treatment was tomudex 3 mg/m² and, after two weeks, MTX, 200 mg/m² by 30 infusion after hydration with 1500 ml saline solution, followed on day 2 by 5-FU, 600 mg/m² and leucovorin, orally, 15 mg for six times every 6 hours, beginning 24 hours after MTX. Cycles were repeated every four weeks. Tumor response assessment was performed after three cycles.Results: Thirty-four patients were enrolled in this study, of whom twenty-four had liver metastases, nine local relapse, five lymph node involvement, four lung metastases, and three peritoneal carcinomatosis. Four patients achieved objective responses (one complete and three partial), for an overall response rate of 12% (95% CI: 0%–22%). Twelve patients had stable disease and 18 progressed on therapy. Median survival for all patients was 13 months. Two patients experienced grade 3 WHO neutropenia while hepatotoxicity was reported in 13 patients (6 grade 1, 3 grade 2, 3 grade 3, 1 grade 4), suggesting that this combination could increase hepatic toxicity in comparison to tomudex or MTX/5-FU alone.Conclusions: Our results suggest that this regimen does not warrant further investigation in advanced colorectal cancer patients, at least not with this schedule and doses.     

Mitoxantrone, 5-fluorouracil and high-dose leucovorin (NFL) in the treatment of metastatic breast cancer: randomized comparison to cyclophosphamide,methotrexate and 5-fluorouracil (CMF) and attempts to improve efficacy by adding paclitaxel

The combination of mitoxantrone (12 mg/m² i.v., day 1) 5-fluorouracil (350 mg/m² i.v. days 1–3) and leucovorin (300 mg i.v. days 1–3) is an active and well-tolerated regimen for metastatic breast cancer. We compared this regimen to a standard CMF regimen (cyclophosphamide 600 mg/m² i.v. day 1; methotrexate 40 mg/m² day 1; 5FU 600 mg/m² i.v. day I) in a randomized, phase II study. One hundred and twenty-eight women receiving first-line chemotherapy for metastatic breast cancer were treated. NFL produced lugher response rates (45% vs. 26%) and longer remissions (9 months vs. 6 months) than did CMF; overall survival was not different (19 months vs. 16 months). Both regimens were well tolerated. In an attempt to improve efficacy, we added paclitaxel(l35 mg/m² i.v. 1-h infusion) to the NFL regimen. Although this regimen was active (51 % response rate in first-second-line treatment], myelosuppression was greater than expected. These results confirm the utility of NFL as an active, well-tolerated regimen for the palliative treatment of metastatic breast cancer.     

A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer.

BACKGROUND: Trimetrexate (TMTX) biochemically modulates 5-fluorouracil (5-FU) and leucovorin (LCV). Two phase II trials demonstrated promising activity for TMTX/5-FU/LCV in patients with untreated advanced colorectal cancer (ACC). This trial was designed to demonstrate the safety and efficacy of TMTX/5-FU/LCV as first-line treatment in ACC. PATIENTS AND METHODS: Eligible patients with ACC were randomized in double-blind fashion to receive placebo or TMTX (110 mg/m2) intravenously (i.v.) followed 24 h later by i.v. LCV 200 mg/m2, and 5-FU 500 mg/m2 plus oral LCV rescue. Both schedules were given weekly for 6 weeks every 8 weeks. Patients were evaluated for progression-free survival (PFS), overall survival (OS), tumor response, quality of life (QoL) and toxicity. RESULTS: A total of 382 eligible patients were randomized. Significant toxicities were noted more frequently with TMTX/5-FU/LCV. Diarrhea was the most common grade 3 or 4 side-effect (41% and 28% on the TMTX and placebo arms, respectively). QoL scores and response rates did not differ between treatment arms. PFS was 5.3 months and 4.4 months in the TMTX and placebo arms, respectively (P = 0.77; Wilcoxon). OS was 15.8 months and 16.8 months, respectively (P = 0.73; Wilcoxon). CONCLUSIONS: The addition of TMTX to a weekly regimen of 5-FU/LCV worsened grade 3 or 4 diarrhea. The inclusion of TMTX did not yield any significant improvements in response rate, PFS or OS.