Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid

We report the results of an expanded trial of 5-fluorouracil (5-FU) combined with high-dose folinic acid for treatment of patients with advanced colorectal or advanced gastric adenocarcinoma. In each treatment course, the patients received both 5-FU (340 to 400 mg/m2/d by intravenous (IV) infusion for a period of 15 minutes) and folinic acid (200 mg/m2/d by IV bolus) for 5 consecutive days, with a 21-day interval between courses. Eighty-six patients with colorectal carcinoma were evaluated. The combined complete and partial response rates were 39% for 54 patients who did not receive prior chemotherapy and 22% for 32 patients who had previously received chemotherapy. Four patients who were previously resistant to 5-FU attained objective responses. The median time to disease progression for the 28 responders was 10 months. The median survival time of responders was 19.5 months, and the probability of their being alive at 2 years was 40%. Of 27 patients with gastric adenocarcinoma, 13 (48%) responded to therapy. Their median time to disease progression was 5.5 months. The median survival time of responders was 11 months, and their probability of being alive at 15 months was 30%. Toxicity was within acceptable limits. Toxic effects included stomatitis, diarrhea, conjunctivitis, skin rash, and mild myeloid hypoplasia. In a separate study, plasma concentrations of L-folates greater than 10(-5) mol/L were achieved after a rapid single IV injection of 200 mg/m2 of folinic acid. Comparisons of our results with those reported in previous studies on 5-FU administered as a single agent suggest that, in advanced colorectal and gastric adenocarcinoma, folinic acid administered in high doses enhances the effectiveness of 5-FU administered concomitantly. Furthermore, some colorectal tumors that were previously resistant to 5-FU become sensitive to this drug. The survival of the patients who responded to therapy was markedly improved over that observed in reported series of untreated patients with advanced colorectal and gastric adenocarcinomas.     

Protracted infusional 5-fluorouracil plus high-dose folinic acid combined with bolus mitomycin C in patients with gastrointestinal cancer: a phase I/II dose escalation study

The aim of this study was to define the maximum tolerated dose (MTD) of bolus mitomycin C (MMC) in combination with 24 h-continuous infusion of 5-flourouracil (FU) plus folinic acid, and to assess the toxicity and activity in patients with previously treated colorectal and gastric cancer. Escalating doses of MMC starting from 6 mg m(-2) in 2 mg m(-2)-steps to a maximum of 10 mg m(-2) were applied on days 1 and 22, given to fixed doses of 5-FU (2.600 mg m(-2)) as 24 h infusion and folinic acid 500 mg m(-2) prior to 5-FU weekly for 6 weeks. At least three patients were treated at each dose level. A total of 16 patients have been included in the phase I study. At the highest dose level (MMC 10 mg m(-2)), grade III thrombocytopenia, dyspnoea, mucositis and diarrhoea were observed in one patient each (17 %). In the phase II study 45 patients, 33 with colorectal cancer and 12 with gastric cancer, 23 patients after failure of first- and 22 patients after at least second-line or subsequent chemotherapy have been treated. Seven partial responses (PR) were registered (16%), one (3%; CI(95%), 0-16) in colorectal and six (50%; CI(95%), 21-79%) in gastric cancer patients. In all, 17 (38%) achieved disease stabilisation, 15 colorectal (45%, CI(95%), 28-64%) and two gastric cancer patients (17%; CI(95%), 2-48%). The median progression-free survival was 3.1 months (range, 0.9-9.1) in colorectal and 4.6 months (range, 0.7-12.4) in gastric cancer. The median overall survival time was 6.6 months (range, 1.9-15.6) in colorectal and 7.1 months (range, 1.7-20.8) in patients with gastric cancer. This regimen was considered to be safe and well tolerated for pretreated patients with gastrointestinal adenocarcinoma. In gastric cancer,MMC plus infusional 5-FU/folinic acid may be a potential second-line regimen with promising antitumour activity.     

Adjuvant Bi-Weekly Combination of Cisplatin,Infusional 5-fluorouracil and Folinic Acid Followed by Concomitant Chemoradiotherapy with Infusional Fluorouracil for High Risk Operated Gastric and Gastroesophageal JunctionAdenocarcinoma

Purpose: Chemotherapy and radiotherapy are approved in clinical practice of adjuvant treatment of gastriccarcinoma. In present study, we retrospectively evaluated the efficacy and tolerability of an adjuvant treatmentprotocol including bi-weekly cisplatin, infusional 5-fluorouracil (5-FU) and folinic acid followed by continuous5-FU infusion during radiotherapy. Patients and Methods: Between May 2005 and Dec 2008, 65 curativelyresected gastric and gastroesophageal junction adenocarcinoma patients (stage III in 38 and stage IV M0 in27) received chemotherapy including 50 mg/m2 cisplatin, 200 mg/m2 iv folinic acid, 5-FU 400 mg/m2 iv bolusfollowed by 5-FU 1600 mg/m2 46h-continuous infusion (CFF) bi-weekly. After 4 cycles of CFF, concomitant200 mg/m2/day continuous infusion 5-FU and 4500 cGy radiotherapy were administered for 5 weeks. After thischemoradiotherapy an additional 4 cycles of CFF were given. Results: The median follow-up was 15 (6-36)months. Fifty seven (87.7%) patients completed at least 90% of the planned treatment. Median disease freesurvival was 18 months (95% CI:13.9-22.0) and median overall survival was 19 months (95% CI:15.2-22.8).Common adverse events of all grades were nausea and vomiting (53.8%), leucopenia (42.6%), anemia (30.7%)and diarrhea (20%). The most common grade 3 and 4 toxicities were leucopenia (9.2%), anemia (7.6%), febrileneutropenia (6.1%) and diarrhea (4.6%). Conclusion: Bi-weekly CFF chemotherapy followed by continuous5-FU infusion during radiotherapy is an effective and tolerable regimen for locally advanced operated gastricand gastroesophageal junction adenocarcinoma.     

High-dose folinic acid and 5-fluorouracil in advanced colorectal cancer

Twenty-three patients with advanced colorectal cancer were treated with folinic acid (200 mg/m2/day 1-5 IV bolus injection) and 5-fluorouracil (400 mg/m2/day 1-5 IV in 15 minutes) every 28 days. Only three patients were pretreated. Objective response was observed in 6 (30%) of 20 evaluable patients (three complete and three partial responses). The median duration of response was 9 months (range 5-15) and time to disease progression ranged from 2 to 12 months (median 6 months). Median survival was 21 months (range 12-23+) for responders. Another 6 (30%) patients had stabilization of disease. Toxicity was generally gastrointestinal (mucositis, diarrhea, nausea); moderate leukopenia was noted. The response rate found in this study indicates that folinic acid administered in high doses enhances the effectiveness of 5-FU administered concomitantly in colorectal cancer.     

表阿霉素联合顺铂和氟尿嘧啶治疗晚期胃癌的临床探讨

目的 观察表阿霉素联合顺铂和氟尿嘧啶(PELF方案)治疗晚期胃癌的疗效和安全性.方法 经病理组织学证实为晚期胃癌的101例患者接受PELF方案化疗,其中R0切除术后辅助化疗者37例,无法手术切除仅接受姑息化疗者64例.PELF方案具体药物的用法为表阿霉素50～80mg/m2(姑息化疗)或40～50 mg/m2(辅助化疗),静脉注射,第1天;顺铂10～20 mg/m2,静脉滴注2 h,第1～5天;氟尿嘧啶425～600 mg/m2(姑息化疗)或425～500 mg/m2(辅助化疗),静脉滴注4 h,第1～5天,或持续静脉输注120 h;甲酰四氢叶酸100～200 mg/m2,静脉滴注2 h,第1～5天;每3～4周重复.化疗两个周期后进行疗效评价.结果 37例R0切除术后辅助化疗的患者中,有17例仍无病生存,20例复发(其中19例死亡),中位无病生存期为36.1个月,5年生存率为36.0%.64例仅接受姑息化疗者中,一线治疗47例,其中34例可评价疗效,有效率为26.5%,中位疾病进展时间为6.6个月,中位生存期为13.7个月;二线治疗17例,其中10例可评价疗效,有效率为20.0%,中位疾病进展时间为5.1个月,中位生存期为8.9个月.全组患者最常见的不良反应是中性粒细胞减少和胃肠道反应,且多为Ⅰ、Ⅱ级,Ⅲ、Ⅳ级中性粒细胞减少、贫血和血小板减少的发生率分别为19.8%、1.0%和2.0%.结论 PELF方案作为辅助化疗或姑息化疗用于晚期胃癌均有较好的疗效,且毒副反应患者基本可以耐受,安全性较好.     

Clinical studies of biochemical modulation of 5-fluorouracil by leucovorin in patients with advanced colorectal cancer by the North Central Cancer Treatment Group and Mayo Clinic

The North Central Cancer Treatment Group (NCCTG) and Mayo Clinic are collaborating in an ongoing, prospective, randomized clinical trial of new approaches to the chemotherapy of advanced metastatic colorectal cancer. Single agent 5-fluorouracil (FUra) given by intensive-course rapid intravenous administration serves as a control. Included among the experimental treatments are two regimens consisting of FUra plus leucovorin (folinic acid). One of these regimens uses folinic acid at a dose level of 200 mg/m2 daily for 5 days based on earlier studies by Machover et al. (4). The second regimen uses folinic acid at 1/10 the dose level (20 mg/m2 daily for 5 days), since this lower dose of folinic acid has been shown to produce peak serum levels equivalent to the concentration of folinic acid required in culture medium to produce optimal inhibition of L1210 cells by FUra in vitro, and because of the great expense of folinic acid when given at the higher dose levels. As of January 1986, 78 patients had been randomized to receive treatment with FUra alone or one of the FUra-folinic acid regimens. The toxicity of the folinic acid regimens has been clinically tolerable, with stomatitis and, to a lesser extent, diarrhea being dose-limiting. Hematologic toxicity has been very mild. There is suggestive evidence that folinic acid given at the higher dose level in combination with FUra at a constant dose produces more severe effects on the oropharyngeal mucosa. Preliminary tumor response and survival data remain blinded in accordance with NCCTG policy. Further patient accrual and follow-up are required to assess the therapeutic effect of these folinic acid regimens compared to FUra given alone.     

奥沙利铂联合氟脲嘧啶、亚叶酸钙治疗晚期胃癌临床观察

目的：观察奥沙利铂联合氟脲嘧啶、亚叶酸钙治疗晚期胃癌的疗效和安全性。方法：26例晚期胃癌，采用L-OHP130mg／m^2静滴4小时第1天；CF200mg／m^2静滴2小时后5-Fu500mg／m^2静滴4小时第1—5天，每三周重复。结果：26例晚期胃癌中，CR 2例(7．7％)，PR 11例(42．3％)，CR PR 50．0％。中位缓解期为5．5个月，中位生存期为11．0个月。毒性反应主要是感觉神经毒性(65．4％)，其次为恶心呕吐(53．8％)和腹泻(46．2％)。骨髓抑制毒性小。结论：L-OHP联合5-Fu、CF治疗晚期胃癌疗效肯定，耐受性良好，值得临床进一步应用。     

Schedule-selective biochemical modulation of 5-fluorouracil in advanced colorectal cancer: a multicentric phase II study.

We have recently reported high clinical activity against advanced colorectal cancer of a regimen-alternating bolus FUra, modulated by methotrexate (MTX), and continuous infusion FUra, modulated by 6-s-leucovorin (6-s-LV). Considering the low toxicity of the bolus part of this regimen and our recent in vitro finding of a strong synergism between bolus FUra and natural-beta-IFN (n-beta-IFN), this cytokine was incorporated in the bolus part of our treatment programme. Fifty-six patients with untreated, advanced, measurable colorectal cancer were treated with two biweekly cycles of FUra bolus (600 mg m(-2)), modulated by MTX (24 h earlier, 200 mg m(-2)), and n-beta-IFN (3 x 10(6) IU i.m. every 12 h, starting at the time of FUra administration for four doses), alternating with a 3-week continuous infusion of FUra (200 mg m(-2) daily), modulated by 6-s-LV (20 mg m(-2) weekly bolus). After a 1-week rest, the whole cycle (8 weeks) was repeated if indicated. A total of 5 complete and 17 partial responses were obtained (response rate, 41%; 95% confidence limits, 28-55%) in 54 assessable patients. After a median follow-up time of 36 months, five patients are still alive. Overall, the median time to treatment failure was 6.4 months. The median duration of survival was 15.0 months. There was one treatment-related death after a course of MTX --> bolus FUra/n-beta-IFN and grade III-IV toxicity occurred in 18% of the patients. As the addition of n-beta-IFN results in high toxicity, whereas the efficacy seems to be similar to that of the same regimen without the cytokine, our groups are currently randomizing the original regimen, without IFN, against standard modulated bolus FUra.     

Mitomycin C plus infusional 5-fluorouracil in platinum-refractory gastric adenocarcinoma: an extended multicenter phase II study

OBJECTIVE: To assess the toxicity and activity of bolus mitomycin C (MMC) in combination with a 24-hour continuous infusion of 5-fluorouracil (5-FU) in gastric cancer patients who had received at least one prior chemotherapy regimen. PATIENTS AND METHODS: Patients were treated with MMC (10 mg/m(2)) on days 1 and 22, 5-FU (2.6 g/m(2)) as a 24-hour infusion, and folinic acid 500 mg/m(2) weekly for 6 weeks. RESULTS: Thirty-four patients with gastric cancer, 16 after failure of first-line chemotherapy and 18 after failure of at least two prior chemotherapies, were included. In the intent-to-treat analysis, 9 (26.5%) of the 34 patients had a partial response and 10 (29.4%) a disease stabilization (disease control rate 56%). The median time to progression was 3.3 months (CI95: 2.8-3.7), and the median overall survival was 7.2 months (CI95: 5.9-8.4). Grade III/IV thrombocytopenia occurred in 14.7% of patients (n = 5), while the most frequent nonhematological grade III/IV toxicities were mucositis and diarrhea, each affecting 9% of patients. CONCLUSIONS: As the tested regimen was generally safe and well tolerated by the patients, MMC plus infusional 5-FU/folinic acid may be a potential second-line regimen for patients with advanced gastric cancer.     

Final analysis of colorectal cancer patients treated with irinotecan and 5-fluorouracil plus folinic acid neoadjuvant chemotherapy for unresectable liver metastases

We have previously reported that neoadjuvant therapy with modified FOLFIRI enabled nearly a third of patients with metastatic colorectal cancer (mCRC) to undergo surgical resection of liver metastases. Here, we present data from the long-term follow-up of these patients. Forty patients received modified FOLFIRI: irinotecan 180 mg m(-2), day 1; folinic acid, 200 mg m(-2); and 5-fluorouracil: as a 400 mg m(-2) bolus, days 1 and 2, and a 48-h continuous infusion 1200 mg m(-2), from day 1. Treatment was repeated every 2 weeks, with response assessed every six cycles. Resected patients received six further cycles of chemotherapy postoperatively. Nineteen (47.5%) of 40 patients achieved an objective response; 13 (33%) underwent resection. After a median follow-up of 56 months, median survival for all patients was 31.5 months: for non-resected patients, median survival was 24 months and was not reached for resected patients. Median time to progression was 14.3 and 5.2 months for all and non-resected patients, respectively. Median disease-free (DF) survival in resected patients was 52.5 months. At 2 years, all patients were alive (8 DF), and at last follow-up, eight were alive (6 DF). Surgical resection of liver metastases after neoadjuvant treatment with modified FOLFIRI in CRC patients achieved favourable survival times.     

5-Fluorouracil, high-dose folinic acid, and mitomycin C combination chemotherapy in advanced gastrointestinal adenocarcinomas. A pilot study

Fifteen patients, median age 64 years, presenting with advanced gastrointestinal adenocarcinomas, were included in this study. The treatment combination consisted of folinic acid (200 mg/m2, IV bolus injection) followed by 5-fluorouracil (5-FU; 400 mg/m2, 30-min infusion) for 5 consecutive days and mitomycin C (10 mg/m2, IV bolus injection) on day 1, the therapy being resumed every 21 days. An objective response was noted in 7 of 15 patients (47%): 1 complete and 6 partial responses, including 4 of 5 patients who had received no prior chemotherapy and 3 of 10 patients who previously failed to respond to 5-FU. Objective responses were encountered in 4 of 7 stomach cancers, 2 of 3 pancreas tumors, and in only 1 of 5 colorectal carcinomas. Furthermore, 9 of 11 patients were completely relieved of their abdominal pain. The median duration of remission was 5 months. The median survival time of patients who responded to treatment was 7 months. Toxicity was acceptable, with mainly leukopenia and/or thrombocytopenia (5 patients) and oral mucositis (3 patients), leading to dose reduction. The combination of 5-FU+ folinic acid + mitomycin C appears to be a potentially effective regimen in the treatment of advanced gastrointestinal tumors, even in patients previously treated with 5-FU.     

FOLFOX4方案治疗晚期胃癌临床研究

目的观察奥沙利铂（L-OHP）联合氟尿嘧啶（5-Fu）、亚叶酸钙（CF）双周（FOLFOX4）方案治疗晚期胃癌的疗效及不良反应。方法45例晚期胃癌患者接受FOLFOX4方案化疗,至少化疗2个周期后评价疗效、不良反应和总有效率,计算疾病进展时间（time to progression,TTP）和总生存期（overall survival,OS）。结果全组男性30例,女性15例,中位年龄53岁（25～74岁）,全身状况ECOG评分均为0-2分,其中ECOG0分和1分者占53．3％。中位化疗4个周期（2—12个周期）,完全缓解（complete response,CR）2例,部分缓解（partial response,PR）14例,疾病稳定（stable disease,SD）15例,疾病进展（progressive disease,PD）14例。中位随访8个月（2～20个月）,共有2例失访,11例存活,32例死亡。中位TTP8个月（1～19个月）,中位OS9个月（2～20个月）。Cox回归分析显示OS的预测因素是ECOG评分,TTP的预测因素包括ECOG评分和化疗疗效。最常见的不良反应是血白细胞减低（73．3％）和消化道反应（71．1％）,其次为周围神经毒性（11．1％）。结论FOLFOX4方案治疗晚期胃癌近期疗效较好,不良反应可以接受,但与传统化疗方案相比,生存期无明显优势。     

Preliminary analysis of a randomized comparison of 5-fluorouracil versus 5-fluorouracil and high-dose continuous-infusion folinic acid in disseminated colorectal cancer

In this study, 50 patients were randomly assigned to treatment with 5-fluorouracil (FUra) or FUra plus high-dose continuous-infusion folinic acid. Five of 27 evaluable patients in the FUra group versus 10 of 21 patients in the FUra plus folinic acid arm of the study had objective partial remissions, P = 0.02. Time to progression was 3.9 months for FUra and 8.0 months for FUra and folinic acid, P = 0.006; however, median survivals (11.9 versus 14.5 months) were not different in this crossover study. Toxicity in both treatment arms was mild, although patients receiving FUra plus folinic acid experienced significantly more stomatitis than patients treated with FUra alone. This study suggests that high-dose, continuous-infusion folinic acid, which produces a steady-state level of biologically active folates of 10 microM, significantly increases the therapeutic activity of FUra.     

Fluorouracil combined with the pure (6S)-stereoisomer of folinic acid in high doses for treatment of patients with advanced colorectal carcinoma: a phase I-II study.

BACKGROUND: Potentiation of the antitumor activity of fluorouracil (5-FU) by folinic acid has been demonstrated in patients with colorectal adenocarcinoma. Modulation is due to the interaction of thymidylate synthase, fluorodeoxyuridine monophosphate, and methylene tetrahydrofolate, which leads to the formation of a stable ternary complex with concomitant enzyme inactivation. Folinic acid consists of a mixture of equal parts of two stereoisomers differing in chirality at the C-6 carbon of the pteridine ring. Only the levorotatory (6S)-stereoisomer of folinic acid is transformed into active folate cofactors. However, the (6R)-stereoisomer of folinic acid is not inert; it was shown to interfere with the (6S) form at the cellular level. PURPOSE: The possibility of a deleterious effect of the unnatural stereoisomer on the modulation of 5-FU led us to carry out a phase I-II study of 5-FU combined with the (6S)-stereoisomer of folinic acid given in high doses for treatment of patients with advanced colorectal carcinoma. We also determined the plasma pharmacokinetics of folates after intravenous (IV) injection of (6S)-folinic acid at the dose used in this study. METHODS: Treatment consisted of 5-FU (350-550 mg/m2 per day by IV infusion for 2 hours) and (6S)-folinic acid (100 mg/m2 per day by IV bolus injection) given for 5 consecutive days; the treatment was repeated every 21 days. Twenty-five patients with advanced colorectal carcinoma, who had had no prior chemotherapy, were evaluated for antitumor activity. The quantity of folates in plasma was measured using a microbiological assay. RESULTS: The median follow-up time was 9 months (range, 3.5-15.2 months). The response rate was 52% (complete response, 12%; partial response, 40%). The median time to disease progression for responding patients was 9.2 months (range, 5.9-15+ months). The estimated probability of survival at 12 months was 73%. Palliative improvement in quality of life was achieved in most patients who had symptoms due to the tumor before the start of treatment. The dose-limiting toxic effects were grade 3 diarrhea, dermatitis, and oral mucositis. Grade 4 toxicity did not occur. Myeloid toxicity was minor. After IV injection, (6S)-folinic acid was rapidly cleared from plasma (mean half-lives: alpha = 7.2 minutes and beta = 126 minutes). The mean concentration of the unchanged compound 2 hours after injection was 5.8 mumol/L. CONCLUSION: The (6S)-form of folinic acid potentiates the antitumor effect of 5-FU given concomitantly. IMPLICATION: Our results justify a more complete exploration of the pure active stereoisomer as a modulator of the fluoropyrimidines.     

Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients.

BACKGROUND: The aim of this study was to observe the effects of neoadjuvant therapy with irinotecan and 5-fluorouracil (5-FU)/folinic acid (FA) on the resection rate and survival of colorectal cancer patients with initially unresectable hepatic metastases. PATIENTS AND METHODS: Forty patients received neoadjuvant chemotherapy comprising irinotecan 180 mg/m(2) administered intravenously (i.v.) on day 1, FA 200 mg/m(2) i.v. on days 1 and 2, 5-FU 400 mg/m(2) i.v. bolus on days 1 and 2, and 5-FU 1200 mg/m(2) as a continuous 48-h i.v. infusion on day 1. The treatment was repeated every 2 weeks and response was assessed every 12 weeks (six cycles). RESULTS: The objective response rate to chemotherapy was 47.5% (n = 19), with two complete responses and disease stabilization in 11 (27.5.%) patients. Responses were unconfirmed for 11 patients undergoing surgery within 2 weeks. Treatment was well tolerated and adverse events were typical of the chemotherapy agents used. Twenty-seven (67.5%) patients reported hematological toxicity (35.0% grade 3/4) and 14 (35.0%) reported gastrointestinal toxicity (12.5% grade 3/4). Thirteen patients (32.5%) underwent potentially curative liver resection following chemotherapy. Chemotherapy was particularly effective in patients with large metastases on entry to the study. The median time to progression is 14.3 months and, at a median follow-up of 19 months, all patients are alive. CONCLUSIONS: Neoadjuvant therapy with irinotecan combined with 5-FU/FA enabled a significant proportion of patients with initially unresectable liver metastases to undergo surgical resection. The effects of treatment on survival have yet to be determined.     

Weekly 24-hour infusion of high-dose 5-fluorouracil plus folinic acid in combination with mitomycin C for the treatment of advanced gastric cancer

PURPOSE: This study was performed to investigate the activity and safety of high dose 5-fluorouracil (5-FU) given as a weekly 24-hour infusion in combination with folinic acid plus mitomycin C in patients with advanced gastric cancer. PATIENTS AND METHODS: Chemonaive patients with locally advanced inoperable, recurrent or metastatic gastric cancer were treated with 15 mg/m(2) i.v. mitomycin C as bolus on day 1 of a 7-week cycle followed by a 2-hour infusion of folinic acid (500 mg/m(2)) and a 24-hour infusion of 5-FU (2,600 mg/m(2)) given on days 1, 8, 15, 22, 29, and 36 as outpatient treatment. RESULTS: Thirty evaluable patients (median age 58 years and median ECOG performance status 1) received 1-4 cycles (median 3). 53% of the patients had liver metastases. Treatment-related toxicity was low with 10% of patients experiencing diarrhea >/=grade 3, 3% mucositis grade 3 and 3% nausea grade 3 (CTC). Hematological toxicity was mild with 13% thrombopenia grade 3 and no leukopenia grade 4. Eleven patients achieved a partial remission (major response rate 37%; 95% confidence interval 22-53%). Median time to progression was 5 months and median overall survival time was 7 months. CONCLUSION: This regimen is a well-tolerated outpatient treatment for patients with advanced gastric cancer with efficacy being comparable to other chemotherapy protocols.     

奥沙利铂联合5-氟尿嘧啶和醛氢叶酸钙时辰治疗晚期胃癌的初步临床研究

目的观察奥沙利铂(L-OHP)联合5-氟尿嘧啶(5-Fu)、醛氢叶酸钙(FA)方案(FFL方案)时辰输注法治疗晚期胃癌的疗效和不良反应。方法FFL方案时辰输注法治疗26例晚期胃癌患者,L-OHP 25 mg.m-2.d-1,5-Fu 600 mg.m-2.d-1,FA 300 mg.m-2.d-1,多通道程控时辰输液泵连续给药4 d,每14 d为1个周期,至少用2个周期。结果26例晚期胃癌患者中,完全缓解(CR)2例(7.7%),部分缓解(PR)13例(50.0%),稳定(SD)6例(23.1%),进展(PD)5例(19.2%),总有效率为57.7%。在共80个周期的化疗中,最常见的不良反应为血液学毒性、胃肠道毒性、外周神经毒性,但均以Ⅰ度为主,Ⅲ度中性粒细胞减少发生2例次,血小板减少、呕吐和口腔黏膜炎分别发生1例次,未出现Ⅳ度不良反应。中位缓解时间为3.5个月,中位肿瘤进展时间为4.5个月,全组患者中位生存期为8个月。结论FFL方案时辰输注法是治疗晚期胃癌安全有效的化疗方案。     

Second line chemotherapy for metastatic colorectal carcinoma

25 patients with metastatic colorectal carcinoma previously treated with 5-fluorouracil and folinic acid for advanced disease, were treated with mitomycin C 8 mg/m(2) i.v. bolus on day 1, adriamycin 40 mg/m(2) i.v. bolus on day 1, and lonidamine 150 mg per os t.i.d. starting one day before chemotherapy and stopping 2 days after the end of chemotherapy. Treatment was repeated every 4 weeks. All patients had previous surgery and systemic chemotherapy with 5-fluorouracil and folinic acid given as first line chemotherapy for metastatic tumor. Sites of disease included liver, lung, nodes, abdomen, and bone. All enrolled patients were evaluable for objective response. Only one patient, affected by rectal carcinoma, showed a partial response (4%) which lasted 5.8+ months. No complete response was seen. Stable disease was recorded in 4 cases (16%) with a mean duration of 4.6+ months. All remaining patients had progressive disease. Median overall survival was 8.7+ months. Toxicity was significant. Grade 3 thrombocytopenia was seen in 8 cases (32%), and grade 3 leukopenia in 5 cases (20%). Grade 3 vomiting was observed in 9 patients (36%). The combination of mitomycin C, adriamycin and lonidamine is not effective in the treatment of metastatic colorectal adenocarcinoma resistant to 5-fluorouracil-based chemotherapy. These data suggest that lonidamine is not able to potentiate antineoplastic activity of chemotherapeutic drugs in humans and its use in colorectal cancer should be avoided since it has no or little impact on response rate and survival.     

Phase II trial of trimetrexate for patients with advanced gastric carcinoma: an Eastern Cooperative Oncology Group study (E1287).

BACKGROUND: A Phase II study was conducted to evaluate the response, duration of response, and duration of survival of patients with measurable gastric carcinoma treated with trimetrexate (TMTX) who had not had prior chemotherapy. METHODS: Thirty-three patients with unresectable or metastatic gastric adenocarcinoma who had not received previous chemotherapy were treated with intravenous TMTX 12 mg/m(2) daily for 5 days. The dosage of TMTX was reduced to 8 mg/m(2) daily for 5 days for those who had received prior radiotherapy. The cycle was repeated every 3 weeks until disease progression or unacceptable toxicity occurred. RESULTS: Thirty-three patients could be analyzed with follow-up data. There was one Grade 5 (lethal) toxicity and four Grade 4 toxicities. Hematologic toxicity was the most common. The overall response rate was 21%, the overall median progression free survival was 2.7 months, and the overall median survival was 5.9 months for the entire cohort. No patients were alive at last follow-up. CONCLUSIONS: Though TMTX as a single agent has activity in gastric carcinoma with manageable toxicity, it cannot be recommended for routine use as a single agent due to the brief duration of response and median survival.     

PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial

BACKGROUND: In patients with locally advanced adenocarcinoma of the oesophagogastric junction (AEG), early metabolic response defined by 18-fluorodeoxyglucose-PET ([(18)F]FDG-PET) during neoadjuvant chemotherapy is predictive of histopathological response and survival. We aimed to assess the feasibility of a PET-response-guided treatment algorithm and its potential effect on prognosis. METHODS: Between May 27, 2002, and Aug 4, 2005, 119 patients with locally advanced adenocarcinoma of AEG type 1 (distal oesophageal adenocarcinoma) or type 2 (gastric cardia adenocarcinoma) were recruited into this prospective, single-centre study. All patients were assigned to 2 weeks of platinum and fluorouracil-based induction chemotherapy (evaluation period). Those with decreases in tumour glucose standard uptake values (SUVs), predefined as decreases of 35% or more at the end of the evaluation period and measured by PET, were defined as metabolic responders. Responders continued to receive neoadjuvant chemotherapy of folinic acid and fluorouracil plus cisplatin, or folinic acid and fluorouracil plus cisplatin and paclitaxel, or folinic acid and fluorouracil plus oxaliplatin for 12 weeks and then proceeded to surgery. Metabolic non-responders discontinued chemotherapy after the 2-week evaluation period and proceeded to surgery. The primary endpoint was median overall survival of metabolic responders and non-responders. Secondary endpoints were median event-free survival, postoperative complications and mortality, number of residual tumour-free (R0) resections, and histopathological responses. This study has been registered in the European Clinical Trials Database (EudraCT) as trial 2007-003356-11. FINDINGS: 110 patients were evaluable for metabolic responses. 54 of these patients had metabolic responses (ie, decrease of 35% or more in tumour glucose SUV) after 2 weeks of induction chemotherapy, corresponding to a response of 49% (95% CI 39-59). 104 patients had tumour resection (50 in the responder group and 54 in the non-responder group). After a median follow-up of 2.3 years (IQR 1.7-3.0), median overall survival was not reached in metabolic responders, whereas median overall survival was 25.8 months (19.4-32.2) in non-responders (HR 2.13 [1.14-3.99, p=0.015). Median event-free survival was 29.7 months (95% CI 23.6-35.7) in metabolic responders and 14.1 months (7.5-20.6) in non-responders (hazard ratio [HR] 2.18 [1.32-3.62], p=0.002). Major histological remissions (<10% residual tumour) were noted in 29 of 50 metabolic responders (58% [95% CI 48-67]), but no histological response was noted in metabolic non-responders. INTERPRETATION: This study confirmed prospectively the usefulness of early metabolic response evaluation, and shows the feasibility of a PET-guided treatment algorithm. These findings might enable tailoring of multimodal treatment in accordance with individual tumour biology in future randomised trials.