大剂量甲氨喋呤治疗时不同四氢叶酸解救方法的研究

目的：探讨不同四氢叶酸解救方法对大剂量甲氨喋呤（ＨＤＭＴＸ）的毒性作用和疗效的影响。方法：对１５例８０次ＨＤＭＴＸ治疗应用２种不同四氢叶酸解救方法，每次１５ｍｇ／ｍ＾２于１２ｈ开始和每次１２ｍｇ／ｍ＾２于２４ｈ开始，观察毒副作用和疗效，应用荧光偏振免疫分析法测定血清ＭＴＸ浓度。结果：试验组４例ＨＤＭＴＸ静滴结束后２４ｈ和４８ｈ的血清药物浓度均未达到毒浓度。２种四氢叶酸解救方法的毒副作用发生率和恢复     

MDLF方案治疗晚期胃癌近期疗效分析

目的 探讨进展期胃癌化疗的有效方案。方法 对２８例晚期胃癌患者进行ＭＤＬＦ方案化疗。具体如下：氨甲喋呤３０ｍｇ（ｍ＾２．ｄ）静滴第一天；甲酰四氢叶酸钙（ＬＶ）３０ｍｇ／ｄ．５－氟脲嘧啶（５－ＦＵ）５００ｍｇ／ｄ静滴第２至第９天；顺铂（ＤＤＰ）６０ｍｇ／（ｍ＾２．ｄ）静滴第２天，第９天。以上治疗，每四周重复，使用２周期为一疗程。结果 完全缓解（ＣＲ）４例（１４．３％），部分缓解（ＰＲ）１５例（５３．     

HDCF,5—Fu,Me—CCNU,VCR联合治疗晚期大肠癌38例疗效分析

目的：评价大剂量醛氢叶酸（ＨＤＣＦ）、氟脲嘧啶（５－Ｆｕ）、长春新碱（ＶＣＲ）、甲亚硝脲（Ｍｅ－ＣＣＮＵ）联合治疗晚期大肠癌疗效。方法：经病理证实的晚期大肠癌３８例，其中术后复发的２５例，不能手术的１３例，ＣＦ２００ｍｇ／ｍ＾２静滴２小时第１－４天，５－Ｆｕ５００ｍｇ／ｍ＾２静推第１－４天，ＶＣＲ１．４ｍｇ／ｍ＾２静推第１、８天。上述药物每３周重复；Ｍｅ－ＣＣＮＵ１７５ｍｇ／ｍ＾２和１天口服，第６     

血药浓度监测下含大剂量甲氨喋呤的联合方案治疗非霍奇金淋巴瘤的临床观察

甲氨喋呤（MTX）用于治疗恶性肿瘤始于上世纪中叶，四氢叶酸的解救方法使大剂量MTX的应用成为可能，目前已应用于淋巴造血系统肿瘤及骨肉瘤中，由于一些难以预测的毒性，在没有血药浓度监测下难以推广应用。我院自2005年开始将MTX血药浓度监测应用于临床，至2007年7月以该疗法为主的联合化疗共治疗27例非霍奇金淋巴瘤，大剂量MTX共64疗程，现将其应用过程、临床毒副反应及血药浓度监测结果进行总结，并结合文献讨论。     

亚叶酸钙与生化调节

亚叶酸钙（ＣａｌｃｉｕｍＦｏｌｉｎａｔｅ,醛氢叶酸钙,名称柠胶因子ＣｉｔｒｏｖｏｒｕｍＦａｃｔｏｒ,ＣＦ或Ｌｅｕｃｏｖｏｒｉｎ,ＬＶ）,即甲酰四氢叶酸的钙盐。在小剂量（１０～３０ｍｇ／ｍ２·ｄ）时,临床上常用于预防甲氨蝶呤（ＭＴＸ）等过量或大剂量治疗...     

大剂量甲氨喋呤治疗前后T淋巴细胞亚群及甲状腺功能检测

大剂量甲氨喋呤治疗前后Ｔ淋巴细胞亚群及甲状腺功能检测廖宁，黄丽莉，陈剑锋应用大剂量甲氨喋呤四氢叶酸钙（ＨＤ－ＭＴＸ－ＣＦ）在小儿恶性血液病诱导治疗完全缓解（ＣＲ）早期进行庇护所治疗，可延长此类病人的持续完全缓解期及预防脑膜白血病和睾丸白血病的发生。近...     

大剂量甲氨蝶呤治疗急性淋巴细胞白血病血药浓度及不良反应观察

 目的　探讨大剂量甲氨蝶呤（HD-MTX）治疗急性淋巴细胞白血病（ALL）的血药浓度与患者不良反应的关系。方法　分析12例完全缓解期的ALL患者HD-MTX化疗后不良反应。结果　HD-MTX化疗后患者以骨髓抑制（7／12）、胃肠道反应（8／12）、肝损害（5／12）为常见的不良反应。化疗后24 h MTX血药浓度为（23.688±9.607）μmol／L,经甲酰四氢叶酸钙（CF）解救后,44、68 h血药浓度降低为（0.338±0.247）μmol／L,（0.045±0.033）μmol／L。结论　HD-MTX治疗时保证充分水化、碱化,正确使用CF解救是保证HD-MTX方案顺利进行的关键因素。     

MF－MDCF方案联合治疗晚期胃癌20例

ＭＦ－ＭＤＣＦ方案联合治疗晚期胃癌２０例山顺林我们最近共用丝裂霉素（Ｍ）、５－氟脲嘧啶（Ｆ）、中剂量甲酰四氢叶酸钙（ＭＤＣＦ）（ＭＦ－ＭＤＣＦ）联合化疗方案持续１２０小时治疗晚期胃癌２０例，现总结报告如下：１资料与方法１．１一般资料男１７例、女３例。...     

奥沙利铂单药或与氟尿嘧啶—甲酰四氢叶酸联合应用治疗晚期大肠癌Ⅱ？…

目的 观察奥沙利铂治疗晚期大肠癌的临床疗效和安全性。方法 根据ＧＣＰ指导原则开展多中心Ⅱ期随机临床研究：Ａ组奥沙利铂单药１３０ｍｇ／ｍ＾２静脉滴注２ｈＤ１，加甲酰四氢叶酸钙（ＣＦ）２００ｍｇ／ｍ＾２＋５－氟尿嘧啶３００ｍｇ／ｍ＾２静脉滴注４ｈＤ１到Ｄ５，每３周一次。治疗３周期后评定疗效。有效病例在４周后确认疗效，结果：共收入１１４例，在可统计近期疗效的１００例中，ＣＲ１例，ＰＲ２６例，ＳＤ３２例，     

超大剂量化疗合并APBSCT治疗恶性肿瘤四例报告

目的 为了探讨超大剂量化疗（ＨＤＣＴ）合并自体外周血造血干细胞移植（ＡＰＢＳＣＴ）治疗恶性肿瘤的临床意义，方法 经病理证实的４例晚期恶性肿瘤接受了该治疗，采用小剂量Ｇ＿ＣＳＦ加或不加化疗动员外周血造血干细胞（ＰＢＳＣ），均获得足够的干细胞数量。３例患者采用ＣＴＸ５．６ｇ／ｍ＾２＋ＶＰ－１６１４００ｍｇ／ｍ＾２＋ＣＢＰ１０００ｍｇ／ｍ＾２，１例患者采用ＣＴＸ４．０ｇ／ｍ＾２＋ＥＰＩ１３０ｍｇ／ｍ＾２     

Serum and cerebrospinal fluid distribution of 5-methyltetrahydrofolate after intravenous calcium leucovorin and intra-Ommaya methotrexate administration in patients with meningeal carcinomatosis

Serum and cerebrospinal fluid (CSF) concentrations of citrovorum factor (CF) and 5-methyltetrahydrofolic acid (5-MTHFA) were measured after i.v. infusion of leucovorin (50 or 100 mg/sq m) in seven patients undergoing treatment for meningeal carcinomatosis by intra-Ommaya reservoir injection of methotrexate (MTX). Serum CF levels rapidly rose after leucovorin administration as did 5-MTHFA, its conversion product. A small amount of CF entered the CSF, but peak CSF 5-MTHFA increased about 10-fold. The concentration X time (C X t) of additional 5-MTHFA in the CSF was greater [114.4 +/- 36.1 (S.E.) microgram/ml X min] after 100-mg/sq m doses of leucovorin than after 50 mg/sq m [14.2 +/- 4.3 micrograms/ml X min] (p less than 0.05). The CSF MTX concentration exceeded CSF 5-MTHFA by 2 to 3 logs throughout the 48 hr of observation, while serum 5-MTHFA and CF exceeded serum MTX by 0.5 to 2 logs. This study demonstrates that leucovorin administered i.v. to patients receiving intra-Ommaya MTX does not increase CSF concentrations of "rescue" folate above those of CSF MTX and are unlikely to interfere with MTX action against meningeal tumor. On the other hand, i.v. leucovorin does permit serum "rescue" folate to operate, thus reducing the systemic toxicity that may follow intraventricular administration of MTX.     

The effect of prior cisplatin therapy on the pharmacokinetics of high-dose methotrexate

The pharmacokinetics of high-dose methotrexate (MTX, 5-15 g/m2) were evaluated in 11 children and adolescents who had previously received two to eight doses of cisplatin (90 mg/m2) in the treatment of malignant solid tumors. The half-life for disappearance of MTX from serum during the first 24 hours after infusion was determined from serum samples obtained at the end of a six-hour infusion and six, 12, and 24 hours after infusion. These values were compared to a mean half-life of 2.83 (+/- 0.34) hours following 489 courses administered to 71 patients who had not received cisplatin. Stepwise multiple linear regression analysis of patient variables revealed cumulative cisplatin dosage and time from last cisplatin dose as the best predictors of MTX half-life (r2 = 65.4%, p less than 0.001). The best predictors of 24-hour serum concentration were cumulative cisplatin dosage and MTX dosage (r2 = 54.2%, p less than 0.001) in the multiple linear regression model. Patients with delayed MTX clearance received additional leucovorin and experienced no severe toxicity. Patients receiving up to 270 mg/m2 of cisplatin appear to have minimal increases in MTX half-life, while the likelihood of delayed clearance increases in patients who have received 360 mg/m2 or more of cisplatin. All patients who have previously received cisplatin should be treated cautiously with high-dose MTX and prospective pharmacokinetic monitoring should be routinely performed.     

大剂量甲氨蝶呤治疗成人急性淋巴细胞白血病的药物代谢研究

目的：研究大剂量甲氨蝶呤（HD-MTX）治疗成人急性淋巴细胞白血病时的药物代谢作用及不同解救方案的价值。方法回顾性分析2003至2010年收治的124例成人患者（共190例次 HD-MTX 治疗）的临床和实验室资料。结果190例次患者的甲氨蝶呤血药浓度降至0.1μmol/L 以下的中位时间是72 h（48～342 h）,76例次（40%）发生延迟排泄;延迟排泄组患者的不良反应显著增高（P＜0.05）,其体质指数和甲氨蝶呤治疗第7日的血清肌酐水平均显著高于正常排泄组（分别为 P=0.046和 P＜0.001）。甲酰四氢叶酸钙联合左旋门冬酰胺酶解救不优于单用亚叶酸钙（P=0.849）。缩短甲氨蝶呤输注时间并提前亚叶酸钙的解救时机不能改善甲氨蝶呤的延迟排泄,但可减轻血液学不良反应。结论体质指数、血清肌酐水平影响甲氨蝶呤的代谢。适度缩短甲氨蝶呤输注时间和提前亚叶酸钙的解救时机或能改善甲氨蝶呤的排泄和不良反应。     

High-dose methotrexate in small cell lung cancer. Lack of efficacy in preventing CNS relapse

Few studies have incorporated high-dose methotrexate (MTX) with leucovorin rescue in the treatment of small cell lung cancer (SCLC). Potentially therapeutic levels of MTX can be achieved in the central nervous system (CNS) by systemic administration of high doses of this drug. Utilizing a combination chemotherapy program of Adriamycin, vincristine, cyclophosphamide, and methotrexate, 31 patients were sequentially assigned to receive either low-dose MTX (40 mg/m2), or high-dose MTX (500 mg/m2) with leucovorin rescue. Radiation therapy to the primary site was also administered. At these dosage levels there were no statistically significant differences in response rate or survival between the two groups. High-dose MTX did not prevent the appearance of CNS disease; there being 2/15 and 3/15 CNS relapses in the HD MTX and LD MTX treated groups, respectively. The occurrence of CNS disease did not significantly affect overall survival as compared to patients not similarly affected.     

The CMF-regimen. Modulation of cyclophosphamide uptake and clearance by methotrexate and fluorouracil

Influence of the 2 antimetabolites used in the CMF-regimen, methotrexate (MTX, M) and fluorouracil (FUra, F) on in vivo pharmacokinetics of orally administered cyclophosphamide (CY, C), were studied in WAG/Rij rats. Blood plasma concentrations of CY following oral administration were monitored in single-agent CY, in CY + MTX (CM), in CY + FUra (CF) and in CY + MTX + FUra (CMF) treatments. Each treatment group consisted of at least 10 rats. CY was determined in 50 microliters of plasma by capillary gas chromatography on the first day of chemotherapy. Statistical analysis of blood plasma concentration data revealed a significant influence of both MTX and FUra on CY input/output function (p:0.01). MTX and FUra significantly increased the area under the plasma concentration time-curve, whereas tmax was significantly prolonged in CF and CMF treatment groups (p:0.01). It is suggested that MTX and FUra interact at the site of CY pre-systemic metabolism, including first-pass metabolism, subsequently resulting in prolonged absorption.     

Serum monitoring of methotrexate (MTX) and 7-hydroxymethotrexate concentrations in patients treated with MTX using high-pressure liquid chromatography (HPLC) and comparison of serum MTX levels between HPLC method and fluorescence polarization immunoassay (FPIA)

In order to measure simultaneously the serum levels of methotrexate (MTX) and its major metabolite, 7-hydroxymethotrexate (7-OH-MTX), in samples obtained from patients treated with MTX, we have investigated the reversed-phase high-pressure liquid chromatographic assay using ion-pairing reagents. The mobile phase consisted of 77.5% solution of 0.005M tetrabutylammonium and 22.5% acetonitrile. SEP-PAK C18 Cartridges were used for the precolumn. The detectable range of MTX and 7-OH-MTX were 0.02-0.03 and 1.0 mumol/l respectively. A significant positive correlation was observed (r = 0.983) between FPIA and HPLC methods. Serum MTX levels with FPIA were significantly (p less than 0.05) higher than those of HPLC method. The serum 7-OH-MTX levels at 24 hr and 48 hr were 4.857 +/- 1.383 (n = 10) and 1.835 +/- 0.286 (n = 6) mumol/l respectively with the dosage of 400 mg/m2. The serum 7-OH-MTX levels at 48 hr were 6.254 +/- 3.053 mumol/l (n = 5) with the dosage of 3,000 mg. The serum half lives of MTX and 7-OH-MTX were 8.05 +/- 1.03 (n = 4) and 14.8 +/- 1.35 (n = 6) hours respectively between 24 hr and 48 hr after administration. The T1/2 7-OH-MTX/MTX ratio was 1.8. Percent cross-reactivity of 7-OH-MTX with concentrations ranging from 1-10 mumol/l were 0.6-2.0% by FPIA. However, patients' serum levels of 7-OH-MTX were 15-85 times (n = 21) higher than those of MTX. MTX levels of containing both MTX and 7-OH-MTX (7-OH-MTX/MTX ratio was 50/1) were significantly higher than those of containing MTX alone by FPIA.     

Raised plasma methotrexate concentrations following intrathecal administration in children with renal dysfunction

Plasma methotrexate (MTX) concentrations were measured following intrathecal (IT) MTX treatment in four patients with acute lymphocytic leukemia and acute renal dysfunction. All four patients had raised serum MTX concentrations to potentially cytotoxic concentrations for a prolonged period of time, (96-120 h). In contrast, serum MTX concentrations after the same dosage of IT treatment ranged from undetectable to 0.11 microM by 15-24 h in seven control patients with normal renal function, and were undetectable by 48 h in all controls. The terminal MTX T1/2 was 19-44 h in the patients with renal dysfunction. Decreased renal clearance or a rapid efflux of MTX from cerebrospinal fluid, or both, could account for the high and sustained concentrations. Plasma MTX concentrations after IT treatment were normal in two patients treated after their renal function returned to normal. Patients with renal dysfunction should be carefully monitored for plasma MTX concentrations and may require leucovorin to prevent systemic side-effects after IT MTX treatment.     

大剂量氨甲蝶呤为主的疗法与辅用威猛疗法对晚期肺癌的疗效对比

大剂量氨甲蝶呤(HD-MTX)可以提高晚期肺癌的治疗有效率,威猛(VM_(26))则有增强氨甲蝶呤疗效的潜力。多次行化疗的晚期肺癌患者29例随机分为两组:A组15例HD-MTX结合VM_(26);B组14例,以HD-MTX化疗为主。在HD-MTX滴注完毕后即刻,24小时、48小时、72小时以FPIA法测定MTX血药浓度。结果:A组在HD-MTX应用后的24和48小时血浆中MTX的浓度高于B组,但在72小时则无明显差异。虽然A组26.66％有效率对于已行多次化疗的晚期肺癌患者来说是达到了预期的效果,但A组的化疗方案与B组相比并未见明显的临床优势,如何改进化疗方案以提高晚期肺癌疗效有待于进一步探索。     

Serum Methotrexate (MTX) Concentrations and Prognosis in Patients with Osteosarcoma of the Extremities Treated with a Multidrug Neoadjuvant Regimen

Summary

The relationship between the serum concentration of methotrexate and the prognosis has been studied in 108 patients with osteosarcoma of the extremities treated from September 1986 to December 1989 at the Chemotherapy Department of Rizzoli Hospital.

The protocol of neoadjuvant chemotherapy included high doses of methotrexate (HDMTX) adriamycin, cisplatinum, ifosfamide and VP-16. After a median follow-up of 40.4 months (range 24-62), 84 (77.7%) of the patients studied remained continuously disease-free (CDF) and 24 relapsed. Significantly higher mean serum MTX concentrations were observed in the patients who remained CDF (669.5 μmol/1) than in the patients who relapsed (571.9 μmol/1) ( p < .004). The breaking point of prognostic significance for the serum MTX levels seems to be 700 μmol/1. In fact, according to the mean MTX concentrations, the patients with less than 700 μmol/1 showed a significantly lower disease-free survival than the patients with higher mean MTX concentrations (68.12% vs 94.87% p < .0013). The distribution of prognostic variables between the two groups was the same in terms of site and histological type of tumor and alkaline phosphatase serum levels at diagnosis. In the group which had more than 700μmol/1 MTX, a higher percentage of good histological response after primary chemotherapy was observed. This is probably independent from the MTX because no significant preoperative MTX serum levels between good and partially responding patients were observed.

These data suggest that in neoadjuvant chemotherapy of osteosarcoma there is a correlation, even in patients treated with multidrug regimens, between serum concentrations of MTX and the prognosis; for this reason the patients who show low MTX serum concentrations should be treated with increased amounts of MTX to achieve upper 700 μmol/1 MTX serum levels.     

Anal submucosal injection: a novel modality for the treatment of advanced rectal cancer.

AIMS: To investigate the efficacy of methotrexate (MTX) submucosal anal injection in the treatment of advanced rectal cancer. METHODS: Thirty-six patients (age 36-66 years; 21 men, 15 women; 20 patients with stage T3N1M0 and 16 with T4N1M1 rectal cancer) were injected with MTX in the anal submucosa. A comparative group of eight patients (age 38-62 years: five men, three women; four with T3N1M0 and four with T4N1M1 rectal cancer) was injected with MTX intravenously. The dose in both groups was 100 mg every 5 days for five consecutive doses and the course was repeated at 3-week intervals. MTX serum and tumour concentrations were estimated 30 and 60 min after MTX injection. The patients received MTX as outpatients. RESULTS: In the anal group, six of 20 patients with T3 tumour showed complete tumour regression and were alive 28-46 months after the start of the treatment. Partial response occurred in 25 patients: 14 of stage T3 and 11 of T4. The 14 T3 patients underwent combined excision operation and 9/14 were alive 26-68 months from the time of operation. Five of the 16 T4 patients showed tumour and metastatic progression. Mild toxicity occurred in six of 36 patients while the haematological reserve was unchanged in all the patients. All eight patients in the parenteral group showed progress of the malignant lesions under treatment and toxic manifestations were so severe that the treatment had to be interrupted. The MTX concentration in serum was significantly higher after parenteral than after anal injection, while in tumour tissue it was higher after anal administration. CONCLUSIONS: The results show that MTX submucosal anal injection is effective in treatment of T3 rectal cancer due to high MTX concentration in the tumour. Toxicity was mild owing to low level of serum MTX. The anal route of administration is safe, well tolerated and can be used on an outpatient basis.