Cycles Of Methotrexate Research Articles

2,4-Diamino-7-hydroxy-pteridines in biological fluids of patients on high-dose methotrexate

Concentrations of 2,4-diamino-7-hydroxy-pteridines in plasma and cerebrospinal fluid (CSF) are reported for the 0.5–8 g/m 2 dose range of methotrexate in children with acute lymphoblastic leukemia or non-Hodgkin's lymphoma. This experiment has revealed that: (1) there is a wide inter-individual but relatively narrow intra-individual variability of the maximal concentrations of2,4-diamino-7-hydroxy-pteridines in plasma during consecutive methotrexate cycles; (2) the increase in the level of the metabolites in plasma was related to increments of the methotrexate dose, but not above 5 g/m 2: this can be explained by a saturable conversion of methotrexate to 2,4-diamino-7-hydroxy-pteridines; (3) significant correlations were found between simultaneous values of 2,4-diamino-7-hydroxy-pteridines in plasma and CSF; (4) the formation of 2,4-diamino-7-hydroxy-pteridines did not depend on the ages of patients receiving the same dose of methotrexate. The presence of these compounds in plasma and CSF in significant amounts creates the potential for a number of competitive interactions with pteridine-dependent metabolism which may open up new possibilities for understanding the metabolic side-effects of methotrexate therapy.

Advanced Bladder Cancer (Stages pT3b, pT4a, pN1 and pN2): Improved Survival after Radical Cystectomy and 3 Adjuvant Cycles of Chemotherapy. Results of a Controlled Prospective Study

A total of 49 bladder cancer patients with tumor stages pT3b, pT4a and/or pelvic lymph node involvement without microscopic or macroscopic evidence of residual tumor was randomized into 2 comparative groups: the chemotherapy group was to receive 3 adjuvant cycles of methotrexate, vinblastine and cisplatin plus doxorubicin (M-VAC) or epirubicin (M-VEC) after radical cystectomy. The control group received no additional treatment. The protocol was activated in May 1987. Patient recruitment was concluded in December 1990 because an interim analysis of the 49 randomized patients revealed a significant prognostic advantage in favor of 26 patients randomized to the chemotherapy group compared to 23 in the control group (p = 0.0015, log rank test for relapse-free survival curves). Of the 26 patients randomized for adjuvant chemotherapy 18 were treated with M-VAC or M-VEC (3 cycles in 16 patients and 2 cycles in 2). Of the remaining 8 patients 7 refused chemotherapy before or during cycle 1 and 1 received chemotherapy without cisplatin because of impaired renal function. An update of the patients in August 1991 revealed a further increase in the prognostic difference between the 2 trial arms (p = 0.0012). Of 18 patients who received treatment with M-VAC or M-VEC only 3 have had tumor progression to date compared to 18 of 23 patients in the control group.Further statistical analysis of the data was performed on the basis of Cox’s regression model, incorporating various criteria as explanatory variables, including patient sex and age, pT stage and number of involved lymph nodes. This multivariate analysis revealed a significant decrease in the risk of tumor recurrence (p = 0.0007, 2-sided) after adjuvant chemotherapy. The number of lymph nodes involved was also of prognostic significance (p = 0.0028, 1-sided). The results indicate that the survival time after radical cystectomy can be prolonged considerably by adjuvant polychemotherapy in cases of locally advanced bladder carcinoma. Fortunately, all of these conclusions are not affected by switching from an intent-to-treat analysis to an analysis of the therapy actually performed. The p values obtained from the latter are 0.0005 (log rank test) and 0.0001 (Cox model with the same set of additional regressors).

The effects of postinduction intensification treatment with cytarabine and daunorubicin in adult acute lymphocytic leukemia: a prospective randomized clinical trial by Cancer and Leukemia Group B.

Cancer and Leukemia Group B undertook a randomized trial of intensification treatment in adults aged 15 to 79 years with acute lymphocytic leukemia (ALL) in complete remission (CR). Daunorubicin (DNR), prednisone, vincristine (VCR), intrathecal (IT) methotrexate (MTX), and asparaginase produced 177 CRs in 277 patients. One hundred fifty-one patients were randomly assigned to receive treatment as follows: 74 received intensive cytarabine and DNR, and 77 received cycles of mercaptopurine (6-MP) and MTX, followed by 6MP, MTX, VCR, and prednisone for 3 years in all. One hundred twelve patients received CNS prophylaxis. Intensification produced major myelosuppression but did not improve remission duration (median, 21 months). Of the 151 patients with CRs who entered the intensification phase, 29% remain in continuous CR (43 to 117 months); in 19 patients, CRs have lasted for longer than 7 years. No relapses occurred after 60 months. Median survival from the time of randomization was 30 months. Those under 30 years of age responded more frequently, with longer CR and survival. While 53% of those aged 15 to 19 years remain in continuous CR, 92% of patients over 59 years have relapsed. The presence of a myeloid antigen on the leukemic cells was adversely prognostic for CR achievement and for survival. Pretreatment WBC and platelet levels independently affected CR duration and survival. Early M1 marrow development presaged longer remissions. CNS relapse occurred in 47 of 256 patients with normal CSF before treatment, in 29 before CNS prophylaxis. CNS disease occurred after CNS prophylaxis in 18 patients: 13 of 61 who had received standard premaintenance and five of 51 who received intensification. No advantage in CR duration or survival resulted from intensive treatment with DNR and cytarabine following induction of CR.

Neoadjuvant Chemotherapy for Nonmetastatic Osteosarcoma of the Extremities

Between September 1986 and December 1988, 125 patients with osteosarcoma of the extremities entered the second neoadjuvant study at the authors' institution. Patients received preoperatively two cycles of methotrexate (MTX) intravenously, followed by cisplatinum (CDP) intraarterially, plus adriamycin (ADM) intravenously. After surgery, the patients classified as "good responders" (more than 90% tumor necrosis) received ADM, MTX, and CDP, while the "poor responders" (less than 90% tumor necrosis) had a longer chemotherapy that included ifosfamide and etoposide (VP-16) in addition to MTX, ADM, and CDP. Limb salvage was possible in 85% of patients, 8% had an amputation, and 7% had a rotationplasty. The surgical margins were adequate (radical or wide) in 88% of cases and inadequate (marginal or intralesional) in 12%. At an average follow-up period of 28 months (range, 13 to 41), 109 patients (87%) remained continuously disease free, 15 (12%) relapsed with pulmonary metastases, and one patient (0.8%) had a local recurrence. Compared with the first neoadjuvant study at the authors' institution that used only MTX and CDP preoperatively, the percentage of limb salvages, "good responders," and continuously disease-free survival at two years was significantly higher in the second Rizzoli neoadjuvant study (85%, 74%, and 87% versus 77%, 52%, and 59%). Systemic toxicity because of chemotherapy was superimposable. A retrospective analysis of the real dose intensity for each patient demonstrated a correlation between the intensity of chemotherapy and prognosis.

Interval Report of a Phase I-II Study Utilizing Multiple Modalities in the Treatment of Invasive Bladder Cancer: A Bladder-sparing Trial

Clinicians at the Massachusetts General Hospital have used two cycles of methotrexate, cisplatin, and vinblastine (MCV) before radiotherapy and cisplatin in 53 patients with muscle-invasive bladder cancer. Eleven patients did not complete the protocol, but overall, the toxicity was not formidable. Of the total patients accessioned, 34 are alive. Of the 34 patients in the series who completed the full treatment protocol, the estimated survival rate at 54 months is 77%. This interim analysis suggests that the treatment is achieving at least limited success in saving lives and bladders.

Curative radiotherapy following chemotherapy for invasive bladder carcinoma (a preliminary report)

Twenty-five patients with invasive transitional cell carcinoma of the bladder (Stage T 2, T 3, T 4) received combined modality therapy using four cycles of methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) chemotherapy followed by surgery or radiation therapy (RT). Sixteen patients had complete (N = 8) or partial (N = 8) response to MVAC. Curative RT was delivered to 11 responders with T 2 or T 3 disease and to 2 patients with T 4 disease. All 11 with T 2 and T 3 disease are currently alive, 7 with normal bladder function. The two with T 4 disease are dead of disease. Three patients required salvage cystectomy for local recurrence and one patient had cystectomy for bladder stones. Follow-up ranged from 11 to 50 months with a median of 31 months. No late chemo-radiotherapy treatment-related complications to the intestines or in bladder function (other than one bladder stone formation) occurred. These preliminary results are encouraging and warrant further evaluation of this innovative approach in treating invasive carcinoma of the bladder. T 2 and T 3 patients with a complete or partial response to MVAC may be excellent candidates for a bladder-sparing treatment.

High-Dose Cyclophosphamide-High-Dose Methotrexate with Coordinated Intrathecal Therapy for Advanced Nonlymphoblastic Lymphoma of Childhood

The Pediatric Oncology Group (POG) investigated a high-dose cyclophosphamide (CPM) high-dose methotrexate (MTX) regimen to determine therapeutic efficacy in confirmed advanced nonlymphoblastic non-Hodgkin's lymphoma (NHL) (stages III and IV) and B-cell acute lymphatic leukemia (B-ALL) in children. Another goal was to determine the comparative effectiveness of shortened maintenance treatment (2 versus 6 courses) in the study population. Systemic induction therapy included vincristine, prednisone, cyclophosphamide, and intermediate-dose MTX with leucovorin rescue. Superimposed intrathecal (IT) therapy included cytosine arabinoside for 2 successive days followed on day 3 by MTX. Intrathecal MTX was given 3 times during induction. At the end of induction, 2 days of triple (hydrocortisone, MTX, and cytosine arabinoside) therapy were given intrathecally (TIT). All patients then received a consolidation course of 4 doses of TIT, 2 doses of cyclophosphamide, and 4 more courses of vincristine and MTX with leucovorin rescue. Patients were then randomized to receive either 2 or 6 cycles of vincristine plus MTX with leucovorin rescue. The TIT was given with each cycle. Complete response rates by histology and Murphy stage (1) were as follows: undifferentiated lymphoma (DUL) stage III, 84/105 (80%): stage IV, 5/12 (42%); and other NHL [primarily large cell lymphoma (LCL)] stage III, 21/28 (75%); stage IV, 2/3 (67%). Event-free survival (EFS) at greater than 2 years was similar for patients with DUL and LCL, i.e., 65 and 61%, respectively. No significant difference in outcome was noted between patient groups receiving 2 or 6 maintenance treatments (p = .76). Treatment was notable for its modest toxicity following the early change to single-dose CPM therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Primary chemotherapy and delayed surgery (neoadjuvant chemotherapy) for osteosarcoma of the extremities the istituto rizzoli experience in 127 patients treated preoperatively with intravenous methotrexate (high versus moderate doses) and intraarterial cisplatin

Between March 1983 and June 1986 127 patients with localized osteosarcoma of the extremity were treated with neoadjuvant chemotherapy. Preoperative chemotherapy consisted of two cycles of methotrexate (MTX) (high or moderate doses) followed by 6 days by cisplatin (CDP). Surgery was an amputation or a rotation plasty, or a limb salvage. Necrosis was good in 52% of cases, fair in 36%, and poor in 12%. Postoperative chemotherapy consisted of Adriamycin (doxorubicin [ADM]) and bleomycin (BCD) for poor responders; and ADM, MTX, and CDP for fair responders. Good responders were treated as fair responders or with only MTX and CDP. At a 47-month follow-up, 66 patients remained continuously disease free and 61 patients developed metastases. Six of these patients had also a local recurrence. According to the grade of necrosis, the cumulative disease-free probability at 5 years was 67% for good responders, 42% for fair responders, and for poor responders 10% at 45 months. According to the doses of MTX, survival at 5 years was 58% for patients who received high doses and 42% for patients treated with moderate doses. No differences in the rate of survivors were observed between amputated patients and patients treated with limb salvage. The authors conclude that (1) a limb salvage procedure is possible in about 70% of cases and as safe as demolitive surgery, if adequate surgical margins are achieved; (2) good responders have a better prognosis than fair and poor responders if postoperative chemotherapy is sufficiently prolonged and also includes ADM; (3) a different postoperative chemotherapy for poor responders did not improve their prognosis; and (4) a multidrug regimen using high doses of MTX is probably more effective than moderate doses.

A phase II study of sequential methotrexate and 5-fluorouracil in colorectal carcinoma

Nineteen patients with locally recurrent or metastatic colorectal carcinomas were treated with 3-weekly cycles of methotrexate (MTX) given as a loading dose of 100 mg m-2 and a subsequent 12 h infusion of 400 mg m-2, followed by 5-fluorouracil (5-FU) 900 mg m-2 as a bolus injection on completion of infusion. No objective responses were seen in 14 evaluable patients. One early death was treatment related, and four patients were withdrawn from the study after a single course as toxicity was considered unacceptable. The results suggest that in this regimen of sequential MTX and 5-FU, any synergism may be restricted to drug toxicity as no therapeutic benefit was evident.

Methotrexate Inhibits the Human C5a-Induced Skin Response in Patients With Psoriasis

In this study we examined the effects of intradermal injections of human complement split product C5a in 10 patients with psoriasis in long-term treatment with methotrexate (MTX). The C5a was injected at the end of the weekly MTX cycle just before the intake of the first MTX dose and 3 h after the second of the 3 doses. The C5a-induced skin response was evaluated by measuring the diameter of the wheal and the area of the flare and by erythema index (EI), which was determined objectively by reflectance spectrophotometry. In all patients the skin response was significantly depressed when C5a was injected after MTX intake. The decrease of wheal, flare, and EI averaged 61.6%, 71.1%, and 57.5%, respectively, when all parameters were obtained at maximal skin response. The in vitro chemotaxis of peripheral blood neutrophils and monocytes from the patients toward C5a was markedly inhibited after intake of MTX (p less than 0.01). The skin biopsies obtained after C5a injection before intake of MTX revealed a perivascular inflammatory infiltrate and considerable dermal edema. After MTX intake the number of infiltrating leukocytes and the degree of dermal edema was markedly reduced. This study indicates that MTX is a potent inhibitor of C5a-induced skin inflammation, and that this inhibition may be caused by a direct effect on circulating neutrophils and monocytes. The results obtained in this work support the idea that anti-inflammatory effects of MTX may be partially responsible for its antipsoriatic effect.

Effect of dose and repeat intravenous 24 hr infusions of methotrexate on cerebrospinal fluid availability in children with hematological malignancies

This pharmacokinetic study examined the relationship between methotrexate (MTX) dose and drug concentrations in blood and cerebrospinal fluid (CSF) during repeated 24 hr infusions. Two regimens were used: an intermediate dose (ID) of 0.5 g/m 2 ( 7 patients, 23 cycles) and a high dose (HD) of 2.5 g/m 2 ( 8 patients, 39 cycles). Inter-patient variability in the drug concentration was apparent in serum and CSF for both doses. The dispersion was particularly wide in CSF for HD MTX. Considering median values serum and CSF MTX were linked to dose escalation. Individual CSF/serum drug ratios were not modified by the dose ( 1.1% for ID MTX versus 1.4% for HD MTX). A potentially cytotoxic drug level in CSF ( 10 −6 M ) was never obtained for ID MTX cycles, but was achieved in 44% of HD MTX cycles: for HD MTX, this corresponded to 88% of patients ( 7 8 ). Total body clearance did not modify the degree of CSF MTX passage. A positive, significant correlation ( r = 0.62, P < 0.05) was observed for ID MTX between individual serum and CSF MTX; no such relationship was seen with HD MTX. Individual cycle-to-cycle variations in the MTX concentration were particularly marked in CSF and for HD MTX, without strict concordance with blood levels.

Kinetics of 7-hydroxy-methotrexate after high-dose methotrexate therapy.

Kinetics of 7-hydroxy-methotrexate (7-OH-MTX) excretion after high-dose methotrexate (MTX) (12 g/m2) therapy were monitored in 93 consecutive drug cycles of 19 adolescent patients with osteosarcoma. A reversed-phase HPLC method was used. Serum elimination was found to be monophasic with a mean half-life of 5.5 h. Shortly after the 4-h MTX infusion period 7-OH-MTX levels exceeded those of the parent compound. By 12 h after MTX infusion 7-OH-MTX levels were 16.5 times higher than those of MTX itself. Autostimulation of MTX metabolism leading to enhanced 7-OH-MTX production after repeated drug cycles was not observed. The production of 7-OH-MTX decreased significantly from the first to the last high-dose MTX cycle of the adjuvant chemotherapy protocol.

Adjuvant Methotrexate and Leucovorin in Head and Neck Squamous Cancer: Two-year Follow-up of a Pilot Project

A series of 17 patients with stage III and IV head and neck cancer received three cycles of methotrexate and leucovorin calcium during an interval of two weeks prior to surgery and/or radiotherapy. The dosage of methotrexate was sequentially escalated to produce mucositis (the usual dose-limiting toxicity). All patients have been followed up for a minimum of two years (range, 24 to 44 months). Two recurrences and two second primary tumors occurred in seven patients with stage III cancer, and one recurrence and one postoperative death (pulmonary embolism) occurred in ten patients with stage IV cancer. Seventy-six percent of patients survived, with 71% disease free. Mucositis occurred in 88% but was transient and prevented oral fluid intake in only one patient. Bone marrow suppression was usually mild and did not delay surgery. Escalation of dosage was thought to be important in achieving these encouraging results. A controlled trial is under way to better define the degree of efficacy of this regimen of adjuvant chemotherapy.