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PubMed2004

Reactivation of latent Epstein-Barr virus by methotrexate: a potential contributor to methotrexate-associated lymphomas.

BACKGROUND: Patients with rheumatoid arthritis or polymyositis treated with methotrexate (MTX) develop Epstein-Barr virus (EBV)-positive lymphomas more frequently than patients treated with other, equally immunosuppressive regimens. Here we determined whether MTX, in contrast to other commonly used medications for rheumatoid arthritis or polymyositis, is unique in its ability to induce the release of infectious EBV from latently infected cells. METHODS: The effect of MTX and other immunosuppressant drugs on EBV replication in vitro was assessed using latently infected EBV-positive lymphoblastoid and gastric carcinoma cell lines. Inhibitors of signal transduction pathways were used to define requirements for induction of lytic infection. Drug effects on transcription of the two EBV immediate-early promoters (BRLF1 and BZLF1) and on promoter constructs lacking cis-acting sequences required for activation by other effectors was examined using reporter gene assays. EBV viral load in rheumatoid arthritis and polymyositis patients receiving MTX was compared with that in patients receiving other immunosuppressive medications. Statistical tests were two-sided. RESULTS: MTX activated the release of infectious EBV from latently infected cell lines in vitro, and MTX treatment was associated with activation of the two viral immediate-early promoters in reporter gene assays. Induction of lytic EBV infection by MTX required the p38 MAP kinase, PI3 kinase, and MEK pathways and specific cis-acting motifs in the two viral immediate-early promoters. Patients treated with MTX-containing regimens had statistically significantly higher mean EBV loads in their blood than patients treated with immunosuppressing regimens that did not include MTX (40 EBV copies per 10(6) cellular genomes versus 5.1 copies; geometric mean fold difference in copies = 10.8, 95%, confidence interval = 3.0 to 38; P = .011). CONCLUSION: MTX may promote EBV-positive lymphomas in rheumatoid arthritis and polymyositis patients by its immunosuppressive properties as well as by reactivating latent EBV.

Arthritis, Rheumatoid↗

PubMed1995

Local injection of methotrexate dissolved in saline versus methotrexate suspensions for the conservative treatment of ectopic pregnancy.

To compare the local injection of methotrexate (MTX) dissolved in saline and MTX suspensions for the laparoscopic treatment of ectopic pregnancy in terms of success rate and postoperative tubal patency. A total of 26 patients with unruptured ectopic pregnancies were selected from among 60 women with ectopic pregnancies admitted to the Nagasaki University clinic. Of these patients, 12 were treated with MTX dissolved in saline solution (solution group) and 14 with MTX suspensions consisting of lipiodol (LPD) with phosphatidylcholine (PC) added as a dispersing stabilizer (suspension group). Except for one case treated under transvaginal guidance, all the patients were treated by laparoscopy. Persistent ectopic pregnancy was recognized in seven cases (58%) in the solution group but in only two cases (14%) in the suspension group. Moreover, rupture occurred in two cases in the solution group but in no case in the suspension group. A patent treated tube was found in seven of 10 cases in the saline group and in 10 of 12 cases in the suspension group. During the follow-up period of 6-31 months, five women in the saline group and three women in the suspension group had an intrauterine pregnancy. In this study, the local injection of MTX is considered to be a reasonable method for the treatment of unruptured ectopic pregnancy, and the MTX suspension seems to be more effective and useful than MTX solution.

Adolescent↗

PubMed1989

Synovial and serum levels of methotrexate during methotrexate therapy of rheumatoid arthritis.

Methotrexate (MTX) levels were studied following intravenous MTX in both serum and synovial fluid (SF) of rheumatoid arthritis patients. Two hours after injection serum MTX levels were higher than those of SF. At 24 hours SF levels of MTX exceeded those of the serum, while at 72 hours both blood and SF concentrations were undetectable. The localization of parenteral MTX in the SF may have importance in the understanding of its mechanism and site of action in rheumatoid arthritis.

Arthritis, Rheumatoid↗

PubMed1994

Combination of methotrexate and sulphasalazine vs methotrexate alone: a randomized open clinical trial in rheumatoid arthritis patients resistant to sulphasalazine therapy.

To compare efficacy, toxicity, and the pharmacokinetics of the combination of sulphasalazine (SASP) and methotrexate (MTX) vs MTX alone in the treatment of SASP-resistant RA we conducted a controlled open clinical trial. Forty RA patients with active arthritis despite adequate SASP therapy, were allocated randomly to regimes of either SASP+MTX or MTX alone. The patients were evaluated openly by a single observer for 24 weeks. In the first 15 patients using the combination, pharmacokinetics of MTX without and with SASP were studied. Thirty-eight patients completed the trial. The mean decrease in the disease activity score in the group of patients receiving the combination was significantly greater than in the MTX group (-2.6 vs -1.3 respectively). The same pattern was seen concerning the other efficacy variables. There was no difference in the occurrence of toxicity. SASP had no influence on the pharmacokinetics of MTX. In conclusion in this open study the efficacy of the combination of MTX and SASP seems to be superior to MTX alone, the toxicity of both therapies was similar. This effect was not explained by the pharmacokinetics of MTX which were not altered by concomitant SASP administration.

Adult↗

PubMed2003

Radiographic progression in early rheumatoid arthritis: a 12-month randomized controlled study comparing the combination of cyclosporin and methotrexate with methotrexate alone.

OBJECTIVE: To determine whether patients with early rheumatoid arthritis (RA) treated with cyclosporin A (CsA) and methotrexate (MTX) in combination for 12 months show a lower rate of radiographic deterioration than those treated with MTX alone. METHODS: In this controlled and randomized single-blind trial, 61 consecutive patients with untreated RA of less than 2 yr duration were treated with either CsA + MTX combination therapy (n = 30) or MTX alone (n = 31). The primary end-point was radiographic progression after 12 months, measured using the damage score (DS) of the Sharp and van der Heijde method. RESULTS: Although there was a significant difference between the mean baseline and 12-month DS in both treatment groups (MTX/CsA, 1.93 +/- 0.90; MTX, 7.47 +/- 2.03), it was significantly less in the combination arm (P = 0.018). Of the 30 evaluable CsA + MTX patients, 16 (53%) were ACR20 responders, 15 (50%) ACR50 and 14 (47%) ACR70; the corresponding figures in the MTX arm were 19 (61%), 13 (44%) and 6 (19%). Toxicity was acceptable in both groups. CONCLUSIONS: In patients with early RA, CsA + MTX combination therapy led to a significantly lower rate of 12-month radiographic progression, was effective on inflammatory articular symptoms, and was well tolerated.

Adult↗

PubMed1994

Selective delivery of a greater amount of methotrexate to regional lymph nodes using a new dosage formulation, methotrexate adsorbed on activated carbon particles, in rats.

A new dosage formulation (MTX-CH) comprising methotrexate (MTX) adsorbed onto a suspension of activated carbon particles was developed for the treatment of lymph node metastases. In vitro studies showed that activated carbon particles adsorbed a great amount of MTX. Subcutaneous injection of MTX-CH into the left hind foot pad of rats distributed a greater amount of MTX selectively to the regional lymph nodes (the left popliteal node and the para-aortic nodes) for a longer period of time than similar administration of MTX aqueous solution with a smaller amount of MTX distributed to the rest of the whole body.

Adsorption↗

PubMedDate not supplied

Intermediate dose methotrexate is as effective as high dose methotrexate in preventing isolated testicular relapse in childhood acute lymphoblastic leukemia.

PURPOSE: We evaluated the influence of three different dosages of methotrexate (MTX) during consolidation on the incidence of testicular relapse in children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: One thousand one hundred forty-four boys with newly diagnosed ALL, enrolled in three consecutive trials of the Berlin-Frankfurt-Münster group (ALL-BFM 81, 83, 86), were retrospectively evaluated for the influence of MTX on testicular relapse-free interval. The basic treatment design was similar in all trials. No intravenous MTX was used in trial ALL-BFM 81 in the group who received cranial irradiation (CRT) except for a part of standard risk patients. Four courses of intermediate dose MTX (IDM) (0.5 g/m2) were introduced for all patients in trial ALL-BFM 83 (IDM group), which were replaced by high dose MTX (HDM) (5 g/m2) in trial ALL-BFM 86 (HDM group). The media observation time was > 9 years. RESULTS: The cumulative incidence of isolated testicular relapses was significantly higher in the CRT group as compared to the IDM and HDM groups (6.7% versus 2.5% and 2.3%, p = 0.02 and 0.01). HDM decreased neither the incidence nor the rate of isolated testicular relapses any further. Event-free survival (EFS) for boys was similar between trial ALL-BFM 81 and 86 (64% versus 69%, p = 0.35), but differed significantly between trials ALL-BFM 83 and 86 (61% versus 69%, p = 0.0078). CONCLUSION: The introduction of IDM reduced the incidence of isolated testicular relapses significantly by a factor two, but had no significant influence on overall survival. HDM did not result in a more effective prevention of testicular relapses, but resulted in better systemic control and hence better survival than IDM.

Antimetabolites, Antineoplastic↗

PubMed1985

Entry of methotrexate into Streptococcus pneumoniae: a study on a wild-type strain and a methotrexate resistant mutant.

Entry of methotrexate (MTX) into the folate prototrophic bacterium Streptococcus pneumoniae was poorly inhibited by folate or its natural derivative folinic acid, suggesting that if MTX is transported via a folate transporter, the affinity of that transporter for MTX is higher than for folate. In the range of concentrations tested, MTX uptake was non-concentrative and decreased in ATP-depleted bacteria. When the external concentration of MTX was increased from 1 X 10(-7) M to 1 X 10(-6) M, uptake became saturated and was insensitive to ionophores. However when external MTX concentrations were increased to 1 X 10(-5) M, uptake increased linearly, and was inhibited by the ionophores carbonyl cyanide m-chlorophenylhydrazone (CCCP) and valinomycin, suggesting that the process was energized by the protonmotive force (delta p) at this concentration. A model for MTX entry in S. pneumoniae is proposed with respect to these results. The high level of resistance to MTX of the nonsense mutant amiA9 cannot be entirely explained by a decrease in MTX uptake.

Amino Acids↗

PubMed1995

Methotrexate therapy of psoriasis: differential sensitivity of proliferating lymphoid and epithelial cells to the cytotoxic and growth-inhibitory effects of methotrexate.

Although methotrexate (MTX) is one of the most clinically effective therapies employed to treat psoriasis, the mechanism by which low-dose MTX acts to modulate the hyperplasia of psoriasis, leading to the restoration of clinically normal skin, is only partially understood. MTX has been considered a cytotoxic agent that mediates its effect primarily on proliferating or cycling epidermal cells. Recently, proliferating lymphoid cells have been identified in psoriatic lesions, raising the possibility that proliferating lymphoid cells could be another target cell that is killed by MTX. In this study, we examined the growth-inhibitory and cytotoxic effects of MTX on proliferating lymphoid cells [THP-1 (macrophage), and MOLT-4 (T cell)], epithelial cells (HeLa, and HaCat), and normal human keratinocytes (NHK) in vitro. The proliferating cells were exposed to MTX for 24 h, and placed in fresh media to mimic the transient MTX blood levels that result from once-weekly therapy. THP-1 and MOLT-4 were found to be 10-100 times more sensitive to the cytotoxic effects of MTX than were HeLa and HaCat, and more than 1000 times more sensitive than primary human keratinocytes. At MTX concentrations that would be expected to occur in vivo during once-weekly therapy, a large percentage (> 95%) of proliferating lymphoid targets would be killed, and only a small percentage (< 10%) of proliferating epidermal cells would be affected. This in vitro data suggests that in psoriasis proliferating lymphoid cells are more likely than epithelial cells to be a major cellular target of MTX in vivo.

Cell Division↗

PubMed1990

Reversal of methotrexate cytotoxicity to human bone marrow cells and leukemic K562 cells by leucovorin: methotrexate polyglutamates formation as a possible important factor.

Methotrexate (MTX) is metabolized intracellularly to MTX-polyglutamates (MTX-PGs), which markedly inhibit several folate-dependent enzymes. Polyglutamation defect, therefore, is one of the important factors in drug resistance. In this study, reversal of MTX cytotoxicity by l-leucovorin (l-LV) was investigated using normal human bone marrow granulocyte progenitor cells (G-CFCs), and MTX-sensitive and -resistant leukemic K562 cell lines; the latter showed diminished polyglutamation. Cytotoxicity of 10(-7)M MTX to G-CFCs was completely reversed by an equimolar concentration of l-LV, but with higher MTX concentrations, relatively more l-LV was required. The reversal of MTX cytotoxicity by l-LV was more effective against bone marrow cells than MTX-sensitive K562 cells; this reversal seemed to be correlated to the total intracellular MTX levels as well as MTX-PG formation (low in bone marrow cells and high in K562 cells). When MTX-sensitive and -resistant K562 cells were incubated with MTX under conditions in which the total intracellular MTX levels of both cells were similar, successful reversal of MTX toxicity by l-LV was demonstrated in MTX-resistant cells, but not in MTX-sensitive cells, suggesting that an increase of MTX-PG formation in MTX-sensitive cells may explain the failure of l-LV to overcome MTX cytotoxicity. In addition to competitive reversal of MTX cytotoxicity by LV, noncompetitive reversal relating to variable formation of MTX-PGs is suggested to be another important factor in the mechanism of the reversal of MTX cytotoxicity by LV.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1987

Lack of correlation between methotrexate concentrations in serum, saliva and sweat after 24 h methotrexate infusions.

1 Methotrexate (MTX) concentrations were studied in serum, mixed saliva and sweat during and after 24 h continuous MTX infusions (0.5-6 g m-2) in 14 patients with various malignant diseases. 2 The serum-MTX concentrations declined in a biphasic manner, but the MTX elimination in saliva and sweat varied to a much greater extent. 3 Saliva/serum and sweat/serum ratios during the MTX infusion were 2.3% and 0.55% respectively. The ratios had increased significantly 20 and 44 h postinfusion. 4 No correlations were demonstrated between salivary- and serum-MTX concentrations during the MTX infusion or 20 and 44 h later. 5 Markedly delayed renal MTX excretions were demonstrated in two patients. In one of them the salivary MTX elimination was also retarded, whereas this was not seen in the other one. 6 We conclude that measurements of MTX concentrations in mixed saliva cannot substitute for serum-MTX determinations in the monitoring of patients after 24 h MTX infusions.

Humans↗

PubMed1977

Liver biopsies from psoriatics related to methotrexate therapy. 3. Findings in post-methotrexate liver biopsies from 160 psoriatics.

The purpose of this paper is to report findings in post-MTX liver biopsies from 160 psoriatics treated with Methotrexate (MTX) in single biopsy and B. 68 patients with serial biopsies. At the time of liver biopsy the 92 patients had received a mehosis and six patients had fibrosis. Comparing these 7 patients with patients having normal liver histology (13 patients) revealed no statistically significant difference in cumulative doses of MTX, but a statistically significant higher admitted alcohol intake during MTX therapy (p less than 0.002) and an older age (p less than 0.01) in the patients with cirrhosis or fibrosis. in the 68 patients MTX had accumulated to a mean dose of 3940 mg (range 32k-8355 mg) at the time the latest liver biopsies were taken. Among the latest liver biopsies were 14 cirrhosis (21 per cent, 95 per cent confidence limits: 12-32 per cent) and 16 fibrosis (24 per cent, 95 per cent confidence limits: 14-35 per cent). The 14 patients with cirrhosis when compared to patients with normal histology (9 patients), had taken an equal total dose of MTX at the latest liver biopsy, but had consumed a statistically significant higher amount of alcohol (p less than 0.05) during MTX therapy and also tended to be older (p less than 0.006). Comparison of a material A and B indicates that the prevalence of cirrhosis and fibrosis among MTX treated psoriatics increases rapidly beyond a cumultative dose of two to four grams of MTX. No MTX treated psoriatics should thus be allowed to pass this dosage range without having a liver biopsy performed.

Adult↗

PubMed2004

A prominent low-pH methotrexate transport activity in human solid tumors: contribution to the preservation of methotrexate pharmacologic activity in HeLa cells lacking the reduced folate carrier.

Whereas the major folate transporter, the reduced folate carrier (RFC), has a physiological pH optimum, transport activities for folates and antifolates have been detected with low pH optima. Because the interstitial pH in solid tumors is generally acidic, the mechanisms by which antifolates are transported at low pH could be an important determinant of drug activity under these conditions. The current study quantitated the low pH methotrexate (MTX) transport activity in human solid tumor cell lines from the National Cancer Institute tumor panel and other sources. MTX influx at pH 5.5 was equal to, or greater than, influx at pH 7.4 in 29 of 32 cell lines. To assess the role of RFC in transport at low pH in one of these cell lines, a HeLa clonal line (R5) was selected for MTX resistance due to a genomic deletion of the carrier gene. MTX influx was depressed by 70% in R5 versus wild-type HeLa cells at pH 7.4. At pH 6.5, influx in these two lines was similar; as the pH was decreased to 5.5 influx increased in both cell lines. Similarly, whereas net MTX uptake over 1 h was markedly decreased in R5 cells at pH 7.4, net uptake in HeLa and R5 cells was comparable at pH 6.5. Also, as compared with MCF7 breast cancer cells, MTX uptake was markedly decreased at pH 7.4, but only minimally at pH 6.5, in the MDA-MB-231 human breast cancer cell line that lacks RFC expression. When grown with folic acid (2 micro M) at pH 7.4, the IC(50) for MTX was 14-fold higher in R5 as compared with wild-type HeLa cells; the difference was only 4-fold when cells when grown at pH 6.9; the IC(50)s were identical at this pH when the medium folate was 25 nM 5-formyltetrahydrofolate. These data demonstrate that transport activity at low pH is prevalent in human solid tumors, is RFC-independent in R5 cells and MDA-MB-231 breast cancer cells, and can preserve MTX activity in the absence of RFC at an acidic pH relevant to solid tumors in vivo.

Antimetabolites, Antineoplastic↗

PubMedDate not supplied

Significance of methotrexate serum level achieved in patients with gastrointestinal malignancies treated with sequential methotrexate, L-folinic acid and 5-fluorouracil.

Twenty-one patients affected by advanced carcinoma of the digestive tract, all but 2 previously treated, received on day 1 every 2 weeks a 2-hour intravenous (i.v.) infusion of methotrexate (MTX), 250 mg/m2, followed 24 h later by a 2-hour i.v. infusion of L-folinic acid (LFA), 250 mg/m2, and 5-fluorouracil (FU), 600 mg/mg2 as an i.v. bolus. Only 1 previously untreated patient obtained a partial response. The MTX serum level assessed 24 h after its infusion (24-hour sMTX) ranged from 0.3 to 5.7 (median: 0.9) microM, and in only 8/21 patients reached a concentration > or = 1 microM. A further 46 patients (of whom 22 had been previously treated) received the same treatment as above but with a double dosage (500 mg/m2) of MTX. Twelve of these 46 patients (26%, 95% confidence interval = 14-41%) achieved a partial response with this regimen. Responses were obtained in chemotherapy-naive patients (8/24) and in previously treated patients (4/22). The 24-hour sMTX ranged from 1.2 to 9.5 microM)(median: 2.3) and was > or = 2 microM in 30/46 patients. Among patients showing a 24-hour sMTX value > or = 2 microM, the response rate was 39% (45% in previously untreated patients), while no patient with a 24-hour sMTX value below 2 microM at 24 h obtained a major response (p = 0.0017). Our findings demonstrate that 500 mg/m2 of MTX given as a 2-hour i.v. infusion is required to reach a serum concentration of at least 1 microM for 24 h. Furthermore, the double biochemical modulation of FU may obtain an objective response in patients previously treated with fluoropyrimidines.

Adult↗

PubMed1996

Accumulation of methotrexate polyglutamates in lymphoblasts is a determinant of antileukemic effects in vivo. A rationale for high-dose methotrexate.

Methotrexate (MTX) is one of the most widely used drugs for the treatment of childhood acute lymphoblastic leukemia (ALL) and is commonly given in high doses. However, the rationale for high-dose MTX (HDMTX) has been challenged recently. To determine whether higher MTX polyglutamate (MTXPG) concentrations in ALL blasts translate into greater antileukemic effects, 150 children with newly diagnosed ALL were randomized to initial treatment with either HDMTX (1,000 mg/m2 intravenously over 24 h) or lower-dose MTX (30 mg/m2 by mouth every 6 h x 6). ALL blasts accumulated higher concentrations of MTXPG and long-chain MTXPG (MTXPGLC) after HDMTX (P < 0.00001). Of 101 patients evaluable for peripheral blast cytoreduction, MTXPG concentrations were higher in patients whose blast count decreased within 24 h (P = 0.005) and in those who had no detectable circulating blasts within 4 days (P = 0.004). The extent of inhibition of de novo purine synthesis in ALL blasts was significantly related to the blast concentration of MTXPGLC (IC95% = 483 pmol/10(9) blasts). The percentage of patients with 44-h MTXPGLC exceeding the IC95% was greater after HDMTX (81%) than LDMTX (46%, P < 0.0001). These data indicate that higher blast concentrations of MTXPG are associated with greater antileukemic effects, establishing a strong rationale for HD-MTX in the treatment of childhood ALL.

Adolescent↗

PubMed2004

Disparate mechanisms of antifolate resistance provoked by methotrexate and its metabolite 7-hydroxymethotrexate in leukemia cells: implications for efficacy of methotrexate therapy.

Methotrexate (MTX) is one of the leading drugs in the treatment of leukemia, but extensive metabolism to 7-hydroxymethotrexate (7-OHMTX) can limit its therapeutic efficacy. In this study we investigated whether 7-OHMTX itself can provoke anti-folate resistance that may further disrupt MTX efficacy. For this purpose, we developed resistance to 7-OHMTX as well as MTX in 2 human leukemia cell lines (CCRF-CEM and MOLT-4) by stepwise exposure to increasing concentrations of 7-OHMTX and MTX. Consequently, both leukemia cell lines displayed marked levels of resistance to 7-OHMTX (> 10-fold) and MTX (> 75-fold). The underlying mechanism of resistance in the MTX-exposed cells was a marked decrease (> 10-fold) in reduced folate carrier (RFC)-mediated cellular uptake of MTX. This was associated with transcriptional silencing of the RFC gene in MTX-resistant CCRF-CEM cells. In contrast, the molecular basis for the resistance to 7-OHMTX was due solely to a marked decreased (> 95%) in folylpolyglutamate synthetase (FPGS) activity, which conferred more than 100-fold MTX resistance upon a short-term exposure to this drug. This is the first demonstration that 7-OHMTX can provoke distinct modalities of antifolate resistance compared with the parent drug MTX. The implications of this finding for MTX efficacy and strategies to circumvent MTX resistance are discussed.

Antimetabolites, Antineoplastic↗

PubMed2005

Methotrexate dosage reduction in patients with rheumatoid arthritis beginning therapy with infliximab: the Infliximab Rheumatoid Arthritis Methotrexate Tapering (iRAMT) trial.

OBJECTIVE: Infliximab plus methotrexate (MTX) is approved for the treatment of rheumatoid arthritis (RA). Based on the benefit/risk profile of this combination therapy, lower doses of MTX would be preferable when infliximab efficacy can be maintained. We evaluated the ability of patients receiving infliximab plus MTX to achieve and maintain a clinical response while the dose of MTX was tapered. METHODS: Infliximab infusions were administered at a minimum dosage of 3 mg/kg at 8-week intervals (following three loading doses at weeks 0, 2, and 6) to patients who had an inadequate response to MTX. MTX tapering was initiated at week 22 or later when at least a 40% improvement in the combined tender and swollen joint count was achieved; dosages were reduced by 5 mg every 8 weeks to a protocol-specified minimum dosage of 5 mg per week. If the required dosage of MTX after a flare was greater than the baseline dosage, the patient was considered a treatment failure. RESULTS: Of the 210 patients enrolled, 159 (76%) achieved a 40% or better improvement in the combined tender and swollen joint count and had their MTX doses tapered. In these 159 responders, the median (mean) dose of MTX was reduced from 15 (16.5) mg per week at baseline to 5 (7.1) mg per week at week 54. From the time of initial response, 79% of these patients had a zero- or a one-vial increase in infliximab, corresponding to an approximate dose increase of 1 mg/kg, through week 54. CONCLUSION: Approximately 75% of the patients participating in this trial achieved at least a 40% reduction in the combined swollen and tender joint count (correlating with an American College of Rheumatology 20% [ACR20] response in 83% of patients) while reducing the mean MTX dose by 57%.

Adolescent↗

PubMed1989

A comparison of carboplatin plus methotrexate versus methotrexate alone in patients with recurrent and metastatic head and neck cancer.

Patients with recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN) were stratified by performance status, extent of disease, and prior radiotherapy and subsequently randomized to receive carboplatin (CBDCA; Bristol-Myers, Wallingford, CT) administered intravenously (IV) monthly, initially at doses of 400 mg/m2 in combination with methotrexate (MTX) given IV weekly at doses of 40 mg/m2 or MTX alone at the same dose/schedule. Significant dose-limiting myelosuppression required CBDCA dose reductions to 300 mg/m2 and, subsequently, 200 mg/m2. Nonhematological toxicities were not significant. Our study objective was to determine whether CBDCA plus MTX produce a substantial improvement in response rate over single-agent MTX. A response rate of 50% (complete [CR] plus partial response [PR]) for CBDCA plus MTX compared with 25% for MTX was specified as the difference to be detected. We employed a two-stage study design for randomized trials that allowed for early termination of studies involving relatively ineffective treatment regimens. With this design, the study could be closed after the first stage (20 patients entered onto each treatment arm) if the number of responders to CBDCA plus MTX were not superior to MTX. Five of 20 patients responded to treatment in each arm, and we were able to conclude that the addition of CBDCA to MTX is unlikely to result in a twofold increase in response rate compared with MTX alone in this group of patients. This two-stage design represents a simple and efficient method of testing the relative efficacy of new combinations containing at least one active agent against a suitable control arm in this disease. It addresses scientific and ethical issues of continuing testing with relatively ineffective treatments, and at the same time provides a reliable method for identifying very active regimens likely to represent significant therapeutic advances.

Adult↗