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Oncology (Williston Park, N.Y.) Mar 1997Clinical trials to develop paclitaxel (Taxol)-containing combinations started in 1992 with several approaches to combine doxorubicin and paclitaxel. Schedule-dependent... (Review)
Review
Clinical trials to develop paclitaxel (Taxol)-containing combinations started in 1992 with several approaches to combine doxorubicin and paclitaxel. Schedule-dependent toxicity limited doses in the initial trials, although antitumor activity was high. More recently, a well-tolerated, highly effective doxorubicin/paclitaxel regimen was developed with the use of bolus anthracycline administration and a 3-hour infusion of paclitaxel. Combinations of paclitaxel with cisplatin have provided mixed results. Paclitaxel combined with fluorouracil (5-FU) and folinic acid proved effective in patients with extensive prior chemotherapy; the addition of mitoxantrone (Novantrone) to this combination was feasible, well tolerated, and possibly enhanced the efficacy of paclitaxel and 5-FU. Combinations of paclitaxel with cyclophosphamide (Cytoxan, Neosar), vinorelbine (Navelbine), edatrexate, and radiation continue in clinical development.
Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cisplatin; Cyclophosphamide; Doxorubicin; Female; Humans; Paclitaxel
PubMed: 9110340
DOI: No ID Found -
Oncology (Williston Park, N.Y.) Jul 1995Numerous new antifolate drugs have been developed in an attempt to overcome the potential mechanisms of tumor cell resistance to methotrexate, which can include... (Review)
Review
Numerous new antifolate drugs have been developed in an attempt to overcome the potential mechanisms of tumor cell resistance to methotrexate, which can include decreased drug transport into cells; decreased polyglutamation, leading to increased drug efflux from cells; decreased drug affinity for folate-dependent enzymes; mutations of dihydrofolate reductase (DHFR), a key enzyme required for the maintenance of adequate intracellular reduced folate levels that is inhibited by methotrexate; and increased expression of the DHFR protein. Promising antifolate compounds undergoing clinical testing as anticancer agents include trimetrexate (which was recently approved by the FDA for the treatment of Pneumocystis carinii pneumonia), edatrexate, piritrexim, Tomudex, and lometrexol. The mechanisms of action, dosage, pharmacokinetics, clinical toxicity, and antitumor activity of these drugs are profiled.
Topics: Aminopterin; Antimetabolites, Antineoplastic; Antineoplastic Agents; Drugs, Investigational; Folic Acid Antagonists; Humans; Neoplasms; Pyrimidines; Quinazolines; Thiophenes; Trimetrexate
PubMed: 8924375
DOI: No ID Found -
Journal of Clinical Oncology : Official... Jul 1995To compared the response rates and the toxicity of the new antifolate edatrexate (EDX) with that of methotrexate (MTX) in a randomized trial in patients with metastatic... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: a European Organization for Research and Treatment of Cancer Head and Neck Cancer Cooperative Group study.
PURPOSE
To compared the response rates and the toxicity of the new antifolate edatrexate (EDX) with that of methotrexate (MTX) in a randomized trial in patients with metastatic or recurrent squamous cell cancer of the head and neck (SCC) and to compare the durations of response and survival.
PATIENTS AND METHODS
Two hundred seventy-three patients with SCC were randomized to receive either EDX or MTX as a weekly intravenous (IV) bolus injection. Doses of EDX were initially 80 mg/m2/wk, but because of the toxicity, this was later reduced to 70 mg/m2/wk. MTX was administered at a dose of 40 mg/m2/wk throughout. In both arms, two dose increments of 10% were scheduled in case of no toxicity.
RESULTS
Of 264 eligible patients, 131 were treated with EDX and 133 with MTX. There were five treatment-related deaths: four on EDX and one on MTX. Overall, toxicity was similar in both arms; however, stomatitis, skin toxicity, and hair loss were more pronounced on the EDX arm. The overall response rate was 21% (six complete responses [CRs] and 21 partial responses [PRs]) for EDX and 16% (nine CRs and 12 PRs) for MTX (P = .392). Responses were mainly seen in patients with locoregional disease. Tumors that originated from the hypopharynx responded poorly in comparison to tumors from other sites. The median duration of response was 6.1 months for EDX and 6.4 months for MTX (log-rank P = .262). There was no difference in overall or progression-free survival. The median survival duration was 6 months on both treatment groups.
CONCLUSIONS
Both EDX and MTX are moderately active against SCC. In this large phase III study, response rates, time to treatment failure, and overall survival appeared to be similar for both antifolates. However, EDX had more side effects than MTX and therefore cannot be recommended for routine palliative treatment of patients with SCC.
Topics: Agranulocytosis; Aminopterin; Antineoplastic Agents; Carcinoma, Squamous Cell; Drug Administration Schedule; Female; Head and Neck Neoplasms; Humans; Injections, Intravenous; Lung; Male; Methotrexate; Respiratory Distress Syndrome; Thrombocytopenia
PubMed: 7602354
DOI: 10.1200/JCO.1995.13.7.1649 -
Annals of Oncology : Official Journal... Sep 1994The methotrexate analogue edatrexate (10-ethyl-10-deaza-aminopterin, or 10-EDAM) has demonstrated greater activity than methotrexate has against murine tumors and human... (Clinical Trial)
Clinical Trial
BACKGROUND
The methotrexate analogue edatrexate (10-ethyl-10-deaza-aminopterin, or 10-EDAM) has demonstrated greater activity than methotrexate has against murine tumors and human tumor xenografts. Phase II trials of edatrexate have already demonstrated its activity against breast, lung, and head and neck carcinomas. A phase II trial of edatrexate was conducted in patients with advanced hepatocellular carcinoma.
PATIENTS AND METHODS
Seventeen patients with previously untreated unresectable hepatocellular carcinoma were enrolled on the study. Edatrexate, 80 mg/m2 weekly for 5 weeks, was administered intravenously. The treatment course was repeated every 6 weeks. Tumor response was evaluated by computerized tomographic scan after 2 courses.
RESULTS
No complete or partial responses were observed in this trial. Two minor responses, each lasting less than 12 weeks, were observed. Twelve patients had elevated serum alpha-fetoprotein (AFP) levels at entry into the study; 4 of the 12 patients experienced a > or = 25% decrease in the level of this tumor marker; 3 of the 4 had a > 50% reduction in AFP level. Grade 3 and 4 toxic effects were granulocytopenia, thrombocytopenia, anemia, oral mucositis, skin reactions, fatigue, anorexia, and diarrhea.
CONCLUSIONS
Edatrexate administered at this dose and schedule appears to have little therapeutic efficacy against advanced hepatocellular carcinoma.
Topics: Adult; Aged; Agranulocytosis; Aminopterin; Antineoplastic Agents; Carcinoma, Hepatocellular; Female; Folic Acid Antagonists; Humans; Liver Neoplasms; Male; Middle Aged; Remission Induction; Thrombocytopenia; alpha-Fetoproteins
PubMed: 7527654
DOI: 10.1093/oxfordjournals.annonc.a058939 -
Annals of Oncology : Official Journal... May 1999The antifolate edatrexate and the microtubule-stabilizing agent paclitaxel have both demonstrated single-agent activity in lung and breast cancer. In vitro, the... (Clinical Trial)
Clinical Trial
BACKGROUND
The antifolate edatrexate and the microtubule-stabilizing agent paclitaxel have both demonstrated single-agent activity in lung and breast cancer. In vitro, the sequential combination of edatrexate followed by paclitaxel produced synergistic antitumor effects. This trial was designed to find the maximum tolerated doses of edatrexate and paclitaxel when given every two weeks utilizing this sequential schedule.
PATIENTS AND METHODS
Thirty-four patients with solid tumors received edatrexate intravenously on days 1 and 15 and paclitaxel intravenously as a three-hour infusion on days 2 and 16 of each 28-day cycle. Edatrexate was escalated from 40 to 120 mg/m2 and the paclitaxel dose fixed at 135 mg/m2. When the maximum-tolerated dose was not reached, edatrexate was fixed at 120 mg/m2 and paclitaxel escalated to 175 and 210 mg/m2.
RESULTS
All 34 patients were assessable. The maximum tolerated doses were 120 mg/m2 of edatrexate and 210 mg/m2 of paclitaxel. Grade 3 myalgia, peripheral neuropathy, leukopenia, and an infusion-related reaction occurred. Eight patients with non-small-cell lung cancer and one with bladder cancer achieved major objective responses.
CONCLUSIONS
The recommended phase II doses are 120 mg/m2 of edatrexate days 1 and 15 and 175 mg/m2 of paclitaxel as a three-hour infusion days 2 and 16 of a 28 day cycle. These results warrant phase II trials of the combination leading to phase III studies comparing the two drugs to a single agent to confirm the preclinical evidence of synergy.
Topics: Adult; Aged; Aminopterin; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Male; Middle Aged; Neoplasms; Paclitaxel
PubMed: 10416013
DOI: 10.1023/a:1026404812699 -
Oncology (Williston Park, N.Y.) Jan 1998Non-small-cell lung cancer (NSCLC) will increasingly come under better control as the current approaches to therapy are more broadly employed and as new therapies are... (Review)
Review
Non-small-cell lung cancer (NSCLC) will increasingly come under better control as the current approaches to therapy are more broadly employed and as new therapies are deployed against recently elucidated molecular pathways. In the United States, real progress is finally being made in decreasing tobacco consumption and in lung cancer incidence. The traditional chemotherapeutic compounds that became available earlier this decade (paclitaxel [Taxol], docetaxel [Taxotere], gemcitabine [Gemzar], vinorelbine [Navelbine], irinotecan [Camptosar], topotecan [Hycamtin], and edatrexate) have all been tested as single agents and as doublets with cisplatin (Platinol) and carboplatin (Paraplatin). Paclitaxel with cisplatin or carboplatin and vinorelbine, docetaxel, or gemcitabine with cisplatin have all demonstrated significant activity that now appears clearly better than the prior standard therapy of etoposide (VePesid)/cisplatin. Phase III studies sorting out their benefit relative to each other should be completed in the next 1 to 2 years. To date, no triplet therapy appears better than the corresponding doublet. Non-platinum-containing doublets are just completing their first round of assessments. Aside from new drugs and applications, the use of "small" molecules to inhibit either signal transduction pathways or gene activation is likely to accelerate. Most of the newer chemotherapeutic agents can be interdigitated with radiation and surgery, although evaluations into sequence and dose issues continue. The superior outcomes seen with the newer regimens should translate to the adjuvant and preoperative or preradiotherapy settings relatively quickly. It is now clear that NSCLC is as responsive to therapy as small-cell lung cancer (SCLC) and that outcomes are superior for NSCLC. The enthusiasm for treating SCLC displayed by nononcologists and nonthoracic medical oncologists should be shared for NSCLC.
Topics: Carcinoma, Non-Small-Cell Lung; Forecasting; Humans; Lung Neoplasms
PubMed: 9516620
DOI: No ID Found -
Pharmaceutical Research Aug 1997Low-dose methotrexate (MTX) is approved for the treatment of recalcitrant rheumatoid arthritis (RA). The objective of this study was to determine the effect of vehicles...
PURPOSE
Low-dose methotrexate (MTX) is approved for the treatment of recalcitrant rheumatoid arthritis (RA). The objective of this study was to determine the effect of vehicles and penetration enhancers on the percutaneous absorption of MTX and its analog edatrexate (EDAM), and develop transdermal (TD) delivery systems of the drugs for the treatment of RA.
METHODS
From previously published pharmacokinetic parameters with low-dose MTX therapy, and considering a 50 cm2 diffusional area, the target steady state in vitro TD flux for MTX was calculated to be 35 micrograms/cm2/hr. Modified Franz diffusion chambers and hairless mouse skin were used for in vitro skin permeation studies. Hairless mice were used for in vivo studies. Delivered amounts of MTX and EDAM were determined by assaying the receiver phase fluid (or blood) with validated reversed phase HPLC methods.
RESULTS
Intrinsic partition coefficient of MTX was low (log P = -1.2). Target MTX fluxes of > or = 35 micrograms/cm2/hr were achievable only with 1-15% (v/v) Azone in propylene glycol (PG). Flux of EDAM (85 micrograms/cm2/hr) was higher than MTX from an isopropyl alcohol (IPA)-5% (v/v) Azone system. Clinically significant steady state in vivo blood concentration of MTX and EDAM was achieved using delivery systems containing > or = 2.5% Azone in PG. Area under the drug concentration-time curves (AUC0-24 hr) for MTX were 2379 and 3534 ng*hr/ml from PG-2.5% Azone and PG-7.5% Azone systems respectively. AUC0-24 hr of EDAM was 6893 ng*hr/ml using a PG-2.5% Azone system.
CONCLUSIONS
Results of this study show the feasibility of using a transdermal delivery system of MTX and EDAM for the treatment of rheumatoid arthritis.
Topics: Administration, Cutaneous; Aminopterin; Animals; Antirheumatic Agents; Azepines; Caprylates; In Vitro Techniques; Methotrexate; Mice; Mice, Hairless; Permeability; Pharmaceutical Vehicles; Skin Absorption; Solubility
PubMed: 9279889
DOI: 10.1023/a:1012109513643 -
The Oncologist 1999New agents for the palliative treatment of metastatic breast cancer have emerged in the 1990s. This review summarizes the response rates of these agents with an emphasis... (Review)
Review
PURPOSE
New agents for the palliative treatment of metastatic breast cancer have emerged in the 1990s. This review summarizes the response rates of these agents with an emphasis on recent findings, such as presentations from the 1998 Meeting of the American Society of Clinical Oncology.
METHODS
The English medical literature was reviewed to identify clinical trials involving monotherapy for the treatment of metastatic breast cancer. Three agents--paclitaxel, vinorelbine, and docetaxel--are emphasized because their databases are extensive enough to allow interesting comparisons. Liposomal-encapsulated anthracyclines, losoxantrone, gemcitabine, oral surrogates of continuous-infusion fluorouracil, raltitrexed, LY 231514, edatrexate, topoisomerase I inhibitors, and trastuzumab are reviewed briefly.
RESULTS
Many of the new agents produce response rates approaching or even surpassing those achievable with doxorubicin monotherapy. Compared with older agents, some new agents have improved or at least different safety profiles, and some are easier to administer.
DISCUSSION AND CONCLUSIONS
The new agents offer useful therapeutic options that make them suitable for combining with each other and with older agents, which could result in more effective regimens for metastatic disease, and, ultimately, primary disease in the adjuvant setting. The chemotherapeutic paradigms governing the management of breast cancer for the past three decades are likely to change as we move into the 21st century.
Topics: Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Docetaxel; Dose-Response Relationship, Drug; Female; Humans; Paclitaxel; Palliative Care; Taxoids; Vinblastine; Vinorelbine
PubMed: 10337368
DOI: No ID Found -
Oncology (Williston Park, N.Y.) Mar 1997The proven safety profile and antitumor activity of paclitaxel (Taxol) in the treatment of metastatic breast cancer led investigators at Memorial Sloan-Kettering Cancer... (Review)
Review
The proven safety profile and antitumor activity of paclitaxel (Taxol) in the treatment of metastatic breast cancer led investigators at Memorial Sloan-Kettering Cancer Center (MSKCC) to further examine the agent's potential in the treatment of advanced breast cancer. Efficacy and tolerability studies of paclitaxel as single-agent therapy were undertaken, along with parallel investigations of quality-of-life parameters. The studies examined the effects of 96-hour infusion schedules of paclitaxel and are currently assessing the feasibility of a weekly 1-hour infusion schedule. Researchers at MSKCC also compared the results of a variety of two- and three-drug paclitaxel-containing regimens to determine possible synergism and better define safety profiles. They examined the combination of paclitaxel and edatrexate, as well as a promising combination of paclitaxel and a monoclonal antibody directed at growth factor receptors. The latter ongoing trial will include both laboratory studies that examine possible cellular mechanisms for the combination's observed synergy and a clinical trial that combines paclitaxel with a monoclonal antibody directed against the epidermal growth factor. In conclusion, the investigators discuss the optimal integration of paclitaxel into doxorubicin/cyclophosphamide (Cytoxan, Neosar)-based adjuvant therapy for node-positive stage II-III resectable breast cancer.
Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Drug Administration Schedule; Female; Humans; Paclitaxel; Quality of Life
PubMed: 9110339
DOI: No ID Found -
Annals of Oncology : Official Journal... Mar 1994The methotrexate analogue 10-ethyl-10-deazaaminopterin (10-EdAM, or edatrexate) has shown antitumor activity in preclinical testing and clinical studies of patients with... (Clinical Trial)
Clinical Trial
BACKGROUND
The methotrexate analogue 10-ethyl-10-deazaaminopterin (10-EdAM, or edatrexate) has shown antitumor activity in preclinical testing and clinical studies of patients with breast, lung and head and neck carcinomas. A phase II study was conducted in patients with advanced pancreatic adenocarcinoma.
PATIENTS AND METHODS
Forty patients were enrolled on the clinical trial. Edatrexate was administered intravenously at a dose of 80 mg/m2 weekly for 5 weeks. The treatment course was repeated every 6 weeks.
RESULTS
Two partial responses were observed. Both of these patients had partial responses which lasted 2 and 3.5 months. The median survival for all patients was 3.5 months. Serious (grade 3 or 4) toxic effects were primarily mucosal, hematologic, and dermatologic. Two patients experienced severe pulmonary toxic reactions.
CONCLUSION
At the dose and schedule used, edatrexate was poorly tolerated and did not demonstrate significant antitumor activity.
Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Aminopterin; Antineoplastic Agents; Female; Humans; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Survival Rate
PubMed: 8186177
DOI: 10.1093/oxfordjournals.annonc.a058810