Methotrexate is used in the treatment of trophoblastic neoplasms (choriocarcinoma, chorioadenoma destruens, and hydatidiform mole) in women except in those with impaired renal or hepatic function or who have failed to respond to previous therapy with methotrexate. These latter patients may be treated with dactinomycin. Methotrexate therapy is most effective in patients who have had the disease for only a short period prior to initiation of chemotherapy, who have low initial gonadotropin concentrations, and who do not have metastases. Complete remissions have been attained in about 75% of patients with metastases and in a higher percentage of patients without metastases. Methotrexate has also been used prophylactically against malignant trophoblastic disease in patients with hydatidiform mole.
In contrast to uterine choriocarcinoma, testicular choriocarcinomas are usually resistant to methotrexate alone. In patients with metastatic tumors of the testes, combination therapy utilizing methotrexate, dactinomycin, and chlorambucil has produced objective responses, as evidenced by decrease in size of metastases and tumor masses and/or lowered urinary chorionic gonadotropin concentrations in approximately 33-50% or more of patients treated. Following initial treatment, repeated courses of therapy at 1- to 3-month intervals for several years appear to be necessary in order to suppress tumor growth. In a few patients there has been an apparently permanent remission but control of tumor growth is often of only short duration.
Methotrexate also is used as a component of various chemotherapeutic regimens in the palliative treatment of acute leukemias. Present regimens are most effective in the treatment of acute lymphocytic (lymphoblastic) leukemia and have been reported to produce remissions in 90% of patients treated. Methotrexate has been used with corticosteroids to induce remissions, but the drug is now most frequently used alone or in combination with other antineoplastic agents for maintenance therapy following induction of remission with vincristine sulfate and prednisone. Combination chemotherapy usually produces longer remissions than use of a single drug. Methotrexate alone rarely is effective in the treatment of acute myeloblastic leukemia; remissions are short with relapses common and resistance develops rapidly. Methotrexate, however, may produce remissions in adults who have responded initially to mercaptopurine and who have become resistant to this drug. In addition, methotrexate has been used in combination regimens in induction of remissions of acute myeloblastic leukemia.
Leukemic infiltration into the meninges and CSF has been relieved temporarily by intrathecal administration of methotrexate. The drug may be effective in patients whose systemic disease has become resistant to methotrexate since leukemic cells in the CNS usually retain their original degree of sensitivity to methotrexate; however, poor responses generally occur in patients with initial methotrexate resistance. Focal leukemic involvement of the CNS may not respond to intrathecal methotrexate and usually responds best to radiation therapy. Methotrexate is also used prophylactically against meningeal leukemia.
High-dose methotrexate, followed by rescue therapy with either leucovorin or levoleucovorin, is used in combination chemotherapy regimens as an adjunct to surgical resection or amputation of the primary tumor in patients with nonmetastatic osteosarcoma. These regimens appear to prolong the relapse-free survival in such patients. Methotrexate is designated an orphan drug by the US Food and Drug Administration (FDA) for use in osteogenic sarcoma.
Methotrexate has been used alone or, more commonly, in combination chemotherapy for the treatment of breast cancer.
Combination chemotherapy used as an adjunct to surgery has been shown to increase both disease-free (i.e., decreased recurrence) and overall survival in premenopausal and postmenopausal women with node-negative or -positive early (TNM stage I or II) breast cancer. Adjuvant combination chemotherapy in early breast cancer has produced overall reductions in the annual rates of recurrence and death of 28 and 16%, respectively, with overall 5-year disease-free survival rates of 58.8 versus 49.6% for patients receiving combination chemotherapy versus those who did not. Adjuvant combination chemotherapy that includes methotrexate, cyclophosphamide, and fluorouracil has been used most extensively and is considered a regimen of choice. Although adjuvant hormonal therapy with tamoxifen (with or without combination chemotherapy) generally is used for node-positive, estrogen-receptor-positive postmenopausal women, adjuvant combination chemotherapy (with or without tamoxifen) also can be used in such patients, but differences in toxicity profiles may influence the choice of regimen. For node-positive premenopausal women, adjuvant combination chemotherapy (with or without tamoxifen) generally is used. Adjuvant therapy with combination chemotherapy and/or tamoxifen has been used in women with node-negative disease.
Controversy currently exists regarding which patients with node-negative and estrogen-receptor-negative breast cancer are most likely to benefit from such adjuvant therapy following surgery , but such patients with poor prognosis are reasonable candidates for adjuvant chemotherapy with an effective regimen (e.g., 6-12 months of methotrexate, cyclophosphamide, and fluorouracil initiated within 6 weeks of surgery); other node-negative patients also may be suitable candidates, but toxicities, costs, and other quality-of-life considerations should be weighed in assessing potential benefit. All patients with node-negative breast cancer are at some risk of recurrence, and effective adjuvant combination chemotherapy can increase both disease-free and overall survival, albeit less markedly than in patients with node-positive disease.
In patients with node-positive early breast cancer (i.e., stage II), an effective regimen of adjuvant combination chemotherapy (e.g., methotrexate, cyclophosphamide, and fluorouracil; cyclophosphamide, doxorubicin, and fluorouracil; cyclophosphamide and doxorubicin with or without tamoxifen) is used to reduce the rate of recurrence and improve survival in both premenopausal and postmenopausal patients once treatment to control local disease (surgery, with or without radiation therapy) has been undertaken. These combinations have been tested and established as providing therapeutic benefit, and are superior to single-agent therapy with conventional agents; numerous other combination regimens providing apparently similar outcomes also have been used but are less common or have been studied less extensively. Although long-term (e.g., 6 months or longer) chemotherapy with adjuvant regimens is clinically superior to short-term (e.g., preoperative and perioperative) adjuvant regimens, clinical superiority between 6- versus 12-month regimens has not been demonstrated. There is some evidence that the addition of doxorubicin to a regimen of methotrexate, cyclophosphamide, and fluorouracil can improve outcome further in patients with more than 3 positive axillary lymph nodes, and that sequential (i.e., administering several courses of doxorubicin first) regimens are more effective than alternating regimens in such patients; in patients with fewer positive nodes, no additional benefit from doxorubicin has been demonstrated. The dose intensity of adjuvant combination chemotherapy also appears to be an important factor influencing clinical outcome in patients with early node-positive breast cancer, with response increasing with increasing dose intensity; therefore, arbitrary reductions in dose intensity should be avoided. In women with stage II disease and more than 10 positive lymph nodes, high-dose chemotherapy and autologous bone marrow transplant is an option currently being evaluated.
In stage III (locally advanced) breast cancer, combination chemotherapy (with or without hormonal therapy) is used sequentially following surgery and radiation therapy for operable disease and following biopsy and radiation therapy for inoperable disease; commonly employed effective regimens include methotrexate, cyclophosphamide, and fluorouracil; cyclophosphamide, doxorubicin, and fluorouracil; and methotrexate, cyclophosphamide, fluorouracil, and prednisone. These and other regimens also have been used in the treatment or more advanced (stage IV) and recurrent disease.
Methotrexate may also be useful in the treatment of Burkitt's lymphoma, advanced stages (III and IV, Peters' Staging System) of lymphosarcoma, especially in children when used with other drugs, and in advanced cases of mycosis fungoides (cutaneous T-cell lymphoma). Although radiation therapy is generally used for treatment of localized histiocytic lymphoma, lymphosarcoma, and mycosis fungoides, chemotherapy may be useful in the treatment of generalized stages of these diseases. Hodgkin's disease responds poorly to methotrexate therapy.
Methotrexate is used in carefully selected patients in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy; however, the drug is not curative. Methotrexate should be used in the treatment of psoriasis only after the diagnosis has been definitely established, as by biopsy and/or after dermatologic consultation. Although methotrexate has been reported to produce beneficial effects in up to 75% of patients with psoriasis, there has been only one brief controlled study and the long-term effects of the drug and optimal dosage have not been established. Prior to initiation of methotrexate therapy, patients should be carefully screened to exclude pregnant women and patients with renal, hepatic or hematopoietic disease, or infections. The potential benefit to the patient must be carefully weighed against the possible risks involved and patients should be informed of potential toxicity.
Methotrexate has also been used topically in the treatment of psoriasis; however, results of one study indicated that the drug had little visible effect on the psoriatic lesions and another reported that the usefulness of topical methotrexate was limited by adverse effects on the surrounding skin.
Methotrexate is used for the management of rheumatoid arthritis in adults whose symptoms progress despite an adequate regimen of nonsteroidal anti-inflammatory agents (NSAIAs). Methotrexate is one of several disease-modifying antirheumatic drugs (DMARDs) that can be used when DMARD therapy is appropriate.
Pharmacologic therapy for rheumatoid arthritis usually consists of combinations of nonsteroidal anti-inflammatory agents (NSAIAs), DMARDs, and/or corticosteroids. The ultimate goal in managing rheumatoid arthritis is to prevent or control joint damage, prevent loss of function, and decrease pain. Although NSAIAs may be useful for initial symptomatic treatment of rheumatoid arthritis, these drugs do not alter the course of the disease or prevent joint destruction. DMARDs have the potential to reduce or prevent joint damage, preserve joint integrity and function, and reduce total health care costs, and all patients with rheumatoid arthritis are candidates for DMARD therapy. DMARDs should be initiated early in the disease course and should not be delayed beyond 3 months in patients with active disease (i.e., ongoing joint pain, substantial morning stiffness, fatigue, active synovitis, persistent elevation of erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP], radiographic evidence of joint damage) despite an adequate regimen of NSAIAs. DMARDs commonly used in the treatment of rheumatoid arthritis include methotrexate, etanercept, hydroxychloroquine, infliximab, leflunomide, and sulfasalazine. Less frequently used DMARDs include azathioprine, cyclosporine, minocycline, penicillamine, and/or oral or injectable gold compounds. The role of anakinra, a recombinant human interleukin-1 (IL-1) receptor antagonist, in the management of rheumatoid arthritis remains to be established.
While many factors influence the choice of a DMARD, methotrexate has substantially greater long-term efficacy than other DMARDs and is used as the initial or anchor DMARD in many patients with rheumatoid arthritis. Because residual inflammation generally persists in patients receiving maximum dosages of a single DMARD, many rheumatoid arthritis patients are candidates for combination therapy to achieve optimum control. Although the most effective combination regimen of DMARDs has not been determined, regimens that have been found efficacious in clinical studies include combinations of methotrexate and cyclosporine, etanercept, hydroxychloroquine, infliximab, leflunomide, or sulfasalazine.
Low-dose oral corticosteroids and local injection of corticosteroids are effective in relieving symptoms in patients with active rheumatoid arthritis. In addition, limited evidence indicates that low-dose corticosteroids slow the rate of joint damage.
Several international groups of rheumatologists have issued consensus reports that address the role of tumor necrosis factor (TNF) blocking agents (e.g., etanercept, infliximab) in the management of rheumatoid arthritis. These groups state that use of TNF blocking agents is most appropriate in patients with active disease (5 swollen joints and elevated acute-phase response [ESR of 28 mm/hour or greater, or CRP level of 2 mg/dL or greater]) despite adequate exposure to methotrexate or other effective DMARD. A course of methotrexate in a dosage of at least 20 mg weekly (or lower dosage if toxicity develops) for 3 months is considered an adequate course of DMARD therapy, and failure with such a course should prompt consideration of modification of the therapeutic regimen (e.g., initiation of a TNF blocking agent). Other factors to consider when deciding whether to use a TNF blocking agent in the treatment of rheumatoid arthritis are differences in the aggressiveness of the disease, extent of structural damage, effects of the disease on quality of life, and toxicity of previously used DMARDs.
Once therapy with a TNF blocking agent has been started, patients should be assessed for therapeutic response (e.g., a 20% reduction in swollen joint count with a 20% reduction in acute-phase response). While therapy should be continued indefinitely in those who have responded to therapy and are not experiencing substantial adverse effects, therapy with the TNF blocking agent should be discontinued in patients who have not responded after 12 weeks.
Administration of methotrexate alone is not a complete treatment for rheumatoid arthritis, and the drug should be used only as part of a comprehensive treatment program, including nondrug therapies such as rest and physical therapy. Most patients with active rheumatoid arthritis will show some benefit from methotrexate therapy, although improvement often plateaus during the first 6 months of therapy with the drug (occasionally being maintained for 2 years or longer) and may wane during continued use. There is no substantial evidence that methotrexate permanently arrests or reverses the underlying disease process, although the drug slows its progression in some patients. NSAIA and/or low-dose corticosteroid therapy may be continued when methotrexate therapy is initiated; however, the possible increased risk of toxicity with concomitant use of methotrexate and NSAIAs should be considered. (See
Drug Interactions: Protein Bound Drugs and Weak Organic Acids, and also Nonsteroidal Anti-inflammatory Agents.) Depending on the patient's response to methotrexate, corticosteroid dosage may be gradually reduced. The manufacturer of methotrexate states that combined use of methotrexate and gold compounds, penicillamine, hydroxychloroquine, sulfasalazine, or other antirheumatic cytotoxic or immunosuppressive agents has not been adequately studied to date and may increase the risk of adverse effects.
Head and Neck Cancer
Methotrexate is used alone and in combination therapy for the palliative treatment of recurrent or metastatic head and neck carcinoma. When used alone, at a dosage of 40-60 mg/m once weekly, methotrexate produces an average objective response rate of 30%. Duration of response is short at an average of 4 months.
In a randomized study, patients with recurrent or metastatic squamous cell carcinoma of the head and neck who received cisplatin and fluorouracil, carboplatin and fluorouracil, or methotrexate alone had objective response rates of 32, 21, or 10%, respectively. Although the objective response rate achieved with cisplatin and fluorouracil was greater than that observed with methotrexate alone, combination chemotherapy was associated with increased toxicity and no difference in survival was observed. In patients with recurrent or metastatic head and neck cancer who cannot tolerate combination therapy with cisplatin and fluorouracil, weekly low-dose methotrexate may be used.
Methotrexate frequently is used in combination regimens with other antineoplastic agents (e.g., bleomycin, fluorouracil, vincristine). Combination therapy with cisplatin, methotrexate, bleomycin, and vincristine has been used for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck. Further study is needed to establish the comparative benefit of methotrexate-containing regimens in the treatment of advanced head and neck cancer.
Methotrexate has been used for its anti-inflammatory effects in the management of Crohn's disease. Results of several open-label, and double-blind, placebo-controlled studies in adults indicate that use of methotrexate can result in clinical response (including clinical remission) in patients with chronically active Crohn's disease who have not responded to prior therapies (e.g., corticosteroids, other immunosuppressants), although efficacy of orally administered methotrexate has not been consistently reported in placebo-controlled clinical studies.
Safety and efficacy of parenteral methotrexate in the management of active Crohn's disease was evaluated in a double-blind placebo-controlled multicenter 16-week study that included 141 adults with chronically active Crohn's disease who had inadequate response to a corticosteroid (i.e. , prednisone). To be included in the study, patients had to have a chronically active disease unresponsive to a minimum of 3-months of therapy with prednisone (12.5 mg daily) with at least one attempt to discontinue the corticosteroid. At baseline, patients had a median Crohn's Disease Activity Index (CDAI) of 181-190. The CDAI score is based on subjective observations by the patient (e.g., the daily number of liquid or very soft stools, severity of abdominal pain, general well-being) and objective evidence (e.g., number of extraintestinal manifestations, presence of an abdominal mass, use or nonuse of antidiarrheal drugs, the hematocrit, body weight). Patients were randomized to receive IM methotrexate (94 patients; 25 mg once weekly) or placebo (47 patients). Patients continued to receive prednisone, which was tapered over 10 weeks (starting 2 weeks after randomization), unless their condition worsened; however, no other drugs used for management of Crohn's disease (e.g., oral or topical derivatives of 5-aminosalicylic acid, budesonide, other immunosuppressive agents, topical corticosteroids) were allowed. The primary outcome was clinical remission (defined as a CDAI index of 150 points or less and discontinuance of prednisone) at the end of the trial (16 weeks). Clinical remission at the end of the study was reported in 39 or 19% of patients receiving methotrexate or placebo, respectively. In addition, patients receiving methotrexate used less prednisone overall and had a lower mean average CDAI score than those receiving placebo (170 points for methotrexate versus 193 points for placebo). Many patients in this study who entered remission after 16-24 weeks of treatment with IM methotrexate (25 mg weekly) were enrolled in a new trial which evaluated the safety and efficacy of parenteral methotrexate for maintenance therapy of Crohn's disease. In this multicenter, double-blind, placebo-controlled trial, 76 patients with chronically active Crohn's disease in remission were randomized to receive 15 mg of IM methotrexate once weekly (40 patients) or placebo (36 patients) for 40 weeks; no other treatment for Crohn's disease was allowed. After 40 weeks, a greater proportion of patients receiving methotrexate were free of relapse (defined as an increase of baseline CDAI of 100 points or more, or the need to initiate therapy for active disease) than those receiving placebo (65% for methotrexate versus 39% for placebo); in addition, a smaller proportion of patients receiving methotrexate required prednisone therapy for relapse when compared with those receiving placebo (28% for methotrexate versus 58% for placebo).
Safety and efficacy of oral methotrexate in the management of chronically active Crohn's disease was evaluated in 2 other randomized double-blind, placebo-controlled trials in 59 corticosteroid-dependent adults. Patients received a weekly oral methotrexate dosage of 12.5 mg for 9 months in one trial and 15-22.5 mg for up to 1 year in the other. Efficacy (measured by reduction of dosage of corticosteroids, reduction in CDAI, or reduction in Harvey Bradshaw index) of oral methotrexate was similar to that of oral mercaptopurine (50 mg daily) in one of the studies and to placebo in both studies.
Some clinicians state that pediatric patients with corticosteroid-dependent or corticosteroid-resistant, moderately to severely active Crohn's disease who had an inadequate response to or were intolerant of azathioprine or mercaptopurine, may receive methotrexate (10-15 mg/m weekly) for the management of such disease.
(See Cautions: Pediatric Precautions.)
Methotrexate is used in combination regimens with cisplatin and vinblastine, with or without doxorubicin, for the treatment of invasive and advanced bladder cancer. Because methotrexate is absorbed through the ileum, placement of a Foley catheter or frequent emptying of the reservoir is advised in patients with long ileal loops or internal reservoirs during administration of methotrexate-containing regimens for the treatment of advanced or metastatic bladder cancer. Because elimination of methotrexate may be impaired and risk of toxicity increased in patients with renal dysfunction, edema, pleural fluid collections, or ascites, use of leucovorin rescue or deletion of methotrexate is advised if methotrexate-containing regimens are being considered for the treatment of advanced or metastatic bladder cancer in such patients.
Methotrexate has been used in second-line therapy for the treatment of recurrent small cell lung cancer. Although methotrexate is labeled for use in the treatment of the squamous cell type of non-small cell lung cancer, other agents are preferred for the treatment of this neoplasm.
Methotrexate has been used in treating a variety of solid tumors. In some studies, the drug has been administered by intra-arterial infusion alone or in conjunction with IM leucovorin calcium in the palliative management of carcinomas capable of being infused via a single artery. Low-dose oral methotrexate has been used in patients with chronic progressive multiple sclerosis. Results of several clinical studies indicate that low-dose methotrexate (7.5 mg weekly for up to 2 years) reduces both disease activity (as assessed by magnetic resonance imaging [MRI]) and sustained progression of disability (as assessed by the Expanded Disability Status Scale, the Ambulation Index, and standardized tests of upper extremity function). Patients with secondary progressive multiple sclerosis benefited the most from methotrexate therapy.
Methotrexate has been used for its immunosuppressive and/or anti-inflammatory effects in the treatment of psoriatic arthritis, systemic lupus erythematosus, vasculitis, dermatomyositis, polymyositis,Wegener's granulomatosis, and a variety of dermatologic and chronic refractory ocular diseases. Controlled studies have shown that oral or parenteral methotrexate therapy is effective in the short-term management of psoriatic arthritis; however, because of its potential toxicities, methotrexate is generally used in the management of this condition only in patients whose disease is severe and/or unresponsive to conventional therapy.