Cookie policy: This site uses cookies (small files stored on your computer) to simplify and improve your experience of this website. Cookies are small text files stored on the device you are using to access this website. For more information please take a look at our terms and conditions. Some parts of the site may not work properly if you choose not to accept cookies.

Join

Subscribe or Register

Existing user? Login

From cancer to rheumatoid arthritis treatment: the story of methotrexate

In this month’s article on landmark drugs, Jenny Bryan takes a look at how the use of methotrexate evolved from treating cancer to managing rheumatoid arthritis

By Jenny Bryan

In this month’s article on landmark drugs, Jenny Bryan takes a look at how the use of methotrexate evolved from treating cancer to managing rheumatoid arthritis

Scan through chemotherapy regimens from the 1970s, 80s and 90s, and one of the agents most frequently in the mix for a wide range of cancers is methotrexate (Maxtrex). The drug was developed for its antifolate properties following the discovery in the late 1940s that a dietary deficiency of folic acid resulted in a decrease in leukaemia cell count.1 A number of companies, including Lederle (now part of Pfizer), synthesised folic acid analogues,2 and methotrexate proved to be the compound with the right balance of efficacy and toxicity when it was used clinically.2,3

“I’ve been using methotrexate for as long as I’ve been an oncologist treating breast cancer. It’s been a very useful drug, a pathfinder in the 1970s which helped us realise that chemotherapy could be useful as adjuvant treatment in operable breast cancer — and not just for metastatic disease — and then later as a real ‘jobbing’ type of chemotherapy, which we’ve used right up until the last few years,” explains Trevor Powles, emeritus professor at the Institute of Cancer Research, London.

A promising start

Early interest in anti-folate agents as cancer treatment gathered momentum with publication of promising experience with the use of aminopterin in improving blood and bone marrow cell counts and inducing temporary remission in five children with acute lymphoblastic leukaemia (ALL).4 However, the toxicity of aminopterin sent researchers at Lederle and elsewhere to look for better tolerated drugs, and to investigate the mechanism of the anticancer effects.

Aminopterin was shown to inhibit dihydrofolate reductase (DHFR), the enzyme responsible for the reduction of folic acid to its active form, which is an essential cofactor for purine and thymidylic acid synthesis, and hence DNA production.5

Meanwhile, clinicians using the next folate analogue out of the Lederle laboratories, methotrexate, reported complete and, in many cases, sustained responses in women with choriocarcinoma.6

Animal studies suggested that methotrexate had a better therapeutic index than aminopterin (although the two drugs did not go head to head in a clinical setting), and so it was methotrexate which was extensively investigated and subsequently found a role in a wide range of cancers, including breast cancer, ALL, some forms of lymphoma, head and neck cancer, bladder cancer and osteogenic sarcoma.2

Methotrexate in advanced breast cancer

During the 1960s, a variety of single agent cytotoxic agents was used to treat advanced breast cancer and, of these, methotrexate was a popular choice. Indeed, in a review of systemic therapies for advanced breast cancer published in 1970, methotrexate topped the list for objective responses — ahead of chlorambucil, thio-TEPA, vinblastine, fluorouracil, cyclophosphamide and nitrogen mustard.7

However, partial tumour regression rates for single agent treatment were only about 10–30 per cent.8 Noting that cytotoxic combinations were proving far more effective than single agents in increasing survival in leukaemia and Hodgkin’s lymphoma, oncologists started taking a similar approach in advanced breast cancer.

In a small early study, 68 per cent of women with advanced metastatic breast cancer responded to cyclical chemotherapy with a combination of methotrexate, cyclophosphamide and fluorouracil (CMF), with tolerable toxicity, and sustained survival.8  In a second study higher response rates were seen with CMF than with adriamycin/vincristine (65 per cent versus 58 per cent), and responses were more durable.9

Breakthrough for operable breast cancer

What established methotrexate as a firm favourite in breast cancer chemotherapy was the discovery that the CMF combination was highly effective as adjuvant treatment in operable breast cancer.10 As Professor Powles points out, women with no sign of metastases at primary surgery still had a 50 per cent chance of relapse but, until the mid-1970s, chemotherapy was not started until relapse occurred.

That all changed in 1976 when preliminary results were reported by Gianni Bonadonna and colleagues from a large Italian study in nearly 400 women who had undergone radical mastectomy for primary breast cancer with positive lymph nodes.10 Patients were randomised to receive 12 cycles of CMF or no treatment. After 27 months, treatment failure (local, regional or distant recurrence) had occurred in just 5.3 per cent of the CMF group, compared with 24 per cent of the control group. Toxicity was deemed acceptable, given that a high percentage of CMF dosage could be administered, although the authors urged caution until the long-term impact on survival and possible long-term side effects were known.

“CMF was one of the first reported schedules for operable breast cancer, and the Bonadonna study had a big impact on the way breast cancer was treated. It and subsequent studies established the place of adjuvant chemotherapy in the treatment of women found to have positive axillary lymph nodes during breast cancer surgery,” says Professor Powles.
In a 30-year follow up of a series of Italian studies in operable breast cancer, Bonadonna confirmed that adjuvant CMF was associated with a significant 29 per cent reduction in risk of relapse and a 21 per cent reduction in death (P=0.04).11 Six cycles of CMF appeared to be as effective as 12 cycles, and no long-term adverse effects were seen.
Professor Powles explains that one of the good things about methotrexate was its tolerability. “As methotrexate is an antimetabolite rather than a cytotoxic agent, you can use it in high doses for its anticancer effects, and then use folinic acid as ‘rescue treatment’ to reduce bone marrow and gastric side effects.”

This tolerability made it a useful agent to include alongside more toxic drugs, such as mitomycin and mitoxantrone, in the MMM combination, which continues to be used for breast cancer treatment in some centres. “In breast cancer treatment, methotrexate has largely been superseded by other more effective treatments, such as the anthracyclines and taxanes. But methotrexate was a useful drug in its time. It was effective, had low side effects, was easy to give and was an important part of treatment for thousands of women with breast cancer,” concludes Professor Powles.

Making its mark in RA

Oncologists had been using methotrexate for about 20 years by the time it moved into rheumatology practice. Phil Platt, consultant rheumatologist at Newcastle upon Tyne Hospitals, NHS Foundation Trust, recalls a low-key introduction.

“Methotrexate came in slowly. Pharmaceutical companies weren’t interested in doing big studies in RA because methotrexate was off patent and very cheap to use. Rheumatologists were wary of using a drug from the cancer arena, but there was some experience of it in psoriasis, so we gained from that. Even so, methotrexate was used in RA for about 10 years before it was actually licensed for the indication.”

Initially, methotrexate was reserved for RA patients who had failed to respond to the other disease-modifying antirheumatic drugs (DMARDs) in use at the time — gold, penicillamine and sulphasalazine. But, as small, clinician-led studies, carried out at rheumatology units, started to suggest that it was more effective than standard treatments12 and had a greater impact on disease progression,13 methotrexate moved up the pecking order. Doses were much smaller than those used to treat cancer patients and rheumatologists were pleasantly surprised at how well their patients tolerated treatment, with the once-weekly oral regimens adding to its popularity.

“We started using it earlier and earlier and, for the past 10 years, methotrexate has been the most commonly used first drug treatment for RA,” Dr Platt points out.

Changing the treatment paradigm

Ironically, it was the arrival of the biological therapies for RA which underlined just how good methotrexate really is. In large scale trials of antitumour necrosis factor (TNF) therapy, methotrexate is generally used alone or in combination as the comparator treatment, and has proved its worth as the gold standard for RA.

“We have much better information about methotrexate now, and the comparator studies have clearly shown its efficacy. Manufacturers of biological agents have had to work hard to create something better and, although some are now superior to methotrexate, the differences are not orders of magnitude greater. The advantages of biologicals are subtle and tend to occur in patients who have failed on methotrexate,” says Dr Platt.
In its 2010 guidelines, the European League Against Rheumatism concluded that the clinical efficacy of methotrexate had not been surpassed either by other synthetic DMARDs or consistently by TNF inhibitor monotherapy.14 Both EULAR and the National?Institute for Health and Clinical Excellence, therefore, recommend that methotrexate be included in first-line DMARD therapy as soon as possible in newly diagnosed RA patients.15

“NICE recommends multiple drugs from day 1, which reflects the approach of some enthusiasts. Personally, I prefer to escalate the methotrexate dose and add other agents depending on response — much as you would with blood pressure treatment,” says Dr Platt.

In the 1980s, when methotrexate arrived in rheumatology clinics, DMARDs were not initiated so early in RA treatment. The toxicity of early DMARDs had meant that rheumatologists preferred to wait until patients showed signs of joint damage before taking the DMARD route.

Today, the emphasis is on getting in with methotrexate or other DMARDs as early as possible before any permanent inflammatory damage is done. “Clinics are very different places from when I started and RA patients have much lower levels of disability. The number of RA patients I send to orthopaedic surgeons for knee replacements is probably only about 10 per cent of what it was 10 to 20 years ago and methotrexate has played a key part in that change,” says Dr Platt.

Although methotrexate has been superseded in breast cancer treatment, it is still very much a part of the RA armamentarium, and will be for the foreseeable future, predicts Dr Platt.

“Methotrexate is not only effective, it is also cheap. Prices of biological products may come down, but they are unlikely ever to be as low as for methotrexate. In addition, 90 per cent of patients can use oral methotrexate, while the biologicals have to be injected subcutaneously, which is never as popular with patients. Even if we get new oral small molecules with equivalent efficacy to biologicals, I’d be surprised if methotrexate lost its place in the next decade. Methotrexate really enabled us to turn a corner in the treatment of RA, and it’s undoubtedly been the most important drug for rheumatology in over 30 years of my career.”

References

1 Heinle RW, Welch AD. Experiments with pteroylglutamic acid and pteroylglutamic acid deficiency in human leukemia. Journal of Clinical Investigation 1948;27:539.
2 Milestones in drug development: methotrexate. Edited by BN Cronstein and JR Bertino. Basel: Birkhaüser Verlag; 2000.
3 Jolivet J, Cowan KH, Curt GA et al. The pharmacology and clinical use of methotrexate. NEJM 1983;309:1094–104.
4 Farber S, Diamond LK, Mercer RD et al. Temporary remission in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamin acid (aminopterin). NEJM 1948;238:787–93.
5 Osborn MJ, Freeman M, Huennekens FM. Inhibition of dihydrofolic reductase by aminopterin and amethopterin. Proceedings of the Society for Experimental Biology and Medicine 1958;97:429–31.
6 Hertz R, Li MC, Spencer DB. Effect of methotrexate therapy upon choriocarcinoma and chorioadenoma. Proceedings of the Society for Experimental Biology and Medicine 1956;93:361–6.
7 Fracchia AA, Farrow JH, Adam YG et al. Systemic chemotherapy for advanced breast cancer. Cancer 1970;26:642–9.
8 Canellos GP, Devita VT, Gold GL et al. Cyclical combination chemotherapy for advanced breast carcinoma. BMJ 1974;1:218–20.
9 De Lena M, Brambilla C, Morabito A et al. Adriamycin plus vincristine compared to and combined with cyclophosphamide, methotrexate, and 5-fluorouracil for advanced breast cancer. Cancer 1975;35:1108–15.
10 Bonadonna G, Brusamolino E, Valagussa P et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. NEJM 1976;294:405–10.
11 Bonadonna G, Moliterni A, Zambetti M et al. 30 years’ follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort study. BMJ 2005;330:217. Epub 2005 Jan 13.
12 Weinblatt ME. Efficacy of methotrexate in rheumatoid arthritis. British Journal of Rheumatology 1995;34 (suppl 2):43–8.
13 López-Méndez A, Daniel WW, Reading JC et al. Radiographic assessment of disease progression in rheumatoid arthritis patients enrolled in the cooperative systematic studies of the rheumatic diseases program randomized clinical trial of methotrexate, auranofin, or a combination of the two. Arthritis Rheumatology 1993;36:1364–9.
14 Smolen JS, Landewé R, Breedveld FC et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Annals of the Rheumatic Diseases 2010;69:964–75. Epub 2010 May 5. Review. Erratum in: Annals of the Rheumatic Diseases 2011 Aug;70:1519.
15 National Institute for Health and Clinical Excellence. Rheumatoid arthritis. The management of rheumatoid arthritis in adults. CG 79, 2009.

 

Citation: The Pharmaceutical Journal URI: 11106439

Have your say

For commenting, please login or register as a user and agree to our Community Guidelines. You will be re-directed back to this page where you will have the ability to comment.

Recommended from Pharmaceutical Press

  • Patient Care in Community Practice

    Patient Care in Community Practice

    Patient Care in Community Practice is a unique, practical guide for healthcare professionals or carers. Covers a range of non-medicinal products suitable for use at home.

    £22.00Buy now
  • Clinical Pharmacokinetics

    Clinical Pharmacokinetics

    A practical guide to the use of pharmacokinetic principles in clinical practice. Includes case studies with questions and answers.

    £33.00Buy now
  • Drugs of Abuse

    Drugs of Abuse

    A concise, easy-to-read guide for healthcare professionals who encounter drug abuse.

    £38.00Buy now
  • Pharmaceutical Toxicology

    Pharmaceutical Toxicology

    Explains the methodology and requirements of pre-clinical safety assessments of new medicines. Includes registration requirements and pharmacovigilance.

    £40.00Buy now
  • Strategic Medicines Management

    Strategic Medicines Management

    A practical guide to influencing the availability of medicines, and policies of their use. Focuses on the strategic elements of medicines management.

    £33.00Buy now

Search an extensive range of the world’s most trusted resources

Powered by MedicinesComplete
  • Print
  • Share
  • Comment
  • Save
  • Print Friendly Version of this pagePrint Get a PDF version of this webpagePDF

Jobs you might like

Newsletter Sign-up

Want to keep up with the latest news, comment and CPD articles in pharmacy and science? Subscribe to our free alerts.