The CFS symptoms of slightly over half the participants in a Norwegian study improved after receiving chemotherapy.

Cancer drug helped patients with chronic fatigue syndrome (CFS/ME)

Twenty-two of 40 patients with CFS, chronic fatigue syndrome, achieved clear improvements in physical function after receiving chemotherapy, according to a Norwegian study. But a CFS specialist sees shortcomings in the study.

People with CFS, also known as ME (myalgic encephelomyelitis), suffer extreme fatigue which does not improve with rest. Their fatigue can also worsen when they engage in physical or strenuous mental activities. This downturn can last for days or weeks and leads to impaired functional mobility.

The cause of the disease is a mystery and no established treatment has been found to give documented improvements.

“Many ME/CFS patients are plagued by a very poor quality of life, so research on the disease is vital,” says Chief Medical Officer Ingrid Gurvin Rekeland of Haukeland University Hospital in Bergen to

She works with a ME/CFS research group associated with the Department of Oncology and Medical Physics at Haukeland. They are trying to uncover the mechanisms behind the disease and find a useful treatment.

A new study now shows that half the participants with ME/CFS reported improvements after treatment with a cytotoxic (chemotherapy) drug. Their findings have been published in Frontiers in Medicine.

The group is led by the physicians Øystein Fluge and Olav Mella in collaboration with Alexander Fosså of the Oslo Radium Hospital.

Surprising ME/CFS improvements among cancer patients

A random observation years ago attracted the research group’s interest in finding a treatment that curbs the immune system’s negative processes linking to ME/CFS.

“From 2004 to 2014 we observed a number of patients with long-term ME/CFS who had also suffered from cancer reporting that their chemotherapy had decreased their ME/CFS symptoms,” says Rekeland.

These ME/CFS patients had received chemo treatment which included cyclophosphamide. This gave an inadvertent positive effect:

“Improvements of ME/CFS symptoms were surprising,” she says.

In 2014 the research group treated four ME/CFS patients, none with cancer, using the chemo drug cyclophosphamide, and two reported a long-term response, which is to say their improvement was long-lasting.

Intravenous infusions

The same research group carried out the new study of 40 patients with ME/CFS at Haukeland University Hospital and the Oslo Radium Hospital from 2015 to 2017.

Those among them who had never had cancer were given a trial treatment with the cytotoxic drug cyclophosphamide. This medicine is usually given to cancer patients and patients with certain autoimmune afflictions.

“We think that ME/CFS in a sub-group of patients can be an autoimmune disease,” say Øystein Fluge and Ingrid Gurvin Rekeland in the ME/CFS research group at Haukeland University Hospital.

All the participants received six intravenous infusions of this chemotherapy drug through the course of six months.

Twenty-two of the patients, or 55 percent, reported slight-to-moderate, moderate or major improvement of typical ME/CFS associated symptoms for at least six consecutive weeks.

The improvements lasted several years for 15 of them.

But could the placebo effect partially explain this betterment among half the patients in this study?

“We cannot rule out that placebo mechanisms and natural variations of the symptoms have contributed to the observed improvement. That is why we have had a focus on the long-term follow-ups of the patient for four years,” says Chief Medical Officer Ingrid Gurvin Rekeland, who participated in the study.

Improved quality of life and physical functionality

The researchers examined the participants regularly for a year after the chemotherapy. Then they controlled them again in a follow-up four years after the trial.

The participants were equipped with armbands monitoring physical activity. They also informed of changes in their ME/CFS symptoms and their functionality.

They filled out standard questionnaires gauging their self-reported life quality and physical function on a scale of 1 to 100.

The self-reported scores in physical functionality for the 22 who felt improvements rose from 35 at the start to 70 points on average.

Facts about ME/CFS

  • Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS) are interchangeable designations. Another name is SEID (systemic exertion intolerance disease).
  • The condition is characterised by fatigue and a feeling of illness after exertions.
  • These patients are usually examined over a lengthy period before being given the diagnosis.
  • No laboratory tests or blood sample analysis can give a secure diagnosis. The syndrome is diagnosed by exclusion, a process of elimination, which is based on matching a set of criteria when no other medical cause for the symptoms is found.
  • Other symptoms are a lack of restitution after resting, reduced levels of functionality, pains, cognitive impairments (memory problems) and a generally high level of symptom burdens.
  • Typically, when patients have exerted themselves, they experience the aggravation of their symptoms, known as post-exertional malaise (PEM), and this deterioration can last from days to weeks.
  • The intensity of symptoms can vary. Some patients are completely incompacitated, bedridden and need help with household chores and cooking. Others can get out of the house but have trouble with housework, cooking etc.
  • The course run by ME/CFS differs as well. Some patients improve in time and some even recover their health.
  • Other patients suffer a chronic course of the illness year by year.

The general population mean is approximately 84 points.

These participants became more mobile, from 3,600 to 5,600 steps per day.

Fifteen of these participants reported lasting physical improvements, also four years after the start of the study.

Lack of control group

But the researchers had no control group for comparison. This is the first study investigating this treatment method for patients with ME/CFS, so the study can thus be considered exploratory, explains Ingrid Gurvin Rekeland.

Larger studies need to be performed with a control group receiving an alternative treatment or a placebo to confirm or rule out whether this treatment is effective on ME/CFS patients, stresses Rekeland.

It is too early to recommend such treatment before further trials are conducted.

“But we interpret the results of this study as positive enough to merit the planning of a study involving a control group. We know it will be hard to blind-test with a control group, as this involves chemotherapy,” she adds.

Those who are not actually given the cytotoxin might easily understand this because they will not be getting the side-effects such as nausea.

Different grades of ME/CFS

All the participants fulfilled the Canadian consensus criteria for a ME/CFS diagnosis.

“With these relative stringent criteria, about 0.2 per cent of the population has this diagnosis. It’s important to differentiate between ME/CFS and a more general fatigue, which strikes several per cent of the population,” says Rekeland.

The illness occurs with various degrees of severity. Those in the test had mild to moderate, moderate, moderate to severe or severe degrees of the syndrome.

Patients with mild degrees or very severe degrees of the disease were omitted.

The mean age of the participants was 41.7 years when the treatment commenced. Half of the participants had been sick with the disease at least ten years.

Many had also tried several treatments beforehand. Over half had attempted various types of cognitive therapy at least once.

Research on the efficacy of cognitive therapy and training has been controversial

Combination of reasons

The physician Paul Kavli has worked with patients’ fatigue problems in his private practice for years. He has several remarks about the study:

“The placebo effect in such a study can be quite powerful when it comes to ME/CFS. So, the prospective usefulness of treating ME/CFS with cyclophosphamide has to be investigated with a blinded, placebo-controlled study,” he says to

He asserts that the criteria for the diagnosis are also subjective and based on judgement, which can be a clear source of error when included in the study.

Rekeland of the Haukeland University Hospital disagrees that the Canadian consensus criteria can be described as an ‘unclear and subjective condition’.

“These patients score lower in quality of life than cancer patients, for example. They have a characteristic and comprehensive array of symptoms,” she writes in an email.

Kavli thinks the causes of ME/CFS are biopsychosocial, an amalgam of elements from genetic makeup, childhood and life history to stresses and infections – to name a few.

He would like to see more solid research on the illness.

Close to the edge

“Both camps, those who swear by a bio-medicinal explanation and those who think cognitive training works, are too implacable,” he says.

He does not think there is necessarily just one approach to research of this disease; it is more of a jigsaw puzzle.

“The placebo effect in studies like this can be quite considerable when it comes to ME/CFS,” says Physician Paul Kavli who treats ME patients

“It’s great that a broad scope of research is conducted on ME/CFS, bio-medicinal, rehabilitation-related, techniques for mental training and considerations of the impact of stress,” says Kavli to

“Studies ought to be well-justified and without risks. I think this study with a prospective follow-up study is close to the border line,” says Kavli.

“The study has been approved by an ethics committee, the Norwegian Medicines Agency and is a thoroughly conducted clinical study – we discuss the weaknesses freely,” asserts Rekeland.

No improvement for those worst off

In any case, none of the six participants in the study with the most severe ME/CFS experienced any improvement.

Why did those who were sickest not get better?

“Several of them were unable to complete all the treatment or come to the check-ups. This is a problem with ME/CFS studies, the hardest hit patients are often not included,” says Rekeland.

Patients who are worst afflicted are mostly bedridden and just getting to the hospital for treatment is tough and will lead to an increase in symptoms.

Curbs immune cells

The cancer medicine cyclophosphamide is especially hard on the cells of the immune system. Researchers don’t know exactly how the drug gives relief to individuals with the disease.

Cyclophosphamide works on both the innate and the acquired immune system, according to Rekeland.

“Cyclophosphamide gives a comprehensive muting of several types of immune defence cells and after treatment there is a moderate drop in various types of lymphocytes,” explains Chief Medical Officer Rekeland to

In the laboratory part of the research project, the team is pursuing the issue of how this connects with the symptom reduction among the patients. In part this involves tests with blood samples taken in the course of the study.

An immune system illness?

A high occurrence has been found of well-known autoimmune system dysfunction diseases among first-degree relatives of the patients, i.e., parents, siblings and children. Many who contract ME/CFS get it following an infection. It afflicts three to four times as many women as men.

This indicates the involvement of the immune system, explains Rekeland.

Other patients with autoimmune diseases have been previously found to get beneficial effects from cyclophosphamide treatment. These include patients with MS, rheumatoid arthritis, vasculitis (inflammation of blood vessels) and systemic lupus erythematosus (SLE).

Does this indicate that ME/CFS could be an autoimmune disease?

“Yes, we think ME/CFS among a subgroup of patients can be an autoimmune disease,” says Øystein Fluge.

The researchers assert the study bolsters their hypothesis in this regard.

Physician Paul Kavli does find it intriguing that 55 percent have close relatives with autoimmune disorders.

“But it’s not known what the average is for the general population. The idea that this is an autoimmune issue is primarily hypothetical, in my view.”

A study from 2016 showed that many patients under treatment for ME/CFS actually have a mental disorder. They suffer from anxiety and depression in particular, according to the Norwegian news website ABC Nyheter.

More side-effects

Like most drugs, cyclophosphamide is not without its side-effects.

The most common are nausea and a feeling of general malaise for days or weeks after treatment.

“The participants reported more nausea and feeling unwell during the treatment period than do cancer patients with corresponding doses,” says Rekeland.

This might be because ME/CFS patients are generally sensitive to medications and physical burdens,” she explains.

Four of the 32 female participants also informed that their menstrual cycles were impacted and two in their 40s went into early menopause.

“It’s disturbing that these patients with a vague and subjective condition should be considered capable of chemotherapy with strong side-effects, based on a hypothesis of autoimmunity,” says Kavli.

He points out that one patient who participated in the study died later.

“This has not been discussed beyond concluding that the cause of death was unknown. The person’s age and other diseases are not specified,” he says.

“This patient died four years after the start of the study and more than three-and-a-half years after receiving treatment. She was taken out of the study because she did not want a second follow-up,” informs Rekeland.

“The cause of death is unknown, but from the available information it is very unlikely this had anything to do with side-effects of the medication”, she says.

Test of a different cancer medicine

The research group previously tested another cancer medication to treat ME/CFS.

A pilot study using rituximab seemed to have positive results. But later a larger double-blinded study with a control group showed that rituximab did not have an effect on ME/CFS. This was a huge disappointment for many ME/CFS sufferers.

“Cyclophosphamide is a type of cytotoxin which works much differently than rituximab. Whereas rituximab works on one type of immune cells, cyclophosphamide works on several parts of the immune system,” says Rekeland to

Risk genes

In another recent study, Asgeir Lande and several other researchers investigated a sequence of genes called human leukocyte antigens (HLA) that are key to the regulation of the immune system in patients with ME/CFS.

They published this in Scientific Reports.

Lande found two specific gene variants occurring more often in ME/CFS patients than in healthy control subjects.

In the study with cyclophosphamide the researchers viewed the effect on the basis that the participants had these gene variants.

“Among the participants in the cyclophosphamide study, 30 percent had one or both of these risk genes.”

These participants had a greater chance of response to the treatment.

Worked on eight of ten risk genes

Over 80 percent of the participants in the study who had these HLA gene variations reported improvement when receiving cyclophosphamide.

This was nearly twice the share seen among participants who lacked these risk genes.

“This can point toward a possible link between these gene variants and the treatment effect of cyclophosphamide. Such a connection between HLA genes and the effect of treatment has also been seen with other autoimmune diseases,” says Rekeland.

The researchers are engaged in further work to shed light on the disease mechanisms and identify patients with a probable immunological background for the disease.

The Kavli Trust has contributed to the financing of the ME/CFS research, and since 2011 supported the research on the causes and disease mechanisms of ME/CFS. See more here.

Paul Kavli is not a close relative to those who founded the Kavli Trust.

Translated by: Glenn Ostling


I. G. Rekeland et al.: Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study. Frontiers in Medicine, 29 April 2020.

A. Lande et al.: Human Leukocyte Antigen alleles associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Scientific Reports, 24 March 2020.


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