Our milestones: A recipe for success – the birth of combination chemotherapy

In the latest Our Milestones series post, we look at the role we played in the advent of a 1970s cancer treatment revolution: combination chemotherapy.

During the spring of 2003, while studying for her GCSEs, 15 year old Jade Chambers began losing a lot of weight. She also developed a bad cough. Worried, Jade’s parents took her to the GP who sent her to the hospital for tests.

The results were a shock. Jade was diagnosed with advanced stage IV Hodgkin lymphoma.

She remembers: “I was in the really late stages and told I might not survive and would not be able to have children.”

Jade’s doctors immediately began treating her with a combination of the chemotherapy drugs adriamycin, bleomycin, vinblastine and dacarbazine  – a combination known as ABVD.

Every two weeks for an entire year Jade received ABVD chemotherapy in eight hour sessions that left her feeling really ill.

She lost all her hair too.

Despite these difficulties Jade kept going – and thankfully the chemotherapy worked.

Today – 12 years later – she’s in good health, “happily married with a beautiful little girl” – and is “proof that cancer can be beaten.”

But if Jade had been diagnosed 30 years earlier in the 1970s, things could have turned out very differently.

Back then treatments for Hodgkin lymphoma weren’t as good as they are today.

Patients were given chemotherapy drugs one at a time – known as ‘monotherapy’.

But monotherapy didn’t always work very well. A lot of people diagnosed with Hodgkin lymphoma didn’t survive.

Something had to change.

Enter Professor James Malpas and his colleagues at St. Bartholomew’s (Barts) hospital.

The way we were

In 1971 US President Richard Nixon declared ‘war on cancer’ and aimed to focus America’s scientific minds on understanding cancer’s biology. Their ultimate goal was to find new cancer treatments.

At the same time, on this side of the Atlantic, Professor James Malpas was in charge of a smaller organisation with a similar passion: he was Dean of Barts Medical School and worked as a doctor there. Like President Nixon, Professor Malpas wanted to improve cancer treatments.

In particular, he was interested in finding new ways to treat Hodgkin lymphoma.

Unlike today when patients are increasingly given treatments tailored to their specific cancer type, in the 1970s most types of cancer were treated with a simple combination: surgery followed by whole-body radiotherapy.

Sometimes patients also received chemotherapy, although as Professor Malpas recalls, the number of useful chemotherapy drugs available at the time was “really very small”.

On top of this, doctors were still working out the best way to use the drugs they had. “It was a step by step process,” he told us. “You used one drug until the patient relapsed, then they had the next drug and the next drug and so on.”

And unfortunately, those drugs that did work generally caused some pretty bad side effects.

When treating Hodgkin lymphoma patients, Professor Malpas remembers putting up drips with nitrogen mustard (mustine) “which made everybody terribly sick, because we hadn’t really got very good control of the side effects in those days.

“Nevertheless it would take away the awful cancer symptoms they had – the sweating, the fever, the masses on their neck,” he says. “But although patients were relieved of their symptoms, survival was not good.”

Professor Malpas and his colleagues at Barts suspected they could make things better.

What they didn’t know at the time was that they already had part of the solution. But it would take a trip to America by their friend and colleague, Professor Gordon Hamilton Fairley, to help them realise it.

Children of the revolution

In those days Malpas remembers how most pharmacologists had a principal that you should “use one chemotherapy drug at a time”. But a visit to cancer centres around the United States made Professor Hamilton Fairley realise this way of thinking was changing.

Across the pond in the US, doctors were testing what happened when patients were simultaneously given several different chemotherapy drugs.

According to Professor Malpas, this was “a revolutionary feeling: you could put groups of drugs together that were good at killing cancer cells but didn’t have the same side effects as each other. You could balance it out”.

This new way of thinking would revolutionise treatment for Hodgkin lymphoma – and most other types of cancer.

We can work it out

Hodgkin lymphoma doctors in the US were testing a combination of four drugs, known by their initials – mustine (M), vincristine (O), prednisolone (P) and procarbazine (P). This combination was known as ‘MOPP’.

Doctors already knew that each drug was effective on its own, as a monotherapy. What they didn’t know was if giving the drugs at the same time – as combination chemotherapy – was better.

So they did what all good clinical scientists do: they tested their theory in a trial.

And it worked. In fact, MOPP worked extremely well.

Hodgkin lymphoma patients recovered completely and for long periods of time. In fact, it was an unprecedented finding. Combined chemo drugs were vastly more effective than monotherapy.

Encouraged by his US colleagues’ breakthrough, Professor Hamilton Fairley returned to the UK ready to make some changes.

“We’re not going to give single treatments anymore – we’re going to give combination chemotherapy,” Professor Malpas remembers him saying.

But there was a downside. Vincristine caused a very bad side effect that affects patient’s nerves, known as neuropathy. Malpas remembers Hamilton Fairley telling him how, in the US, the treatment caused severe neuropathy, “to the point where patients were getting really bad peripheral nerve paralysis”.

The times they are a-changing

So Professor Hamilton Fairley tweaked the combination slightly. He swapped vincristine for vinblastine (V), a drug which has a similar chemical shape and structure to vincristine and kills cancer cells in pretty much the same way.

The change created the combination MVPP – mustine, vinblastine, prednisone and procarbazine.

This small change made a big difference. It was enough to reduce the really bad neuropathy patients experienced with MOPP. But importantly, it didn’t affect how well the drugs worked.

In their game changing paper, Professor Malpas and his colleagues at the hospital’s medical oncology department looked at patients with advanced Hodgkin lymphoma, who had never been treated before, or who had previously received chemotherapy, or whose cancer had come back after radiotherapy.

The team looked at how well each group responded to MVPP and how long patients survived after receiving this new combination.

What they saw was remarkable.

Incredibly, after they received MVPP two thirds (65 per cent) of patients who hadn’t been treated before – and nearly nine out of ten (86 per cent) of patients who relapsed after radiotherapy – survived their disease for at least five years.

Even today it’s easy to see how surprised Professor Malpas is that MVPP worked so well.

He remembers: “The results were dramatic – I mean the disease would disappear. Seeing these patients in the wards within two or three weeks absolutely back to normal and with no trace of disease – I was amazed”.

He continues: “It was a remarkable breakthrough because it was the first time it was possible to cure a cancer which had spread”.

But not everyone was convinced. In a debate that seems strangely familiar to modern ears, some doctors thought the MVPP drugs were too expensive and shouldn’t be paid for by the NHS. Professor Malpas remembers: “I had some very unpleasant meetings in the medical council where we were accused of taking the resources of the hospital because these drugs were so expensive”.

Nevertheless, the overwhelming evidence shone through and MVPP became the standard treatment for Hodgkin lymphoma. It was used by haematologists in cancer centres around the country – and the world – for many years.

It ain’t easy

But there’s another reason this story is a true ‘milestone’ in our history. It may not seem as important as the discovery of a new treatment, but, arguably, it’s had an even more profound effect on patients today – and it’s to do with how cancer medicine is handled as a medical discipline.

Every day across the UK, specialist cancer doctors called medical oncologists work in partnership with other experts to help save the lives of cancer patients, using their skills to provide patients with the best care and treatment.

And without their specialised knowledge and dedication to studying cancer, survival rates wouldn’t be where they are today.

This is why it’s so bizarre to think that in the 1970s there was no such thing as specialised medical oncologists.

“A lot of people, including doctors, didn’t believe there should be such things as specialised cancer doctors,” Professor Malpas tells us.

But he and his Barts colleagues thought differently. They believed that medical oncology should be recognised as a speciality like surgery and paediatrics.

“Gordon fought hard at the college of physicians to establish medical oncology as a distinct area of medicine,” Malpas recalls.

Not only did Hamilton Fairley fight hard – he won. “He got medical oncology recognised as a sub-speciality of general medicine. That was an important advance because it meant that young people could train in that area and look to having posts in the future. It was very, very far sighted.”

Sadly, Professor Hamilton Fairley didn’t get the chance to see the impact his hard work, dedication and visionary thinking made to the field of medical oncology and – ultimately – to patients for generations to come.

On the 23^rd October 1975, in Kensington, London, Professor Gordon Hamilton Fairley was killed by a Provisional Irish Republican Army car bomb intended for Sir Hugh Fraser.

He was just 45 years old.

A plaque in the crypt of St. Paul’s Cathedral dedicated to his memory reads, “It matters not how a man dies but how he lives”.

New Horizons

With medical oncology now recognised as a speciality, Professor Hamilton Fairley and Professor Sir Eric Scowen who also worked at Barts decided to establish the first department of medical oncology in the UK. Professor Malpas was also heavily involved, and remembers asking the University for its support in the endeavour.

“I remember I had to write a letter to the University and it was a very dramatic letter. We all waited with baited breath for them to decide. And thank goodness, they said yes!”

Funding for the new department came from the Imperial Cancer Research Fund, which later joined with Cancer Research Campaign to become Cancer Research UK.

“The ICRF really were very, very generous. They gave us £250,000 a year which, in those days, could give you a professor, three senior lectures, two registrars and supporting staff. And they continued to support us, increasing their financial support over the years”.

With a little help from my friends

Professor Malpas, Professor Hamilton Fairley and their colleagues worked hard to bring combination chemotherapy to the UK. The benefits of this hard work can still be seen today.

For example, even though MVPP isn’t used to treat Hodgkin Lymphoma anymore, elements of the combination are still included in treatments today: ABVD – the combo that cured Jade – uses vinblastine, while another combination, BEACOPP, includes procarbazine and prednisolone.

Introducing combination chemotherapy to the UK also had a huge positive impact on how we treat other cancers. And today, it remains a cornerstone treatment for cancer along with surgery and radiotherapy.

We also can’t underestimate the impact of establishing medical oncology as its own speciality on cancer research in the UK and the world. Thousands of young doctors choose to become medical oncologists every year, dedicating their lives to studying cancer and finding new ways to prevent, diagnose and treat the disease.

Heroes

Through their forward thinking Professor Malpas, Professor Hamilton Fairley and their colleagues showed for the first time that cancer could be cured and that the ‘war on cancer’ could, one day, be won.

They have also helped save the lives of countless cancer patients, both as doctors and as pioneering leaders in their field.

And although retired, Professor Malpas is still active in the research world, giving lectures and keeping up-to-date with the latest findings.

Speaking to him, it’s easy to see how much he loved doing cancer research and using the information he learned to better care for his patients and help them overcome their disease.

And when he tells us that over 200 people he treated for cancer as children attended his retirement party to say thank you, it’s clear how much his patients care for him too.

-Aine McCarthy

Images

Image of chemotherapy drugs via Wikimedia Commons

Other photographs courtesy of Cancer Research UK and Professor James Malpas