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Our milestones: How a combination of events led to a cure for choriocarcinoma

by Emily Howlett | Analysis

15 August 2017

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This entry is part 27 of 30 in the series Our milestones

In this instalment, we go back to the 1950s to find out how one of our scientists helped to transform the outlook for women with a rare cancer called choriocarcinoma – a tumour that develops from the placenta in about 1 in every 50,000 pregnancies.

“It all started with a woman who crawled into my clinic on her hands and knees,” recalls Professor Kenneth Bagshawe, now 92 years old. It was 1956 and, unknowingly, this was Bagshawe’s first encounter with choriocarcinoma.

“She had dragged herself to the clinic that day and when she arrived at the hospital steps she was intensely short of breath. We thought she had high blood pressure in her lungs so we carried out an ECG test and chest x-ray,” he says.

“Sadly, this turned out not to be the case. She died three days later.”

At that time, women with choriocarcinoma were often misdiagnosed as little was known about the cancer and there were no effective treatments for people with advanced disease.

This, along with the tragic loss of his patient, inspired Bagshawe’s medical career and ultimately his life’s work that transformed the outlook for women with choriocarcinoma.

The first encounter with choriocarcinoma

Choriocarcinoma is one of a group of tumours known as gestational trophoblastic tumours. They develop from tissue that forms in the womb during pregnancy. And in choriocarcinoma the tumour spreads rapidly to other parts of the body, commonly to the lungs.

This is what had happened to Bagshawe’s patient in 1956. And he was shocked by what he saw during the autopsy. It looked like an infection that had spread from her womb to her airways, he recalls.

Time to re-write the textbooks?

The pathologist who performed the autopsy had seen an identical case 10 years before, and persuaded Bagshawe to take a trip to the pathology museum at Hammersmith Hospital on a Saturday morning. The museum held a sample from the first recorded case of a particular form of choriocarcinoma. On inspection of the archived tissue, it was clear that Bagshawe’s patient had indeed died from the same rare cancer.

From this point on Bagshawe became fascinated by choriocarcinoma, reading everything he could about this unusual disease. According to the textbooks, the chances of him seeing another case in his lifetime were unlikely. So when, just 3 months later, he encountered a second patient with identical symptoms to his first, he was more than a little surprised.

‘Millions to one…’

Much like the first, this new patient was becoming breathless and deteriorating at an alarming rate. Fuelled by thoughts of his first encounter, Bagshawe quickly wanted to rule out the possibility of choriocarcinoma, however unlikely it seemed.

“I thought the chances of it being another case of this incredibly rare form of choriocarcinoma were millions to one, but I kept it in the back of my mind,” he says.

“Her condition continued to go downhill. I thought we’d be crazy not to find out what was wrong. So I wanted to get a pregnancy test done.”

The same hormone that pregnancy tests detect is also is produced by choriocarcinoma cells. This hormone, called human chorionic gonadotropin (HCG), acts as a signal which tells the cancer cells to grow and spread.

I thought we’d be crazy not to find out what was wrong

– Professor Bagshawe

Back in 1956 pregnancy tests measured levels of HCG as they do today, but unlike modern kits the tests involved rabbits.

A woman’s urine was injected into a female rabbit and then the animal’s ovaries were examined a few days later. If the HCG hormone was present it would cause a detectable change in the ovaries, confirming a positive result.

The problem was that this patient’s medical notes clearly stated that she had undergone surgery to remove her womb. So persuading the hospital technician to spare a rabbit to test for HCG in a woman who couldn’t possibly be pregnant was a bit tricky, to say the least.

“I was determined to rule out choriocarcinoma, so I devised a plan to give the urine sample under a pseudonym… and it worked,” says Bagshawe.

“The results came back on a Friday night strongly positive. I knew then that this woman had the same cancer that had killed my first patient only a few months before.”

A combination of brains and bravery

During the 1950s, most cancer patients were treated with surgery, radiotherapy and sometimes with early chemotherapy drugs that were just entering the clinic, which we’ve blogged about before. At the time of this case mercaptopurine was the only cancer drug available in Bagshawe’s hospital. So he went up to the pharmacy, checked out the drug and administered a dose, but woke up the next day fearing the worst.

“On Friday she wasn’t any better,” he says. “By Sunday I thought she was nearly dead.

The bed where she’d been was empty

– Professor Bagshawe

“When I arrived at the hospital early on Monday morning, the bed where she’d been was empty.”

But down the corridor on the next ward he was amazed to find that she was out of the oxygen tent that had been helping her to breathe, and she was sitting up eating breakfast.

The drug had worked. But Bagshawe was concerned that the cancer could quickly return.

Better together

As with other diseases at that time, such as tuberculosis (TB), doctors had learnt to be sceptical of seemingly miraculous recoveries. In the time it took Bagshawe to train as a junior doctor he’d seen the depressing failure of the single antibiotic treatment that had held so much promise as a cure for TB. As the bacteria causing the disease developed ways to evade the antibiotic, patients were left with fewer treatment options than before.

The tables turned with the discovery that a combination of drugs could hit the bacteria twice as hard. This research ushered in a new era of combination treatment for TB, making it once again a curable disease.

This struck a chord with Bagshawe.

Two drugs are better than one

A combination of drugs had worked where a single drug had failed – a revelation that would stick with him for the rest of his career.

So when the hospital received a newly invented and approved chemotherapy drug, methotrexate, Bagshawe decided to take a leap of faith and combine this with the one he’d already given.

His patient survived, living for over 50 more years.

Bagshawe described this fascinating case in a scientific paper, along with results of other patients he and colleagues treated in subsequent years who had similar astonishing responses to the combination treatment. This suggested he was on to something. And in 1963 Bagshawe reported further research funded by the Cancer Research Campaign (which merged with the Imperial Cancer Research Fund to become Cancer Research UK), that confirmed the astonishing effect of this combination therapy: in a larger group of 23 patients; 17 were treated successfully and were still cancer-free months and years later.

The combination of drugs was saving lives, even in patients with advanced disease where their cancer had spread to other areas of the body. And, incredibly, it could stop the cancer from coming back. This breakthrough marked the start of many more women being cured of choriocarcinoma and set a precedent for using combination treatments to prevent cancers coming back.

Combine and conquer

According to colleagues, by the 1970s Bagshawe had developed a reputation as the ‘Godfather’ of cancer medicine. He had set up the first labs in Charing Cross Hospital dedicated to testing for choriocarcinoma and other trophoblastic diseases.

Former Cancer Research UK scientist and winner of our Lifetime Achievement Award, Professor Stan Kaye, remembers working as a trainee doctor in Bagshawe’s lab during this remarkable time. Together the team developed the idea that a change in the number of cancer cells was responsible for varying HCG levels in the blood seen in choriocarcinoma patients.

It was the first time we’d seen a marker that was so exquisitely linked to a cancer

– Professor Kaye

This meant HCG levels could be used as a way to tell which patients’ tumours were responding to treatment. If HCG levels dropped, this indicated that the drugs were working and the tumour was shrinking.

“Tuesdays and Fridays were crucial times in the lab,” says Kaye. “This was when the results of the HCG tests came in and it was my job to write the results up on the board, which Ken would be waiting anxiously for.

“The fascinating thing was that we kept seeing the HCG levels go down in patients who were having treatment. This meant the cancer was disappearing, and we could track the response as it was happening in real-time. It was the first time we’d seen a marker that was so exquisitely linked to a cancer.”

From then to now

We now understand much more about choriocarcinoma. And although the HCG test is still the gold-standard technique to detect and monitor the disease, patients can now be told if they’re at low or high risk of it spreading. This allows treatments to be tailored more specifically to each individual’s disease.

High risk choriocarcinoma patients, like Vickie from Leicester, receive a combination of 5 chemotherapy drugs known as EMA-CO, developed by researchers at Bagshawe’s Charing Cross labs.

As soon as I heard the ‘c’ word I was petrified that I would die

– Vickie

Vickie was 31 when she was diagnosed with choriocacinoma shortly after the birth of her baby, Oliver. She had the EMA-CO combination every week for three and a half months and responded really well.

“As soon as I heard the ‘c’ word I was petrified that I would die,” says Vickie.

“Now I would say to people with choriocarcinoma that treatment is very successful, so trust that you’ll come out the other side.

“I’m incredibly thankful and grateful for the work of Professor Bagshawe. His work has been life changing for people like me.”

Although Vickie finished treatment 5 years ago, like many women who have had the disease, she still has tests for levels of HCG and will be monitored for the rest of her life.

A legacy of life-saving research

More than half a century on from Bagshawe’s pioneering work, Charing Cross Hospital remains a focal point of research for trophoblastic cancers like choriocarcinoma. HCG testing and the EMA-CO combination treatment also continue to be used across Europe, demonstrating the breadth of Bagshawe’s impact.

More importantly, since the 1950s, survival for choriocarcinoma has soared. From a time when most patients wouldn’t survive the disease, today all women with low risk disease are cured, and those with high risk choriocarcinoma have more than a 90% chance of beating of their cancer.

From a first encounter at the steps of his clinic, to his life-saving research journey at Charing Cross Hospital, Bagshawe has left an incredible legacy in tackling this rare cancer.

And it’s one that continues to transform the lives of women diagnosed with choriocarcinoma today.