Our milestones: Nudging breast cancer radiotherapy in the right direction

In this instalment, we take look at how the START trials provided crucial evidence to change practice for women having radiotherapy for early stage breast cancer.

The journey from discovering x-rays to using them to treat cancer was a quick one.

It began in the winter of 1895 in a physicist’s lab in central Bavaria, Germany. While he was experimenting with electricity and gases, Professor Wilhelm Röntgen produced what he called ‘a new kind of ray’.

Word of the ray travelled quickly, and its use in medicine soon followed. Within 3 years of the discovery, the first documented case of using x-ray radiation against cancer emerged.

Researchers from Sweden reported that 6 patients with cancer in the nose and cheek had their tumours destroyed by a single, large dose of x-ray radiation. But that single radiation hit caused severe burns to their skin.

It was only a couple of decades later, in 1914, that these side effects were addressed.

In Lyon, a radiologist called Claudius Regaud had been thinking about ways to kill cancer cells using x-rays while sparing healthy cells.

After comparing how normal cells and cancer cells behave under radiation, he suggested that breaking up radiation treatments into many smaller doses might be just as effective as one big radiation hit. On top of that, he proposed that the breaks in treatment would give healthy cells time to recover and repair themselves from the radiation.

Regaud believed this combination was a kinder option. Little did he know that he’d invented a new way of giving radiotherapy called fractionation.

The Great War was now rumbling and alongside military duties, Regaud kept up his work on understanding the effects of radioactivity on human cells.

While peace came and went in Europe, a follower of Regaud in Manchester, called Ralston Paterson, started to experiment with radiation doses for treating cancer. From this he drew up a dosage system that determined how much radiation was needed to kill different types of tumours.

By now it was the 1940s and Britain was in a second world war.

Using his new knowledge of the different effects of radiation doses on tumours, Paterson started experimenting with fraction size. He used larger doses of radiation than Regaud and began working out how much should be given to patients in each session.

The beginning of START

Through the years, radiotherapy centres started to experiment with fractionation too, splitting the total dose of radiation into smaller ones.

Soon enough a wide range of radiotherapy regimens emerged across the globe.

Over in South Africa in the early 1950s, a scientist called Dr Lionel Cohen attempted to figure out what the vast majority of radiotherapy centres were doing. He gathered and compared information from hospitals throughout the world to see how effective fractionation was and what was the most common regimen.

By the ‘80s, the recommended radiotherapy schedule outside of the UK for breast cancer after surgery was giving 2 Gray (Gy) of radiation 25 times (or in 25 fractions) over 5 weeks. A Gy is a unit of radiation used to measure how much radiation energy a tissue absorbs. This meant the average patient received in total 50 Gy of radiation over the course of their treatment.

If you count small differences in prescriptions there was something like 34 different radiotherapy schedules in the UK in the 1980s, so we really needed to put the house in order.

Professor John Yarnold, The Institute of Cancer Research

Although this dose kept tumours under control, women often reported life-long scarring and hardening of their breast tissue.

Even after Cohen’s attempts to bring consistency to radiotherapy dosing, there still wasn’t much robust evidence to suggest which fraction size worked best, how many fractions a patient should receive and how quickly the treatment could be done.

It was clear the field needed some direction to establish a standard of care, but it wasn’t until around 30 years later that the tide started to change.

A team of researchers in Canada decided to go over Cohen’s work with a fine-tooth comb. They concluded that breast cancer responded to radiotherapy treatment differently compared to most other cancers.

If this was true, it could mean that the standard 25 dose regimen might not be the most effective way of treating patients.

“If you count small differences in prescriptions there were something like 34 different radiotherapy schedules in the UK in the 1980s, so we really needed to put the house in order,” recalls John Yarnold from the Institute of Cancer Research, London (ICR) and the Royal Marsden.

Yarnold set to work with a team at Cheltenham General Hospital to address these housekeeping challenges. They organised a randomised clinical trial with the help of 1410 patients receiving radiotherapy as part of their breast cancer treatment. They found that giving the total radiation dose in fewer hospital visits – meaning at each visit the patient received a larger dose than was previously being offered – was safe and effective.

This gave them the green light to get things moving.

They teamed up with their ICR colleague, Judith Bliss, and united experts from around the UK to set up two of the most influential radiotherapy breast cancer trials to date: the START Trials.

Using money from Cancer Research UK, the UK Medical Research Council and the UK Department of Health the trials would soon create enough evidence to change practice worldwide.

Team science

Between 1998 and 2003, 35 radiotherapy centres across the UK worked together to recruit 4450 women with early breast cancer for the two trials, called START A and START B.

This was the first time such a large number of radiotherapy experts put their heads together, and for Bliss and Yarnold this collaboration was key to the trials’ success.

“It was team science. That’s how you’re successful in medicine, by building a team,” says Yarnold.

In START A, women were randomly allocated to one of three groups after surgery. Each group received a different radiotherapy schedule.

In the first group, patients received 50 Gy of radiation in total. They had to visit the hospital 25 times and so at each session received 2 Gy of radiation, the international standard.

These patients received radiation in fractions which means a dose of radiation 2 Gy or less.

What made this trial different was that it tested the standard against ‘hypofractions’. Hypofractions are doses of radiation over 2 Gy.

This meant in the second and third groups, patients received higher radiation doses at each session – 3 and 3.2 Gy respectively.

Because the team wanted to spare damage to healthy tissue, which the standard 50 Gy was known to cause, they also chose a lower total dose for groups 2 and 3.

This meant only 13 fractions were needed, reducing hospital visits to 13 instead of the usual 25. Groups 2 and 3 received a total 39 and 41.6 Gy respectively.

The results showed that the cancer was under control in all three groups, making the schedule in group 2 the best as side effects were the least severe.

This proved that both breast cancer cells and healthy cells noticed the difference in fraction size.

Perhaps more importantly, it suggested that what had been deemed standard treatment was exposing women to an unnecessary amount of radiation.

Two studies are better than one

If organising one large-scale trial wasn’t enough, Yarnold and Bliss designed another, called START B, to run at the same time as START A.

“START B was actually the practice-changing trial when the 5-year results were published in 2008,” says Yarnold.

The test schedule of radiotherapy outlined in START B was already widely used in UK hospitals, but the team wanted to collect enough evidence to prove this was best for patients.

Half of the 2215 women with early-stage breast cancer received a total of 40 Gy of radiation, over 3 weeks, in 15 fractions. That meant they got 2.7 Gy at each hospital visit.

As with START A, they compared this to the international regimen, 2 Gy per treatment, 25 times, over 5 weeks.

Again, the number of patients whose disease returned was similar in both groups, but those who received higher doses per visit over a shorter period of time (hypofractionation therapy) reported fewer side effects and a better quality of life 5 years on.

“The side effects were about 15-20 per cent less frequent in women who were given 15 fractions of 2.7 Gy,” says Yarnold, adding that women who received around 40 Gy had less scarring, less hardening of the breast and less change in the breast appearance.

But even though practice has moved towards the regimen in START B, one trial could not have been so successful without the other.

START B suggested that giving radiotherapy in fewer, higher doses was overall gentler on healthy tissues and that treatment could be just as successful when given over a shorter period of time.

START A proved that fraction size mattered when treating breast cancer.

“The results of START B have more weight because they’re entirely consistent with START A,” says Bliss.

To add even more weight to START’s results, doctors monitored all START A and B patients for 10 years. These results matched those at 5 years, and reassured the radiotherapy community that moving towards 15 hypofractions of 2.7 Gy was the way to go.

In 2009, the results were the tipping point for the National Institute for Health and Care Excellence (NICE) to update its guidelines and recommend this schedule for all patients.

“There had been a general direction of travel and NICE’s decision helped standardise UK treatments,” says Bliss.

Now nearly all patients in the UK receive 15 fractions of radiotherapy after surgery for early stage breast cancer.

It wasn’t just the UK that START influenced.

“The spread is patchy but it’s now growing fast,” says Yarnold. “It’s also a standard of care for many patients in Norway and Sweden.”

Hypofractionation: a patient’s perspective

Thanks to the community of radiotherapy researchers, women all over the world can expect a better quality of life after this particular breast cancer treatment plan.

Chris was diagnosed with breast cancer in 2013, just a couple of years before her grandson was born.

“It all happened within a week,” she says. “My first reaction was to ask them to remove both breasts, but they said they wanted to try and shrink the tumour so they didn’t have to. “

I don’t have any scarring. I’m really lucky in that way.

– Chris, breast cancer survivor

After surgery to remove the tumour, Chris received radiotherapy in multiple fractions for three weeks, like the schedule that START B tested 10 years before.

“You have to go in every day for treatment, which is the most tiring bit. But luckily I had just been given my over 60s bus pass so the journey wasn’t too bad,” she says.

For her, the treatment was very quick and relatively comfortable. “I don’t spend a lot of time lying down and doing nothing so it was quite nice to have a rest!” she says.

Chris’ treatment plan meant she received less radiation overall with the aim of keeping her side effects to a minimum.

“I don’t have any scarring,” she says. “I’m really lucky in that way.

“You’d get a bit of a burn afterwards but apart from that I had no discomfort from the radiotherapy really.” Chris was back swimming and walking her dogs in no time.

“Research is everything!” she says. “I’m so lucky because I still have an amazing life. I have a lot to look forward to now.”

Only the beginning for START

The team isn’t stopping at START. Using evidence from the trials they hope to refine radiotherapy guidelines for breast cancer even further.

The risk of a patient’s disease coming back has dropped dramatically since the 1980s, from around 10 in 100 people seeing their cancer return at 5 years to now between 1 and 2 in 100 people.

The aim now is to find a way to identify those patients who are least likely to need radiotherapy as part of their treatment.

“This new study will use biomarkers and clinical data to predict the risk of disease return,” says Yarnold.“We’re now trying to find those women who don’t need any radiotherapy at all.”

Even though the START trials produced fantastic evidence that shaped treatment for women with early stage breast cancer, both Bliss and Yarnold agree their impact runs deeper.

They say the radiotherapy community was always close, but none of these trials would have been possible without the researchers that built the foundations around START.

“This wasn’t a one off partnership to deliver a clinical study,” says Bliss, adding that Cancer Research UK’s contribution was much wider than project funding.

“By helping us to develop partnerships back in the 80s we have created the infrastructure to continue and develop our practice-changing trials.”

It seems the START trials are defined by more than just changing clinical practice. They mark the beginning of a research network that continues to move radiotherapy research forward and improve the lives of women with breast cancer.

Gabi