How cutting doses of cancer therapy can reduce side-effects… but be just as effective

Sarah Hymas was in the shower when she felt a lump under her right armpit and immediately knew something was wrong.

An ultrasound scan quickly confirmed it was a large 3cm tumour, which further tests revealed to be triple-negative breast cancer — a more difficult form of the disease to treat because it doesn’t have receptors for hormones such as oestrogen (for which there are targeted therapies).

‘It was such a shock. I’ve always been very health-conscious,’ says Sarah, 58, a psychotherapist, who is divorced with two grown-up children and lives in the South West. ‘Although I was diagnosed with triple-negative breast cancer, it was never found in my breast, only in a lymph gland in my armpit — but doctors were confident it had originated in my breast.’

At the end of 2020, her doctors put her on immunotherapy drugs for six weeks and chemotherapy for six months to destroy the cancer.

Women with this form of breast cancer — which accounts for 15 per cent of the 55,000 new cases each year in the UK — generally then go on to have surgery, in Sarah’s case an axillary lymph node dissection.

This involves removing most or all of the lymph nodes under the arm — these filter waste and toxins from the lymph fluid as it travels around the body — as a way to prevent cancer spreading.

The procedure is often successful but can also cause nasty side-effects such as lymphoedema, where parts of the body, such as the arm, swell because of damage to the lymph system, causing tightness and movement difficulties.

Sarah, however, was able to benefit from a ‘kinder’ version of the procedure called targeted axillary dissection (TAD), which she underwent in June last year.

This involves surgically removing only the abnormal lymph nodes rather than all of them (the number a woman has varies but can be up to 40) with conventional treatment — but with the same success rate.

Sarah was ‘delighted’ to have just five lymph nodes removed instead of her 20. ‘The procedure only involved an overnight stay and later I found out the cancer had completely disappeared, which was amazing.

‘The diagnosis and treatment really took it out of me; I lost a lot of weight and at times felt so unwell. So I was really pleased to avoid further side-effects. Seven months after surgery, my arm still hurts a little but I have full movement.’

The search for smarter — better, shorter and less toxic or damaging — cancer treatments, with better outcomes, such as TAD is now a holy grail of cancer research.

The first real breakthrough in this ‘de-escalation’ or ‘optimisation’ approach was a British trial published in The Lancet in 2005, which found a single dose of chemotherapy was just as effective — and less toxic — for treating early-stage testicular cancer post-surgery as three weeks of radiotherapy, the treatment offered for nearly 50 years.

This transformed the care of thousands of men, and now the search is on for similar gains across a range of cancers instead of ‘throwing the kitchen sink at the disease to try to treat it’, says David Cameron, a professor of medical oncology at Edinburgh University.

Professor Cameron explains: ‘What we are doing is changing the focus of research to see if we can get the same outcomes with less treatment and to improve the experience for cancer patients so they suffer fewer side-effects, can preserve their fertility or don’t develop heart muscle damage, in the case of breast cancer, as a result of their treatment.’

As well as reducing side-effects, de-escalation trials are about finding more effective treatments for patients with less intervention.

Last year, researchers from the Institute of Cancer Research and Manchester University revealed giving people with bladder cancer that has spread into the surrounding muscle a shorter, higher-dose radiotherapy regimen reduces the risk of the disease returning.

The study, published in the journal The Lancet Oncology in February 2021 found that patients who had 20 high doses of radiotherapy over four weeks instead of the standard 32 doses over six and a half weeks, had a 29 per cent lower risk of cancer returning after five years.

It’s thought bladder cancer cells regrow quickly, after about four weeks — so killing them off over a shorter period with a higher dose of radiotherapy, gives them less time to grow back.

The study authors called for the approach to be adopted by the NHS. Professor Robert Huddart, a consultant in urological oncology at The Royal Marsden NHS Foundation Trust and one of the authors, said that the findings were especially important during the Covid era when there is an ‘imperative to keep patients out of hospital.’ 

‘Kinder’ cancer treatment 

From lower doses to less surgery, here are some of the ways cancer treatments are becoming kinder to patients. 

Reducing doses of chemotherapy 

Lower doses of chemotherapy are as effective at controlling advanced cancer of the stomach or oesophagus (the gullet) in elderly or frail patients, leading to fewer side-effects such as diarrhoea and lethargy, according to research presented at the American Society of Clinical Oncology conference in 2019.

Conventional treatment for these patients is three chemotherapy drugs. But when the participants were given just two drugs at full strength, medium or low doses, the researchers, funded by Cancer Research UK, found that medium and lower doses of just two drugs was as effective as the full-strength dose of the three drugs for controlling the cancer. Taking quality of life into account, the lowest dose came out best.

Professor Matt Seymour, co-chief investigator at Leeds Teaching Hospitals NHS Trust, said: ‘Doctors can confidently give people a lower dose of chemotherapy, sparing them side-effects without worrying that it’s compromising their chance of survival.’

Gentler drug therapy

A ground-breaking trial in 2018 identified a ‘kinder’ treatment for women with incurable triple-negative breast cancer that has spread, who also have the faulty BRCA gene.

The treatment options for these women are limited and the UK trial found that the chemotherapy drug carboplatin was both ‘kinder’ than the existing treatment docetaxel and more successful at delaying disease progression — increasing the length of time before the disease progressed by 54 per cent (6.8 months compared with 4.4 months), according to the results published in the journal Nature Medicine.

And nearly twice as many women saw their tumours shrink compared to those treated with docetaxel. 

Shorter treatment 

Treating women with ductal carcinoma in situ (DCIS) — abnormal cells in the milk ducts in the breast — with three weeks of radiotherapy is just as good as having it for five weeks, according to an international study published in the journal Cancer Research last year.

Meanwhile, halving the amount of time breast cancer patients spend on the drug Herceptin significantly reduces side-effects —and is just as effective, according to a major trial in 2019.

Herceptin targets a protein called human epidermal growth factor receptor 2 (HER2) on the surface of cancer cells, stopping them growing and dividing. But it can affect the heart’s pumping ability (because there are HER2 receptors in heart muscle, too), causing breathlessness and palpitations — leading to around one in ten women stopping the drug.

In a study involving more than 4,000 women with early stage, HER2-positive breast cancer, six months of treatment was as effective as the standard 12-month course, The Lancet reported, with significantly fewer heart problems, aches and pains and fatigue.

Less surgery

A radical hysterectomy — removing the womb, cervix, nearby lymph tissue and upper vagina — is often recommended for early stage cervical cancer, which can cause long-term urinary incontinence problems and pain during sex.

A major international trial (involving Sheffield Teaching Hospitals NHS Foundation Trust) is investigating whether patients could do just as well with removing less tissue around the womb. Results are expected in 2023.

Separately, TAD has now been used for three years after a series of studies showed it was as effective as more major surgery for some women — and a review of 13 studies, published in the journal Cancers last year, concluded that these procedures can ‘safely replace more radical surgery in women who have responded well to up-front [initial] drug treatment’.

Yet many women are not benefitting from these new approaches, says Professor Kefah Mokbel, a breast surgeon at the Princess Grace Hospital in London, one of the team who carried out this latest review and who treated Sarah privately.

‘The updating of national guidelines often lags behind research results by approximately five years.’