Impact case study database

Coles and Earl’s research has directly informed clinical practice, sparing major side effects for patients while markedly reducing healthcare costs.

Impact on practitioners and the delivery of professional services

Changing national guidelines and practice for breast cancer therapy: Cambridge research has had a direct impact on national and international clinical practice for the treatment of Stage I-II breast cancer:

• As a result of IMPORT Low, NICE 2018 guidance for early and locally advanced breast cancer: diagnosis and management [A] states: ‘Consider partial breast radiotherapy (as an alternative to whole breast radiotherapy) for women who have had breast conserving surgery for invasive cancer (excluding lobular type) with clear margins and low absolute risk of local recurrence’.

• UK Royal College of Radiologists breast radiotherapy consensus guidelines recommends partial breast radiotherapy for low risk patients (patients 50 years with grade 1-2, 30mm, oestrogen receptor positive and HER2 negative with minimum 1mm surgical resection margins and no lymphovascular invasion) [B].

• As a direct result of IMPORT LOW, regional NHS guidelines have been introduced by the North East Yorkshire and Humber Clinical Alliance and the West Midlands Expert Advisory Group for Breast Cancer, recommending the use of surgical clips on the wall of the tumour bed to enable partial radiotherapy as a standard approach, via increased accuracy of radiotherapy [C].

• As a direct consequence of the PERSEPHONE trial, UK recommendations have been developed by an optimal duration of trastuzumab working group. In a 2020 survey of breast specialists, the majority (78%) agreed with 6 months as a standard option for those receiving single agent trastuzumab [C]. In addition, the 3,200 breast cancer patients treated with single agent trastuzumab each year in the UK could now benefit from reduced-duration 6-month treatment [D].

Changing international breast cancer therapy practice: Internationally, the results of IMPORT Low have motivated numerous countries to change standard practice, implementing partial breast radiotherapy for low risk breast cancer patients. These include the Netherlands and Denmark, where national breast cancer guidelines have been changed to incorporate these new radiotherapy parameters [E]. IMPORT Low partial breast radiotherapy is now being used routinely in some of the largest and most technologically advanced cancer centres worldwide including: Australasia, Canada (Princess Margaret Cancer Centre), Canada Cancer Centres, and USA (Memorial Sloan Kettering Cancer Center) [E].

Impact on health and wellbeing of people

Reducing side effects for woman receiving radiotherapy: The IMPORT Low trial demonstrated that women with low risk breast cancer can be treated safely and effectively with reduced-dose or partial breast radiotherapy, causing fewer side effects than standard treatment. Importantly, this includes halving the number of women reporting marked changes in breast appearance or hardness that are associated with significant psychological sequelae. In the UK alone, 10,000 women per year are eligible for partial breast radiotherapy [F], which annually equates to 1,200 women spared physical changes in breast appearance and 500 patients spared breast hardness because of treatment [1,2]. Partial breast radiotherapy halves the mean heart dose for patients with left-sided cancer, which reduces the predicted absolute lifetime risk of life-threatening cardiac events to less than 0.5%, i.e. reducing from 50 to 25 such events per year (DarbyS *et al.*NEJM 2013). The reduction from 15 to 5 radiotherapy treatments will also have a positive effect on the patient experience, by minimising hospital visits and treatment-associated side-effects.

Reducing side effects for women receiving targeted therapy: The PERSEPHONE trial provides evidence for safe reduction of single agent trastuzumab therapy from 12 to 6 months. This reduced therapy, provides the same excellent survival benefit, but 5% (365/1929 vs 460/1935) fewer patients treated now suffer severe side effects and only 3% (61/1977) of women who receive 6 months of trastuzumab are likely to have to stop treatment because of heart problems, compared with 8% (146/1941) who receive 12 months [D]. Patients on trastuzumab most frequently report severe aches and pains (9.3% - 524/5610) and fatigue (8.2% - 461/5610), which can be minimised by reduced treatment [D].

Establishing therapy-reduction research for patient benefit:** Both IMPORT Low and PERSEPHONE were completed within the NHS Clinical Research Network with active patient advocate partnership throughout design, recruitment, analysis and dissemination [G]. The success of these two trials with non-inferiority design, has been pivotal in establishing a priority theme of treatment reduction in National Cancer Research Institute (NCRI) breast cancer trials and has received consistent and positive feedback from doctors and patients [G]. Benjamin Smith, Professor of Radiation Oncology and Health Services Research at The University of Texas MD Anderson, said regarding IMPORT Low: “ In my opinion, this is one of the most important articles on early breast cancer to be published in this decade.” Maggie Wilcox, who is the patient lead for the PERSEPHONE trial, said “ I am delighted to have been part of this landmark trial which is an important step to reduce the length of treatment whilst not changing effectiveness.” Professor Hywel Williams, Director of the NIHR HTA Programme that funded the PERSEPHONE study said: “ This is a hugely important clinical trial that shows that more is not always better. Women will now have the potential to avoid unnecessary side effects of longer treatment without losing any benefit. In turn, this should help save vital funds for the NHS and prompt more studies in other situations where the optimum duration of treatment is not known. It is unlikely that research like this would ever be done by industry, so I am delighted that the NIHR are able to fund valuable research that has a direct impact on patients.” [H].

Extending excellence in care to Low- and Middle-Income Countries (LMICs): Trastuzumab has had World Health Organisation Essential Medicine designation since November 2015. However, the cost associated with 12 months of treatment precludes its widespread use in LMICs where it is estimated that over 1,000,000 people are diagnosed with breast cancer; ~120,000 of these patients have HER2+ disease. Demonstration by PERSEPHONE that 6 months of treatment are as effective as 12 months has increased directly the use of the drug in several LMICs, resulting in improvement in the uptake of this curative treatment [I]. IMPORT Low uses a simple technique and conventional, widely available radiotherapy equipment, so can be implemented in any centre worldwide.

Impact on commerce and the economy

Standard whole breast radiotherapy consists of 25 fractions over 5 weeks in many countries worldwide. Based on UK tariffs (GBP159 per fraction), a reduction to 15 fractions of partial breast radiotherapy saves GBP1,590 per patient. The 2020 publication of the FAST Forward trial has enabled seamless adoption of just 5 radiation fractions for partial breast radiotherapy in the UK and in countries where 15 fractions are standard of care. Around 10,000 women are eligible for partial breast radiotherapy per year in the UK where the standard of care is 15 fractions: this saves 100,000 fractions of radiotherapy per patient and a saving of ~GBP16,000,000 per year for the NHS. Each year the NHS treats ~3,200 women with 12 months of single agent trastuzumab (GBP22,000/patient) total ~GBP70,000,000). The Health Economic Analysis in PERSEPHONE showed within-trial cost savings of GBP9,793 per patient by reducing treatment to 6-months of trastuzumab [J]. Patients receiving single agent trastuzumab, which accounts for approximately half of all HER2+ cases, equates to an annual cost-saving of ~GBP30,000,000 to the NHS.