Personalising radiotherapy

Scientists at the Institute of Cancer Research and the Royal Marsden Hospital pioneered intensity-modulated radiotherapy and in 2007 conducted the first clinical trial of IMRT in breast cancer. Two new trials are aiming to continue to improve radiotherapy treatment for women with breast cancer

Radiotherapy was first used to treat cancer shortly after the discovery of x-rays in 1895. Over 100 years later it remains one the mainstays of treatment and more than 120,000 cancer patients are treated with radiotherapy each year in the UK. 

Very early radiotherapy was delivered in one large dose from a single beam, and carried severe side-effects. Over time, x-ray machines became more powerful, allowing the beams to penetrate further into the body and causing less damage to the skin. In addition multiple beams can now be used to deliver doses of radiation with high accuracy.

A significant advance to radiotherapy treatment was the invention of computed tomography (CT) scans in the early 1970, which allowed doctors to more accurately direct the radiation dose at the tumour site in three dimensions. Medical imaging technologies, such as such as magnetic resonance imaging (MRI) in the 1970s and positron emission tomography (PET) in the 1980s, has led to advanced radiotherapy techniques such as intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT). These advances have allowed radiation oncologists to better see and target tumours, improving cure rates, preserving more normal healthy cells and giving fewer side effects.

Breast cancers that are detected early can often be treated with breast conserving surgery. Research shows that a course of radiotherapy after surgery for breast cancer significantly lowers the risk of the cancer recurring either in the remaining breast tissue or in lymph nodes.  

Usually whole breast radiotherapy is given after lumpectomy meaning that healthy breast as well as the ribs, lungs and when the breast cancer is in the left breast, the heart, can also receive a dose of radiation. In some cases this can lead to long term side-effects including hardening of the breast tissue, breast pain and distortion of breast appearance, lymphodema and rarely, breathlessness.

Significant advances in radiotherapy technology have been made during the last ten years. Linear accelerators have the capability to deliver multiple fields and dynamic beam deliveries, while treatment planning systems have sophisticated algorithms for accurately targeting treatment. These technologies have enabled the development and clinical application of IMRT in a number of UK centres.  

In IMRT the radiation beam is then controlled – or “modulated” – to fit the tumour shape allowing for the maximum dose of radiation to be applied to the tumour, while radiation to neighbouring normal tissue is lessened or avoided completely. This in turn should lead to a reduction of side-effects and better chance of cure.

The first clinical trial of IMRT in breast cancer was conducted by scientists and doctors at the Institute of Cancer Research (ICR) and the Royal Marsden Hospital (RMH) in 2007. The study of 306 women showed that IMRT did lead to fewer side effects than seen for conventional radiotherapy¹.

Now scientists and clinicians at the ICR and RMH are continuing this pioneering work and are leading studies that aim to improve radiotherapy treatment for women with breast cancer.  

The risk of recurrence of breast cancer after conservative surgery is particularly high in a subgroup of mainly younger women. In most cases the cancer recurs close to the original tumour site – known as the tumour bed. Therefore following conservative surgery radiotherapy is delivered to the whole breast followed by a boost dose to the tumour bed.  

Scientists postulate that a reduction in the dose given to non-target tissues away from the site of the primary tumour should not lead to an increase in local tumour recurrence but should significantly reduce the risk of treatment related morbidity and improve quality of life. IMRT offers a novel alternative to conventional radiotherapy techniques for delivering treatment post surgery.  

IMPORT HIGH is a multicentre Phase III trial testing IMRT after conservation surgery for women with higher than average local recurrence risk early breast cancer. The trial entered its first patient in March 2009 and expects to recruit 840 patients by early 2012. The study aims to determine if IMRT can, while still preventing local recurrence, reduce side effects compared to standard line therapy.

Import HIGH will recruit a total of 840 women into three treatment arms. The first group – the control arm – will receive the standard treatment of 40Gy in 15 fractions to the whole breast and then a boost dose of 16Gy in eight fractions to the tumour bed. The second and third groups of women will receive IMRT of 36Gy to the whole breast, 40Gy to the part of the breast from where the cancer was removed and a boost dose to the tumour bed of either 48Gy (test group 1) or 53Gy (test group 2) in 15 fractions. In the control arm treatments will be given in a little over four and a half weeks while patients in the test arms will received 15 treatments over  three weeks.

Trial leader Professor John Yarnold of the ICR and RMH says: “We hope that these studies will be able to allow us to improve radiotherapy treatment for women with breast cancer by reducing side effects while maintaining or perhaps even improving the number of women cured by this treatment”

Currently x-rays are used to direct radiotherapy treatment to the area of the breast from where the tumour was removed. However they reveal only the position of surrounding organs and bones and not the exact location of the tumour bed. A safety margin must therefore be added to ensure the tumour bed always falls in the treatment area, with the result that a high dose of radiotherapy has to be given to twice as much healthy breast tissue as would otherwise be necessary, which can lead to side effects.

An important innovation in IMPORT HIGH is a national agreement of breast surgeons to mark the boundaries of the surgical excision with small titanium clips allowing the tumour bed to be directly seen before each treatment. The clips will allow the researchers to use IMGT and more accurately target the tumour bed. This should reduce the amount of radiotherapy given around the tumour.

A subgroup of 250 women in the IMPORT HIGH trial will be used to measure the accuracy of IGRT compared to standard imaging (IMPORT IGRT). The scientists will firstly be able to assess the positional accuracy of the IGRT compared to standard treatment and then be able to compare in a single patient the amount of breast tissue treated by IGRT compared to what would have been treated using standard imaging. The scientists can then evaluate how effective the IGRT technique is in reducing the volume of tissue treated at a high dose, and determine the consequent reductions in risk to normal tissue compared with the standard technique.

“Our early experience² and calculations suggest that safety margins around the tumour bed can be greatly reduced, leading us to expect a lower rate of long-term complications such as breast shrinkage, hardness, pain and rib fracture,” says Professor Evans. “In this study, we will be able to calculate exactly how much breast tissue we were able to spare and the implications this will have on side-effects.”

Professor Yarnold adds: “Once developed and tested IMRT and IGRT are likely to be more efficient and cost-effective than technologies in current use.”

References
1.    Donovan, E., et al., Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy. Radiother Oncol, 2007. 82(3): p. 254-64.
2.    Coles, C.L., et al., Evaluation of implanted gold seeds for breast radiotherapy planning and on treatment verification: A feasibility study on behalf of the IMPORT trialists. Radiother Oncol, 2011.