Testing new radiotherapy techniques for breast cancer
Radiotherapy is one of the key treatments for cancer. More than 120,000 cancer patients in the UK are treated with radiotherapy each year and it continues to cure more people than all existing drugs combined. The Institute of Cancer Research founded its department of radiotherapy in the early 1940s and has been at the forefront of a number of important developments that have improved patient care.
Although radiotherapy has been used to treat cancer for more than 100 years, the mode of delivery has become infinitely more sophisticated over recent decades. The ICR and the Royal Marsden Hospital (RMH) pioneered intensity modulated radiotherapy (IMRT) and in 2007 reported on the first randomised trial of IMRT in breast cancer. The team are still leading research to further refine this targeted radiotherapy technique.
Radiotherapy is a type of cancer treatment that uses radiation to destroy cancer cells. The treatment works by damaging the DNA of cells, leading to breaks in the DNA strand. When cells divide their DNA is particularly susceptible to damage. Cancer cells generally divide more often than normal cells and are also not able to repair or fix breaks in their DNA as well as healthy normal cells. This subsequently leads to the death of the cancer cells.
The dose of radiotherapy given to patients, measured in gray (Gy), varies depending on the type and stage of the cancer. The dose is divided and spread over a number of different treatments, called fractions. The number of fractions also varies with cancer type and stage. A course of radiotherapy is usually given over a number of days or weeks. Fractions are usually given once a day from Monday to Friday with a rest at the weekend. Giving the radiotherapy over time allows normal cells to repair themselves between fractions and also ensures that cancer cells are hit with radiation when they are at the most sensitive stage of cell division, when the effects of DNA damaging radiation is at its greatest.
Very early radiotherapy was delivered in one large dose from a single beam, and carried severe side-effects. It is a bit like an actor on a stage – you can illuminate the actor with a single spot light but the actor and also the area around are lighted. 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 were being used to deliver doses of radiation to very specific points. If you now imagine the actor on the stage but they are lit up with a series of smaller spot lights coming from different angles – it is then possible to illuminate just the actor – or perhaps even just their face. Modern radiotherapy is a bit like that.
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.
Newer medical imaging technologies, such as magnetic resonance imaging (MRI) in the 1970s and positron emission tomography (PET) in the 1980s, has lead to advanced radiotherapy techniques known as intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT). These advances have allowed radiation oncologists to better see and target tumors, improving cure rates, preserving more normal healthy cells and giving fewer side effects.
Radiotherapy in breast cancer treatment
Breast cancers that are detected early can often be treated with surgery that removes the cancer but spares the rest of the breast. Research shows that a course of radiotherapy after surgery for breast cancer lowers the risk of the cancer coming back either in the remaining breast tissue or in lymph nodes. Usually radiotherapy is given to the whole of the remaining breast tissue after surgery however this means that healthy tissue as well as the ribs, lungs and 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, pain, distortion of breast appearance, lymphodema (a swelling in the arm) and, in rare cases, breathlessness. Scientists have therefore been looking at ways to reduce the amount of radiotherapy delivered to healthy tissue, while continuing to reduce the chance of recurrence.
The ICR pioneers Intensity Modulated Radiotherapy (IMRT)
Intensity Modulated Radiotherapy (IMRT) is an advanced type of high precision radiotherapy that uses 3D modelling to determine the shape of the tumour. The radiation beam is then controlled - or “modulated” - to fit the tumour shape. This allows for the maximum dose of radiation to be applied to the tumour, while radiation to neighbouring normal tissue is lessened or avoided completely. Meaning that the central part of the cancer receives the highest dose of radiotherapy and a surrounding area of tissue gets lower doses. 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 ICR and the RMH in London. The study of 306 women with breast cancer confirmed in 2007 that IMRT led to fewer side effects than seen for conventional radiotherapy.
Scientists at the ICR are continuing this pioneering work, leading studies that aim to further improve radiotherapy treatment for women with breast cancer.
The IMPORT HIGH trial
The risk of cancer coming back 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. For this reason, women with a higher risk of recurrence are also given a boost dose of radiation to the tumour bed.
The first patient joined the IMPORT HIGH trial in March 2009 and 840 patients are expected to be recruited by early 2012. The study is assessing the effectiveness of IMRT in women who have a higher than average chance of the cancer coming back and a poorer chance of survival. Women in the study all have early stage breast cancer that has been treated with breast conservation surgery, in which just the cancer and not the whole breast is removed.
The trial will compare the standard radiotherapy treatment with IMRT. Standard treatment is radiotherapy is delivered to the whole breast followed by a boost dose to the tumour bed. Patients in the test arms are having a more targeted treatment - a standard dose of radiotherapy to the tumour bed and a lower dose to breast tissue further away from the original tumour site. They will also have a boost dose to the tumour bed. This “test” group of patients will be further split, with one group receiving a higher boost dose than then other. The standard treatment gives the boost dose of radiation after whole breast irradiation but in the test arm using IMRT the boost dose is able to be given at the same time as radiotherapy to the whole breast. Therefore patients in the test groups will to receive fewer radiotherapy treatments.
Trial leader Professor John Yarnold of the ICR and The Royal Marsden Hospital (RMH) says: “We hope that these studies will show that we can 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.”
Guiding the radiotherapy beam to the target - Image guided radiotherapy (IGRT)
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 within 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. This can lead to additional side effects.
An important innovation in the new study is a national agreement that breast surgeons will 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 more accurately target the tumour bed and reduce the amount of radiotherapy given around the tumour bed, compared to standard imaging and radiotherapy techniques.
Scientists will examine a subgroup of 250 women in the IMPORT HIGH trial to measure the accuracy of IGRT compared to radiotherapy using standard imaging. The scientists will firstly be able to assess the accuracy of the IGRT compared to standard treatment. Secondly, they will compare, in a single patient, the amount of breast tissue treated by IGRT 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 reductions in risk to normal tissue compared with the standard technique.
“Our pilot studies 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.”
More information on the new studies
The studies are a collaborative effort with several teams within the ICR and RMH contributing to the study. Scientists involved in the IMPORT HIGH and IMPORT IGRT come from the ICR’s section of academic radiotherapy, the ICR and RMH department of physics and the ICR section of clinical trials.
IMPORT HIGH, is led by Professor Yarnold of the ICR and Dr Charlotte Coles of Addenbrookes Hospital. IMPORT HIGH is recruiting 840 women across the UK who are at average or above risk of breast cancer coming back. For more details see the ICR's IMPORT HIGH page.
IMPORT IGRT is led by Dr Phil Evans from the ICR and aims to look at 250 women from the original IMPORT HIGH study.
The IMPORT HIGH study is funded by Cancer Research UK and The IMPORT IGRT trial is supported by a research grant awarded by the Efficacy and Mechanism Evaluation (EME) programme, which is funded by the Medical Research Council and managed by the National Institute for Health Research.