Summary
Intensity-Modulated Radiotherapy (IMRT) is effective but can have debilitating side effects. To address this, the team at the Royal Marsden Hospital, in collaboration with the Institute of Cancer Research (ICR), significantly refined the technique.
The modified procedure has been rolled out nationally and internationally, and it is now being used to treat an estimated 300,000 patients worldwide. The most significant impact has been reducing the risk of patients suffering xerostomia (dry mouth) and trials show that the risk was reduced to approximately 20 per cent compared with patients who had an 80 per cent risk from traditional radiotherapy.
IMRT is now used to treat head and neck cancer patients in all UK cancer networks and the technology has also been adopted around the world as a treatment for tumours in many other parts of the body including breast, prostate, paediatrics, CNS and pancreas.
Challenge
Head and neck cancer affects 7,500 people a year in the UK and approximately 600,000 individuals worldwide. While treatment with chemotherapy and radiation is often curative, it can produce long-term permanent and sometimes severe affects on the patient’s quality of life.
Traditionally radiotherapy treatment for a number of head and neck cancers such as mouth, pharynx, larynx or oesophagus has involved targeting the tumour side-on with radiation. While this is effective against the tumour, it can damage nearby healthy tissue or organs. One of the most notable side-effects is xerostomia or dry mouth – a lack of saliva caused by radiotherapy damage to the saliva glands that can permanently affect speaking, eating and oral health.
With eight out of ten head and neck cancer patients at risk from this condition, improved techniques for delivering radiotherapy have been the focus of considerable concern and research.
The team’s work in refining Intensity-Modulated Radiotherapy (IMRT), shapes the beams to fit the outline of the tumour more precisely, taking advantage of advances in computer software and accelerator hardware. This coincided with similar work undertaken at other centres in Europe and North America.
Objectives
The objective of the programme was first of all to develop IMRT that was safe and which could be effectively applied to patients. There was then a need to evaluate the benefits or drawbacks of this treatment in terms of reduced long-term side effects and quality of life, and compare outcomes with results that could be obtained using traditional radiotherapy techniques.
We also needed to evaluate the effects of IMRT on tumour control for more advanced, and potentially more problematic to treat head and neck cancers. We therefore set out to establish a treatment technique that could be replicated and rolled out nationally for all head and neck cancer patients.
Furthermore, we wanted to contribute to the possibility of this technique being implemented internationally. This we aimed to achieve by disseminating the results of our research, teaching and publication in leading medical and oncology journals. The IMRT treatment underwent Phase I and II trials and secured funding for a larger-scale Phase III trial, sponsored by Cancer Research UK (CRUK).
Three randomised phase III trials were established with each trial designed to test for outcomes in relation to a specific side effect.
Solution
The PARSPORT trial was designed to test whether IMRT could reduce long-term dry mouth and involved 94 patients at six UK cancer networks. Half were treated with traditional therapy and the other half with IMRT.
The second trial, COSTAR, again involved a randomised group of head and neck cancer patients, designed to assess whether sparing the cochlea could reduce long-term hearing impairment, another significant side-effort for people undergoing radiotherapy of the parotid glands near the earlobes. Published data suggests that 40-60 per cent of patients in this group experience permanent post-radiation sensori-neural hearing loss.
ART-DECO (Accelerated RadioTherapy—Dose Escalation versus Conventional dose), was the third randomised trial. It aimed to assess whether increased radiation dose to tumours of the larynx could increase local control rate and cure. Specifically it was designed to determine the potential of dose-escalated IMRT to improve loco-regional failure free rate (LRFFR) and laryngeal preservation in patients with locally advanced laryngeal and hypopharyngeal cancers, without increasing the incidence of severe acute and late toxicities to unacceptable levels.
When the results from these above trials were available the team engaged with the radiotherapy community in the UK through collaboration with the National Radiotherapy Implementation Group and the Royal College of Radiologists. Internationally the results of the trials were disseminated through international head and neck cancer research meetings and educational visits.
Results
PARSPORT demonstrated that the incidence of severe dry mouth could be reduced from over 80 per cent to approximately 20 per cent. At 12 months xerostomia side-effects were reported in 73 of 82 surviving patients. Grade 2 or worse xerostomia was significantly lower in the IMRT group than in the conventional radiotherapy group (38 per cent as opposed to 74 per cent). At 24 months the difference was even more marked, at 83 per cent for those given conventional therapy against 29 per cent for those given IMRT.
The trial presented compelling evidence that sparing the parotid glands with IMRT significantly reduces the incidence of xerostomia and leads to recovery of saliva secretion and improvements in associated quality of life.
As a consequence of these results, the Department of Health made a strong recommendation that all cancer networks in the UK offer IMRT for head and neck cancer patients and this has largely been achieved.
Similarly, ART-DECO has progressed to a seven-year phase III trial following highly encouraging outcomes from Phase I&II trials showing a 15 per cent increase in cure rates for laryngo-hypopharyngeal cancers.
The research involved 60 patients with advanced cell cancer of the larynx and hypopharynx who were divided into two groups. These groups received IMRT at different dose levels, combined with chemotherapy. At 36 months, the second level (DL2) of dose-escalated chemotherapy–IMRT delivered high rates of locoregional control, progression-free survival, and organ preservation.
Evaluation
The work to develop and refine IMRT has highlighted a number of areas of learning for the benefit of those involved in oncology care. The research involved a network of centres around the country to take part in the clinical trials. One area of learning is the importance of educating the teams at widely dispersed centres through workshops so they have a better understanding of the objectives.
The research also highlighted the importance of having a solid foundation of evidence in developing new techniques of treatment. Most care professionals would agree that organising a randomised trial is a daunting task, but the development of IMRT owes its success to the rigour of the research behind the programme.
While PASPORT has been seminal research, work on refining IMRT has been ongoing. Plans include developing and testing molecular-imaging-guided radiation dose escalation to targets of relative radio-resistance such as hypoxia and proliferation.
To further improve the delivery of radiotherapy, a current research project involves using the database of acute and late reactions together with dose-volume information to determine the predictors of toxicity and generate hypotheses to further optimise treatment planning.
Another area of development is further refinements in tumour and normal tissue imaging.
Impact
IMRT is now being used worldwide thanks to our ground-breaking research which has demonstrated its clear benefits in reducing debilitating side-effects and improving quality of life. In the UK, the technique is now used routinely following a recommendation by the Department of Health. Worldwide it is estimated that 600,000 patients suffer with head and neck cancer, and it is estimated that because of the dissemination of the technique, 300,000 of them are benefitting from IMRT.
In areas where head and neck cancer is particularly prevalent, for example in China, Asia and the Indian sub-continent, these treatments are now widely available.
IMRT for head and neck cancer has been found to be highly cost effective with an estimated cost-per-QALY (quality adjusted life year) of under £1,000.
The reduction in long-term side effects and improvement in quality of life mean that it is also highly effective socio-economically, allowing patients a better chance of returning to normal work and life following treatment.
IMRT has also made a difference across a wide range of cancer treatments and is currently used to treat cancers such as prostate, breast and some types of brain tumours, in addition to head and neck cancers.
