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The latest generation of radiotherapy devices are delivering focused X-rays precisely on the target cancer tumour

Developments in intensity-modulated radiotherapy, now delivered by revolving arms in an arc, allow a higher dose of radiation to be concentrated on tumours without increasing the toxicity of neighbouring tissue, thus cutting side-effects

Dr Tom Roques
Consultant clinical oncologist and clinical director for oncology and haematology

Dr T.V. Ajithkumar

Norfolk and Norwich University Hospital NHS Foundation Trust England, UK

Radiotherapy – the therapeutic use of high energy X-rays to destroy the DNA of cells in their path – is a potentially curative treatment modality for any cancer that remains localised to one area of the body. A better appreciation of cancer biology and improvements in hardware and software of the linear accelerators that produce the X-rays have revolutionised radiation therapy over the last two decades.
From a combination of 1-4 rectangular- shaped beams chosen on the basis of bony anatomy on 2-D images, radiotherapists are now able to define the complex 3D tumour volumes on a CT scan as well as delineating possible sites of spread and the adjacent critical organs which need to receive a limited radiation dose if long- term damage is to be avoided. One of the key tools for the 21st century oncologist is IMRT – intensity modulated radiotherapy.
IMRT has been in clinical use for more than a decade. It provides a precise and targeted dose of radiation to conform to the size and shape of a complex-shaped tumour while optimally sparing adjacent healthy tissue, so reducing side-effects.
One of the most elegant ways to achieve this is to move a gantry of 5mm pieces of radio-opaque lead (a multi-leaf collimator, MLC) across each beam while it is on. By varying the position and speed of the MLC leaves, a complex dose map can be produced by each beam. If several beams are combined, it becomes possible to treat complex, concave shapes with radiation while relatively sparing nearby healthy tissues.
IMRT is being increasing utilised as an innovative tool for treating cancers that have traditionally been difficult to target because of their nature and proximity to crucial structures within the body, such as cancers of the head and neck or prostate, and those close to the spine. Despite the challenges of cost of implementation, IMRT is being rapidly adopted by many radiotherapy centres on the basis of computer planning studies showing better tumour volume coverage and sparing of radiotherapy dose to critical structures compared with conformal radiotherapy.
For a long time, the controversy continued as to whether the dosimetric advantages of IMRT really translated into relevant clinical benefits, though there is now increasing evidence in support of this. There remains a lack of outcome data to support calculations into the cost-effectiveness of IMRT, which is mainly used in three situations:

1. Minimising dose to critical organs to avoid long-term radiation toxicity
Cancers of the mouth, throat and larynx lie close to a number of critical structures such as parotid and submandibular salivary glands, the swallowing musculature, optic apparatus, brain stem and spinal cord. The long-term side-effects of radiotherapy to these structures will lead to significant compromise on quality of life from a dry mouth to potential spinal cord damage.
But many head and neck cancers are curable with radiation (usually combined with chemotherapy) without the need for potentially mutilating surgery. Head and neck cancers are, therefore, an ideal tumour site for investigation of IMRT as a means of reducing radiation side-effects.
IMRT has been used extensively used for certain head and neck sub-sites such as naso­pharynx and oropharynx. Studies show that IMRT results in higher and faster recovery of simulated salivary flow and that xerostomia-related variables of quality of life are significantly better with IMRT. The benefit of IMRT in terms of overall and disease-free survival remains to be proven.

2. Delivering a higher dose of radiotherapy (‘dose escalation’) without increasing toxicity of adjacent normal organ
In prostate cancer there is a clear relationship between cancer control and radiation dose above 68Gy. IMRT is being used in prostate cancer, mainly to increase the dose to the cancer without causing significant toxicity to adjacent structures such as the bladder and rectum. Studies show that IMRT results in less risk of late gastrointestinal toxicity. Quality-of-life studies have also shows significant positive outcome, suggesting that better physical dose distribution will lead to fewer side-effects and better quality of life.

3. Repeating curative radiation to same site
It has been radiotherapy dogma that curative doses can only be given once to any body site, but very precise re-irradiation with IMRT (eg in head and neck cancers) has been shown to be effective in curing second cancers while limiting radiation damage to acceptable levels.

Challenges of IMRT
Although IMRT doses can be given very accurately to complex stationary targets on a CT scan, the movement of the patient and individual organs between or during fractions of treatment are important concerns. Radiation dose falls steeply over a small distance from the tumour in IMRT, consequently patient and organ motion can result in significant over- or under-dosage potentially causing increased normal organ toxicity and tumour recurrence respectively.
Various techniques are being investigated to address the issue of potential errors in tumour position. Respiratory gating enables the radiation beam to be selectively turned on during certain phases of respiration. 4D CT scanning allows the targets to be defined throughout a movement cycle on different sets of CT images. Image-guided radiotherapy (IGRT) uses imaging technology at the time of each treatment to verify accurate position.
A number of image-guided systems are in use, such as implantable gold seeds to verify the position of the prostate gland, and cone beam CT to enable a CT scan to be taken on the treatment machine before the day’s dose is delivered. Ideally, an adaptive radiotherapy system would be able to re-optimise the treatment plan on a daily basis depending on the relative positions of the tumour and critical organs.
The delineation of the target volumes based on clinical examination as well as optimal imaging modalities continue to be challenging and is arguably the weakest link in the process. More accurate definition of the tumour may avoid geographical misses of tumour outside the precise IMRT dose envelope or may enable smaller target volumes to be defined that can receive higher doses of radiation leading to increased cure rates. MRI images can be fused with the radiotherapy planning CT to allow more accurate target volume definition in the brain or pelvis.
Functional/molecular imaging is increasingly being incorporated into routine clinical practice. For example, FDG-PET is of proven benefit in staging lung cancer accurately but has also been used to define more accurate radiotherapy volumes. Functional/molecular imaging holds the promise of being able to select subvolumes of tumour which are more metabolically active to increase the dose to these regions and achieve maximum chances of tumour control – so called ‘dose painting’. However, most of these techniques are still in the experimental stage.
Although IMRT focuses precise high doses of radiation, it also leads to more tissues receiving a low dose than conventional treatments. The potential long-term carcinogenic risks of IMRT on adjacent tissues remain unknown and mandate careful follow-up of patients.

New techniques to deliver IMRT
Norfolk and Norwich University Hospital (NNUH) remains one of the few UK hospitals to offer IMRT in routine practice. It also uses portal dosimetry to verify the radiation dose for each patient rather than relying on more time-consuming ion chamber measurements. At one stage, it was one of only two centres in the world to use this.
A number of measures are in place in NNUH optimise tumour delineation. We work closely with our radiologists who are expert at looking at images to help us define the volume to be treated. Further research is being planned to evaluate co-registered PET/CT-planning CT scans and to incorporate fused MRI-CT images in more treatment sites.
Volumetric modulated arc radiotherapy (VMAT) is a novel method of delivering IMRT that combines 3D volumetric imaging and IMRT with arc treatment delivery. Not only do the MLC leaves move while the beam is on, but the linear accelerator gantry revolves around the patient enabling treatment with one two arcs rather than 5 or 7 stationary beams. Leading university hospitals in Germany and Switzerland (Gottingen and Zurich) have recently begun to use RapidArc IMRT for head and neck cancers. NNUH will be start treating similar patients with RapidArc in early 2010 before rolling out both VMAT and IGRT to other tumour sites.
The physics and imaging advances in radiotherapy hold the promise of extremely high-precision IMRT delivered quickly to complex tumour volumes. The challenge is to incorporate our evolv­ing knowledge of tumour biology to make sure that we really are targeting the cancer cells which need to be hit while sparing nearby tissues from the consequences of late radiation damage.