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Phase I/II studies of IMRT in thyroid,
larynx, hypopharynx cancer
Larynx/hypopharynx
In treatment of cancer occurring in the neck using current
radiation techniques, radiation dose is limited by both acute and
late side effects. In this throat cancer treatment, the dose-limiting structures are the spinal cord
and the oesophagus. The dose to the target volume sometimes has to
be compromised in order to prevent late spinal cord damage. The acute
side effects of cancer chemotherapy as a throat cancer treatment are dominated by effects of radiation on the skin and
mucous membranes, which lie close to the target volume.
For patients with advanced cancer of the larynx and hypopharynx, the
anatomical position of the tumour and regional lymph nodes relative
to the spinal cord preclude delivery of radiotherapy in a single phase,
and requires the matching of photon and electron fields around the
spinal cord (Nutting et al 1999 BJR). The matching of photon and electron
fields may lead to inhomogeneities in radiotherapy dose close to the
tumour or lymph nodes in the neck. These areas of dose inhomogeneity
may, at least in part, be the cause of local recurrence of tumours
of this region. Using IMRT, this treatment volume can be delivered
in a single phase without the need to match photons and electrons
(Nutting et al R&O submitted). The resultant dose distributions
are more homogeneous and should give a higher chance of tumour control.
Additionally, single-phase treatment with IMRT should require less
treatment planning time and be delivered faster than conventional
radiotherapy improving the efficiency of radiotherapy delivery.
Thyroid
For patients with thyroid cancer considered at high risk of loco regional
recurrence after thyroidectomy, external beam radiotherapy is used,
sometimes in addition to radio-iodine. With present radiotherapy techniques used for throat cancer treatment,
32% do not obtain a complete response (CR), and of those obtaining
CR 39% relapse within the radiation portals especially in the thyroid
bed. Techniques that enable safe dose escalation to the thyroid bed
and or nodal areas may be able to improve local control. We have performed
a radiotherapy planning study of thyroid irradiation. This has shown
that the maximal spinal cord dose can be reduced, so that the dose
to the thyroid bed can be escalated above the standard dose of 60Gy,
and possibly to doses of 65-68Gy. Moreover the coverage of the thyroid
and node target volume is also significantly improved with IMRT (Nutting
et al. R&O 2001;60:173-180). This project is to test the
feasibility of delivering these novel radiotherapy techniques to
patients, and to perform a phase I/II dose escalation study to assess
the effects on tumour control, acute and late side effects of increasing
the radiotherapy dose. Once the safe level of dose escalation has
been established, then the new techniques cancer chemotherapy and radiation will be compared to standard
therapy in a randomised trial. The rarity of these tumours necessitates
multi-institution collaboration, and we hope to recruit other radiotherapy
centres in the UK and Europe to these trials when they develop the
capability to deliver IMRT. In parallel to the clinical study, information
regarding treatment times and planning will be collected and compared
to conventional treatment methods.
Integration of Imaging into radiotherapy
planning/new targets
- MRI to define tumour and normal tissue structures
MRI planning for head and neck neck or throat cancer patients with tumours attached
to the skull base is being investigated in a clinical study. Target
volumes and organs at risk segmentation based on CT images are
compared to fused MRI and CT images. This project will expand
to incorporate the use of contrast media, and then the assessment
of nodal targets in the neck using the ultrasmall paramagnetic
iron oxide contrast media. The identification of involved nodes
by this imaging technique as part of cancer treatment will develop complex targets which will
be most optimally treated with IMRT.
- PET/CT for target definition and staging
The benefits of structural imaging can be enhanced by the addition
of functional imaging. In head and neck and throat the use of FDG
PET has been shown to add additional information to structural
images, and the instalation of a PET/CT at the RMH in mid 2003
will allow the assessment of this technique. In the future it
is hoped that the use of hypoxia imaging agents will allow the
generation of new targets for dose escalation, and that these
targets would be treated with integrated boosts using IMRT. The
development of these new imaging techniques is paramount to the
potential of IMRT to optimise purposefully inhomogeneous dose
distributions.
Phase III study of parotid-sparing IMRT
in head and neck cancer
This randomised trial of parotid sparing IMRT aims to investigate
the ability of this new technology to reduce xerostomia and increase
quality of life in head neck and throat cancer patients. The study includes
two European and five UK centres. The end points are patient-assessed
salivary toxicity (primary end point), measured salivary flow, quality
of life, local control, survival, acute and late side effects (secondary).
Statistics and sample size calculation is based on the published
data from the University of Michigan. This has shown a reduction
in xerostomia in head and neck cancer patient treated with IMRT
[Eisbruch et al 1996 and 1998]. The results of this study, compared
to standard outcomes are shown below.
| Technique |
Reduction
in salivary flow rate (cf pre-RT levels) |
| Conventional radiotherapy |
90% |
| IMRT |
40% |
In order to detect a 50% difference between the two study groups
with 90% power, and one-sided p value of 0.05, the minimum sample
size would be 17 patients in each group. If the difference between
the two groups were 40% or 30%, the corresponding patient numbers
in each arm would be 27 and 48 respectively. We would therefore
aim to recruit a total of 80-100 patients between the participating
centres, with a planned interim analysis after 60 patients have
been recruited.
The entry criteria for the study include patients with squamous
cell carcinoma of the head and neck region undergoing radical radiotherapy,
where the clinician anticipated that there was a high risk of radiation-induced
xerostomia. This will include patients with tumours of the oro-pharynx,
and hypo-pharynx, where the irradiated volume encompassed both parotid
glands, and the patient was at high risk of xerostomia.
References
1. Eisbruch A, et al. Parotid gland sparing in
patients undergoing bilateral head and neck irradiation: Techniques
and early results. Int J Radiat Oncol Biol Phys 1996;36:469-80
2. Eisbruch A, et al. Comprehensive irradiation
of head and neck cancer using conformal multisegmental fields: Assessment
of target coverage and non-involved tissue sparing. Int J Radiat
Oncol Biol Phys 1998;41:559-568
3. Ship JA, et al. Parotid sparing study in head
and neck cancer patients receiving bilateral radiation therapy:
One year results. J Dent Res 1997;76:807-813
4. D’Hondt E, et al. The influence of pre-radiation
salivary flow rates and radiation dose on parotid salivary gland
dysfunction in patients receiving radiotherapy for head and neck
cancers. Special Care in Dentistry 1998;18:102-108
Immobilisation assessment, development
of new frame system
Clinical studies to assess accuracy of present immobilisation systems
in head and neck cancer are ongoing. We have designed and built a
new head and neck immobilisation frame based on a bite block which
will allow a full range of beam orientations to the patient without
the use of the thermoplastic shell.
Portal imaging with low Z beams
The delivery of safe high-dose radiation to patients with head and
neck cancer requires the patient to be reproducibly immobilised each
day for a course of treatment lasting for 4-6 weeks. In radiotherapy
we are constantly striving to increase the accuracy and quality of
radiation delivery and verification. During treatment portal images
are taken to ensure that the radiation beam is correctly positioned.
The high energy of therapy radiation makes portal images difficult
to interpret due to the lack of definition of high and low molecular
weight structures (e.g. bone vs soft tissue). This project assesses
the use of a low energy radiation beam to improve the quality of portal
images, to give better definition between bone and soft tissues and
should increase the accuracy of quality control in head and neck radiotherapy.
The main aim of project is to investigate in patients the degree of
improvement in portal images possible with low-energy therapy photons.
This is an observational study of 20 patients with head and neck/throat cancer.
Patients undergoing radiotherapy treatment will have a low energy portal image
as well as conventional portal image taken during treatment sessions.
This will be done daily during the first week and weekly thereafter
as is our standard practice. Clinicians and radiographers will score
the quality of the portal images using a quantitative assessment scale
of 0-10. The observer will be blinded to the method used to obtain
the image to avoid bias. Scores of quality of portal images will be
collected. Paired non-parametric analyses will be used to compare
the scores for each pair of portal images, i.e. the low energy vs
6MV image.Statistics: Images of 20 patients will be adequate to assess
if improvements in quality of portal images are significant. A pilot
study of images from a humanoid phantom has shown a 50% increase in
clinician scores of image quality. Patients will have an additional
image taken of their treatment fields. This will take about 2 minutes
of their time and may lead to an improvement in treatment accuracy.
The additional radiation dose has been estimated at 0.5cGy (i.e
approx 0.001% of the total radiotherapy dose). This will be performed
up to 5-10 times during a six week course of radiotherapy treatment.
Voice preservation and dose escalation.
What are the components of a successful voice preservation strategy
in larynx cancer? This study will evaluate voice characteristics before,
during and after radiotherapy to quantify the characteristics of successful
voice preservation. The aim is to correlate the voice characteristics
with technical details of larynx irradiation to assess the organs
at risk for voice preservation strategies. This is a key element of
dose escalation studies
Assessment of other sites, optimisation
in head and neck
The assessment of other sites in the head and neck region is important
in selecting further sites for clinical IMRT investigation. These
include parotid gland-sparing total mucosal irradiation, oral cavity
irradiation, oropharyngeal (including tongue base) irradiation, paranasal
sinuses, minor salivary glands.
Chemo IMRT/biologicals (EGFR)
Radio-inducible promoters in head and neck cancer
Gene Therapy approaches to head
and neck cancer
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