Trial Information

Efficacy of Stereotactic Conformal Radiotherapy (SCRT) Compared to Conventional Radiotherapy in Minimising Late Sequelae in Children and Young Adults With Brain Tumours: a Randomised Clinical Trial

1.0 BACKGROUND AND RATIONALE

Brain tumours are the commonest solid tumours in children and with appropriate treatment,
nearly half of them achieve long term cure. Radiotherapy is essential in the management of
a majority of these tumours. Conventional radiotherapy alone or in combination with surgery
and/or chemotherapy in tumours such as optic gliomas, hypothalamic gliomas,
craniopharyngiomas, germ cell tumours, and other low grade tumours achieves excellent long
term control rates ranging from 70 to 95%. However, while the tumour control has been
effective, there have been concerns about treatment related morbidity.

which included cognitive dysfunction in 38%, motor deficit in 25%, visual impairment in 20%,
hormonal dysfunction in 20% and psychological-emotional problems in 14% of the survivors.

It is difficult to ascertain from these reports the exact contribution of each of these
factors and how they interact with each other. Radiotherapy is believed to be at least
partly responsible although its exact role is yet to be quantified. Most of the evidence
regarding post-radiotherapy neuropsychological and cognitive dysfunction is from
retrospective studies involving whole brain radiotherapy.

Neuroendocrine dysfunction is well-documented late sequelae following treatment of patients
with brain tumours. This could either be due to direct involvement of the pituitary
hypothalamic axis (PHA) by the tumour or as a result of surgical or radiation injury to this
region. For tumours not directly involving the PHA, the commonest cause of neuroendocrine
dysfunction is cranial irradiation. PHA region unavoidably receives radiation with whole
brain radiotherapy or if the tumour itself is arising from this region. For the treatment of
tumours adjacent to PHA but not involving it, it may be frequently a part of radiotherapy
planning target volume, which includes the gross tumour and a margin to account for any
microscopic disease and possible daily set up inaccuracies and thus receive significant
doses. The region may also sometimes come in the entry / exit path of radiation beams during
treatment of tumours even away from this region. Radiation induced hormonal abnormalities
are generally dose dependent and may develop many years after irradiation. To reduce the
impact of endocrine dysfunctions on physical, mental and sexual development, it is important
to detect and treat them timely. Early growth hormone replacement is the only way to
minimise growth retardation caused by its deficiency but the treatment is expensive with
significant financial implications, especially in our country. The annual cost of GH
replacement is approximately Rs 200,000.00, which is prohibitive for the vast majority of
the Indian parents as is the cost of LHRH analogues, which is useful to prevent early
epiphyseal fusion and stunted growth in children with post radiation or tumour related
precocious puberty.

1.4 Evolution of Stereotactic conformal radiotherapy (SCRT) Conventional radiotherapy
techniques generally involve the use of 2-3 radiation beams covering the tumour and a margin
of 1-3 cms for any subclinical disease and physical inaccuracies in the daily treatment
delivery. The last decade has seen tremendous technological advances in radiotherapy
planning and accurate treatment delivery. Stereotactic radiosurgery (SRS) and stereotactic
radiotherapy (SRT) techniques involve firm and accurate immobilisation with fixed or
relocatable frames, high precision three-dimensional (3-D) target localisation with
CT/CT-MRI fusion and focused radiation delivery. This is achieved either with a multiple
source cobalt unit (gamma knife) or with multiple arcs using a modified conventional linear
accelerator. Such conventional stereotactic irradiation techniques typically produce
spherical high dose volumes and are therefore suitable only for small spherical lesions. A
majority of the brain tumours considered for radiotherapy however are not spherical and
frequently extend to adjacent structures. To treat large non-spherical volumes with
conventional SRS requires the addition of multiple small spherical high dose volumes
described as multiple isocentre treatment. The overlap of high dose spheres results in dose
inhomogeneity, which has been associated with a higher incidence of radiation induced
complications. It has been previously demonstrated that the optimum way of delivering high
precision localised irradiation to larger non-spherical targets is with the use of multiple
conformal fixed fields with individualised shielding of each radiation field conforming to
the shape of the target. This principle of conformal therapy combined with the precision of
stereotactic localisation and focused radiation delivery is described as stereotactic
conformal radiotherapy (SCRT).

Traditionally, stereotactic irradiation has been delivered in a one session as single
fraction radiosurgery. High doses of radiation given in one fraction are known to be
associated with a high risk of radiation induced damage to normal tissue and this is
particularly true for the central nervous system. Giving radiation in small individual doses
allows the delivery of higher radiation doses without serious injury to the normal tissues,
which is especially important for normal CNS structures. Single fraction SRS has been shown
to be associated with considerable neurological toxicity to the optic apparatus the cranial
nerves and normal brain. With the application of high precision relocatable non-invasive
means of immobilisation, it has become possible to deliver stereotactic irradiation in a
fractionated manner. The technique of SCRT combines the precision of focused radiation
delivery and the radiobiological advantages of fractionation. It also ensures homogenous
dose distribution within the irradiated volume further reducing the risk of damage.

The basic aim of high precision SCRT is to achieve a high dose differential between the
tumour and the surrounding normal tissues. This allows for either an increase in the tumour
dose to improve local control or for a potential decrease in radiation damage to the normal
tissues. Further optimisation of the technique involving 3-4 conformal non-coplanar field
arrangement has shown a significant dose reduction to the normal brain. Preliminary
experience, mainly in adults has shown this technique to be feasible during the routine
practice of a busy radiotherapy department. Early results in terms of local control are
same as that with conventional radiotherapy, with an increased sparing of the surrounding
normal brain and adjacent critical structures. While the experience is limited in young
children, a few reports have suggested it to be feasible in this population also. The
technique has the potential to minimise the dose to any critical site close to the tumour
like pituitary-hypothalamic complex, cochlea, brain stem, optic apparatus and the mesial
temporal lobes, which are believed to be the common sites of radiation injury leading to
late morbidity.

NEED FOR THE PRESENT STUDY The finding of significant long-term effects in a large
proportion of brain tumour survivors mandates the development of treatment strategies
designed to minimise their impact on the quality of life. Although the precise role of
radiotherapy in the causation of various post treatment sequelae is not established, it is
generally believed to be at least partly responsible for these effects. There have been
attempts to modify the management in terms of avoiding, delaying radiotherapy or reducing
the total radiation dose to the tumour with a view to reduce its impact on the long-term
toxicity. However, reduction of radiotherapy doses to the tumour has been shown to result in
poorer local control rates. Also, a majority of the patients in whom the radiation is
delayed eventually do require radiotherapy at later stages (37). There is also evidence that
radiotherapy given upfront yields superior disease control than radiotherapy given at the
time of tumour progression (38,39). In light of this data, there is therefore, an
ever-increasing need to explore techniques of radiotherapy minimising the irradiation to the
normal brain and critical structures without compromising radiotherapy doses essential for
tumour control. SCRT is a modern high-precision radiotherapy technique, which reduces the
volume of normal brain irradiated and has the capability to minimise the doses to critical
structures.

The evidence of long term effects of focal irradiation so far is from retrospective studies
and a few small prospective trials. There is therefore, a great need to evaluate this issue
in a prospective manner in a large number of patients. The present study is designed to
prospectively estimate the incidence and severity of neuropsychological, cognitive and
neuroendocrine dysfunction following radiotherapy delivered with conventional and
stereotactic techniques and would be one of the most comprehensive studies providing very
important longitudinal and reliable data regarding these sequelae. The study involving 200
patients would be to the best of our knowledge not only the largest ever study conducted so
far but also the only randomised trial assessing these sequelae in patients receiving focal
brain irradiation.

The study also examines whether the physical advantages of modern technological progress
translate in clinical benefit. This could have significant implications in the
radiotherapeutic management of children and young adults with brain tumours. The study is
unique in design in terms of evaluating the efficacy of SCRT with respect to conventional
radiotherapy in terms of long term tumour control and treatment related complications.

If the present trial succeeds in reducing the incidence and severity of radiotherapy related
sequelae by SCRT technique, it would undoubtedly result in a tremendous benefit to these
patients. A possible reduction in the neuroendocrine sequelae not only will improve the
quality of life of the patients but would also result in major financial saving. This is
critical in patients living in the developing countries where the cost of endocrinological
management in terms of hormonal assays and their replacement is largely prohibitive.

We have until Januray 2009 accrued 128 patients so far in the trial