Trial Information

A Pilot Study Evaluating Minimized Time to Beam Hypofractionated IMRT With PET-Assisted Target Definition in Patients With High Grade Gliomas

A Pilot Study Evaluating Minimized Time to Beam Hypofractionated IMRT with PET Assisted
Target Definition in Patients with High Grade Gliomas

BACKGROUND INFORMATION Standard Treatment High grade gliomas (HGG) comprise the vast
majority of primary brain tumors. With conventional treatment, tumor recurrence and
subsequent patient death is expected in all but a small minority of patients. Conventional
treatment consists of maximal surgical debulking followed by radiation therapy (RT) and
temozolomide (TMZ) chemotherapy. Typically the radiation therapy is given in 2 Gy fractions
to a total dose of 60 Gy to the planning target volume (PTV).

What is the Optimal PTV? Currently it is not know what target volume constitutes the optimal
PTV for an individual patient with a HGG. With conventional MRI-based target definition, a
common practice is to draw a gross tumour volume (GTV) to include the contrast enhancing
lesion seen on T1C images. An additional uniform margin of approximately 1.5 cm is added
to address clinically occult glioma cells and create the clinical target volume (CTV), plus
an additional 0.5 cm to create the final PTV. This practice is based on pattern of
recurrence studies. In these studies, 80-90% of the HGGs tended to recur within 2 cm of the
original T1C enhancing lesion. The addition of a uniform 2 cm margin to the initial GTV
dramatically increases the volume of apparently normal brain irradiated, and the volume of
brain irradiated is a principal determinant of subsequent radiation toxicity. By using
positron emission tomography (PET) imaging to better characterize which regions harbour
glioma cells, we hope to be able to minimize the size of the uniform margins applied to the
GTV, and thus produce a more optimized PTV for each patient.

PET Imaging For this pilot study we will be using novel PET agents including F19AZA and C11
Methionine to assist in the construction of a more patient optimized PTV. The volumes
constructed based on MRI reflect the underlying anatomy or structure of the tumor. On the
other hand the volumes constructed base on PET imaging reflect the underlying physiology and
thus will be referred to as the biological target volume (BTV) to distinguish it from the
MRI base GTV. The clinician will then use the complementary information provided by the GTV
and BTV to construct a composite CTV, and this will be grown with a uniform 0.5 cm margin
into the PTV. The PET imaging will be carried out under a separate research protocol
submitted by nuclear medicine, and the patient will need to sign an informed consent for
each agent used. At the investigators discretion, the patient will be given the choice to
undergo imaging using the full complement of PET agents or a selected subset of these
agents.

IMRT 3D conformal RT (3D CRT) is the standard treatment technique used to treat HGGs at many
centres. With the advancement of IMRT techniques, clinicians are able to deliver more
sophisticated RT plans. With these more sophisticated approaches clinicians should be able
limit the volume of apparently uninvolved brain encompassed in the high dose treatment
volume. In our recent protocol we gained experience using helical tomotherapy-base IMRT.
In the current protocol, we plan to use Linac-based IMRT. One of the advantages of
Linac-based IMRT over helical tomotherapy is that the plan may include non-coplanar beams.
This additional degree of freedom is expected to result in better plan conformation. Also,
Linac-based IMRT plans can be added to the conformal plan of phase I and thereby adjusted
accordingly.

Overcoming Radio-Resistant Tumor Clonogens In this protocol we plan to use hypofractionated
RT (60 Gy in 20 fractions over 4 weeks). Hypofractionation has the advantage of shortening
the overall treatment time (which minimizes the opportunity for tumor repopulation during
the treatment course). The larger dose per fraction is also expected to be more
biologically effective against radio-resistant tumor clonogens. An identical fractionation
scheme was reported to be safe in a recent study of patients with HGG (IJROBP 58 1 247-252
2004 Sultanem) and a similar fractions scheme was used in our recent glioma protocol 60 Gy
in 22 fractions over 4.5 weeks). As of yet, we have not observed any obvious increased
toxicity in these patients (Personal Observation).

Minimizing Time to Beam HGGs are locally aggressive and rapidly growing tumors. The typical
presenting symptoms are usually related to the mass effect of the tumor on the adjacent and
distant nerve cells. Once the intracranial pressure (ICP) has begun to rise, any subsequent
growth of the tumor within the confined space of the skull results in a dramatic increase in
ICP and subsequent neuron damage (usually permanent). Hence it is imperative that the
initiation of therapy not be delayed. Unfortunately the design of sophisticated IMRT plans
base on advanced imaging technology is a complex and potentially time consuming process.
When treatment is delayed as a consequence of this process, the patient frequent
deteriorates clinically possibly resulting in a permanent decline in quality of life, a
decision to discontinue RT or even death. In this protocol we plan to explore the
feasibility of a combined approach using 3D CRT and IMRT. The first half of the treatment
(2 weeks) will be given using a simple 3D CRT approach based on the patient's preoperative
MRI images. This will have the advantage of facilitating a rapid start of RT and hopefully
arrest any evolving clinical deterioration which may have occurred (minimizing the time to
beam). The goal will be to start the RT as soon as possible from the first OPD visit. The
planning, evaluation and QA of the IMRT plan will progress while the patient is undergoing
phase I of the treatment.

OBJECTIVES

Primary End Point:

1. Time from initial OPD visit to start of RT compared with historical controls receiving
helical tomotherapy base IMRT (Time to Beam)

Secondary End Points:

1. Overall Survival

2. Disease-free survival

3. Patterns of recurrence

4. Toxicity

5. Quality of life

6. Number of patients who complete treatment

STUDY DESIGN

Schema Radiation Therapy Phase I 30 Gy in 10 fractions to PTV1 Using 3D CRT

GTV1 = Intra and peri-tumoural edema seen on preoperative MRI CTV1 = GTV1 + 1.5 cm margin
PTV1 = CTV1 + 0.5 cm margin

Note: The 1.5 cm margin added to create the CTV1 may be reduced at the discretion of the
clinician in areas of anatomical barriers to glioma spread (i.e. skull, tentorium, etc.)

Phase II 30 Gy in 10 fractions to > 90% of the PTV2

GTV2 = Contrast enhancing lesion BTV = Extent of tumor seen on PET imaging CTV2 = (Union
of GTV2 and BTV) + >0.5 cm margin PTV2 = CTV2 + 0.5 cm margin

Note: The margin added to the CTV2 may be enlarged at the discretion of the clinician to a
maximum of 1.5 cm. The dose received by the PTV2 regions which encroach within 3 mm, or
overlap, a dose limiting critical structure should be restricted to the dose constraints
allowed for that particular critical structure. Exceptions may be made at the clinician's
discretion when the dose limiting critical structure is grossly involved by tumor.

Chemotherapy Patients will also be offered standard TMZ chemotherapy, but patients who
refuse TMZ or are unable to tolerate/receive it, may still enroll in the study.

PET Imaging Studies will be done at baseline and post RT (0, 2, 4, 6, and 12 months).

INCLUSION CRITERIA Histopathologically-confirmed grade III or grade IV supratentorial glioma
Age > 18 KPS > 70 No prior radiation therapy to the brain No active prior malignancy Signed
study-specific consent form

EXCLUSION CRITERIA No histopathologically-confirmation of grade III or grade IV
supratentorial glioma Age < 18 KPS < 70 Prior radiation therapy to the brain Active prior
malignancy

RECRUITMENT Number of patients 25 (High Grade Glioma)

STATISTICAL ANALYSIS This is a pilot study comprising a total of 25 high grade glioma
patients.

STOPPING RULES Both acute and late toxicities will be of interest in this study as well as
disease-free survival, patterns of recurrence and quality of life assessments. Patients
will be closely followed by their treating Radiation Oncologist and / or the Research Nurse
and any sever adverse events will be reported to the Principal Investigator and the Research
Ethics Board as per the set REB guidelines.

DATA SAFETY MONITORING COMMITTEE Any serious adverse event that occurs from the time the
consented patient has begun study treatment until 30 days after the end of study treatment
must be reported to the participating institution's Research Ethics Board within their REB
set reporting guidelines. Any SAE that occurs after the one month post study treatment
timeframe that is felt to be related to the study treatment must be reported to the
participating institution's Research Ethics Board within the REB set reporting guidelines.
If a death is related to study treatment, the REB should receive notification within 24
hours of the event, with a full report to follow. All deaths that occur during a study or
within 30 days after last study treatment, regardless of the relationship to the treatment,
need to be reported to the REB. A research nurse and / or a radiation oncologist will be
responsible for regular monitoring of patients on study treatment. If the number of events
meets the stopping criteria listed in point 12.0, accrual will be halted and the Principal
Investigator will inform the Research Ethics Board in a timely manner.