Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT02055859 |
| Other study ID # |
PR-Rt acouneu |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
March 15, 2011 |
| Est. completion date |
May 2025 |
Study information
| Verified date |
February 2021 |
| Source |
Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Most vestibular schwannomas are benign and slow-growing. Based on that fact, conservative
management with serial imaging is a viable alternative. For patients who undergo treatment
because of tumor growth, progressive symptoms, or personal preference, options include serial
observation, microsurgical resection, fractionated stereotactic radiotherapy, and
stereotactic single-session radiosurgery.
Despite improved radiosurgical techniques and lower marginal doses, a recent report has shown
a somewhat disappointing 10-year actuarial hearing preservation rate of 44.5%, with hearing
loss developing as much as 6 years after.
Fractionation of the prescribed dose may takes some advantages from radiobiologic principles
to reduce toxicity and maintain tumor control.
Staged frame-based radiotherapy using a 12-hour interfraction interval was successfully used
at Stanford university and has shown a hearing preservation rate of 77% at 2 years of
follow-up.
The aim of the present protocol is to evaluate the hearing preservation, the local control
and toxicity after single-session (sSRS) or multi-session (3 fractions) radiosurgery (mSRS)
by using the frameless robotic CyberKnife® system (Accuray Incorporated, Sunnyvale, CA, USA).
In order to investigate about this a randomised controlled double harm (sSRS vs mSRS) trial
was designed.
Description:
Single-session radiosurgery versus multi-sessions radiosurgery for acoustic neuromas.
BACKGROUND Most vestibular schwannomas are benign and slow-growing. Based on that fact,
conservative management with serial imaging is a viable alternative.
For patients who undergo treatment because of tumor growth, progressive symptoms, or personal
preference, options include serial observation, microsurgical resection, fractionated
stereotactic radiotherapy, and stereotactic radiosurgery.
There remains some debate as to how best to manage these tumors. Historically, vestibular
schwannomas have been treated with microsurgical resection.
Loss of hearing and facial nerve injury, however, are not uncommon microsurgical
complications. Fractionated radiotherapy was used initially as an adjunct to microsurgery in
patients who had undergone subtotal resection, and it demonstrated the overall effectiveness
of radiation as a treating modality for vestibular schwannomas.
Stereotactic radiosurgery has emerged as a safe and effective treatment modality for
vestibular schwannomas.
The long-term data of stereotactic radiosurgery now support the efficacy of this treatment
modality in term of local control, but the concerns about hearing preservation still remain
debated.
Over the last decade, attention has been directed to improving the hearing preservation rates
following radiosurgery and reducing other treatment-related morbidities.
Initial radiosurgery series reported hearing preservation rates that ranged from 51% to 60%
with significant rates of facial weakness and numbness. Analysis of the more recent data
suggests that an overall hearing preservation rate of approximately 51% can be expected
approaching 3-4 years after radiosurgical treatment, and the analysis reveals that patients
treated with ≤13 Gy were more likely to have preserved hearing than patients receiving larger
doses of radiation. Furthermore, larger tumors and older patients do not appear to be at any
increased risk for hearing loss after SRS than younger patients or patients with smaller
tumors .
Despite improved radiosurgical techniques and lower marginal doses, a recent report has shown
a somewhat disappointing 10-year actuarial hearing preservation rate of 44.5%, with hearing
loss developing as much as 6 years after.
Studies have demonstrated that the total radiation dose to the cochlea is a critical factor
in hearing preservation. Fractionation of the total dose, or staging, however, also may play
a fundamental role. Staging radiation treatments long has been proposed as a means to reduce
the risk of injury to adjacent critical structures such as the brainstem, cranial nerves, and
cochlea.
Fractionation of the prescribed dose may take some advantages from radiobiologic principles
to reduce toxicity while maintaining tumour control.
Aim of the present study is to compare outcome from single and multisession radiosurgery both
in terms of hearing preservation and local control by using the frameless, robotic
CyberKnife® system (Accuray Incorporated, Sunnyvale, CA, USA).
In fact, from a radiobiological point of view, a high local dose of radiation in a single or
a few fractions would produce better tumour control.
On the other hand, limited fractionation could protect the surrounding normal tissues
(cochlea, brainstem, etc.) from injurious levels of radiation. This could improve the
therapeutic rationale for MSRS, especially for large (3 cm) lesions in proximity to critical
organs such as the brainstem or cochlear apparatus.
PRETREATMENT EVALUATION Prior medical history and physical examination. Complete history,
physical examination including a detailed neurological examination and evaluation of
Karnofsky Performance Status (KPS) will be performed.
Any prior surgery, prior radiation therapy and/or radiosurgery of the brain will be recorded.
Prior surgery at the site of the lesion, prior radiation therapy and/or radiosurgery of the
brain will not prevent the patient from participating in the protocol.
Pre-treatment audiograms (pure tone audiometry and speech comprehension) are obtained within
2 months before treatment to document baseline hearing unless anacusis has been documented
previously. Hearing is graded according to the American Academy of Otorhinolaryngology-Head
and Neck Surgery classification A full neurological assessment will be performed before each
treatment. Special attention will be given to the fifth, seventh cranial nerve examination.
Any baseline deficits or palsies will be registered. Trigeminal nerve function is graded on a
semiquantitative scale as normal sensation, decreased sensation, or no sensation (Barrow
Neurological Institute pain intensity score, Barrow Neurological Institute facial numbness
score, BNS).
Facial nerve function is graded on the House-Brackmann (H-B) scale. Patient written informed
consent will be obtained prior any examinations related to the Cyberknife treatment.
RADIOSURGICAL PROCEDURE:
mSRS and sSRS (CyberKnife) Planning All patients initially are fitted with a custom made
Aquaplast mask and thin foam headrest to ensure consistent positioning from the acquisition
of the imaging studies through the radiotherapy treatment. While in the mask, a thin slice
(1.0 mm) high resolution (CT) scan of the entire head is obtained with Scanner.
A thin slice (2 mm) gadolinium enhanced T1 weighted MRI is also acquired. The acquired images
then are transferred to the Cyberknife treatment planning workstation.
The MRI then will be fused to the CT by using the Cyberknife treatment planning software to
create a composite image for tumor localization.
The treating surgeon then manually defines the tumor volumes and critical structures on the
axial images . Although the axial images normally are used for treatment planning, it is
possible to delineate structures on the either the coronal or sagittal images.
It is usually necessary to adjust the windows and levels of the treatment planning CT dataset
to optimize clarity of the bone of the internal auditory canal to improve definition of the
tumor margins. In addition, the cochlea is defined (mandatory).
Once the tumor and critical structures are delineated, inverse planning using the Cyberknife
treatment planning software provides a highly conformal radiotherapy dose that minimizes dose
to the adjacent critical structures The treatment plan is evaluated and selected based on an
analysis of the volumetric dose and the dose-volume histograms of the target volume and the
adjacent critical structures. The number of paths and beams used for each patient varies and
is determined by the selected individual treatment plan.
Planning target volumes The target volume for CyberKnife radiosurgery will consist of the
tumor outlined in the treatment planning software seen on planning CT and/or MRI with 1 mm of
t margin Dose Treatments will be delivered with hypofractionated schedule or single-session
radiosurgery according to randomisation.
The prescription dose will be to the 70 to 85% In radiosurgery the dose will be 11Gy to 13Gy
(median 13 Gy) In fractionated schedule: dose fraction of 6 to 7 Gy will be delivered. The
number of fractions will be 3 Total dose will be 11 to 21 Gy in relation to proximity of
critical organs (cochlea)
PATIENT ASSESSMENTS Evaluation During Treatment Patients will be seen and evaluated during
CyberKnife radiosurgery with documentation of tolerance, including acute reaction.
Evaluation Following Treatment
Patients will be followed as follows:
The neurologic assessment, the contrast enhanced, thin slice (1 to 3 mm) MRI, and the
audiometric evaluation will be performed every 4 months during the first year post-SRS; every
6 months during the 2nd and the 3rd years and then annually. Tumors volume will be always
recorded. A response classification (CR, PR, SD, PD) will be then assigned.
Whenever possible, patients obtain audiograms at the same center to minimize discrepancies
related to technique.
Criteria for Toxicity Toxicity will be graded per the NCI Common Toxicity Criteria version
3.0. Criteria for Local Control Complete response (CR) is defined as the MRI disappearance of
the lesion. Partial response (PR) is defined as 20%, decrease in the volumetric size of the
lesion on MRI, stable disease (SD) as no change in the size of the lesion, and progressive
disease (PD) increase in any volumetric size of the lesion, confirmed at least a the
following two consecutive MRI.
Data Collection Patients will be allocated a number and their data will be collected on a
Case Report Forms. Data will include information from each protocol visit and will be
completed on a timely manner.
STATISTICAL CONSIDERATIONS Randomization procedure The assignment of patients to group will
be performer through randomization. The randomization number will be assigned to each patient
by an independent institution (Dipartimento di Scienze Sanitarie Applicate, Università di
Pavia) using a computer-generated randomization list.
Determination of sample size The sample size is based on the primary endpoint of proportion
of subjects with hearing preservation. Assuming that the proportion of subjects with hearing
preservation is 50% with the standard technique, 49 patients per group are required to
conclude that the experimental technique reaches a proportion of hearing preservation of 77%,
with 80% power and 5% significance level. Allowing for a 10% drop-out rate, a total of 108
patients will be randomized between single and multisession radiosurgery.
Statistical analysis Demographic data (age weight, height) will be summarized by treatment
group. Quantitative variables will be summarized using descriptive statistics suitable for
continuous variables; qualitative variables will be summarized by frequency distribution.
The primary efficacy variable is the hearing preservation proportion, defined as the number
of the treated patients into the classes A and B on the total number of patients.
The analysis will present the difference in the proportion of subjects with hearing
preservation between the two groups after at least 36 months.
Subgroup analysis will be performed for the primary outcome variable and the secondary
efficacy variables. The results will be presented for demographic subgroups (age, sex, prior
surgery dose to the cochlea, volume of the lesions).
The secondary efficacy variables will be local tumour and toxicity (neurological) evaluation
(facial and trigeminal nerve). Associations between neurological scores (BNI, BPS, BNS) and
facial nerve function and MRI measures will be examined using Spearman's rank correlation
coefficient.
Analyses will be performed using Stata version 10 (Stata Corp,College Station, Tex). All
tests will be performed at the 0.05 level of significance.
