Trial Title:
Hypofractionated Protontherapy in Chordomas and Chondrosarcomas of the Skull Base
NCT ID:
NCT05861245
Condition:
Chordoma
Chondrosarcoma
Conditions: Official terms:
Chondrosarcoma
Chordoma
Conditions: Keywords:
Skull base
Protontherapy
Hypofractionation
Chordoma
Chondrosarcoma
Study type:
Interventional
Study phase:
N/A
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Radiation
Intervention name:
5-fraction hipofractionated protontheray
Description:
The therapeutic schemes that will be proposed to patients based on clinical criteria such
as tumor size and relationship of the tumor with adjacent critical organs are:
- For chordomas: 37.5 Gy in 5 consecutive sessions of 7.5 Gy per fraction.
- For chondrosarcomas: 35 Gy in 5 consecutive sessions of 7 Gy per fraction.
Arm group label:
Skull base chordomas and chondrosarcomas
Summary:
The project is planned as a phase II clinical trial with a low level of intervention, for
the prospective evaluation of the clinical results of radical or adjuvant treatment by
proton therapy in chordomas and chondrosarcomas of the skull base using hypofractionation
schemes in 5 fractions, with the aim of consolidating the scientific evidence that exists
with high-precision techniques with photons, increasing this evidence by adapting this
treatment scheme to the proton technique.
In addition, a cross-sectional prospective evaluation of the quality parameters of the
dosimetry of hypofractionated proton therapy and an evaluation of the quality of life of
these patients will be carried out.
- Primary Objective
1.
- Toxicity according to CTCAE-v5 criteria
2.
- Local control determined by Magnetic Resonance with Gadolinium.
- Secondary Objectives
1. To evaluate the quality of life of the patients, 3 months after the end of the
treatment, using a specific questionnaire.
2. To evaluate the dosimetric benefits using techniques that allow an improvement
in the dose gradient, improving the coverage of the CTV (Clinical Tumor Volume)
and decreasing the dose in surrounding risk organs.
Detailed description:
Chordomas are rare, slow-growing tumors that develop from remnants of the embryonic
notochord in the clivus, sacrococcygeal region, and mobile spine. Although the frequency
of distant metastases is low, these tumors are locally aggressive and have an extremely
high local recurrence rate. Similarly, chondrosarcomas have a potential for slow growth
with a tendency to recur locally. They usually arise at the base of the skull or spine
from mesenchymal cells or from the primitive cartilaginous matrix.
Although chordomas are considered clinically more aggressive than chondrosarcomas, their
tendency to settle in similar anatomical locations and the high risk of local recurrence
of both diagnostic entities have conditioned a similar therapeutic approach.
Standard treatment includes surgical resection that is as radical as possible; however,
complete resection is feasible in less than 50% of cases, as it can be associated with
significant postoperative morbidity and mortality, since these tumors frequently invade
or contact critical structures (vascular, cranial nerves or spinal roots). Therefore,
adjuvant or exclusive irradiation have a fundamental role in long-term local control.
Therefore, optimization of the efficacy of radiotherapy represents a critical step in the
management of these patients. Given their tendency to local recurrence, chordomas require
the prescription of high doses for their local control, which are associated with
potentially critical adverse effects if conventional photon irradiation techniques are
used.
The α/β ratio, according to the linear-quadratic model, represents a measure of the
sensitivity of a tumor to variable dose-per-fraction regimens. Tumors with a low
coefficient (<4 Gy) are considered more sensitive to the effects of hypofractionated
treatments, which involve the administration of higher irradiation doses per session in
fewer sessions.
After analyzing historical studies and institutional experiences, different publications
suggest that the α/β ratio of chordomas is 2.45 Gy and it is assumed to be very similar
for chondrosarcomas. Therefore, the administration of hypofractionated schedules could be
associated with an increase in the sensitivity of these tumors to radiotherapy treatment.
Conventional normofractionated radiation therapy administered adjuvantly after resection
has historically been used with median doses of 60 to 66.6 Gy to 2 Gy per fraction,
offering 5-year local control rates ranging from 23% to 50%. Technological advances in
the field of image-guided intensity-modulated radiotherapy have led to an improvement in
the precision of treatments, allowing the dose for chordomas to be scaled up to 76 Gy
(the biological equivalent dose (BED) taking into account the α/ β of 2.45Gy is 138 Gy)
and for chondrosarcomas up to 70 Gy (BED of 127 Gy), achieving and improvement in 5-year
local control rates of 65% and 88%, respectively for each diagnostic entity.
Although promising, the use of high-dose photons is limited by the lower ability to
protect nearby critical organs. Therefore, particle therapy (protons and carbon ions) has
established its role as a standard technique, due to its potential to achieve greater
conformation and better dose distribution. The main studies with proton therapy for these
tumors appear to show statistically significant results in favor of increased survival
when dose escalation above 70 Gy to 2 Gy per fraction (BED >127 Gy) is compared with
techniques using irradiation with intensity modulated photons (IMRT). The 5-year local
control rate is above 60% for chordomas and above 80% for chondrosarcomas with moderate
toxicity and preservation of critical structures. However, the limited availability of
these facilities together with the administration of very long treatment schedules, often
of seven weeks or more, poses a significant problem for patients and remains an obstacle
to the widespread adoption of this technique as a therapeutic standard.
Due to all these limitations and the important advances in terms of precision and dose
distribution, the concept of hypofractionation has gained weight within radiation
oncology thanks to its potential benefits in terms of reducing the duration of treatment
and costs. The first publications on the hypofractionated treatment of chordomas, mainly
of the skull base, go hand in hand with photon radiosurgery systems, using dedicated
equipment such as the GammaKnife or CyberKnife. In the last 15 years, single-dose or
hypofractionated treatment schemes have been explored as a therapeutic alternative to
escalate the dose, improve the protection of organs at risk and reduce treatment time.
Some studies have evaluated single fraction stereotactic radiosurgery (SRS) in the
management of chordomas and chondrosarcomas mainly located in the skull base with results
comparable to proton therapy. The most relevant studies included series of 22 to 71
patients treated with median doses of SRS ranging from 12.7-24 Gy (BED 78.5-259 Gy).
Five-year local control rates ranged from 21-85%, depending on the doses prescribed
(higher doses, ≥15 Gy, were associated with better relapse-free survival).
However, based on the experience of Kano et al., for single-dose treatments, irradiation
of volumes > 7 cc is associated with a significant worsening of tumor control. It is
essential to emphasize that the tumor volumes that are usually treated in chordomas and
chondrosarcomas, both at the base of the skull and, to a greater extent, in the spine,
exceed, in most cases, 7 cc, since the entire clivus or affected vertebral bodies must be
included in the majority of cases, in order to reduce the risk of marginal recurrence.
For this reason, the role of single-dose radiosurgery loses weight in favor of
hypofractionated stereotactic radiotherapy (HFSRT), which has theoretical advantages
compared to single-dose treatment in volumes greater than 7 cc, including a lower risk of
radiation-induced toxicity in nearby critical structures and the possibility of safely
treating larger tumor volumes with multiple fractions (usually 5).
Several publications evaluate HFSRT for chordomas and chondrosarcomas. The number of
cases included in these series ranged from 9 to 24 patients. The median follow-up was 24
to 46 months. Most patients were treated with 5 fractions with a prescription dose of
24-43 Gy (BED 52.7-194 Gy), depending on histology and therapeutic setting (radical,
adjuvant, or reirradiation). The best local control results at 3 and 5 years obtained
were 90 and 60% for chordomas, respectively, and 100% for chondrosarcomas. The most
widely used regimen was 37.5 Gy in 5 fractions of 7.5 Gy (BED 152.3 Gy equivalent to 80
Gy at 2 Gy per fraction) for chordomas and 35 Gy in 5 fractions of 7 Gy per fraction in
Chondrosarcomas (BED of 135 Gy equivalent to 74 Gy at 2 Gy per fraction). The toxicity
described in most of these studies does not register worse data than those published with
conventional fractionation in proton therapy, when it comes to primary treatments.
This growing evidence, which is described as a justification for the implementation of
hypofractionated regimens, demonstrates that the standard implementation of these
therapeutic modalities in patients who meet the appropriate characteristics can suppose a
great advantage to improve accessibility and comfort for patients, potentially reduce
acute side effects during treatment and increase therapeutic cost-efficiency.
Proton therapy, today, remains a limited resource, with only 99 facilities currently in
operation worldwide in 2021, of which two new centers are in Spain, active since 2020. In
addition, many patients must travel to access to this technology, so reducing the time a
patient is away from home and their support network can have significant financial and
psychosocial implications. Added to all this are the aforementioned radiobiological
advantages of high doses per fraction, in tumors with a low α/β coefficient, such as
chordomas and chondrosarcomas. That is why the implementation of hypofractionation within
proton therapy has gained weight in the last 10 years, increasing the number of
publications in this regard, which reflects the interest in this treatment approach.
Cao et al. presented a dosimetric study comparing different hypofractionated stereotactic
treatment schemes in the treatment of intracranial tumors > 3 cm in greatest diameter.
Treatment plans with GammaKnife, Cyberknife and VMAT were generated compared with proton
therapy plans with or without modulated intensity. The authors suggest that proton
therapy represents a desirable alternative to advanced photon techniques for treating
large, irregularly shaped volumes near critical structures, such as chordomas and
chondrosarcomas.
For all these reasons, a fundamental and necessary challenge today consists of increasing
the scientific evidence of hypofractionated schemes in the treatment of chordomas and
chondrosarcomas, adapting them to protontherapy, to increase clinical experience and
combine the benefits of high-precision hypofractionated treatments to the dosimetric
advantages of protontherapy (ability to treat volumes > 7 cc with a homogeneity index
close to 1 and a decrease in the integral dose in healthy tissue).
In summary, considering the growing scientific evidence available from other studies on
different therapeutic entities, we have a solid basis to reinforce hypofractionation
protocols with protontherapy in the treatment of chordomas and chondrosarcomas.
The research project is based on the performance of a phase II clinical trial with a low
level of intervention, which consists of the prospective evaluation of the clinical and
radiological response after the administration of a treatment using radical or adjuvant
hypofractionated proton therapy in 5 sessions in patients diagnosed with chordoma or
chondrosarcoma of the skull base.
In addition, a cross-sectional evaluation of the quality parameters of the dosimetry of
the hypofractionated proton therapy treatments administered to the patients included in
the study and an evaluation of the quality of life by means of specific questionnaires, 3
months after treatment, will be carried out.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- With a baseline classification on the Karnofsky performance status scale ≥ 70%.
- With confirmed histological diagnosis of chordoma or chondrosarcoma of the skull
base.
- Who have signed the specific informed consent of the protocol, agreeing to
participate in it.
- With a maximum tumor size of 50 cc.
- Whose relationship to organs at risk (OARs) allows compliance with the necessary
dose restrictions to receive hypofractionated proton therapy in 5 fractions.
Patients included in the study must meet dosimetric parameters that include:
- Tumor CTV coverage of at least D95>90%.
- Correct compliance with the dose restrictions, at least in the nominal scenario, for
critical organs (optic pathway, brain stem and spinal cord) according to the
guidelines published and available in the literature:
Dose contnstraints for 5 fractions:
Optic Nerves: D0.03cc ≤ 25 GyRBE, V23.5 < 0.5cc. Chiasm:D0.03cc ≤ 25 GyRBE, V23.5 <
0.5cc. Brainstem:D0.03cc ≤ 31 GyRBE,V23 < 0.5cc. Spinal Chord: D0.03cc ≤ 30 GyRBE, V23 <
035cc.
Exclusion Criteria:
- Patients with distant metastases.
- Patients who have received previous irradiation in the same location.
- Patients whose clinical or dosimetric characteristics do not meet the inclusion
criteria.
- Patients who are simultaneously participating in another study that may affect the
results of this protocol.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Centro de Protonterapia Quironsalud
Address:
City:
Madrid
Zip:
28223
Country:
Spain
Status:
Recruiting
Contact:
Last name:
Morena Sallabanda, MD PhD
Phone:
0034 917226716
Email:
msallabanda@quironsalud.es
Contact backup:
Last name:
Juan Antonio Vera, PhD
Phone:
0034 917226716
Email:
juan.vera@quironsalud.es
Investigator:
Last name:
Morena Sallabanda, MD PhD
Email:
Principal Investigator
Investigator:
Last name:
Juan Antonio Vera, PhD
Email:
Principal Investigator
Investigator:
Last name:
Alejandro Mazal, PhD
Email:
Sub-Investigator
Investigator:
Last name:
Raul Matute, MD
Email:
Sub-Investigator
Start date:
May 24, 2023
Completion date:
May 24, 2033
Lead sponsor:
Agency:
Quironsalud
Agency class:
Other
Source:
Quironsalud
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05861245
https://www.cancerdata.org/resource/doi%3A10.17195/candat.2018.01.1/
