Introduction
Medulloblastoma is a CNS tumor that is among the tumors
of embryological origin and is often located in the
posterior fossa. It is a CNS tumor classified as a grade
4 tumor in the WHO CNS tumor classification due to survival rates and poor pathological features such as a
high proliferation index.[,] It is mostly known as a
childhood tumor and is the second most common tumor
in this age group.[] In adulthood, the incidence
of this disease decreases considerably; it constitutes less
than 1% of CNS tumors in this age group.[]
Medulloblastoma treatment requires a multimodal
treatment regimen, including surgery, radiotherapy,
and systemic agents, which is the standard today.
[] Because they are rarely observed in the adult age
group, studies on treatment were mostly conducted
in the pediatric patient group, and the data obtained
from these studies were applied to the adult age group.
Although there are no studies with high evidence value
for treatment in the adult age group, the guidelines
published by many groups provide guidance for treating
these patients.[-]
Cerebro-spinal fluid (CSF) circulation is important
in the spread of medulloblastomas. The malignant cells
in the CSF circulation must be eradicated to control the
disease. Therefore, radiotherapy applications in standard
treatment are planned as additional boost treatment
to the posterior fossa after craniospinal irradiation
(CSI). CSI requires experience and caution, and
it can be performed with many different techniques;
the fact that the target volume is large, has an irregular
structure, and is close to many critical structures in
this large area makes this irradiation difficult. Especially
when we consider the adult patient group, it is
expected that while the size disadvantage of this area
increases compared to the childhood patient group, the
severity of the expected late side effects will decrease.
Craniospinal irradiation has evolved from determining
the area of the patient with two-dimensional
treatment to tomography-based IMRT techniques or
specialized radiotherapy applications such as proton
therapy.[] The biggest problem of 3D-based planning
and standard IMRT applied in many centers is still planning
with more than one isocenter due to the size of the
area and the difficulty of set-up. The isocenters number
can be up to 3 areas for adult medulloblastoma patients.
Hot areas in the gap junction region may impose extra
care and attention on all treatment practitioners.[]
Tomotherapy treatment means cross-sectional
treatment derived from the word tomography.[]
The main idea is to place a linear accelerator on a CTlike
ring gantry, modulating the treatment beam with
a multi-leaf collimator system (MLC) to irradiate the
patient as the patient moves along the long axis into the
gantry. The system is also capable of cross-sectional imaging
with MVCT for treatment area verification. Technical
differences provide that large areas can be irradiated
with a single plan, and area control can be achieved
more easily than multi-isocentric plans.[] On the
other hand, cross-sectional irradiation (usually a 5 cm
jaw opening) also causes some uncertainties and treatment
concerns. Firstly, the increase in total treatment time and the continuation of CSF circulation makes difficult
the estimation of the radiobiological effect on tumor
control. Again, besides the better dose conformity
provided by this technique, the side effect profile that
will create the high volume low dose area is unclear.
This study aimed to report the characteristics and
treatment results of radiotherapy applied with the helical
IMRT technique in the adult medulloblastoma patient
group.
Methods
In this study, adult medulloblastoma patients who
received radiotherapy with the Helical Tomotherapy
technique in the Ankara City Hospital Radiation Oncology
Clinic between March 2019 and October 2022
were analyzed retrospectively. We used Packer staging
criteria to determine the risk classification of patients.
The data from the planning system of the patients and
their clinical characteristics from the hospital information
system were recorded.
Simulation
Patients were immobilized at 5 points with a thermoplastic
head-neck mask. CT images were obtained in
the supine position in all patients, and the image section
thickness was chosen as 2.5 cm. While the CT imaging
area was determined to include the entire cranium
cranially, the proximal 1/3 of the femur caudally
was included in the imaging area. All patients were informed
about the length of the treatment period and
the importance of simulating in a comfortable treatment
position.
Contouring
Target areas were determined according to the 2-phase
treatment. In the first phase of treatment, all CSF circulation
areas were targeted as CTV_CSI. At the end
of the CTV drawing, the points specified in the SIOPE
guideline were checked to ensure target accuracy and
prevent possible misses due to IMRT.[] The PTV_
CSI margin is generally given differently in the cranial
and spinal sections. The PTV margin was chosen as
5 mm (range 3-5 mm) in the cranial part and 7 mm
(5-10 mm) in the spinal part. The boost area definition
differs between clinicians. Posterior fossa boost or tumor
bed boost was chosen for the boost target.
Planning
In the Planning tab, firstly, target structures (PTV brain,
PTV spinal) and critical organs (OAR) determination are defined. After the target and critical organ separation,
the structures were ranked according to their anatomical
proximity and importance to adjust the dose
modulation. In our clinical routine, the field width
(FW) is determined as 5 cm, the pitch factor is 0.430,
and the modulation factor is 2.00, among the in-device
parameters for craniospinal area irradiations. For boost
plans, after choosing a 2.5 cm jaw width, a modulation
factor of 2.5, and a pitch factor of 0.287, plans were created
with 6 MV energy, which is the only energy value of
the device. Optimization was made so that 100% of the
PTV total volume would cover 95% of the prescribed
dose, and the maximum dose limitation was defined as
not exceeding 110% of the prescribed dose.
Primary Endpoint
Reporting of patients" survival and toxicity results.
Secondary Endpoint
Reporting the technical features of the treatment.
Statistical Analysis
Data exported SPSS. 26 (IBM Corp, Armonk, NY, USA).
Nonparametric tests were used. Categorical demographic
characteristics of the patients were calculated with
Chi-square and Fisher's exact tests. Spearman"s rank correlation
test was used for univariate correlation analysis.
Kaplan-Meier was used in univariate survey analyses
and compared with the log-rank test. The statistically
significant limit was accepted as 0.05 and below.
The study was conducted in accordance with the
Declaration of Helsinki. Ethics committee approval
was obtained from Ankara City Hospital Ethics Committee
with the number E1-22-2759 (29.06.2022).
Results
Seventeen patients aged 18 years and older admitted
with the diagnosis of medulloblastoma in the Radiation
Oncology Clinic of Ankara City Hospital between
March 2019 and October 2022 were analyzed retrospectively.
Two of the 17 patients were excluded. One
patient left the treatment at the seventh fraction, and
the other one did not accept the treatment. Therefore,
the analysis was performed on 15 patients. The median
follow-up time of the study was 9.4 (range 1.2-
34.7). The median age at presentation for RT was 29
(range 20-45). Six (40%) of the patients were female,
and 9 (60%) were male. When evaluated in terms of
risk group, 10 (66.7%) patients were standard risk; 5
(33.3%) were high risk. Spinal seeding was detected in 1 (6.7%) patient at diagnosis. The median time from
surgery to RT was 36 days (range 28-54). All chemotherapy
regimes were applied concurrent with radiotherapy.
Daily oral temozolomide (75 mg/m²/day) was
used for 1 patient; intravenous weekly vincristine (1.5
mg/m²/week) was used for 4; intravenous cisplatin (80
mg/m²/week) one day in a week + etoposide (120 mg/
m²/week) three days in a week were used in 8 patients.
Median RT duration is 42 days (range 36-65). The median
CSI dose is 36 Gy (30.6-36). The median total RT
dose is 54 Gy (54-55.8). The boost volume was posterior
fossa in 10 patients (66.7%) and tumor bed in
5 patients (33.3%). Median treatment time was 607.4
sec (range 422.9-702.4). Median 99.4% (97.3-99.9) by
volume receiving 95% of the target dose, and median
92.2% (85.8-97.5%) by volume receiving 100% of the
target dose. Characteristics are summarized in Table 1.
The mean and median values for planning parameters
are summarized in Table 2.
Table 1 Patient and treatment characteristics
Table 2 Planning parameters
Survival Analysis
All patients were alive at a median follow-up of 9.4
months (1.2-34.7). The median OS is 11.8 (range 3.9-
37.26). No significant correlation was found between
age (p=0.343); gender (p=0.51); risk group (p=0.234);
simultaneous chemotherapy (p=0.517); molecular
profile (p=0.173); total treatment time (p=0.302); the
time between RT-surgery (p=0.315) and overall survival.
During the follow-up period, 2 (13.3%) patients
relapsed; the median PFS was 8.5 (range 1.28-34.73)
months. There is no significant relationship between
PFS and total RT time (p=0.784), gender (p=0.389); age
(p=0.960); seeding (p=0.782); boost volume (p=0.527);
molecular profile (p=0.265); simultaneous CT
(p=0.782); and surgery-RT duration time (p=0.693). A
correlation close to the limit of significance was found
between the risk group and PFS (p=0.051).
Change in Hematological Parameters During
Radiotherapy
Changes were recorded in the blood values of the patients
before the treatment and before the boost treatment.
It was determined that the white blood cell
(p=0.001) and lymphocyte counts (p=0.001) decreased
significantly before the boost treatment. Before switching
to boost volume therapy, two patients (13.3%) had
grade 3 leukopenia, three patients (20%) had grade
3 lymphopenia, and 10 patients (66.7%) had grade 4
lymphopenia. At the end of the treatment, grade 3 leukopenia
was observed in 1 patient (6.7%), and grade
4 lymphopenia was observed in 1 patient (6.7%). The existence of a relationship between body integral dose
and the development of lymphopenia was also tested.
For this purpose, body V20, V25, and V30 values were
recorded. In the analysis, the relationship of these values
with lymphocyte count before boost treatment
could not be shown statistically (Table 3).
Table 3 Relationship between lymphocyte counts and
integral dose parameters
No relationship was found between the development
of lymphopenia and age (p=0.932), gender
(p=0.765), and the presence of simultaneous chemotherapy
(p=0.565). There is no relationship between
pre-treatment blood values and applied dose.
Discussion
In this study, we reported our adult medulloblastoma
radiotherapy experience with tomotherapy to obtain
two data: 1. Treatment results of adult medulloblastoma
patients, a rare patient group, and 2. Experience
using tomotherapy in this disease group. In our cohort
of 15 patients, at a median 9.4-month follow-up, the
median survival was calculated as 11.8 months, and the
median PFS was 8.5 months. No patients were dead at
analysis. Only the disease risk group showed a close relationship
to the significance limit among the variables
examined on survival parameters.
Medulloblastoma has an incidence of 0.6-1 case per
million in adult patients.[] Radiotherapy data most
commonly come from pediatric trials, so craniospinal
radiotherapy is essential for adult patients too.[,] Standard treatment includes maximal safe resection,
craniospinal radiation (CSI), and chemotherapy (CT).
[,,] The difference in treating adult and pediatric
medulloblastoma cases is generally observed in the
chemotherapy schemes. The low tolerance to the systemic
agents selected in childhood in the adult group
caused this difference.[] Although standard care is
still based on clinical classification, molecular classification
began to be translated into clinics.[,]
Although our short follow-up series could not provide
generalizable data in terms of overall survival, it
was thought that acute toxicity data would contribute
to the literature on helical tomotherapy experience and
integral dose effects. Grade 3 nausea, vomiting, dermatitis,
and esophagitis were not reported in any patients.
The hematological toxicity records were evaluated, and
it was observed that the patients experienced severe
hematological toxicities at the end of the CSI phases.
On the other hand, the non-standard use of chemotherapy
and the different selection of systemic agents
make it difficult to comment on the factors affecting
the development of hematological toxicity.
One of the largest series evaluating treatment outcomes
of adult MBL cases is the study by Ma et al.[]
using the SEER database. This study reported treatment
results of 857 patients diagnosed between 1973
and 2015, and overall survival was reported as five
years. One of the interesting results of the study is that
the survival of the patients who received chemotherapy was found to be lower than those who did not (54 m
vs. 67 m / HR 1.4515, 95% CI 1.26-1.671, p<0.001). On
the other hand, the effect of radiotherapy on survival
was also shown in adult patients (66 months vs. 25 m
HR 0.581, 95% CI 0.48-0.70, p<0.001).
In a recent systematic review, the treatment results
of adolescent and young adult MBL cases were evaluated
with 18 studies, and 5-year survival was reported
between 40% and 89%.[] The difficulty created by
the differences in the practices in reaching the general
opinion was also emphasized in this study. Reducing
the heterogeneity in studies with clinical studies and
standardizing treatment parameters related to treatment
timing, chemotherapy selection, and radiotherapy
dose characteristics will provide more accurate data
on survival outcomes.
The second issue we focus on is the clinical experience
regarding the application of the helical tomotherapy
technique in this patient group. Craniospinal irradiation
is a radiotherapy application that is technically
challenging and requires experience due to its field size
and proximity to many critical organs. This issue can
become more challenging in adult patients considering
the area size. The irradiation technique is chosen
in different ways, such as two-dimensional, three-dimensional,
and current IMRT techniques, depending
on the knowledge and experience of the clinic.
We think that the fact that our hospital is a tertiary
center effectively reaches a high number of patient data
in a short time compared to the literature. In our center,
treatment with a helical tomotherapy device is generally
planned for patients undergoing CSI. Especially in the
adult age group, the increase in the number of isocentres
and caused uncertainty has been effective in this trend.
Studies on the use of helical tomotherapy in CSI in
the literature started with dosimetric studies (Table 4),
and then clinical data were contributed. The result generally
obtained in dosimetric studies is HT superiority
in target volume wraps, and on the other hand, integral
dose increases as expected. Another issue to consider
when evaluating these studies is that not all CTs used in
planning belong to the adult patient group.
Table 4 Dosimetric studies on using HT for CSI
Gupta et al.[] reported the results of feasibility
studies on using HT in CSI in 2016. Clinical results of
20 patients with a median age of 15 were reported with
a median follow-up of 5 years. Four (20%) patients
needed growth factor or platelet support during craniospinal
irradiation. Significant late neurotoxicity was
reported in only one (5%) patient. No symptomatic
radiation pneumonia or second new malignancy was
reported in any of the patients.
Schiopu et al.,[] on the other hand, reported a series
of 45 diseases with different diagnoses in 2017. Similarly,
while there were acute hematological toxicities of Gr3 and
above, late toxicity of Gr3 and above was not reported.
A current valuable study on this subject was reported
by Turcas et al.[] in 2023. In this study, 55 publications
evaluating HT in CSI were examined. Nine of
these studies are data of adult patients undergoing CSI
for different diagnoses, and hematological toxicities
have been reported to a large extent. Other noted toxicities
are xerostomia, alopecia, and nausea and vomiting.
The researchers reported that there are studies indicating
better target wrapping with HT, and similar results
were obtained with other techniques in terms of toxicity.
The retrospective nature of our study, the short
follow-up period, and especially the difference in chemotherapy
schemes are its weaknesses. On the other
hand, it is thought to contribute to the literature regarding
adult medulloblastoma cases and report the
results of the HT experience, which has not yet become
widespread in the use of CSI.
Conclusion
Radiotherapy with HT technique of adult MBL cases,
which we rarely encounter in the clinic, has reversible and acceptable acute toxicity rates. More patient data
are needed on the contribution of this technique to
survival in this patient group that has not yet reached a
standard treatment scheme.
Ethics Committee Approval: The study was approved by
the Ankara City Hospital Ethics Committee (no: E1-22-
2759, date: 29/06/2022).
Authorship contributions: Concept - G.A.İ.; Design -
G.A.İ., A.K.A., B.T.; Supervision - G.A.İ., İ.P.A.; Materials -
G.A.İ., İ.P.A., Z.G.; Data collection and/or processing - A.K.A.,
B.T.; Data analysis and/or interpretation - İ.P.A., A.K.A., B.T.;
Literature search - G.A.İ., İ.P.A.; Writing - G.A.İ., İ.P.A., Z.G.,
Y.T., A.K.A., B.T.; Critical review - Y.T., İ.P.A.
Conflict of Interest: All authors declared no conflict of interest.
Use of AI for Writing Assistance: Not declared.
Financial Support: None declared.
Peer-review: Externally peer-reviewed.
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