A Retrospective Analysis of High-Grade Glioma Cases Treated in Menia Cancer Center and Gharbia Cancer Society Egypt in the Period from 2008-2014
Mohamed Mahmoud*, Sherweif Abdelfatah
Aim: To compare
results of treatment of Glioblastoma Multiform (GBM) at Menia Cancer center and
Gharbia Cancer society in Egypt with the internationally recognized results.
Patients and Methods: The data of 122
patients with GBM treated in the period between 2008 and 2014 were collected
including patients' evaluation, data of irradiation process, use of chemotherapy
and follow up data. The GTV was delineated at the contrast-enhancing edge of
the tumor on postsurgical enhanced T1-weighted MRI scans fused with planning
CT. CTV46 = GTV + 25mm, CTV 60 = GTV +15mm. PTV: A 5 mm margin was added to the
CTV.
Results: The Follow up
period ranged between 1-60 months with a median follow up of 7 months. Median
survival time for all patients was 10.6 months and mean survival was 17.2
months. Overall survival at 6 month was 72.8%, at 12 months was 40.3% and at 24
months was 21.8%. The independent prognostic factors in this study were tumor
grade, performance status and radiation dose. Two years overall survival was
better in grade 3 than grade 3 (p=0.001). one year progression free
survival(PFS) was higher in patients with grade 3 and those who have Karnofsky
Score (KS)>70% (p=0.001).
Conclusion: Performance
status of the patient is a crucial factor in treatment, as it affects prognosis
and treatment decision. Implementation of new radiotherapy techniques is highly
encouraged to achieve more effective & precise dose delivery with
limitation of treatment toxicity.
Keywords: Radiotherapy;
GBM
3.
Introduction
In Egypt, there is
no clear data about the incidence of high grade gliomas in the population, but
in National Cancer Institute (NCI), this group constituted only 0.21% of total
malignancy with a slight adult predominance of 54.44% and no sex predilection
(50% each). The low number of such tumors could be attributed to the lack of neurosurgery
practice at NCI [1]. Malignant astrocytoma;
glioblastoma multiform (WHO grade IV), and anaplastic astrocytoma (WHO grade
III) are still the most common primary cerebral neoplasms in adults. These
highly invasive tumors have a strong predilection for cerebral hemispheres.
Glioblastoma Multiform (GBM) comprises 80% of malignant gliomas. While
malignant astrocytoma’s compromise only 2% of all adult tumors at a rate of 5
cases per 100,000 adults per year, their malignant nature makes them the fourth
greatest cause of cancer death [2].
A recursive
partitioning technique was applied to an analysis of 1578 patients accrued to
three successive Radiation Therapy Oncology Group (RTOG) trials [3]. Age, histological appearance, Karnofsky
performance status (KPS), mental status, duration of symptoms, neurological
functional class, extent of surgery, and radiation dose were identified as
significant partitioning covariates. Six patient classes were defined with
different prognosis as favorable (classes I and II), intermediate (classes III
and IV) and poor (classes V and VI). A subsequent
reanalysis of data in glioblastoma patients showed no statistical difference
between class V and VI
with a median survival of 7.5 months [4]. Neurologic
symptoms and signs affecting patients with glioblastomas can be either general
or focal and reflect the location of the tumor. The most common symptom
experienced by patients is headache. Alternatively, patients may present with
generalized symptoms of increased Intracranial Pressure (ICP), including
headaches, nausea and vomiting, and cognitive impairment. Seizures are another
common presenting symptom.
MRI with and
without contrast is the study of choice. These lesions typically have an
enhancing ring observed on T1-weighted images and a broad surrounding zone of
edema apparent on T2-weighted images. Several pathological studies have clearly
shown that the area of enhancement does not represent the outer tumor border because
infiltrating glioma cells can be identified easily within, and occasionally
beyond, a 2-cm margin [5]. Positron Emission
Tomography (PET) scans and magnetic resonance (MR) spectroscopy can be helpful
to identify glioblastomas in difficult cases, such as those associated with
radiation necrosis or hemorrhage. A study by Piroth et al., found that O-(2- [(18)
F] Fluoroethyl-L-tyrosine (FET) PET to measure tumor volume after surgery has a
strong prognostic impact [6].
Upon initial
diagnosis of Glioblastoma Multiform (GBM), standard treatment consists of
maximal surgical resection, radiotherapy, and concomitant and adjuvant
chemotherapy with temozolomide [7,8]. For
patients older than 70 years, less aggressive therapy is sometimes employed,
using radiation or temozolomide alone [9-11]. A
study by Scott et al., found that elderly patients with glioblastoma who
underwent radiotherapy had improved cancer-specific survival and overall
survival compared with those who did not undergo radiotherapy treatment [12]. Recent evidence suggests that in patients over
60 years old, treatment with temozolomide is associated with longer survival
than treatment with standard radiotherapy, and for those over 70 years old,
temozolomide or hypo fractionated radiotherapy is associated with prolonged
survival than treatment with standard fractionated radiotherapy. The
improvement in survival with temozolomide is enhanced in patients with MGMT
promoter methylation [13].
Stupp et al., [14] reported the final results of the randomized
phase III trial for patients with glioblastoma who were treated with adjuvant
temozolomide and radiation with a median follow-up of more than 5 years. Stupp
et al., previously reported improved median and 2-year survival when temozolomide
was added to radiation therapy in glioblastoma. Survival in the combined
therapy group (i.e., temozolomide and radiation) continued to exceed that of
radiation alone throughout the 5-year follow-up (p < 0.0001). Survival of
patients who received adjuvant temozolomide with radiotherapy for glioblastoma
is superior to radiotherapy alone across all clinical prognostic subgroups.
Median time to
recurrence after standard therapy is 6.9 months [15].
For recurrent glioblastoma multiform, surgery is appropriate in selected
patients, and various radio therapeutic, chemotherapeutic, biologic, or
experimental therapies are also employed [16,17].
This is a retrospective analysis of high grade gliomas cases treated in
Radiation Oncology Department at Menia Cancer Center and Gharbia Cancer Society
at Egypt during the period between 2008 and 2014. All treatment data &
results were collected and correlated with the different prognostic factors, in
order to compare our results with the internationally recognized results.
4.
Patients and Methods
This is a
retrospective study of 122 patients with high grade gliomas treated in the
Radiation Oncology Department, Menia Cancer Center, Gharbia Cancer Society
during the period between 2008 and 2014.
i.
Patients'
evaluation was done including age, sex, date of diagnoses, presenting
neurological manifestations, complete clinical examination including
Karnofsky’s performance score (KPS).
ii.
Data
of irradiation process; date, dose, method of planning, overall period of
treatment, and mean dose to the target.
iii.
Use
of chemotherapy (Temodal), whether concurrent or adjuvant after end of
radiation.
iv.
MRI
brain based follow up two to three months (after the end of treatment).
v.
The
date of last follow up and the status of the patient as regards local control
& survival status.
Immobilization of
patients using thermoplastic masks prior to treatment planning with their necks
either in angle 0, hyper flexed or in prone position, according to tumor
location. Serial C-T cuts was taken for the patient with I.V. contrast together
with CT to MRI image registration was used. The GTV is delineated at the
contrast-enhancing edge of the tumor (not edema) on postsurgical gadolinium
enhanced T1-weighted MRI scans fused with planning CT. CTV46 = GTV + 25mm, CTV
60 = GTV +15mm. PTV: A 5 mm margin is added to the CTV.
4.1. 3D planning
Treatment was
given only to the PTV(s) using a 3-D conformal fields shaped to exclude as much
of the normal brain and other critical structures as possible. The beam's eye
view displays must be used to design beam apertures. Field arrangements will be
determined by 3-D planning to produce the optimal conformal plan in accordance
with the volume definition used. Vertex and other non-coplanar fields was done
to reduce dose to adjacent normal brain. The use of beam intensity modulation
therapy is not allowed (except for wedges, compensating filters, and static
beam shaping devices, such as MLC). The treatment plan used for each patient
will be based on the treating physician's analysis of the volumetric dose
including DVH analysis of the PTV and critical normal structures.
4.2. Statistical Analysis
Comparison of
numerical variables between the study groups was done using Student t test for
independent samples in comparing 2 groups when normally distributed and Mann
Whitney U test for independent samples when not normally distributed.
Comparison between more than two groups was done using one-way analysis of
variance (ANOVA) test when normally distributed and Kruskal Wallis analysis of
variance test when not normally distributed.
For comparing
categorical data, Chi square (C2) test was performed. Exact test was
used instead when the expected frequency was less than 5. Kaplan-Meier method
was used to estimate overall survival and progression free survival as a
function of time since start of treatment Comparisons between survival
functions were performed by using the log rank statistic.
5.
Results
The Follow up
period ranged between 1-60 months with a median follow up of 7 months. Median
survival time for all patients was 10.6 months and mean survival was 17.2
months. Overall survival at 6 months was 72.8%, at 12 months was 40.3% and at
24 months was 21.8% Figure 1.
Out of 122
patients in our study, only 94 patients received their scheduled treatment, and
those patients only will be included in our survival analysis. On univariate
analysis, we found that tumor grade, performance status, overall treatment
period and radiation dose were statistically significant prognostic factors. There
was a significant difference in overall survival regarding the grade of the
tumor, where for grade III tumors, overall survival at 6,12& 24 months
respectively were 80.3%, 54.8 % and 33.9% compared to 65.2%, 30.7% and 11.9%
for grade IV tumors (p < 0.001) Figure 2 & Table
1.
Progression free
survival for grade 3 tumors at 6 & 12 months were 77.1 & 48.4%
respectively compared to 61.4 & 25.9 % at 6 & 12 months for grade 4
tumors with p value < 0.001 Figure 3.
Progression free
survival was 93.2 & 71.0 % at 6 &12 months respectively for patients
with KPS of > 70 % compared to 49.8 & 9.2% for those with KPS < 70 % Figure 4.
6. Discussion
High grade gliomas
remain a challenging issue for the oncologists despite the great advances in
the multimodality approach; surgery, chemotherapy and radiation. The present
work is a retrospective study involving 122 patients with high grade gliomas
treated with multimodality therapy.
As regarding the
grade, 53 patients were histologically WHO grade IV (56.38 %), while 43
patients were WHO grade III (43.62 %), which is consistent with other
statistics that reveals that GBM is more common than malignant astrocytoma’s as
shown in Davis F et al., 1998 who demonstrated an 80 % incidence of GBM among
malignant brain gliomas. Overall survival in this study was in accordance to
several important. prognostic factors discussed in RTOG Recursive Partitioning
Analysis (RPA) such as age, histology, Karnofsky performance status scale and
radiation dose (Curran WJ Jr. et al., 1993). Regarding KPS, overall survival
was significantly better for those with P.S > 70% compared to other groups,
being 61.0% at 12 months, compared to 47.5 % for P.S < 70 %, these results
are consistent with results obtained from RTOG RPA, which showed better survival
in patients with better performance status (Curran WJ Jr. et al., 1993).
In our study, we
found a correlation between overall survival and duration of treatment, which
was statistically significant in the favor of duration less than 50 days compared
to those received their planned treatment in a period more than 50 days, where
OS at 6 months were 89 % and 78.9 % for both groups respectively with a
significant p value (p< 0.001). Multivariate analysis of our statistical
data confirmed the significance of tumor grade; radiation dose and KPS score
regarding overall survival and progression free survival, while it was not
significant for overall period of treatment.
Figure 1: Overall survival for all patients.
Figure 2: Overall survival according to tumor grade.
Figure 3: Progression free survival according to
tumor grade.
Figure 4: Progression free survival in relation to
KPS.
|
No. |
OS at 6 Month |
Median OS ± SE |
p-value |
Whole group |
94 |
72.8% |
10.9 ± 4.54 |
|
Grade of lesions |
|
|
|
|
Grade 3 |
41 |
80.3% |
13.1 ± 2.8 |
<0.001 |
Grade 4 |
53 |
65.2% |
9.1 ± 4.4 |
|
Performance status |
|
|
|
|
> 70 |
41 |
93.3% |
21 ± 0.65 |
<0.001 |
≤ 70 |
53 |
63.2% |
6 ± 2.6 |
|
Radiotherapy duration |
|
|
|
|
< 50 days |
49 |
89% |
15.1 ± 4.1 |
<0.001 |
>50 days |
45 |
78.9% |
10.4 ± 5.9 |
Table 1: Overall Survival (OS) for all patients and relations to different prognostic factors at 6 months. (SE: standard error).