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ABSTRACT:

BACKGROUND AND OBJECTIVES:

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GBM also known as glioblastoma multiforma (GBM) is  a WHO grade IV, most common aggressive
malignant brain tumor of adults with high fatality rate.1With the
well known poor survival in this tumor, understanding  clinical and treatment related prognostic
factors can help in tailored treatment. Hence this retrospective analysis was
undertaken to know the influence
of prognostic factors on survival in cases treated in our institute.

METHODS:

All GBM patients treated in our hospital during
2010-2015(n=70) were screened and 46 were included in analysis and divided into
groups based on prognostic factors including age, sex, preoperative seizure as
symptom of presentation, location of tumor, side, lobe involved, ECOG
performance status, antiepileptic drug, type of surgery, gap between surgery
and radiation, usage of concurrent temozolomide, number of cycles of adjuvant temozolomide.
Overall survival(OS) and
disease free survival(DFS) were compared, effect of prognostic factors
was analysed with Kaplan meier method.

RESULTS:

Age at
presentation less than or 45 years and adjuvant chemotherapy with 6 cycles or
more temozolomide improved OS and DFS (P value 0.015, 0.0001; 0.015,
0.0001).Multivariate analysis retained the statistically significant positive
impact of usage of adjuvant temozolomide chemotherapy on OS and DFS (P value
0.0001, 0.0005).

Use of
Levetiracetam had a statistically significant improvement of DFS (P value
0.027)

INTERPRETATION AND CONCLUSION:

Among various clinical and treatment related
prognostic factors evaluated younger age at presentation and addition of
temozolomide chemotherapy to radiation had shown improvement in OS and DFS. Use
of antiepileptic drug levetiracetam had an impact on DFS.

Key words: GBM, prognostic factors, adjuvant
temozolomide

 

INTRODUCTION:

GBM also known as glioblastoma multiforma (GBM), is the
most common malignant brain tumor of adults. Among all gliomas it is the most
aggressive type, with high fatality rate and according to WHO classification it
is grade 4 tumor.1

Symptoms of presentation are headache, vomiting,
drowsiness (non site specific) and site specific symptoms like seizures and
neurological deficits. Rate of symptom onset and extent of nonspecific symptoms
will help in understanding aggression of disease.2 Standard
treatment protocol is maximum safe resection followed by adjuvant concurrent
chemoradiotherapy followed by adjuvant chemotherapy with 6 cycles of temozolomide.
This standard of treatment led to improved survival of patients compared to
historical controls, but most of the patients develop recurrent disease early in
the course of treatment due to multifocal stem cell niche like progenitor cells
and succumb to illness in less than two years.2

Recurrent disease is treated with salvage surgery or
chemotherapy commonly six more cycles of temozolomide once in four weeks. Although
survival is less than two years for majority of patients, long-term survivals (greater
than 3 years) have been published , though long term survival is rare it is
still seen, with less than 10% of patients surviving at least 5 years
post-diagnosis, suggesting heterogenous nature of disease and pretreatment
prognostic factor may help in predicting long term survivor.

Further advances are progressing towards molecular
genetics and prognostic factors at gene level to assess treatment response and improve
survival but day to day practice may not be feasible at genetic level
especially in low income patient population hence clinical factors like age at
presentation, symptom duration, performance status may be handy in
prognostication of patient before treatment. Several clinical studies have
identified factors affecting clinical outcome.3

Identification of clinical and treatment related
prognostic factors helps in tailored treatment.

With this background we have conducted a retrospective
analysis to know the impact of various prognostic factors affecting overall and
disease free survival in GBM patients treated at our institute.

MATERIALS AND METHODS:

All GBM
patients treated in sri
venkateswara institute of medical sciences, a tertiary care institute in
South India during 2010-2015 were included in analysis.

In our hospital all GBM cases were preoperatively evaluated
with complete history and physical examination including presenting symptoms,
performance status, drug usage and were analysed with computed
tomography(CT)/magnetic resonance tomography(MRI) brain scan for tumor site,
location and then maximum possible resection was attempted and
histopathologically confirmed cases of GBM were subjected to  post operative MRI brain scan and patients were
treated with adjuvant radiation of 60 gray(Gy) in 30 fractions at a dose of 2
Gy per fraction 5 fractions per week with 3dimensional conformal radiotherapy(3DCRT).

Concurrent chemotherapy was provided with oral alkylating
agent temozolomide @ 75 mg/m2 body surface area(BSA) for 5 days a week half an
hour before radiation for six weeks and adjuvant chemotherapy was continued
with temozolomide @ 150 mg/m2 BSA once a day for 5 days once  in 4 weeks for 6 cycles and repeat MRI brain study was
done and if residual/recurrent disease not amenable for repeat surgery
was identified then six more four weekly cycles of temozolomide were continued
as institutional protocol. All patients received prophylaxis for pneumocystis
carinii pneumonia with trimethoprim-sulfamethoxazole-160 + 800 mg (one DS
tablet) orally, daily during chemotherapy.

Retrospective
analysis was started after getting institutional ethics committee approval.

Totally 70
patients were screened and patients with incomplete data like preoperative
clinical, surgery details , defaulters for radiation, death during radiation
were excluded and remaining 46 cases were included in analysis.

For analysis we considered various prognostic
factors and grouped them under following categories. (Table 1)

Overall survival(OS): OS was calculated from the day of surgery
till date of death or last follow-up.

Disease free surviva(DFS)l: DFS was calculated from the date of surgery
to date of recurrence or death.

Survival curves were estimated using the
Kaplan-Meier method and are used to compare 
age, sex, preoperative seizure as symptom of presentation, location of
tumor, side of lesion, lobe involved, Eastern
Cooperative Oncology Group(ECOG) performance status on the day of surgery, antiepileptic drug,
type of surgery, gap between surgery and radiation, usage of concurrent temozolomide
drug , number of cycles of adjuvant temozolomide. 95% confidence intervals for
the median survival time of the groups were constructed and log-rank test was
employed to determine if there is statistical evidence of differences between
the survival curves of the groups. 
Finally, the Cox proportional hazard model was used in a multivariate
analysis. Statistical significance was set at a P value <0.05. Statistics were performed using IBM SPSS version 20 (Armonk, New York). RESULTS: The mean and median age of presentation in the whole cohort was 48.5 years (range 21-76 years) and 51 years respectively. Males presented at slightly older age compared to females. The mean and median age of presentation among males was 49 years and 52.5 years respectively while the mean and median age of presentation among females was 47.5 and 50 years respectively. Total excision was done in 36.9% (17/46). 67.3% (31/46) patients received concurrent chemotherapy with temozolomide and 32.6% (15/46) patients completed 6 or more cycles of adjuvant temozolomide, 6.5% (3/46) patients completed 12 cycles of adjuvant temozolomide. Survival data: One year survival was 36.9 % (17/46) and two year survival was 10.8% (5/46). One year DFS was 13.04% (6/46) and only one patient was disease free at two years. Mean and median OS was 10.5 months and 8 months respectively and the mean and median DFS was 7.52 months and 6.5 months respectively in the entire patient population. Survival analysis: Univariate and multivariate analysis was performed to know the impact of various prognostic factors on OS and DFS. Univariate analysis found statistically significant correlation of OS with age at presentation and adjuvant chemotherapy with temozolomide. Age at presentation less than or 45 years and adjuvant chemotherapy with 6 cycles or more temozolomide improved survival in a positive way (P value 0.015, 0.0001 respectively).( Figure1,2) Univariate analysis found statistically significant correlation of DFS with age at presentation, antiepileptic drug and adjuvant chemotherapy with temozolomide. Age at presentation less than or 45 years, usage of antiepileptic drug levetiracetam and adjuvant chemotherapy with 6 cycles or more of temozolomide improved survival in a positive way (P value 0.015, 0.027, 0.0001 respectively). (Figure 3) Multivariate analysis retained the statistically significant positive impact of usage of adjuvant temozolomide chemotherapy of 6 or more than 6 cycles on OS with a P value of 0.0001. Multivariate analysis retained the statistically significant positive impact of usage of adjuvant temozolomide chemotherapy of 6 or more cycles on DFS with a P value of 0.005. Other variables like age, gender, ECOG performance status, side and lobe, location of tumor, type of surgery, gap between surgery and start of radiation, usage of concurrent chemotherapy were not significant. (Table 2) DISCUSSION: In this study we analysed the data of newly diagnosed and treated cases of GBM in a tertiary care institute who completed treatment as per protocol. GBM is WHO grade 4  tumor with incidence of 12-15 % among brain tumors presenting predominantly in age group of 45-70 years with incidence favouring males with male to female ratio of 1.5:1. 4 Our study had shown similar male predominance with a male to female ratio of 1.3:1, and mean, median age of presentation of entire population was 48.5 years and 51 years respectively which were within reported range. As lamborn et al suggested statistically significant impact of younger age improving survival 5 our study also proved significant impact of younger age improving median OS and DFS( P value 0.015, 0.015) on univariate analysis. Mean and median OS was 10.5 months and 8 months respectively and the mean and median DFS was 7.52 months and 6.5 months respectively in the entire patient population in our study which was less than median survival reported in EORTC-NCIC trial6 (14.6 and 6.9 months respectively). But our study data correlated with Indian data reported by Narendra et al as 7.67 months 7 It was reported in literature that median survival in GBM is less than one year 8 and two year survival was less than ten percent. 9 Only 2% cases survive for more than 3 years 10. The present study reported one year OS of 36.9 % (17/46) and two year OS of  10.8% (5/46) which was little higher than reported Indian data of 25.63%, and 7.23%, respectively.7 This might be because of small sample size. Coming to gender wise survival males had a lower 5-year survival rate compared with that of females 11 and our study had shown little higher OS trend in females though not significant (10.75 vs. 10.38 months)  In literature GBM presenting with seizures remained significantly associated with an increased overall survival compared with GBM patients without seizures  by helping in early diagnosis12 but in our study the impact of seizure as symptom of presentation was not significantly affecting OS (mean 13.21 vs. 9.28) or DFS, this may be because, in cases presenting with seizure(14/46) only 6/14(42.8%) underwent complete excision, good performance status and only 7/14(50%) received 6 or more cycles of adjuvant chemotherapy which may have impacted median survivals. Location of tumor may impact prognosis by effecting completeness of surgery i.e. eloquent locations may not permit radical resections while non-eloquent and accessible location may permit more radical surgery13 but our study had not shown any significant impact of cerebral cortex versus sub cortical/deep structure location on OS or DFS. This could be due to unbalanced sample number in two groups. Lesion may be localised on left side or right side of brain or midline, some studies showed that left sided lesions have improved survival 7 while Tait el al suggested better survival with right sided and central tumors. 14 Our analysis had not shown significance of side of lesion similar to reported data. Similarly lesions localised to frontal lobes express better survival because of possibility of radical resections 7 but our study could not prove this effect on OS or DFS. This could be due to other confounding factors. It is well published that good performance status will positively impact survival in all age groups but our study result had a trend of improved survivals but was not statistically significant because of small sample size. 9, 15 Recent studies suggested usage of anti epileptic drug levetiracetam can inhibit malignant glioma cell proliferation and sensitize GBM cells to temozolomide hence can improve survival. 16 Our study showed a trend towards improved OS and statistically significant improvement in DFS (P value 0.027). The importance of surgical completeness was highlighted in many studies, Lacroix M et al suggested that  gross-total tumor resection is associated with longer survival in patients with GBM, especially when other predictive variables are favorable17 and another study by  Almenawer S et al concluded that mean OS was significantly longer with maximum grades of resection.18Moreover, patients undergoing complete resection experienced better functional recovery but the result of our study was not supporting this evidence and this could be due to many factors like small sample size, few patients with complete resection (17 Vs.29) and poor prognostic factor combination neutralising the positive effect of completeness of surgery. Delayed time from presentation to the radiation department until initiation of radiotherapy (RT) is a negative prognostic factor where the hazard of death increased by 2% per day of delay in initiation of RT. 19 another study suggested mean tumour doubling time of 24 days, so that a delay to start radiotherapy would be expected to have an adverse effect. 20A study by Andrea Pirzkall et al suggested tumor regrowth due to increased time gap between surgery and initiation of radiation21 Hence RT is generally started as soon as wound heals but our analysis had not shown any effect of delay in RT beyond 28 days on survival. In the landmark randomized study, Stupp et al. reported that delivery of temozolamide during radiotherapy increased survival, suggesting that this deoxyribonucleicacid(DNA) alkylating agent can increase survival by enhancing radiosensitivity of GBM cells and reported that the overall survival rates with radiation and temozolamide to be 27.2% at two years, 16.0% at three years, 12.1% at four years and 9.8% at five years 6,22 47% of that study population completed six cycles of chemotherapy while our patient population only 32.6% completed six cycles, this could be due to disease progression and death but not due to toxicity of chemotherapy. We did not notice any grade 2 or more toxicity during entire period which had shown that our population tolerated temozolomide well. Mechanism of action of temozolomide: is TMZ- is an alkylating agent prodrug, delivering a methyl group to purine bases of DNA (O6-guanine; N7-guanine and N3-adenine). The primary cytotoxic lesion, O6-methylguanine (O6-MeG) can be removed by methylguanine methyltransferase (MGMT; direct repair) in tumours expressing this protein, or tolerated in mismatch repair-deficient (MMR-) tumours. Thus MGMT or MMR deficiency confers resistance to temozolomide and cytoxicity occurs particularly when O6-MeG adducts are repaired or tolerated. .23 35%–45% of high grade gliomas express methylation of the MGMT promoter24 and patients with GBM containing a methylated MGMT (O6-methylguanine–DNA methyltransferase) DNA-repair gene with epigenetic silencing of the MGMT gene by promoter methylation benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such benefit.25 Both univariate and multivariate analysis retained the statistically significant improvement of OS and DFS with use of adjuvant chemotherapy. So our study may be favouring the trials evaluating the suggestion that adjuvant chemotherapy may be provided to all cases of GBM without considering other prognostic factors. Limitations: The retrospective nature of study is a major limitation and Extent of surgery was based on intraoperative surgeon notes, postoperative MRI brain scan report so volume of residual disease was not considered in analysis.  Non availability of molecular marker like epigenetic silencing of the MGMT (O6-methylguanine–DNA methyltransferase) DNA-repair gene by promoter methylation data on histopathology specimen is limiting. CONCLUSION: Among various clinical and treatment related prognostic factors evaluated in our study younger age at presentation and addition of temozolomide chemotherapy to radiation had shown improvement in overall survival and disease free survival. Use of antiepileptic drug levitiracetam had an impact on disease free survival in GBM patients.

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