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ORIGINAL ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 4  |  Page : 599-603
 

Clinical outcome of patients with primary gliosarcoma treated with concomitant and adjuvant temozolomide: A single institutional analysis of 27 cases


Department of Radiation Oncology, Dr. B.R.A. IRCH, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication10-Mar-2016

Correspondence Address:
G K Rath
Department of Radiation Oncology, Dr. B.R.A. IRCH, All India Institute of Medical Sciences, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.178407

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 » Abstract 

CONTEXT AND AIM: The prognosis of primary gliosarcoma (PGS) remains dismal with current treatment modalities. We analyzed the outcome of PGS patients treated with concurrent and adjuvant temozolomide (TMZ). SETTINGS AND DESIGN: Retrospective single institutional analysis. MATERIALS AND METHODS: We retrospectively evaluated 27 patients of PGS treated with radiotherapy (RT) and TMZ during 2007-2012. STATISTICAL ANALYSIS USED: Overall survival (OS) was estimated by the use of Kaplan Meier method and toxicities were evaluate using common terminology criteria for adverse events version 2.0 (National Cancer Institute, USA). RESULTS: Median age at presentation and Karnofsky performance status was 45 years and 90 respectively and male: female ratio was 20:7. Patients received adjuvant RT to a total dose of 60 Gy at 2 Gy/fraction. All patients except 5 received adjuvant TMZ to a median number of 6 cycles. Grade 2 and 3 hematological toxicity was seen in 8% and 4% of patients respectively during concurrent RT. During adjuvant chemotherapy, 13.6% had Grade 3 thrombocytopenia and 9.5% had Grade 3 neutropenia. Median OS was 16.7 months (1 year and 2 year actuarial OS was 70.8% and 32.6% respectively). Adjuvant TMZ was associated with a better survival (median survival 21.21 vs. 11.93 months; P = 0.0046) on univariate analysis and also on multivariate analysis (hazard ratio 1.82, 95% confidence interval: 1.503-25.58; P = 0.012). CONCLUSIONS: The results of our study, largest series of patients with PGS treated with concurrent and adjuvant TMZ shows an impressive survival with acceptable toxicity. We suggest TMZ be included in the “standard of care” for this tumor.


Keywords: Primary gliosarcoma, radiotherapy, temozolomide


How to cite this article:
Rath G K, Sharma D N, Mallick S, Gandhi A K, Joshi N P, Haresh K P, Gupta S, Julka P K. Clinical outcome of patients with primary gliosarcoma treated with concomitant and adjuvant temozolomide: A single institutional analysis of 27 cases. Indian J Cancer 2015;52:599-603

How to cite this URL:
Rath G K, Sharma D N, Mallick S, Gandhi A K, Joshi N P, Haresh K P, Gupta S, Julka P K. Clinical outcome of patients with primary gliosarcoma treated with concomitant and adjuvant temozolomide: A single institutional analysis of 27 cases. Indian J Cancer [serial online] 2015 [cited 2019 Dec 5];52:599-603. Available from: http://www.indianjcancer.com/text.asp?2015/52/4/599/178407





 » Introduction Top


Primary gliosarcoma (PGS) is a biphasic tumor of the central nervous system with a glial and a mesenchymal component and is considered as a variant of glioblastoma multiforme (GBM).[1] PGS is an aggressive and rare malignancy accounting for 1.8-2.8% of all cases of malignant gliomas and has a poorer prognosis compared to GBM.[2]

Clinical reports on prognosis and outcome of PGS remains limited and these patients have been treated with either radiotherapy (RT) alone [3],[4],[5],[6] or RT in combination with varying regimens of chemotherapy.[7],[8],[9] However, survival using these approaches remains dismal with a median survival ranging from 4 to 11 months.

Meanwhile, the European Organization for Research and Treatment of Cancer-National Cancer Institute of Canada (NCIC) trial[10] showed a significant survival advantage of adding concurrent and adjuvant temozolomide (TMZ) to standard RT regimen in patients with GBM and the regimen used in this trial (referred to as “Stupp's regimen” in the rest of the article) became the standard practice for GBM. The encouraging results from the NCIC trial has been robustly backed by the molecular genetics of GBM. Promoter methylation of O6-methylguanine deoxyribonucleic acid methyltransferase (MGMT) has emerged as one of the strongest predictor for the outcome and benefit from TMZ. [10,11]

Results from this NCIC trial generated enthusiasm in treating patients of PGS with the “Stupp's regimen.” Recent molecular studies have shown that patients with PGS also harbor promoter methylation of MGMT in as many as 30%-50% of the patients [12],[13] supporting the use of TMZ based therapy in patients of PGS. Some studies have evaluated the use of TMZ in patients with PGS.[6],[14],[15],[16] However, the use remains limited to a small subset of patients ranging from 13% to 60% in each cohort with a lot of heterogeneity.

From 2007 onward, all patients of PGS are treated with “Stupp's regimen” at our institution. Hence, we did this retrospective analysis to evaluate patient demographics, treatment details and survival outcomes of this cohort of patients treated uniformly with concurrent chemoradiotherapy with TMZ followed by adjuvant TMZ.


 » Materials and Methods Top


Medical records of the patients treated at our institution from 2007 to 2012 with a diagnosis of PGS were retrieved from our departmental archives. A total of 29 patients with confirmed histopathology were identified. Two patients defaulted after being registered and their complete medical records were missing and were excluded from the analysis. This retrospective analysis was approved by our Institutional Review Board.

Patient related factors including age, sex, symptoms, symptom duration, Karnofsky performance status, medical co-morbidities and treatment related factors viz. pre-operative/operative diagnosis, extent of surgical resection, interval between surgery and start of RT, histopathological findings, details of concurrent and adjuvant chemotherapy and toxicities during and after treatment were recorded from the medical record charts.

All patients underwent maximal safe resection (gross total excision [GTE] [>90% resection], sub-total excision [STE] [<90% resection] or decompression only) followed by concurrent chemo-RT and adjuvant chemotherapy. Steroids, anti-emetics and other supportive treatment were used as per individual patient requirements.

RT was delivered in all patients with three dimensional-conformal RT techniques on a linear accelerator. The initial cancer terminator virus (CTV) included the enhancing tumor and edema with a 2 cm margin all around as seen in the pre-operative T2 weighted/T2 flair magnetic resonance imaging (MRI) scan. The boost phase CTV included the T1 contrast enhancing tumor volume with a 2 cm margin. A uniform expansion of 5 mm was given all around the CTV to generate the PTV. A total dose of 60 Gy was delivered at 2 Gy/fraction (50 Gy in 20 fractions to the initial clinical target volume followed by a boost of 10 Gy in 5 fractions).

Concurrent chemotherapy (TMZ 75 mg/m 2 daily) and adjuvant chemotherapy with TMZ 150 mg/m 2 (for the first cycle) and 200 mg/m 2 (for the subsequent cycles, if well tolerated) were used as per Stupp's protocol.[10] Adjuvant chemotherapy was repeated every 4 weeks and given to a maximum of 6 cycles.

Weekly complete blood counts were done during chemo-RT and were repeated 3-5 days before each cycle of adjuvant chemotherapy. Patients were evaluated for toxicities using common terminology criteria for adverse events version 2.0 (National Cancer Institute, USA). Contrast enhanced MRI of the brain was done after completion of the adjuvant treatment and subsequently every 3 months or earlier based on patient's symptomatology. Response evaluation was done by Macdonald's criteria.[17]

Statistical analysis

Survival outcomes were calculated from the time of diagnosis. Progression free survival (PFS) was calculated from the time of diagnosis to the time of progression or death. Overall survival (OS) was calculated from the time of diagnosis to the time of death from any cause. Kaplan-Meier method [18] was used for survival analysis. Univariate analysis (log rank test) was used to assess the impact of prognostic variables on survival. Multivariate analysis was done by Cox-proportional hazard model. P < 0.05 was taken as significant and SPSS version 12.0 (SPSS Inc., Chicago, IL, USA) was used for all statistical analysis.


 » Results Top


Patient characteristics

Out of 27 patients, 20 were males and 7 were females. Most commonly the patients presented with symptoms of raised intracranial tension (81.5%) followed by sensorimotor impairment (26%). Patient characteristics are as summarized in [Table 1].
Table 1: Patient characteristics

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All patients except 2 (who had only computed tomography [CT] prior to surgery) underwent contrast enhanced MRI. 31% of the patient had their tumor in the temporal lobe and 26% had the multi-lobed disease at presentation. Diagnosis as per the radiologist and as per the operative diagnosis was noted separately. 21 patients (77.7%) were diagnosed as high grade gliomas (most likely GBM), 5 as meningioma (18.5%) and 1 patient as medulloblastoma based on radiological and operative findings.

A total of 20 patients underwent surgery at our institution and 7 patients had it done at a different institute and subsequently referred for adjuvant treatment. About 12 (44%) patients underwent a GTE, another 12 (44%) had a STE and 3 (12%) had a decompression and biopsy of the tumor only as per the notes of the neurosurgeons. There was no mortality or major post-operative morbidity in any of the patients.

On histopathology, tumors characteristically showed a biphasic pattern with glial component staining positive for glial fibrillary acidic protein and the mesenchymal component staining for vimentin and reticulin. Tumors showed a high percentage of MIB-1labeling indexes, median being 15% (range 5-65%). The histopathology of the patients operated outside our institute was re-reviewed by a neuropathologist.

All patients received adjuvant RT to a total dose of 60 Gy at 2 Gy/fraction except 3 patients (one received 8 Gy [interrupted because of raised ICT Intracranial tension] and two patients received 46 Gy [one defaulted and one had raised ICT]). Median interval between surgery and RT was 38 days (range, 17-83 days) and median RT duration was 43 days (range, 6-52 days). All patients except 1 received concurrent TMZ during RT. All patients except 5 (these patients had Grade 3 hematological toxicity either during concurrent or adjuvant phase of chemotherapy) received adjuvant TMZ to a median number of 6 cycles (range, 3-6 cycles).

Acute toxicities during RT were mainly nausea, anorexia, headache, vomiting and dermatitis. Grade 1 nausea was the most frequent accompaniment and seen in 90% of the patients. 15 (55.6%) patients had Grade 2 and no patient suffered from Grade 3 non-hematological toxicities. 2 patients had Grade 2 (one neutropenia and one thrombocytopenia) and 1 patient had Grade 3 (both neutropenia and thrombocytopenia) during concurrent RT. During adjuvant chemotherapy, 3 patients (13.6%) had Grade 3 thrombocytopenia and 2 patients had Grade 3 neutropenia (9.5%).

Median follow-up duration for the entire cohort was 13 months (range, 2-48 months). At the time of last follow-up 13 patients had expired, 4 had progressive disease and 10 patients were asymptomatic and free of disease. Median PFS and OS of the entire cohort were 15 months and 16.7 months [Figure 1] respectively. After 1 year PFS and OS was 58.7% and 70.8% respectively.
Figure 1: OS for the entire cohort (OS = Overall survival)

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Adjuvant TMZ was associated with a significantly better survival (median survival 21.21 months vs. 11.93 months; P = 0.0046) on univariate analysis and also on multivariate analysis (hazard ratio [HR] 1.82, 95% confidence interval [CI]: 1.503-25.58; P = 0.012); [Figure 2]. Rest of the prognostic variables did not impact survival significantly as summarized in [Table 2].
Figure 2: OS of patients treated with or without adjuvant TMZ (OS = Overall survival; TMZ = Temozolomide)

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Table 2: Impact of prognostic variables on survival (univariate analysis)

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Six patients had clinical progression of disease at the local site documented on MRI/CT imaging.

Of the 6 patients, 3 patients underwent re-surgical excision of the recurrent tumor and one of these patient (who recurred after 18 months) received post-operative RT to a dose of 45 Gy at 1.8 Gy/fraction with concurrent TMZ and is now on adjuvant TMZ and asymptomatic at the time of last follow-up. Rest of the two patients did not receive any adjuvant therapy (one of them died 2 months following surgery and another was doing well till 4 months after surgery before being lost to follow-up). Five patients received palliative chemotherapy with bevacizumab and irinotecan (median of 3 cycles, range, 3-6). Of these 5 patients, 3 had a partial response to chemotherapy and rest 2 had progression of the disease. Rest of the 6 patients with clinical progression of the disease received best supportive care.


 » Discussion Top


PGS has a similar demographic and clinical profile to GBM [5],[6],[7] and has been managed similar to GBM with comparable [5],[7] or poorer clinical outcomes.[2],[6] Owing to the rarity of the tumor, prospective trials evaluating prognostic variables and treatment outcomes are lacking and are limited to single institutional case series. This is further complicated by heterogeneity of the patient population and the use of varying treatment regimens.[3],[4],[5],[6],[7],[8],[9] The management strategy, particularly the use of concurrent/adjuvant chemotherapy remains a therapeutic dilemma. The present study shows outcomes of PGS treated at a single institution with a uniform protocol of concurrent and adjuvant TMZ.

The median age at presentation of PGS has been reported to be 60-70 years [2],[3],[15],[19],[21] with a male: female ratio of 1.4-1.8:1. In the present series, the male: female ratio was 2.8:1 in concordance with those reported in the literature. Patients in our study presented at a younger age than those in other series, median age 45 years. Two other series, by Biswas et al.[6] and Kumar et al.[5] from the same part of our country also showed a relatively younger age at presentation (median age in both studies was 50 years) and could represent geographical variation in disease presentation. PGS has a propensity to occur more frequently in temporal lobes [3],[7],[14],[20] and the same has been seen in our study as 31% of the patients had tumors in the temporal lobe.

The management of PGS has also evolved over the time, mostly parallel with the developments in the molecular landscape and treatment strategies of GBM. While, earlier reports [3],[4],[5],[6] suggest the use of post-operative RT alone, more recently the use of concurrent chemotherapy has increased and various chemotherapeutic regimens including nitrosoureas, dacarbazine, mithramycin, doxorubicin, cisplatin etc., has been used for PGS.[7],[8],[9] The median survival in patients treated with RT alone in these series [3],[5],[6] ranged from 7 to 11 months and 4 to 11.5 months in series [7],[8],[9],[19] treating patients with concomitant chemotherapy other than TMZ.

Han et al.[15] showed no difference in survival between patients who received concurrent RT and TMZ compared with those who did not (10.4 months vs. 13.9 months; P = 0.946). Another study by Walker et al.[16] from MD Anderson Cancer Centre did not show a better survival in patient treated with concomitant and adjuvant TMZ compared to those treated with RT alone (2 year OS 20.0% vs. 10.2%; P = 0.68). However, in a study by Salvati et al.[14] patients treated with ” Stupp's regimen” had better survival as compared to those treated with RT alone, though was not statistically significant (median OS 17.4 months vs. 15.75 months; P = NS). In the present series, the median OS was 16.7 months and 2 year OS was 32.6% comparable with results by Salvati et al.[14] and Walker et al.[16] Despite the conflicting results in the literature, one thing is clear that the survival of these patients has improved from 4-11 months (before the TMZ era) to 10.4-17.4 months (in the series using TMZ based therapy). Though, the increased survival in the more recent series could be attributed to the advancement in surgery, conformal delivery of RT and better salvage modalities available now, a randomized trial in this setting remains elusive owing to the rarity of the tumor.

The benefit of TMZ in GBM has been aptly backed by the molecular co-relation of promoter methylation of MGMT with survival outcome and benefit from TMZ.[10],[11] MGMT was methylated in 44.6% of patients with GBM in the study [10] and emerged as the strongest prognostic factor for survival (HR 0·49, 95% CI: 0·32-0·76, P = 0·001). The reports of MGMT methylation in patients of PGS are sparse and conflicting. In a study by Lee et al.,[22] MGMT was methylated in only one of 21 patients of PGS and in another study by Kang et al.[13] 58.3% of the patients showed methylated MGMT and was also associated with longer OS than those who had unmethylated MGMT (15 months vs. 11.3 months; P = 0.045). In a study from our institute by Singh et al.[12] Methylation rates were 31.25% and no correlation was seen with survival (P > 0.05). The conflicting results may arise from the discrepancy in the way MGMT is analyzed in the tissue samples (immunohistochemistry vs. methylation specific polymerase chain reaction), genetic polymorphism in the various populations and positivity of MGMT in non-neoplastic tissues.

Although the results of our study are appealing, several limitations exist. Small sample size and the retrospective nature of our study remains a limitation in itself. Bias in referral of patients with good performance status (no patient in our study had a Karnofsky performance status <80) to our institute (a tertiary care cancer center) and also heterogeneity in baseline prognostic factors are limitation, the impact of which on outcome remains unknown. Nevertheless, ours is probably the largest study till date to have uniformly received treatment as per the “Stupp's regimen,” which is considered the standard for GBM and a median survival of 16.7 months achieved is commendable.


 » Conclusion Top


Gliosarcoma is an aggressive and rare malignancy of the central nervous system with a distinct clinic-pathological profile. The results of our study, largest series of patients with PGS treated uniformly with concurrent and adjuvant TMZ shows an impressive median survival of 16.7 months with acceptable toxicity. Incorporation of “Stupp's regimen” as a standard treatment option for patients of PGS seems reasonable and prudent, based on our study. Further studies in a larger cohort of patients and correlation with molecular markers are needed to optimize the outcome of patients diagnosed with PGS.

 
 » References Top

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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]

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