Radiotherapy with concurrent or sequential by jordan medics

Journal of Medical Imaging and Radiation Oncology 56 (2012) 204–210 bs_bs_banner

RADIATION O N C O LO GY —O R I G I N A L A RTICLE

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Radiotherapy with concurrent or sequential temozolomide in elderly patients with glioblastoma multiforme Sameh A Hashem,1 Ahmed Salem,1 Abdulla Al-Rashdan,1 Najeeb Ezam,2 Ala’a Nour,1 Amer Alsharbaji,4 Chandrababu Rejeeth,5 Issa Mohamad,1 Maher Sughayer,2 Maher Elyan,4 Maysa Al-Hussaini,2 Ala’ Addasi3 and Abdelatif Almousa1 Departments of 1Radiation Oncology, 2Pathology and Laboratory Medicine, 3Medical Oncology, 4Surgery, King Hussein Cancer Center, Amman, Jordan and 5Department of Zoology, School of Life Sciences, Bharathiar University, TamilNadu, India

SA Hashem MD; A Salem MD; A Al-Rashdan MD; N Ezam MD; A Nour MD; A Alsharbaji MD; C Rejeeth MSc; I Mohamad MD; C Rejeeth MSc; M Sughayer MD; M Elyan MD; M Al-Hussaini MD; A Addasi MD; A Almousa MD, PhD. Correspondence Dr Abdelatief Almousa, Department of Radiation Oncology, King Hussein Cancer Center, PO Box 1269 Al-Jubeiha, Queen Rania Al Abdullah Street, Amman 11941, Jordan. Email: aalmousa@khcc.jo Competing interests: None. Submitted 12 April 2011; accepted 17 July 2011. doi:10.1111/j.1754-9485.2011.02325.x

Abstract Objective: The objective of this article was to evaluate therapeutic outcomes of elderly patients with glioblastoma multiforme (GBM) treated by surgery followed by combined modality therapy and compare achievable outcomes to those of a younger age population. Methods and Materials: Seventy-eight adult patients with histologically conﬁrmed grade IV astrocytoma were treated at King Hussein Cancer Center (Amman, Jordan) between September 2004 and December 2008. Records were retrospectively reviewed and included 55 males and 23 females between 19 and 78 years of age (median age 50 years). This case series included 20 patients aged 60 years or older. All patients underwent craniotomy followed radiotherapy and concurrent or sequential temozolomide. The follow-up ranged from 1 to 56 months (median 9.4 months). Results: The median survival for the whole cohort was 13.8 months. The median survival for patients less than 60 years was 14.3 months and for patients 60 years or older was 12.3 months (P = 0.19). Among elderly patients, radical surgical resection (P = 0.002), concurrent delivery of chemoradiation (0.041) and radiotherapy dose ⱖ5400 cGy (P = 0.0001) conferred statistically signiﬁcant improvements in overall survival. Conclusion: Management of GBM in elderly patients should include maximal surgical resection followed by radiotherapy and temozolomide whenever medically feasible. Outcomes comparable to those obtained in younger age groups can be expected. Our results indicate that concurrent chemoradiation is superior to sequential chemoradiation in these patients. Key words: concurrent; temozolomide.

Introduction Despite the widespread adoption of multimodality therapy, the diagnosis of glioblastoma multiforme (GBM) continues to carry a dismal prognosis with a grave overall survival estimate set at 9–12 months.1–3 Historically, surgery followed by radiotherapy was considered the standard of care.3 In 2005, Stupp et al.4 demonstrated that temozolomide administered in addition to adjuvant radiotherapy signiﬁcantly prolongs overall survival. Cur-

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elderly;

GBM;

radiotherapy;

sequential;

rently, temozolomide concurrent with radiotherapy followed by adjuvant temozolomide has been adopted as the new standard of care. Prognosis of elderly patients with GBM is grim with an overall survival ranging from 4 to 8 months.5 Furthermore, management of elderly patients with GBM is still hindered by the paucity of clear protocols due in part to the exclusion of this age group from the majority of randomised trials in this ﬁeld. As a consequence, debate is unfolding as to whether these patients would beneﬁt from aggressive surgical resection

Glioblastoma multiforme in elderly patients

Kaplan–Meier survival analysis was utilised to assess overall survival. Subgroup analysis was based upon KPS, extent of surgical resection, tumour size, radiotherapy dose and concurrent versus sequential delivery of temozolomide. A P-value ⱕ0.05 was considered statistically signiﬁcant. Statistical analysis was performed using SAS version 9.1 (SAS Institute Inc, Cary, NC, USA).

followed by combined modality therapy. In this retrospective review, we assessed the therapeutic outcomes of elderly patients with GBM treated by surgical resection followed by chemoradiotherapy and compared the achievable outcomes with those of a younger age population.

Materials and methods

Results

Charts of consecutive patients with a pathologic diagnosis of World Health Organization grade IV astrocytoma diagnosed and treated at King Hussein Cancer Center between September 2004 and December 2008 were retrospectively reviewed following acquisition of institutional review board approval in an attempt to extract data pertaining to pathological characteristics, clinical status, therapeutic alternatives and disease outcome. Records of imaging studies were made available for this review. Patients ⱕ18 years of age at the time of diagnosis were excluded from this case series. All patients underwent craniotomy followed by radiotherapy and concurrent or sequential temozolomide. Patients who did not receive combined modality therapy were excluded. Patients were classiﬁed into two age groups: those less than 60 years of age (group 1) and those 60 years or older (group 2). Pretreatment performance status was evaluated according to the Karnofsky performance indicator scale (KPS) with scores divided into those above and equal or below than 70%.6 Tumour size was evaluated whenever possible with lesions divided into those more or equal or those less than 5.5 cm. Surgical resection status was designated as partial if only biopsy was performed or radical if an attempt at aggressive resection was undertaken including near total (NTR), subtotal (STR) and gross total resection (GTR). Radiation dose was classiﬁed according to dose: more/equal or less than 5400 cGy. Toxicity data were not available for this review.

Seventy-eight patients met the eligibility criteria of whom 55 were males and 23 were females between 19 and 78 years in age (median age 50 years). Fifty-eight patients were less than 60 years of age at the time of diagnosis (group 1). The median age for this group was 45 years (range 19–59 years). Twenty patients were 60 years or older at the time of diagnosis (group 2). The median age for this group was 65 years (range 60–78 years). Table 1. Supratentorial tumours were found in 52 patients (89.7%) in group 1 and 19 patients (95%) in group 2. Assessment of tumour size was possible in 46 patients (79.3%) in group 1 and 18 (90%) patients in group 2. Tumours were ⱖ5.5 cm in 30 patients (65.2%) in group 1 and in eight patients (44.4%) in group 2. Thirty-five patients (60.3%) in group 1 and 13 patients (65%) in group 2 were designated with KPS score ⱖ70. All patients underwent craniotomy. The extent of surgical resection depended on the location and size of the tumour, patient performance and disease extent. Radical surgical resection was performed in 38 patients (65.5%) in group 1 and 10 patients (50%) in group 2. Upon pathological examination and immunohistochemical confirmation by glial fibrillary acidic protein, GBM was found in 76 patients. Specimens from two patients who harboured gliosarcoma revealed evidence of mesenchymal differentiation and increased deposition of reticulin in areas of sarcomatomous differentiation.

Table 1. Patients characteristics Characteristics Male sex Supratentorial location Tumour size evaluated Tumour size ⱖ5.5 cm KPS ⱖ70 at time of diagnosis Radical surgery (other than biopsy) Type of surgery Biopsy STR/PR NTR/GTR Radiotherapy dose ⱖ5400 Gy Concurrent chemoradiation

<60 years (58 patients), %

ⱖ60 years (20 patients), %

P-value*

41 52 46 30 35 38

(70.7) (89.7) (79.3) (65.2) (60.3) (65.5)

14 19 18 8 13 10

(70) (95) (90) (44.4) (65) (50)

0.95 0.11 0.50 0.37 0.71 0.22

20 29 9 51 38

(34.5) (50) (15.5) (87.9) (65.5)

10 8 2 17 16

(50) (40) (10) (85) (80)

0.52

0.71 0.27

*P-value was calculated based on chi-square or Fisher’s exact test. GTR, gross total resection; KPS, Karnofsky performance indicator scale; PR, partial resection; NTR, near total resection; STR, subtotal resection. © 2012 The Authors Journal of Medical Imaging and Radiation Oncology © 2012 The Royal Australian and New Zealand College of Radiologists

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Fig. 1. Kaplan–Meier survival curve for groups 1 and 2.

Concurrent chemoradiation entailed radiotherapy concurrent with daily TMZ at a dose of 75 mg/m2 to be followed by daily adjuvant temozolomide (TMZ) at a dose of 150 mg/m2 during days 1–5 of a 28-day cycle for six cycles initiated 3–4 weeks following completion of concurrent therapy. Concurrent chemoradiation was delivered in 38 patients (65.5%) in group 1 and 16 patients (80%) in group 2. The remaining patients exhibited poor overall performance and/or unfavourable prognostic variables and received sequential chemoradiation regimen consisting of radiotherapy followed by adjuvant TMZ after 3–4 weeks of rest in the form of 150 mg/m2 during days 1–5 of a 28-day cycle for six cycles. Radiation dose ranged from 5400 to 6000 cGy and was delivered via conventional 180–200 cGy fractionation, 5 days per week for 5–6 weeks. In 10 patients (six in group 1 and four in group 2), suboptimal radiation doses ranging from 4400 to 5000 cGy were delivered because of the dose-limiting tolerance limits of neighbouring normal tissues. No treatment discontinuation or major therapy-induced interruption was reported.

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At a median follow-up of 9.4 months (range 1–56 months), the median survival for the whole cohort was 13.8 months (Figure 1). The median survival for groups 1 and 2 was 14.3 and 12.3 months, respectively (P = 0.19). Because of the small number of patients aged 70 years or older, we cannot draw firm conclusions regarding the outcome of combined modality therapy in these patients (Figure 2). Survival was significantly better in patients who underwent partial (partial resection, STR) or aggressive surgical resection (NTR, GTR) as opposed to those who underwent biopsy for groups 1 and 2 (P < 0.0001 and P < 0.0092, respectively; Figures 3 and 4). Using univariate analysis, survival was significantly better among group 1 patients with KPS ⱖ70% (P = 0.04), who underwent radical tumour resection (P ⱕ 0.0001) and who received radiotherapy dose ⱖ5400 cGy (P = 0.003). Tumour size and chemoradiation sequencing did not confer any statistically significant difference in survival in this age group. Among group 2 patients, univariate analysis demonstrated that radical surgical resection (P = 0.002), concurrent delivery of

Glioblastoma multiforme in elderly patients

Fig. 2. Kaplan–Meier survival curve for patients stratiﬁed according to age.

chemoradiation (P = 0.041) and radiotherapy dose ⱖ5400 cGy (P = 0.0001) all conferred statistically significant improvements in overall survival. Tumour size and KPS did not confer any statistically significant difference in survival in this age group. Using multivariate analysis, radical surgical resection was the only variable that significantly impacted survival in both groups (P ⱕ 0.0001 and P ⱕ 0.029 for groups 1 and 2, respectively).

Discussion In Jordan, central nervous system malignancies account for 3.3% of all newly diagnosed malignant tumours ranking the eight most common cancer. Approximately, 60% of all brain cancers are of astrocytic histology, of which GBM is the most common subtype.7 It has been previously stated that the incidence of GBM is highest in patients 65–84 years of age.8 Demographically, and in variance to such data, approximately two-thirds of GBM cases in Jordanians occur among patients younger than 50 years of age. This ﬁnding is possibly explained by the

differences in age demographics of our population.7 Furthermore, approximately three-quarters of all GBM patients are treated at our institution by combined modality therapy were younger than 60 years of age. The landmark phase III clinical trial conducted by European Organization for Research and Treatment of Cancer and the National Cancer Institute of Canada clearly demonstrated that concurrent radiotherapy plus temozolomide followed by six cycles of temozolomide significantly prolonged survival, with a median survival benefit of 2.5 months compared with radiotherapy alone in patients with newly diagnosed GBM.4 In the updated report published in 2009, survival benefit continued to exhibit statistical significance at 5 years of follow-up.9 Nonetheless, the trend benefit analysis showed a decreasing benefit with increasing age. The hazard ratio was 0.63 for patients 50–60 years of age (P < 0.05), 0.72 for patients 60–65 years of age (P = 0.096) and 0.8 for patients 65–71 years of age (P = 0.340).10 Our study confirms the efficacy of combined modality therapy for elderly patients with GBM. The median sur-

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Fig. 3. Kaplan–Meier survival curve for group 1 patients stratiﬁed according to resection status.

vival for patients less than 60 and patients 60 years or older was 14.3 and 12.3 months, respectively. Although there was a trend towards lower overall survival in GBM patients aged 60 years or older, this difference was not statistically significant. Concurrent delivery of temozolomide and radiotherapy dose in excess to 5400 cGy was statistically significant predictors of improved overall survival in our elderly patient population. One should take the previous statement with caution because normally, it would be expected that patients treated with higher radiotherapy dose and those receiving concurrent temozolomide have improved overall performance and longer life expectancy. As has been previously narrated by Ewelt et al.11; the extent of surgical resection broached as the most significant predictor of therapeutic outcome in both age groups. Elderly GBM patients are generally considered to be less tolerant to combined modality treatment than younger patients.12 This has led some to investigate the efficacy of hypofractionated radiotherapy as a substitute

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to conventional fractionation. In their prospective randomised trial, Roa et al.13 reported no signiﬁcant difference in overall survival of patients 60 years or older treated by standard (6000 cGy/30 fractions) over shortcourse radiotherapy (4000 cGy/15 fractions). During the study period, all our elderly patients received conventionally fractionated radiotherapy. Disappointingly, detailed toxicity data are not available in this report. However, treatment discontinuation or interruption was generally acceptable in our patients.

Conclusions Management of GBM in elderly patients should include maximal surgical resection followed by radiotherapy and temozolomide whenever medically feasible. Outcomes comparable with those obtained in younger age groups can be expected. Our results indicate that concurrent chemoradiation is superior to sequential chemoradiation in these patients. Limitations of our study include the

Glioblastoma multiforme in elderly patients

Fig. 4. Kaplan–Meier survival curve for group 2 patients stratiﬁed according to resection status.

small number patients treated at a single institution. We believe that a prospective randomised trial is warranted to conﬁrm these ﬁndings.

Acknowledgement

We would like to thank Ms Ayat Taqash for her efforts in the completion of the statistical analysis of this paper 5.

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