Edited by: Sean Collins, Georgetown University Hospital, USA
Reviewed by: Brian T. Collins, Georgetown Hospital, USA; Douglas R. Spitz, University of Iowa, USA
*Correspondence: Anand Mahadevan, Department of Radiation Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA. e-mail:
This article was submitted to Frontiers in Radiation Oncology, a specialty of Frontiers in Oncology.
This is an open-access article distributed under the terms of the
Glioblastoma Multiforme (GBM) is an aggressive primary brain neoplasm with dismal prognosis. Based on successful phase III trials, 60 Gy involved-field radiotherapy in 30 fractions over 6 weeks [Standard radiation therapy (RT)] with concurrent and adjuvant temozolomide is currently the standard of care. In this disease, age and Karnofsky Performance Status (KPS) are the most important prognostic factors. For elderly patients, clinical trials comparing standard RT with radiotherapy abbreviated to 40 Gy in 15 fractions over 3 weeks demonstrated similar outcomes, indicating shortened radiotherapy may be an appropriate option for elderly patients. However, these trials did not include temozolomide chemotherapy, and included patients with poor KPS, possibly obscuring benefits of more aggressive treatment for some elderly patients. We conducted a prospective Phase II trial to examine the efficacy of a hypofractionated radiation course followed by a stereotactic boost with concurrent and adjuvant temozolomide chemotherapy in elderly patients with good performance status. In this study, patients 65 years and older with a KPS > 70 and histologically confirmed GBM received 40 Gy in 15 fractions with 3D conformal technique followed by a 1–3 fraction stereotactic boost to the enhancing tumor. All patients also received concurrent and adjuvant temozolomide. Patients were evaluated 1 month post-treatment and every 2 months thereafter. Between 2007 and 2010, 20 patients (9 males and 11 females) were enrolled in this study. The median age was 75.4 years (range 65–87 years). At a median follow-up of 11 months (range 7–32 months), 12 patients progressed and 5 are alive. The median progression free survival was 11 months and the median overall survival was 13 months. There was no additional toxicity. These results indicate that elderly patients with good KPS can achieve outcomes comparable to the current standard of care using an abbreviated radiotherapy course, radiosurgery boost, and temozolomide.
Malignant gliomas, including glioblastoma multiforme (GBM) are the most common primary brain tumors in adults and the age-adjusted incidence of these high-grade gliomas has increased over recent years (Lowry et al.,
Older patients have a worse survival outcome compared with younger patients (Ampil et al.,
In early retrospective series the overall median survival of patients treated with SRS was quite encouraging (Buatti et al.,
In the case of elderly patients with GBM, we hypothesized that the advantages of hypo fractionation (shorter course of radiation using higher daily doses) could be supplemented by SRS to deliver total doses of radiation more in line with Standard RT. We also reasoned that this dose of radiation when combined with concurrent and adjuvant Temozolamide could approximate results obtained with Standard RT and temozolomide as demonstrated in Phase III randomized trials (Stupp et al.,
This was an institutional review board approved prospective single arm phase II study. Patient selection and eligibility criteria required that all patients have histologically confirmed GBM, be 65 years of age or older, have a pre-treatment KPS of >70, and not have contraindications for radiotherapy or temozolomide. Pathology was confirmed with surgical resection when deemed feasible; otherwise a core needle biopsy was obtained. Pre- and post-operative (when resected) MRI along with baseline blood counts and chemistry studies were obtained in all patients. Patients with recurrent glioma, brainstem invasion, and prior radiation to the head and neck area were excluded from the study. Protocol therapy was started within 5 weeks of surgery.
Patients were simulated in a supine position with a thermoplastic immobilization head mask. Planning CT scans with IV contrast were obtained and transferred to the treatment planning station. Pre-operative and post-operative MRI scans were utilized for fusion with simulation CT scans for outlining the target volume. Fused FLAIR/T2 images were used to contour changes in the fused axial CT images to delineate the gross tumor volume (GTV). A 1.5–2 cm expansion was added to the GTV to create the planning target volume (PTV). Non-coplanar egocentric beams with appropriate energy and conformal collimation were used. Isodose distributions, treatment plans, and dose volume histograms were generated to produce a homogenous plan with less than ±10% inhomogeneity within the target volume. The prescribed dose to the PTV was 40 Gy delivered in 15 daily fractions.
Frameless SRS with the CyberKnife system was used to deliver the boost. The target volume was determined by changes in the contrast enhancing T1 MRI. The isodose line covering 95% of the target volume was used as the prescription. The prescribed dose depended on the greatest dimension of the lesion. For lesions less then 2 cm the dose was 22 Gy, for lesions between 2.1 and 3.0 cm the dose was 18 Gy, for lesions between 3.1 and 4.1 cm the dose was 15 Gy, and for lesions larger than 4.1 a fractionated regime of 8 Gy × 3 fractions for a total dose of 24 Gy was used. All patients received anti-edema (dexamethasone) and anti-seizure (leveteracetam) prophylaxis.
The lens and cervical spine were shielded from the direct beam during EBRT delivery. When possible, without shielding the gross tumor, attempts were made to limit the optic chiasm dose to 54 Gy, the retina dose (of at least one, but preferably both eyes) to 50 Gy, the lens dose to 8 Gy, and the brain stem dose to 60 Gy in 2 Gy/fraction equivalents and inclusive of the radiosurgery boost dose.
Temozolomide was prescribed orally (75 mg/m2/day) for 4 weeks during EBRT and during the week of SRS boost therapy. Chemotherapy began 1 h before the first fraction of EBRT and continued during weekends and holidays. Four to six weeks after completion of SRS, Temozolomide (150 mg/m2/day) was prescribed orally for 5 days (days 1–5) of each 28-day cycle. This schedule was continued without interruption, as long as there was no tumor progression and toxicity was ≤grade 3, for 1 year or until completion of 28 treatment cycles (whichever was longer).
All patients were followed with weekly clinical examination and complete blood counts during treatment. Patients were then routinely followed every month for blood counts, clinical assessment, and Temozolamide prescription. Contrast enhanced MRI scans were obtained 1 month after radiation and every 2 months thereafter until progression. Progression was defined as worsening enhancement in MRI in the setting of neurological deterioration.
The primary end point of the study is median and 6 month progression free survival with a secondary end point of overall survival and tolerability. The study was designed to discern a 50% improvement in progression free survival at 6 months over that reported in Roa et al. (
Twenty patients (9 male and 11 female patients) were included in this study. The mean age was 75.4 years (range 65–87 years). All patients completed the protocol treatment as prescribed. After delivery of 40 Gy in 15 fractions for the initial course, three patients received a single fraction SRS boost. The remaining 17 patients had a target volume exceeding 4 cm in greatest dimension. These patients received a total SRS boost dose of 24 Gy delivered in 3 fractions. Table
Sex | |
Male | 9 |
Female | 11 |
Age (>65 years) – mean (range) | 75.4 years (65–87 years) |
Extent of surgery | |
Gross total resection | 10 |
Sub total resection | 3 |
Biopsy | 7 |
Karnofsky performance status | |
70 | 14 |
80 | 2 |
90 | 4 |
100 | 0 |
Salvage therapy | |
Bevacizumab | 5 |
Phase I trial | 2 |
Other systemic therapy | 0 |
Stereotactic radiosurgery | 1 |
No salvage therapy | 9 |
N/A (no progression) | 3 |
At a median follow-up of 11 months (range 7–32 months), 11 patients had tumor progression. Four of these patients deteriorated neurologically in the absence radiological progression. Two patients died of unrelated causes (one from untreated sepsis and the other from a pulmonary embolism from deep venous thrombosis). Five patients were still alive at last follow-up. The median progression free survival was 11 months and the median overall survival was 13 months (Figure
All patients tolerated and completed protocol treatment. All patients experienced fatigue and skin reaction (erythema and alopecia), not requiring and further treatment (Grade I). Four patients required prolonged dexamethasone for symptomatic cerebral edema, which eventually resolved (20% grade II toxicity) in all but two of the patents. These two patients required hospitalization for management. Two additional patients were hospitalized: one for urinary tract infection, and the other for pulmonary embolism. These events were unlikely to be directly related to study participation. Overall four patients (20%) experienced Grade III toxicity. There were no life threatening (Grade IV) complications or treatment related deaths.
The current standard treatment for patients with glioblastoma is 60 Gy of involved-field radiation in 30 fractions delivered over 6 weeks with concurrent and adjuvant Temozolamide. The 6 week duration of this conventional radiation treatment is not well tolerated by the elderly. While lesser doses of radiation have been shown to be equivalent in the elderly with a wide range in performance status, for those patients with a good performance status (KPS > 70) it is possible that conventional radiation doses may be more efficacious. Hence hypofractionation (shorter course of radiation with larger doses per fraction) along with a highly conformal boost could potentially deliver equivalent, but tolerable doses of radiation in short treatment duration with improved outcome and quality of life. To date, this study supports that hypothesis with a median progression free survival of 11 months and a median overall survival of 13 months.
The elderly population is growing and with it the incidence of cancer, especially brain tumors, is increasing in the elderly age group. However, it is unclear whether this increase is a result of improvements in diagnosis or represents a true increase in the incidence of cancer (Lowry et al.,
In a study of post-operative RT for 301 newly diagnosed GBM patients, Barker et al. (
The 1990s saw published reports on several small series of patients treated with SRS boost for the primary treatment of malignant glioma (Buatti et al.,
Our trial aimed at achieving the benefit of delivering adequate radiation in a shortened time with concurrent and adjuvant chemotherapy. The progression free survival in this trial of 11 months compares very favorably to the EORTC/NCIC trial and to that of prior trials for this disease. This is in spite of our trial’s designed inclusion of only elderly patients rather than patients of all ages. This evidence hints that our abbreviated overall course of treatment is not inferior to standard of care treatment.
The steroid dependency rate in out trial was about 20%. In two French studies (Marantidou et al.,
Toxicity | Number (%) | Grade |
---|---|---|
Skin erythema | 21(100) | I |
Patchy alopecia | 21(100) | II |
Steroid dependence | 2(9.5) | II |
Cerebral edema (hospitalization) | 2(9.5) | III |
Possibly related (UTI, PE) | 2(9.5) | III |
One theoretical reason for the improved local control, as reflected in improved progression free survival, could be the delivery of higher stereotactic radiation dose to the contrast enhancement after initial radiation to the surrounding edema. It has been hypothesized that treatment resistant glioma stem cells reside in the areas of enhancement and these may be better treated with higher doses of radiation in the setting of systemic therapy (Cheng et al.,
Old age and poor performance status are the two most significant prognostic factors in patients with Glioblastoma. Elderly patients tolerate a prolonged course of radiation poorly and those with good performance status may benefit from aggressive therapy. Hypofractionated radiation with a stereotactic boost can deliver a shorter course of adequate radiotherapy effectively and safely in the temozolamide era.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.