Journal of Cancer Research and Therapeutics Medknow Publications on behalf of the Association of Radiation Oncologists of India (AROI) ISSN: 0973-1482 EISSN: 1998-4138 Vol. 6, Num. 3, 2010, pp. 272-277

Journal of Cancer Research and Therapeutics, Vol. 6, No. 3, July-September, 2010, pp. 272-277

Original Article

Assessment of compliance to treatment and efficacy of a resource-sparing hypofractionated radiotherapy regimen in patients with poor-prognosis high-grade gliomas

T Gupta, D Dutta, S Trivedi, M Upasani, R Jalali, R Sarin

Department of Radiation Oncology, Tata Memorial Hospital, Tata Memorial Centre, Dr Ernest Borges Road, Parel, Mumbai 400012, India

Correspondence Address:T Gupta, Associate Professor, Radiation Oncology, ACTREC, Tata Memorial Centre Kharghar, Navi Mumbai 410210, India, tejpalgupta@rediffmail.com

Code Number: cr10062

PMID: 21119252

DOI: 10.4103/0973-1482.73353

Abstract

Keywords: Compliance, high-grade glioma, hypofractionated radiotherapy, poor-prognosis

Introduction

Gliomas are the most common primary brain tumors encountered in neuro-oncology practice. ^[1] The World Health Organization (WHO) classifies them into low-grade (Grade I-II) and high-grade gliomas (Grade III-IV) based on histological grading and expected biological behavior. ^[2] The optimal management of high-grade gliomas (HGG) is maximal safe resection followed by adjuvant radiotherapy with or without systemic chemotherapy. Recent evidence has firmly established conventionally fractionated external beam radiotherapy with concurrent and adjuvant temozolomide as the contemporary standard of care for patients with newly diagnosed glioblastomas. ^[3],[4] HGG can be divided into six prognostic classes using known prognostic factors. ^[5] Class V and VI have particularly poor outcomes with median survival of 8.9 and 4.6 months, respectively. A more pragmatic system ^[6] discriminates the favorable-prognosis group from the poor-prognosis group based on age and neurological performance status (NPS) only. The optimal management of poor-prognosis (elderly and/or poor performance status) HGG remains controversial and continues to evolve rapidly. ^[7],[8],[9] It is difficult to make evidence-based recommendations for their management, because most of these patients are treated on institutional or physician preferences without robust scientific evidence and excluded from trial settings. While there is unequivocal evidence that adjuvant radiotherapy improves survival in elderly patients with glioblastoma (a subset of poor-prognosis HGG) compared to best supportive care, ^[10] the optimal fractionation regimen has not been defined as yet. Nevertheless, six weeks of daily fractionated radiotherapy does seem inappropriate in relation to the short expected survival time (median 4-6 months) in patients with poor-prognosis HGG.

An acceptable regimen for such patients should be short, well-tolerated and convenient for the patients as well as the care-givers without compromising on efficacy. ^[11] In this context, the use of few large dose fractions i.e. hypofractionated radiotherapy (hypoRT) has emerged as an attractive option in terms of reducing the overall treatment time (OTT) as well as the number of hospital visits. HypoRT can be delivered either as short-course (five fractions/week) over two-three weeks or as protracted-course (one-two fractions/week) over four-six weeks. Randomized controlled trials have amply demonstrated that daily short-course hypoRT is comparable and not inferior to conventional fractionation in elderly patients with glioblastoma. ^{[12],[13],[14]} HypoRT delivered once weekly for five-six weeks scheduled exclusively over weekends has the potential to provide prompt and adequate treatment without resource implications in busy radiotherapy clinics overburdened with patients and long waiting lists. Such a resource-sparing hypoRT regimen has not been tested rigorously in controlled clinical trials, but continues to be used in clinical practice. The present study is a retrospective analysis of patients with poor-prognosis HGG planned and treated with a resource-sparing once weekly hypoRT regimen in an academic neuro-oncology unit at a comprehensive cancer center with an aim to assess the compliance to treatment and its efficacy.

Materials and Methods

Between January 2004 to October 2009, all patients with poor-prognosis HGG (elderly and/or poor performance status) offered palliative hypoRT following maximal safe resection were included in the study cohort. Patients who were offered palliative hypoRT at initial visit, but improved substantially by the time of simulation/planning and treated with conventional fractionation were excluded. Patients with favorable-prognosis HGG (younger patients with good performance status) treated with once weekly hypofractionation testing the safety and efficacy of a radio-sensitizer in the context of a clinical trial were also excluded. Resource-sparing hypoRT was delivered once weekly (5Gy/fraction) for seven fractions to a total dose of 35Gy/7 fractions over six weeks. This was deemed radiobiologically equivalent to 60Gy/30 fractions over six weeks (conventional fractionation) assuming a low α/β (between 2 and 3) based on contemporary experimental evidence. The treatment was scheduled exclusively on seven consecutive weekends (saturdays) due to logistic considerations. Patient and disease characteristics and treatment details were extracted from medical case records. Compliance to planned treatment was the primary outcome of interest. Factors that could potentially influence compliance were analyzed. Overall survival was a secondary endpoint for patients completing the planned course of treatment and was calculated from date of diagnosis till death or last follow-up. The cut-off date for time-to-event analysis was 31 ^st January 2010. All analysis was done on SPSS version 15.0.

Results

An electronic search of the neuro-oncology database identified 63 patients with poor-prognosis HGG that were offered this resource-sparing hypoRT regimen. Patient and disease characteristics are shown in [Table - 1]. The median age of the study cohort was 58 years (range 40-78 years). Twenty six (41%) patients were >60 years of age. Forty nine (78%) patients had glioblastoma multiforme (WHO grade IV), while the remaining 14 (22%) patients had WHO grade III gliomas (anaplastic astrocytoma, oligodendroglioma, or mixed oligoastrocytoma). The mean (range) and median (interquartile range) interval between registration for radiotherapy and initiation of treatment was 15 (2-46 days) and 12 (8-18 days), respectively. The number of patients offered this hypoRT regimen gradually increased over the years. In the initial years, planning was mostly based on two-dimensional fluoroscopic imaging. In recent times, computed tomography (CT) based planning and three-dimensional conformal radiotherapy was offered to all patients. The contrast enhancing lesion seen on the pre-operative CT scan or T1-weighted magnetic resonance imaging (MRI) was defined as the gross tumor volume (GTV). This was expanded three-dimensionally using a conservative margin of 1-2 cm to create the clinical target volume (CTV). The CTV was appropriately modified to encompass peri-lesional edema as seen on the pre-operative T2/FLAIR images and edited away from natural anatomic barriers (falx, bone). A 5 mm ismetric margin was applied to the final CTV to generate planning target volume (PTV). Steroids were not given prophylactically prior to every weekly fraction. Only patients with recent clinico-radiological evidence of edema (either on post-operative imaging or with clinical features of raised intracranial tension including neuro-deficits) were treated with steroids.

Twenty eight of 63 patients completed the planned regimen of once weekly hypoRT giving a treatment compliance rate of 44%. Seventeen (27%) patients received only a single fraction, while 4 (6.5%) and 8 (13%) patient received 2-3 and 4-6 fractions, respectively. Six (9.5%) patients did not receive even a single fraction of radiation after simulation/planning. The most common reason for non-compliance was progressive neurologic worsening which precluded the care-givers from bringing the patient to the institute for treatment. A univariate analysis was done to identify potential factors that could have influenced compliance [Table - 2]. Performance status (P=0.05) and WHO grade (P=0.04) significantly impacted upon compliance. Age, gender, mode of treatment planning/delivery, and interval between referral and initiation of radiotherapy did not influence compliance significantly. Palliative efficacy of treatment was assessed by symptomatic and neurological improvement and steroid requirements, at completion of planned course of radiotherapy and subsequent follow-up. All 28 patients who completed the planned course of treatment were neurologically stable or better at completion of treatment. The median overall survival for this cohort of 28 patients was 7.4 months (95% confidence interval: 4.4-10.5 months). The Kaplan-Meier estimate of overall survival for patients completing planned treatment was 24% at 1-year [Figure - 1]. Only one patient is a long-term survivor (>5 years) and is alive without significant late sequelae of hypofractionation on follow-up.

Discussion

The optimal management of poor-prognosis HGG remains controversial, but continues to evolve rapidly. ^{[7],[8],[9],[11]} A general consensus is that six weeks of daily fractionated radiotherapy may not be very appropriate for this subset of patients with limited life-expectancy. An ideal regimen should be short, well-tolerated and convenient for the patients and their care-givers without compromising on efficacy. ^[8],[11] Toward this end, hypoRT has emerged as an attractive option in terms of reducing the OTT as well as number of hospital visits by the patients and their care-givers. The outcomes with hypoRT regimens ^{[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31]} have been comparable and not inferior to protracted conventionally fractionated schedules [Table - 3]. The optimal fractionation regimen of hypoRT is not yet clearly defined with diverse fractionation schedules prevalent worldwide [Table - 3]. The basic premise of these hypoRT schedules has been to complete the course of radiation in two-three weeks, with not more than 10-15 visits to the hospital for treatment, which is convenient for patients as well as their care-givers.

The radiotherapy infrastructure in most developing countries suffers from serious resource-constraints and long-waiting times. With a view to be able to offer prompt and adequate treatment to patients with poor-prognosis HGG, this resource-sparing once-weekly hypoRT regimen of 35Gy/7 fractions delivered exclusively over weekends was devised. The radiotherapy treatment could be started immediately (within a few days), patients and care-givers had to attend the hospital only on seven occasions for radiotherapy treatment (once weekly on Saturdays), the dose delivered biologically was high (60Gy conventional fractionation equivalent), and it did not impact upon the already long and ever-increasing waiting-list of patients (planned for daily fractionated radiotherapy to be scheduled on weekdays). However, many of these patients and their care-givers come from far-off places within the country and need to arrange for staying at a place nearby the hospital for >6 consecutive weeks, with attendant financial implications. Even for those from within the city or nearby, the logistics of travel to the hospital can be difficult, particularly when the patients are neurologically compromised and worsening. There could be a small chance that such a large dose per fraction (5Gy) could lead to higher acute toxicity mandating increased steroid doses. The treatment compliance rate in poor-prognosis HGG is quite variable [Table - 3]; however, patients planned for shorter course of treatment are more likely to complete planned treatment as compared to patients with protracted schedules. In this study, 44% of the patients completed planned treatment, while 9.5% did not receive even a single fraction of radiation after treatment planning. Here it is important and pertinent to note that 38 patients (60%) received at least three fractions and hence were on treatment for at least two weeks [Figure - 2]. Thus, a two-week course of hypoRT would have ensured better compliance and may have been more appropriate. Despite level I evidence ^[10] demonstrating survival benefit with adjuvant radiotherapy in elderly patients with glioblastoma, there may be a subset that are unlikely to benefit (such as elderly glioblastoma patients in very poor performance status) and may be more suited to best supportive care alone. ^[32] This extremely unfavorable subgroup is generally excluded from all trial settings. However, in the present study, even such patients were included which may partly explain the unusually low rate of compliance to planned treatment.

The application of hypofractionated stereotactic techniques and accelerated hypofractionated intensity-modulated radiation therapy ^[33],[34] has resulted in impressive outcomes in selected patients with glioblastoma, which may provide impetus to testing such high-precision hypoRT regimens even in poor-prognosis HGG. Nevertheless, such high-precision techniques add enormous complexity to what essentially remains a palliative treatment regimen, the rationale of which would need to be reexamined from the perspective of its impact on quality-of-life, patient and care-giver preferences, local logistics of the treating institution and health-economic considerations. Recently, encouraging results have been reported with upfront temozolomide following surgery with or without deferred radiotherapy in elderly patients with glioblastoma; ^{[35],[36],[37]} however, a primary chemotherapy approach still remains investigational.

This study provides some useful information regarding hypoRT in poor-prognosis HGG, but is not devoid of limitations and suffers from the inherent bias of any retrospective analysis. Information on patients, which were registered in the clinic, but simulation/planning could not be done, was not available. Detailed and systematic evaluation of the reasons for non-compliance was not possible. Although progressive neurologic worsening was the main reason for non-compliance, the final outcome of death was not recorded in a significant proportion of non-compliers. Finally, formal longitudinal health-related QOL assessment using standardized questionnaires at pre-specified time-points was not done in the entire cohort, but was limited to a subset of patients accrued prospectively in a QOL study in the last two years, results of which shall be reported separately later.

Conclusions

The treatment compliance to this resource-sparing once-weekly hypoRT regimen in poor-prognosis HGG has been somewhat suboptimal and discouraging, possibly due to the protracted scheduling over six weeks. Approximately 60% of patients were on treatment for two weeks, suggesting that short-course schedules could more likely ensure compliance. For patients with limited life-expectancy, the choice of the regimen should be based on logistic, financial, and socio-cultural-demographic considerations. An ideal hypoRT regimen should be short, well-tolerated and convenient for the patients and their care-givers without compromising on efficacy.

References

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