While multimodality therapy has been demonstrated to improve overall survival of patients diagnosed with glioblastoma multiforme compared to surgery alone[4
], there is no established schema that has proven optimal for treatment of GBM. GBM is notoriously refractory to therapy, with survival rarely exceeding 2 years. More than 95% of patients with primary GBM receiving an initial therapy of surgery and external beam radiotherapy(EBRT) with or without concomitant and/or adjuvant chemotherapy, fail within 5 years, and recent literature suggests that even this slim margin of survival may be exaggerated[10
Several studies have concluded that local tumor progression was the predominant pattern of failure [11
]. The observation that the vast majority of recurrences are focal, at the initial site of the neoplasm[14
], has provided an impetus for dose delivery to reduced radiotherapy volumes. Subsequent technological advances in external beam radiation therapy have resulted in investigation into more tumor-conformal radiation delivery techniques, such as 3D-CRT. These techniques spare normal brain tissue from the high-dose area of radiation and can theoretically afford higher radiation dose delivery to brain tumors safely. In an effort to explore dose escalation with 3D-CRT, Nakagawa et al. studied survival in GBM patients using multi-leaf collimator conformal radiation therapy[1
]. Approximately 55% of the patients were treated to a dose of 60 to 80 Gy and 44% were treated to 90 Gy in addition to intravenous chemotherapy, which resulted in an alteration of patterns of failure, but no discernable survival benefit.
The inception of IMRT brought with it great optimism with regard to brain tumors, as the radiation dose conformality available with IMRT is unparalleled[15
]. However, since the development of IMRT in the 1990s, few studies in the literature have assessed the survival impact of this radiotherapy modality with regard to GBM. In a recent series, Narayana et al. report on 41 glioblastoma cases out of a total of 58 high grade gliomas treated with standard fractionation IMRT at Memorial Sloan-Kettering Cancer Center[17
]. This series exhibited exceedingly similar results to the current series, with reported overall survival of 9 months for glioblastoma. While the Memorial group used dynamic leaf IMRT, in contrast to serial tomotherapeutic IMRT utilized in the present series, we believe that the nearly equivalent results from both series, in similar numbers of patients, treated with similar dose parameters, add confirmation to the findings reported here.
The majority of other reports of GBM treated with IMRT involve altered fractionation schedules, with the intent of using the amenity of IMRT dose shaping to minimize adjacent tissue dose while maximizing radiobiological parameters in an effort to improve tumor dose in primary tumors. However, the results from such series have failed expectations with regard to added survival. Thilmann et al[18
] examined the feasibility and safety of an integrated IMRT boost in addition to conventional EBRT in 20 patients, and, though survival data is not yet available, a Phase III trial is underway. Suzuki et al [19
] also studied the feasibility of an integrated boost method using intensity modulated radiotherapy (IMRT). The total dose delivered was 70 Gy in 28 fractions of 2.5 Gy. No delay in therapy from radiation toxicity was necessitated in any of the 6 enrolled patients. Sultanem et al[20
] recently published data from a series of 25 patients treated with hypofractionated IMRT (60 Gy in 3 Gy increments). Median survival in said study was 9.5 months, consonant with the survival observed in the present study.
In addition to individuals with primary disease, the conformal dosimetric profiles attainable with IMRT have been examined as a means of treating recurrent GBM. Voynov et al[21
] record a series of 10 patients for whom stereotactic IMRT using serial tomotherapy was implemented in an effort to treat recurrent malignant gliomas, resulting in a median overall survival time of 10 months, and 50% and 33.3% one and two year survival, respectively. The data derived from the present series reveals slightly inferior outcomes for recurrent disease, with median survival of <5 months.
To our knowledge, this dataset represents one of the few extant series of GBM patients treated with standard fractionation IMRT alone, as well as the largest retrospective study to date of survival data with a 3D-CRT/IMRT boost technique. Our study revealed no substantial differential in survival times of patients treated with IMRT conformal techniques from reported survival in the literature of patients treated with conventional methods, and is similar to recent studies exploring alternative fractionation IMRT methodologies [18
]. There are several possible explanations for this observation. Admittedly, this review is retrospective and numerically limited, with several heterogenous treatment schemas. Additionally, dose escalation was not a primary focus of treatment regimens within this series, nor was fraction-size optimization. These caveats draw attention to the necessity of standardized trials designed to optimize the dosage and fractionation schedules utilized in the treatment of GBM. Additionally, while survival was the primary end-point of note in this study, definitive explication of the role of conformal techniques in non-mortality endpoints, such as disease progression, metabolic or anatomical imaging parameters, neurocognitive outcomes, toxicity reduction and/or quality of life enhancement must be explored as they may represent a more realistic aim in IMRT-based interventions than extension of mortality[22
Nonetheless, the preliminary results of our analysis suggest that undue optimism regarding reduction in mortality for GBM treated with IMRT therapies must be tempered by the recalcitrance of this tumor to radiotherapy. No extant IMRT series to date has matched the survival outcomes observed in the control arm of the EORTC trial[24
], where a 12.1 month median survival using 60 Gy in 2 Gy fractions delivered using quality-assured 3D-CRT was achieved. Consequently, it remains to be seen whether the addition of IMRT will improve upon the impressive 14.6 month median survival seen in the same study's experimental arm of 3D-CRT plus concurrent temozolomide.