Although RT remains an important and essential therapy for GBM patients, no uniform target delineation guideline has been established worldwide, leading to immense variation of the treatment volume for GBM patients in different cancer centers. According to Gebhardt et al, for a round tumor with a 5 cm radius, an expansion of 1.0 cm from GTV to PTV will generate a total irradiation volume of 452 cm3. Furthermore, a 2.5 or 3.5 cm total margin will lead to an increase in the consequent treatment volume to 707 or 908 cm3, respectively. Obviously, adding the margin to 2.5 cm would increase the target volume by more than twice, which may result in additional toxicity to the patients . Therefore, we urgently need an accurate expansion distance from GTV to CTV.
Early pattern-of-failure studies showed that 70–90% recurrent lesions occurred within 2–3 cm of the primary tumor, even after whole-brain radiotherapy [18–24]. However, as revealed by McDonald, several limitations inevitably exist in these early studies. Firstly, the data of these studies is based on early-generation CT technology, which has inferior image resolution compared with MRI. Secondly, the assessment of recurrences required cumbersome manual detection between the radiation plan and subsequent imaging and only one or a few slices were usually selected for measuring two-dimensionally, instead of stereoscopically. Moreover, Comparisons were performed on preoperative CT images, whereas contemporary treatment planning was sketched from the postoperative imaging . Owing to the use of planning system, we accurately calculated the center of the recurring tumor, and obtained the distance of the three-dimensional expansion from the edge of the primary tumor to the center, which made up for these deficiencies.
Our results showed that 90.9% (30/33) of distant recurrences occurred outside 3 cm of the original T1 enhanced lesions, 87.9% (29/33) occurred outside 2 cm of the original T2-FLAIR abnormal lesions, which exceeded the current target area of most treatment centers. By contrast, all local recurrences occurred within 2 cm and 94.8% occurred within 1 cm of the original T1 enhanced lesions, all but 1(1.7%) local recurrences occurred within 0.5 cm of the original T2-FLAIR abnormal lesions. It seems that the current diverse target area delineation guidelines can mainly cover local failures, for which the 1 cm margin from T1 enhanced lesions and the 0.5 cm margin fromT2-Flair abnormal lesions are expected to be enough. Actually, over the years, several cancer centers have published their treatment experiences on limited-margin radiotherapy. Gebhardt et al studied the patterns of failure in 95 GBM patients treated with limited-margin according to Adult Brain Tumor Consortium guidelines. The boost and initial target volume included a 1 cm expansion based on the T1-enhancing or T2-flair imaging. Among the 95 recurrent patients, 77 (81%) suffered an in-field relapse, 6 (6%) had a marginal recurrence, and 27 (28%) experienced a distant dissemination. Low incidence of marginal recurrence indicated limited margins may have a negligible effect on the recurrence pattern . Consistantly, Wake Forest examined 161 patients irradiated with 5-, 10, and 15–20 mm CTV margins, and concluded no statistic difference in patterns of recurrence, PFS or OS among patients with various expansion distances .
Deserved to be mentioned, our study revealed that obvious edema (༞1.8 cm) before radiotherapy indicates more local recurrence( 85.3% vs 44.4%, P = 0.00). However, the impact of peritumoral edema on the survival of glioma patients is controversial. The effect of peritumoral edema on the prognosis and recurrence pattern of patients with glioblastoma remains inconclusive. No significant difference in outcome was found in two prospective international studies that allowed application of EORTC and RTOG guidelines [26, 27]. In other words, inclusion of the whole FLAIR hyperintense region or not, did not confer a prognostic benefit. Chang et al. conducted a series of studies on whether the peritumoral edema should be included in the CTV delineation of glioblastoma , which revealed identical recurrence pattern between the two sets of radiation plans. However, we believe that these studies cannot completely rule out the effect of edema on the recurrence patterns of glioblastoma, because even if CTV only comes from the expansion of the MRI enhanced lesion, the edema region was still, more or less included. Other factors significantly influencing local recurrence include age (P = 0.049) and sex (P = 0.049), which need to be confirmed by more studies.
However, there are several limitations in our study. The small sample size restricted the number of variables analyses. In addition, some patients didn’t complete chemotherapy due to the poor economic conditions. Other limitations of the present study stem from the retrospective design. We need to prospectively compare the different planning methods in terms of efficacy and risk of late radiation-induced toxicity.