Adjuvant stereotactic fractionated radiotherapy to the resection cavity in recurrent glioblastoma – the GlioCave study (NOA 17 – ARO 2016/3 – DKTK ROG trial)

Glioblastomas (GBM) refer to the most frequent and most aggressive primary brain tumors in adults; they are associated with a significant treatment resistance, in the primary situation as well as in the case of recurrence [1, 2]. Offering an extensive trimodal course of therapies, containing surgery, postoperative radiochemotherapy as well as adjuvant chemotherapy, survival still remains at a poor level. When first published from a randomized study in 2005, the radiochemotherapy regimen with temozolomide (TMZ) elevated median survival from 12.1 to 14.6 months [3]. However, despite extensive research, only minor progress has been achieved since almost 10 years [4‐8].

In the vast majority of cases, GBM recurs within 1 year [3], and in most cases recurrence occurs locally [9]. Currently no standard of care can be defined for the treatment of relapsed GBM so far [10]. Thus, patients are treated within individual concepts, mostly based on retrospective studies or small, non-randomized trials [11].

Re-irradiation, especially when modern techniques such as radiosurgery (RS) or fractionated stereotactic radiotherapy (FSRT) has been established in the clinical routine and can be considered a safe and effective alternative for the treatment of recurrent glioblastoma [12‐15]. Median overall and progression free survival ranges around 12 and 5 months, respectively, which is comparable to surgery [15, 16]. Generally, re-irradiation is applied in cases with macroscopic tumor remnants, not exceeding a maximum diameter of 4 cm; however, there is much controversy on the ideal target volume, the rationale for imaging during the treatment planning process, as well as to the ideal timepoint of re-irradition. In all cases surgery is evaluated in the case of recurrence, thus is must be discussed whether re-irradiation is only applicable in cases with tumor remnants. To overcome these limitations, it is worth considering multimodal concepts also for recurrent glioblastoma in order to achieve a prolongation of progression free survival.

As a first step, surgery is feasible especially if the tumor recurs in a not eloquent region, in patients with good physical performance status and if the recurrent tumor has a low tumor volume [17]. Furthermore, younger age might be a factor for better outcome [18], yet the prognostic value of second surgery is currently discussed controversially [19, 20].

Combinations of surgery and adjuvant systemic therapy as well as Re-irradiation with concurrent or adjuvant chemotherapy have been reported from several centers [21‐24]. Especially the latter was able to achieve median overall survival of up 15 months, counting from the date of radiosurgery, in some series [16]. If only systemic therapy is possible in recurrent GBM due to its location, an early time point after former radiotherapy or the size, then it is associated with an overall survival of 6–8 month [11, 16].

Re-irradiation after surgery was reported to be superior to surgery alone in one prospective cohort, increasing OS from 13 weeks with surgery alone to 34 weeks with surgery plus chemotherapy or radiotherapy as adjuvant treatment [25]. Unfortunately, no target volumes were reported in these series. However, there is no data from randomized trials comparing observation after complete resection to an adjuvant treatment in the same situation. Bimodal local strategies combining complete resection followed by a second course radiotherapy have been reported in the context of brachytherapy, too. The median survival in several studies ranged from 52 weeks to 64 weeks after gross total resection with concurrent implantation of permanent ¹²⁵Iodine seeds [26, 27]. No case of re-surgery for radionecrosis was reported in these two series, rendering adjuvant radiotherapy after GTR of a recurrent GBM as a safe treatment approach. Within a context of high dose rate brachytherapy, the GliaSite system was tested after maximal safe resection of recurrent glioblastoma in small series, gaining an overall survival of 9–13 months [19, 28]. Low dose rate as well as high dose rate brachytherapy are applied directly after surgery, thereby precluding sufficient MRI-based planning. Thus, residual tumor might have received only insufficient doses in this series. This would explain remarkably early progressive disease (16 weeks) described in Larson et al. in 2004 [26].

Within the present GlioCave study, we will investigate the impact of radiotherapy as an adjuvant treatment to patients that underwent gross tumor resection of a recurrent GBM.

Adjuvant radiotherapy is an established treatment in primary glioblastoma, independent to the extent of resection [3]. For a long time, a second course of radiotherapy was deemed to be unfeasible due to an expected increase in the risk of severe side effects in patients with completely resected recurrences. Adjuvant treatment after GTR of recurrent glioblastoma currently has therefore been limited to chemotherapy. However, during the last decade, re-irradiation-approaches for macroscopic disease have been established successfully with only limited toxicity [11, 15]. With a small margin around the resection cavity, an acceptable amount of brain tissue will undergo re-irradiation (Manuscript under preparation, Straube et al.). It is therefore worth considering to offer a second course of adjuvant radiotherapy to patients with GTR.

GlioCave is the first phase II trial that will investigate the efficacy as well as the toxicity-profile of this approach.