Long-term outcome of stereotactic brachytherapy with temporary Iodine-125 seeds in patients with WHO grade II gliomas

The management of low-grade gliomas WHO grade II (LGGII) is still a difficult undertaking. Several evidence-based clinical practice parameter guidelines have been formulated [1‐6]. The results of the recently published EORTC 22033–26033 study further stress the importance of molecular analyses to individualize LGGII treatment [7].

Stereotactic brachytherapy (SBT) is a safe and effective local treatment option in selected LGGII. The steep dose gradients enable the delivery of a high dose to a defined target volume, while sparing surrounding healthy tissue [8]. Assessing the invasiveness associated with open brain surgery and the treatment-related side effects as well as the lifetime dose limits of external beam radiotherapy (EBRT), Iodine-125 brachytherapy is a suitable modality that leads to only a few complications in patients [9‐11].

The primary objective of this retrospective analysis was to assess survival time and outcome of a large cohort of 106 consecutive patients with histologically verified LGGII treated with SBT with low-activity temporary Iodine-125 seeds. Prognostic factors were analyzed in respect to their relevance on survival time after seed-implantation. Furthermore, the influence of additional applied treatment was considered.

The 5- and 10-years OS after first diagnosis and after SBT of our long-term analysis of 79% and 62%, and 72% and 43%, respectively, confirmed those of other studies on SBT in low-grade gliomas [11]. Mehrkens et al., for example, reported in 2004 a 5-years OS rate of 55% in their subset of patients [9], Kreth et al. found in 2006 5- and 10-years OS rates of 56% and 37%, respectively, for their cohort [13], and Schnell et al. registered in 2008 a 5-years OS of 93% in a selected population [10].

The results of our SBT series also compare well to the outcomes of another high precision radiotherapy mode, stereotactic radiosurgery. With this technique, 5- and 10-years OS rates of 76–89% and 65–74% have been reported [5]. Both treatment modalities are recommended now for selected patients in the evidence-based clinical practice guidelines [5]. However, radiobiology is very different in SBT and stereotactic radiosurgery. While SBT is a protracted dose application, during stereotactic radiotherapy doses are delivered at a high dose rate. Shrieve et al. directly compared SBT and stereotactic radiosurgery in patients with recurrent glioblastoma and found similar survival rates with both modalities [20]. Nevertheless, these results were obtained from high-grade gliomas and are only transferable to LGG to a limited extent.

Our analysis shows similar results to a prospective trial on proton therapy for LGGII, which requires 6 weeks of treatment time [21]. The dosimetric advantages of proton therapy over conventional radiotherapy have been demonstrated in another analysis, especially in organs at risk sparing [22]. With SBT, with its steep dose gradients, organs at risk sparing is guaranteed as well.

In the meantime, it has been shown that the addition of chemotherapy (procarbazine, CCNU, and vincristine) to radiotherapy can improve survival in patients younger than 40 years of age with subtotal resection and in all patients over 40 years of age. Ten-years PFS could be improved from 21 to 51%, and 10-years OS from 40 to 60% [23, 24]. It has not so far been prospectively studied whether survival rates in LGG patients could be further improved through an early treatment combination of SBT and chemotherapy.

Ten-years OS and PFS rates as high as 89.8% and 47.3% have been reported for a combination treatment of SBT and EBRT in oligodendroglial brain tumors WHO grade II [25]. In our patient cohort only 16 specimens were classified as oligoastrocytoma or oligodendroglioma, known to be favorable histologies. Interestingly, histology and LOH 1p/19q were no prognostic factors for OS and PFS in our analysis.

A complication rate of 16% seems high initially. However, it is an overall complication rate that includes not only severe, but all complications and covers not only the periprocedural time, but the entire follow-up period. Severe complications (radionecrosis, local cerebral bleeding, cerebritis) occurred in 6% of cases, which is in line with other brachytherapy studies [11, 25]. Comparison with other radiotherapy methods (e.g. radiosurgery) is challenging, but toxicity seems to be similar [5]. Comparison with surgical complication rates is even more challenging as different techniques (e.g. awake surgery) are used and our study also included tumors in eloquent locations harboring high risks for surgical complications.

These promising results of SBT in low-grade gliomas, in contrast to the disappointing studies of high-grade glioma brachytherapy, may partly derive from target volume definition and to -some extent- selection bias. In our study only well circumscribed low-grade gliomas < 4 cm have been implanted. High-grade gliomas are much more infiltrating and thus not very well suited for a highly focused radiotherapy technique like brachytherapy or radiosurgery [26]. As tumor volume is a negative predictor for survival [15, 27, 28], the good survival rates may have been biased by the small and circumscribed tumor features that were required for SBT [13, 29, 30]. The prognostic scoring system formulated by the European Organization for Research Treatment of Cancer Brain Tumor Cooperative Group and Radiotherapy Cooperative Group, found that in those age ≥ 40 years, astrocytoma histology and largest tumor diameter ≥ 6 cm are unfavorable prognostic factors [31]. The analysis of our patient cohort did not reveal larger tumor volume as negative prognostic factor (though, largest implanted volume was 50.5 ml), and neither astrocytoma histology nor age influenced OS. Again, this stresses the selection bias caused by the maximum implantable tumor volume of SBT, which may have confounded the outcome. On the other hand, tumors in vicinity of eloquent brain areas deemed inaccessible to safe tumor resection have been included in this study, as well. In lesions that are feasible for microsurgical treatment, complete tumor resection is still regarded as the gold standard in LGGII [32‐35]. For eloquently located LGG Schnell et al. have shown that an incomplete but safe surgical resection in combination with SBT is a good option [12]. In our patient cohort 19 patients had a planned partial resection before SBT of the residual disease. Whenever tumor resection is not safe in even small lesions but eloquent brain areas SBT is a minimally invasive, safe alternative with good therapeutic effects.

Beside the mentioned selection bias, another limitation of our analysis is the lack of molecular markers in a large proportion of our patients. The patients of the study were treated between 1997 and 2011 but molecular marker analyses were not introduced until 2004 for LOH, until 2007 for MGMT and until 2008 for IDH. Therefore, the status is unknown in 56%, 52% and 75% of patients, respectively. In recent years, it has become more and more evident that the heterogeneous outcome in patients with low-grade gliomas may be explained in large proportion by molecular markers. Therefore, IDH, LOH and MGMT status are currently included not only in classification but also in prognosis determination and treatment planning [2, 36‐38].

Our analysis further confirmed that SBT is a safe and minimally invasive treatment modality with good outcome in selected patients, which can postpone the application of secondary treatment.

It is an alternative primary treatment method as well as an adjunct to open tumor resection, with acceptable complication rates. SBT can expand the options of interdisciplinary and individualized multimodal treatment of LGGII.