Bevacizumab for radiation necrosis following radiotherapy of brain metastatic disease: a systematic review & meta-analysis

Brain metastasis (BM) is the most common adult intracranial disease, and it is diagnosed in approximately 20 to 30% of cancer patients [1‐3]. The most common primary tumor metastasizing to the brain is lung cancer (up to 50%), followed by breast cancer (up to 25%), melanoma (up to 20%), and to a lesser extent, renal cell carcinoma, colorectal cancer, and others [1‐4]. Nonetheless, the incidence and frequency of BM is growing as newer systemic and immunotherapeutic agents are entering the treatment paradigm of these primary cancers [5‐9]. Patients are living longer and are more prone to experience BM in their lifetime.

Depending on various prognostic factors, management of BM may involve surgical resection and/or radiation therapy in the form of stereotactic radiosurgery (SRS), whole brain radiotherapy, or a combination of two [1, 10‐13]. A surge has been witnessed in the use of radiosurgery in BM patients with the approval of various targeted and immunotherapeutic agents for the management of primary sites of systemic cancers [6‐9, 14]. Targeted agents after SRS for the brain have also been continued and have prolonged survival outcomes for patients with BM [6, 7, 9, 15, 16]. Radiation therapy has long been associated with the development of radiation necrosis (RN) in patients with intracranial disease [17‐21]. The rate of RN following radiotherapy or radiosurgery has been estimated at 10–15% [17‐21]. RN is considered as a dose-limiting toxicity for SRS [20, 21]. An increased incidence of RN has also been reported with a combination of SRS and systemic agents [22, 23]. In fact, the benefits of synergism from a combination of radiation and targeted agents are weighed against RN toxicity [7, 22, 23]. Hence, the management of RN takes a center stage in patients with intracranial disease.

Corticosteroids have long been the mainstay of RN treatment. It inhibits the pro-inflammatory response that promotes radiation necrosis and provides symptomatic relief via edema reduction, but long-term use is associated with serious side effects [19]. Surgery has also been used for resectable progressive RN, which can relieve mass effects and it also provides an opportunity to study tissue samples for diagnosis. However, persistent edema may need close monitoring for weeks [19, 24]. Another treatment strategy employed is hyperbaric oxygen therapy (HBOT) [25]. It can increase oxygen concentration to stimulate angiogenesis, restore blood supply to necrotic lesions, and accelerate healing. It has also shown improvement in RN symptoms alone or in combination with Endostar (a recombinant endostatin product) [25]. Laser interstitial thermal therapy (LITT) has been demonstrated to relieve RN symptoms, reduce progression, and improve survival in patients with RN and brain metastases [26, 27]. It has also been used to complement RN surgery [24]. Bevacizumab (BV) has also made it a treatment paradigm for RN [28‐30]. Recent clinical trials have shown encouraging results [31‐33].

Bevacizumab, an anti-VEGF monoclonal antibody, has been evaluated for RN treatment [28‐30]. Its use in RN stems from the fact that RN tissues have elevated levels of VEGF [34, 35]. Radiotherapy induces vasogenic edema and ischemia, resulting in hypoxia that leads to the induction of hypoxia-inducible factor 1α (HIF1α) [34‐38]. HIF1α upregulates VEGF through astrocytes and endothelial cells [36, 38]. White matter around necrotic areas has been identified as the main VEGF up-regulating site [36]. Immunohistochemistry (IHC) of RN surgical samples has confirmed increased levels of VEGF in reactive astrocytes surrounding the core of necrotic tissue [37]. VEGF is an important regulator of angiogenesis, leading to increased vascular permeability, damage to the blood-brain barrier (BBB), and ensuing brain edema [39]. Bevacizumab reduces vascular permeability and alleviates blood-brain barrier damage and brain edema through its binding to VEGF [28, 35, 39].

Several studies have reported the efficacy of BV in the treatment of RN diagnosed in primary brain tumor, metastatic, and patients with nasopharyngeal carcinoma (NPC) [31‐33, 40‐58]. Two randomized controlled trials have shown its efficacy over placebo or corticosteroid-receiving patients, without any increase in toxicity in primary brain tumors and NPC patients [31, 32]. Recently, a prospective phase II clinical trial has revealed efficacy of BV in patients with metastatic brain disease who have RN [33]. However, the majority of studies had included patients without differentiating for their intracranial disease type [50‐54]. Here, we conducted a systematic review to gather evidence of the clinical efficacy of BV for patients with metastatic brain disease who have RN.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were rigorously followed [59].

Overall, two prospective studies, seven retrospective studies, and three case reports involving 89 patients with RN treated with BV were obtained following the research strategy and study selection process [33, 48‐58]. The PRISMA flow diagram for the same is illustrated in Fig. 1. Among them, 39 patients were male and 50 were female (Table 1). Lung (54, 61%) and breast (12, 14%) cancers constituted the main primary pathology for BM. All patients had developed RN after receiving radiation therapy to the brain [33, 48‐58]. Stereotactic radiotherapy (SRT) (37, 33%), which is SRS delivered in fractions, was the main component of treatment delivered after BM development, followed by single-dose SRS (26, 23%) and whole-brain radiotherapy (WBRT) (22, 19%). SRS was also the main radiation strategy given as radiation boost after conventional radiotherapy (24, 21%) [33, 48‐58]. The time duration from radiotherapy induction to RN development was reported in most studies as the time from RT to RN diagnosis and, in a few studies, as RT to BV induction (Table 1). The mean time from RT to RN diagnosis ranged between 6.5 and 19 months, and for RT to BV induction was between 4.6 and 11 months [33, 48‐58]. All the studies had used various combinations of diagnostic procedures to determine the RN diagnosis, including MRI, magnetic resonance spectroscopy (MRS), methionine positron emission topography (MET-PET scans), and biopsy/pathology [33, 48‐58]. Differentiation between disease progression and RN diagnosis was based on the imaging guidelines reported in previous studies [68‐74]. The imaging characteristics are outlined in Table 2. Most common dose of BV used were 5–10 mg/kg [49‐54, 57]. Other doses applied ranged from as low as 1 mg/kg to as high as 15 mg/kg [33, 48‐58]. The timing of BV induction ranged from every 2 weeks to every 6 weeks [33, 48‐58]. The mean number of treatment cycles completed by patients ranged from two to six cycles. Follow up time also varied from 3.3 to 22.7 months. The details are illustrated in Table 1.

We retrieved studies evaluating the efficacy of BV in the management of RN in patients who had received radiation therapy for brain metastases [33, 48‐58]. Most patients showed a reduction in the edema and RN volume by over 50% on MRI images until their last follow-up [33, 48‐56]. In some studies, edema volume reduction was over 70% in patients with BM [52, 53]. Radiographic responses corresponded with improvements in clinical outlook. Neurological symptoms were stabilized, improved, or completely resolved upon BV induction (Table 3). Several studies have reported a similar efficacy data for BV in patients with primary brain tumors (gliomas and glioblastoma), and NPC [31, 32, 45‐47]. In a study by Wang et al., there were patients with other primary brain tumors who demonstrated a similar efficacy in reducing edema volume (T1 post-gd: 61%, T2 FLAIR: 57%), and showed improvement in neurological symptoms (100%) [50]. Fursue, et al. study, as well, had eight patients who had RN with primary brain tumors, other than the three BM patients [52]. A mean edema volume reduction rate of 45% was revealed for these patients. In addition to BM patients, seven other patients (five primary brain tumors and two arteriovenous malformations (AVM) patients) were also included in the study by Sadraei et al. [54]. The study reported an average reduction of 47.4 and 50.7% on both MRI images (T1W and FLAIR), respectively. Gonzalez et al. conducted a retrospective study showing radiographic and neurological symptom improvement in eight patients who had RN with primary brain tumors after being treated with BV (dosage: 5 mg/kgq 2 w /7.5 mg/kgq 3 w) [45]. Average reduction changes of 48 and 60% on post-contrast T1 and FLAIR MRI images were exhibited after a mean of 8.1 weeks from BV treatment start, respectively. In a separate retrospective study by Torcuator et al., six patients with RN diagnosed using biopsy and treated with BV also demonstrated significant reductions in both MRI images (T1 post-gd: 79%, T2 FLAIR: 49%) [46]. Li, et al., in their study comprising 50 NPC patients, though with a slightly lower response rate of 76.0% (38/50), had reported a significant decrease in edema volume reduction on FLAIR images (72.6%, p < 0.001) [47].

All these studies, however, constitute a low-level clinical evidence for the efficacy of BV therapy [45‐47, 50, 52, 54, 56‐58]. Zhuang et al. conducted a prospective clinical trial involving 21 patients who had RN with brain metastatic disease [33]. All patients, except for one, showed radiographic improvement. There is class I evidence for patients with primary brain and NPC tumors [31, 32]. Levin et al., in a randomized placebo-controlled trial, using a bevacizumab dose of 7.5 mg/kg every 3 weeks for seven patients with biopsy-proven RN with primary brain tumors, showed an average percentage change of 59 and 63% in RN volume on T1W and FLAIR images, respectively [31]. A recently concluded RCT involving 58 NPC patients treated with bevacizumab revealed a 65.5% (38/58) response rate [32]. The mean percentage change in RN volume observed on T1 post-gd and T2W FLAIR MRI were 25.5 and 51.8%, respectively. The mean change between before and after bevacizumab treatment was significant for both detected MRI images. Both these studies have reported significant differences in the radiographic responses and RN volume reduction rates observed on both MRI images between bevacizumab and placebo/corticosteroids, suggesting a better outcome for bevacizumab [31, 32].

In our systematic review, one study reported a very high RN recurrence rate (77%) in BM patients [55]. Other studies have failed to report recurrence of such a magnitude. Other than the two studies mentioned in the Results section, there are few other studies that also have cases of RN recurrence [50, 54]. Two patients in the RCT conducted by Levin et al. reported RN recurrence in glioma patients [31]. NPC patients from two other studies have also shown a moderate rate of recurrence [32, 47]. A recurrence rate of 39.5% was observed in a retrospective study of 50 NPC patients [47]. A similar recurrence rate (36.8%) was also demonstrated in the RCT of 58 NPC patients conducted by Xu et al. [32]. The underlying mechanism has not been exclusively investigated in these patients. Apparently, all three kinds of intracranial diseases (primary brain tumors, metastatic, or NPC) have registered RN recurrence [31, 32, 47, 55]. Recurrence was slightly higher in BM patients as reported, but the study had a low level of evidence. Hence, no conclusions could be drawn about the relationship between RN recurrence and the underlying intracranial disease type. Zhuang et al. identified a correlation between RN recurrence and duration after the initial BV withdrawal [55]. Further, Li et al. indicated that duration from induction of radiation therapy RN diagnosis and BV intervention as predictive factors for RN recurrence [47]. Further investigations are required to establish any underlying cause of RN recurrence. Another important aspect of RN recurrence is its diagnosis. Pathology is the standard for diagnosing RN or recurrence [76‐79]. However, almost all of these studies relied on imaging criteria reported in previous studies for the diagnosis of RN and recurrence [31, 32, 47, 55, 76‐79]. For example, in a case report, re-enlargement of RBN after being on BV for 8 months was attributed to recurrence of lung cancer as resected specimen revealed necrotic areas with viable tumor cells [80]. Hence, an accurate recurrence rate could only be determined with pathology, which could be further examined by larger comprehensively organized trials.

In this systematic review, clinical improvement was observed in a majority of the patients; however, some patients did not show any clinical improvement or experienced symptomatic worsening and progression. Medical literature also reveals similar examples. In the study by Gronier et al., no clinical improvement was observed in all three participants with malignant brain tumors after BV therapy (10 mg/kg per month) [81]. One patient had experienced lymphopenia after one perfusion of bevacizumab; the other had developed a transient ischemic attack and a corneal ulcer. Side effects reported in our review were mild, and only one grade 3 pulmonary embolism was described [33, 54‐58]. Several other investigations have also highlighted similar low-grade adverse events [31, 32, 46, 50, 53]. In the retrospective study of Torcuator, et al. (n = 6), only one patient experienced mild fatigue after BV treatment [46]. Grade 2 AEs, including hypertension, fatigue, and proteinuria, were observed in 18% (3/17) of participants of the study by Wang, et al. [50]. However, the patients’ primary intracranial diseases were not identified. In the study by Yonezawa, et al., 33% (3/11) of participants had also shown grade 1 or 2 side effects such anemia, leukopenia, neutropenia, and lymphocytopenia [53]. More importantly, the class I evidence in this regard has shown the safety of BV therapy in primary brain tumors and NPC patients [31, 32]. Levin et al. reported that six (55%) patients experienced side effects [31]. Three of these adverse events were considered serious, including aspiration pneumonia, pulmonary embolus secondary to DVT, and superior sagittal sinus thrombosis. The other three patients showed ischemic changes due to small vessel thrombosis [31]. Another RCT conducted by Xu et al. reported 40 grade 1 or 2 adverse events experienced by 58 patients with NPC [32]. Only one grade 3 adverse event of ischemic stroke was observed. Furthermore, a similar portfolio was revealed for the corticosteroid-treated group, suggesting that BV treatment may not increase the toxicity experienced by patients with RN [32].

From the literature, it appears that bevacizumab was able to elicit therapeutic efficacy at any prescribed dose or frequency [31‐33, 40‐56]. The initial doses used were 5, 7.5, 10, and 15 mg/kg every 2 weeks to every 6 weeks. All doses were tolerated and were not associated with any increase in toxicity. It has been suggested that BV efficacy is associated with its anti-angiogenic effects rather than the dose [33]. In a case report, BV at a dose as low as 3 mg/kg was shown to be effective [48]. In a prospective clinical trial, patients were exposed to ultra-low doses of BV at 1 mg/kg [33]. Radiographic responses were observed in 20 of the 21 patients. Such a versatile dosing profile makes this treatment reachable to a broader population, as it is an expensive treatment. To date, exact cost-benefit relationship evaluation has not been adequately addressed for bevacizumab therapy [29]. It may cost around 4800 to 19,200 U.S. dollars (USD) for a single four to eight-week course of 5 to 10 mg/kg, administered every other week at a cost of 600 USD per 100 mg [82, 83]. An increase of 2.4 months in survival, a 20% improvement in a patient’s quality of life, or a linear combination of the two was required for bevacizumab treatment to be considered cost-effective according to a basic hypothetical calculation using 10,000 USD cost for a course of BV therapy and a quality-adjusted-life-year (QALY) threshold of 50,000 USD [84]. Hence, further studies are needed to establish a dose requirement for achieving the maximum benefit and to make the bevacizumab treatment cost-effective.

Several observations limit the results of our study. As a systematic review, the incorporated data comes from heterogeneous populations, diverse treatment centers, and a variety of research designs used for investigations. Moreover, the time period in which the case reports/studies were undertaken also varied. We included case reports and some retrospective studies [48‐56]. Retrospective studies are prone to selection bias, recall bias, or misclassification bias and are subject to confounding [85]. Most of these studies mainly constitute class III level evidence, except for two prospective studies [48‐56]. The types of radiation also differed from patient to patient. Moreover, pathology reports are used as standard for the diagnosis of RN; however, these studies mostly used imaging studies for RN diagnosis [48‐56]. Some of the studies reported global adverse events/recurrence rates without differentiating between tumor types; however, they also contained participants other than BM patients [50, 53, 54]. Nonetheless, we presented the recurrence rates in results and side effects in the Discussion section to construct a better recurrence rate/adverse event profile for the readers. The follow-up for different studies also varied. The likelihood of only BV-responding patients being included in the study may also be prone to publication bias.

According to our results, bevacizumab can be considered safe and efficacious for BM patients diagnosed with RN. However, the level of evidence presented was low, making our bevacizumab efficacy results inconclusive. Furthermore, several dimensions of BV treatment for RN were less clarified and should be investigated in future trials. These include the diagnosis standard used for RN, impact of type/dose/fractionation of radiation therapy used on RN, patterns, and underlying mechanism of recurrence. The pending results of a phase II trial (NCT02490878) of BV plus corticosteroids versus corticosteroids plus placebo for radiation necrosis after radiosurgery for brain metastases will further define the role of bevacizumab in the management of radiation necrosis.