An Update on Current and Emerging Therapies for Brain Metastases

What is the Best Treatment Option

Multi-modality management of BMs is continually being researched and improved. Table 2 illustrates recent clinical trials which have compared the success of different approaches to BM management.

Microscopic total resection remains a key treatment for single BMs [3]. Excision is especially indicated for larger brain lesions in non-eloquent areas [7]. Surgery provides immediate relief of neurological symptoms secondary to mass effect [5] and allows for histopathological diagnosis, which can be used to guide future treatment [4]. Surgical resection has also been shown to best improve intracranial hypertension and allows for more rapid tapering of corticosteroids [6]. The extent of the resection is a key factor for prognosis, with complete removal resulting in a significantly better prognosis than incomplete BM resection. Local recurrence of BMs after surgery can be as high as 67%, even after complete resection and post-operative radiotherapy [3].

Stereotactic radiosurgery (SRS) is image-guided and delivers a high dose of radiation to a specific target, minimising the dose to the surrounding brain tissue. It is an outpatient treatment, doesn’t require general anaesthetic [4], and can be delivered in a single session [2]. SRS can target areas of the brain which cannot be easily accessed surgically, and therefore may be the only option for certain tumours [4]. SRS is the main alternative to surgical resection in patients with limited numbers of BMs, good Karnofsky performance score (KPS) and intracerebral tumour volume under 3cm [1, 4, 8]. There is however no clinically important difference in overall survival between these two management options [4]. However, first-line SRS has been shown to have a better local control than surgery and is less likely to need additional treatment than resection [4]. A side effect of radiotherapy is delayed radionecrosis of the brain tissue, which may require subsequent surgical resection (re-do surgery) [4]. This is more commonly seen in whole brain radiotherapy (WBRT) than SRS; however is still important to consider when selecting SRS as treatment of choice. For multiple brain metastases, SRS is commonly reserved for salvage therapy, or as consolidative boost therapy for larger lesions or radio-resistant histologic types e.g. melanoma or renal cell carcinoma [9].

WBRT delivers a relatively low dose of radiation to the entire cranium – destroying microscopic disease at the tumour site and at distant intracranial locations [10]. There are various WBRT fractionation schemes, the most common being 30Gy in 10 fractions, which requires 5-10 hospital visits [4]. WBRT involves the patient lying supine, with the head immobilised. The appointment takes approximately 15 minutes, but the actual ‘beam-on time’ is less than 5 minutes [4]. Possible acute toxicities of WBRT that can impact health- related quality of life (QOL) include: temporary hair loss, mild dermatitis, fatigue and decreased physical functioning [4, 9, 11]. Cognitive and neurologic deficits are more long-term toxicities associated with WBRT, which may occur secondary to transient oedema around the tumour site; which usually responds to initiation of corticosteroids, or a short-term increase in dose [4]. Cognitive decline associated with WBRT may manifest as loss of episodic memory, executive function, processing speed or fine motor control; however WBRT seems to have a particularly pronounced toxicity on episodic memory compared to other cognitive domains [4].

Optimizing BM control with adjuvant radiotherapy

contributes with a beneficial effect to survival. However the decision on modality requires a discussion of trade-offs with patients [4]. As the choice between SRS and WBRT involves trying to balance outcomes of both intracranial control and cognition [12]. SRS in the post-operative setting is a standard of care to improve surgical bed control relative to observation. Relative to WBRT, SRS is inferior in terms of surgical bed control and associated with a shorter time to intracranial failure; however, it is less toxic than WBRT and improves time to and incidence of cognitive decline [12]. Future research is needed to refine SRS technique in order to further improve outcomes such as surgical bed control [4]. Due to the recent understanding of the toxic effects of WBRT on cognition and health-related QOL, the use of WBRT should be limited, and other treatments such as SRS should be approached initially, delaying WBRT to later in a patient’s disease course where appropriate [4].

Up until recently, WBRT has been the standard treatment for patients with multiple BMs. However, due to the side effects and neurological dysfunction associated with WBRT, the use of SRS in patients with a small number of BMs has been investigated. A single-center retrospective study compared SRS to WBRT as the initial treatment for 10–20 BMs from NSCLC [13]. Patients in the WBRT group showed superior intracranial control and time-to-intracranial-progression, with a higher risk of intracranial recurrence seen in the SRS group. However, fewer adverse events were seen in the SRS group, and the study found no significant difference in overall survival between SRS and WBRT. Therefore, SRS may be a useful alternative up-front treatment for 10–20 BMs from NSCLC, prolonging the need for WBRT, and its associated adverse effects. Further prospective randomized studies analyzing neurocognitive complications are needed [13].

Advances in Whole Brain Radiotherapy (WBRT)

Suteu et al. looked at the impact of addition of 3D conformal boost radiotherapy (3DCRT) to WBRT in BM management. This technique is a similar alternative to SRS, as it is a localised treatment that can deliver a high radiation dose to the intracerebral tumour. The study concluded that WBRT+3DCRT did improve the QOL in patients with a limited number of brain metastases. Overall survival rates seemed to be better in patients with a single metastatic lesion and smaller intracranial tumour volumes, suggesting that these patients may benefit the most from WBRT+3DCRT [8].

Hippocampal neural stem-cell injury caused by WBRT may play a role in the memory deficit associated with WBRT [14]. As a result, recent clinical trials have looked at the potential cognitive preservation benefits of neuroprotective strategies during WBRT. RTOG 0614, a multi-institutional phase III trial, observed the administration of memantine (an agent originally used in Alzheimer’s disease patients) during WBRT to reduce the probability of cognitive dysfunction at 6 months by 11%, and achieve better preservation of executive function and processing speed [15].

RTOG 0933, a single arm phase II trial found that hippocampal-sparing WBRT was associated with preservation of memory and health-related QOL [16]. By avoiding the hippocampus with intensity-modulated radiotherapy, the study found that the median decline in Hopkins Verbal Learning Test-Revised Delayed Recall from baseline to 4 months was 7%, compared to 30% seen in control patients who received conventional WBRT [16].

NRG-CC001 was a phase III trial analysing the effects of WBRT and memantine (M) with or without hippocampal avoidance (HA) in patients with BMs. Patients were randomised to WBRT+M or HA-WBRT+M, with WBRT given in 30Gy/10 fractions [17]. At 4 months, HA-WBRT+M was associated with a lower risk of deterioration in executive function. At 6 months, patients reported fatigue, difficulty speaking and problems with memory less frequently in the HA-WBRT+M arm. The results of patient-reported cognition and symptom interference also favoured HA-WBRT+M at 6 months [17]. The study concluded that hippocampal sparing reduces time to cognitive deterioration, while achieving similar intracranial control and survival to standard WBRT.

The on-going clinical trial NCT04277403 is randomizing patients to receive either hippocampal avoidance WBRT with integrated tumor boost (HA-WBRT+SIB) or SRS. It is hoped that the trial will answer whether HA-WBRT+SIB can offer better intracranial control than SRS, whilst both avoiding the neurocognitive side effects seen due to hippocampal neural stem-cell injury following standard WBRT, and delivering high intensity radiation in a more focused manner, similar to SRS.

Approaches to Re-irradiation

Re-irradiation has shown success in the management of the primary brain tumour, Glioblastoma Multiform. High- dose salvage re-irradiation in patients with recurrent/ progressive glioma is associated with: 1) improved or stable QOL (preserved functional domains and reduced symptom burden), 2) improvement in activities of daily living and 3) encouraging survival outcomes [18].

For BMs, the most useful indication for re-irradiation remains unknown. However patients may benefit under certain conditions (e.g. younger age, higher KPS, stable extracranial lesions and smaller tumour volume) whereas patients with peritumoral oedema, cystic BMs and low KPS might not be suitable. Zhou Huang et al. (2017) concluded that re-irradiation is an effective option for patients with BMs secondary to breast cancer [18]. Intracranial failure after re- irradiation may occur either due to the dose administered being too low, or due to radionecrosis. How to choose between SRS or WBRT for re-irradiation of recurrent BMs remains to be clarified. There is emerging evidence that SRS is a reasonable treatment for recurrent BMs, with the RTOG 90-05 protocol having already established the maximum tolerated dosage of SRS in re-irradiation after a course of WBRT. Data on using WBRT following SRS is limited. WBRT can reduce intracranial relapse, especially for distant BMs, and therefore can be considered as salvage therapy if BMs have disseminated recurrence and are thus not suitable for SRS. However, with WBRT come the risks of subacute leukoencephalopathy and neurocognitive dysfunction [19]. Nieder et al. (2018) compared the treatment of locally recurrent metastasis using A) WBRT and two courses of SRT, with B) two courses of WBRT and additional SRT. Usually this extent of re-irradiation is a last resort, with the patients being treatment-resistant and without other options, and thus the rate of adverse effects is not viewed to be as prohibitive. Patients must therefore decide and consent on an individual basis, with the clinician providing them with the best available clinical evidence. Current data is not sufficient to determine if there is a net benefit from re-irradiation (good rate of local control and/or symptomatic improvement without treatment-induced adverse events) [19].