Page 22 - ARNM-2-2

Advances in Radiotherapy
& Nuclear Medicine Melanoma brain metastatic treatment

Available treatment strategies can be applied either alone for 40 – 60% of melanoma patients, target therapy with
18
or in combination. BRAF v600 e/k inhibitor dabrafenib plus the MEK inhibitor
Local treatment is usually recommended as the first trametinib should be considered. The COMBI trial
19
option for symptomatic BM. Single large lesions (>3 cm) reported improved an IRR up to nearly 60%. However,
located in non-eloquent brain areas or smaller lesions it has been reported that patients receiving targeted therapy
with symptomatic potential are usually suggested for experienced therapeutic resistance earlier than those
3
surgery, which would bring immediate therapeutic effects. treated with ICIs, and some authors recommend using
3
Surgery has also been recommended for patients with focal this approach only in case of a large burden of extracranial
brain progression during systemic treatment, although disease. For the patients who are candidates for primary
some authors are more favorable to recommending systemic treatment, focal treatment with surgery or radiation
focal radiation in this context. Surgery is unanimously should be considered in case of intracranial progression.
recommended when a histological diagnosis is needed. Given the lack of phase 3 clinical trials that compare
While the extent of surgical resection has been associated the effectiveness of the previously mentioned therapeutic
with local control, prospective studies have reported local strategies, strong recommendations for the selection of first-
5
recurrence rates up to 50% after surgery alone. It is advised line treatments cannot be made in all cases. Nevertheless,
6
to complete surgery with focal tumor bed irradiation to it is advisable to discuss therapeutic decisions within
increase local control. 7,8 a multidisciplinary tumor board. Besides, controlled
High-dose, highly conformal treatments such as randomized clinical trials are warranted to assess the optimal
stereotactic radiosurgery (SRS) and hypofractionated timing of administering different combinations of therapies.
stereotactic radiotherapy (HFSRT) achieve an ablative effect 3. Concurrent radiation therapy and
comparable to that of surgery. Focal radiation treatments immunotherapy
are recommended for both symptomatic and asymptomatic
lesions when they are presented as 1 – 4 lesions, although In the last few years, the synergic effect arising from
9,10
some authors consider up to 5 – 10 lesions, provided that combining high-dose focal radiotherapy and ICIs to treat
the total irradiated brain volume remains within certain BM has been widely investigated. It is well known that
limits (<15 mL). Radiation can be delivered as SRS, radiation induces cytotoxic tumor cell death through
3,11
which allows to deliver 15 – 24 Gy in a single fraction, or DNA strand damage. Synchronously, radiotherapy
as HFSRT, which delivers 24 – 30 Gy in 3 – 5 fractions. generates an independent bystander effect resulting from
12
The radiation technique selection is determined by the size interactions with the tumor microenvironment and the
of the lesions, their location, and technical availability. host’s immune system, especially when administering high
According to modern guidelines, whole-brain radiation doses. 20-21 In addition, radiotherapy leads to an
radiotherapy (WBRT) is generally discouraged as a increase in the permeability of the blood–brain barrier,
standard approach, and its role is declining in front of which eventually facilitates systemic treatment of brain
focal radiation techniques and new systemic therapies. penetration, favoring the theoretical synergistic benefit of
22-24
WBRT is suggested as a palliative approach if there are no combining it with ICIs.
other therapeutic options, after considering the patient’s Most of the current evidence in this respect stems
performance status and clinical outcomes. Memantine from both phase 1 and 2 studies and retrospective cohort
co-administration and hippocampal-avoidance techniques studies. Despite the limited populations and high inter-
should be considered to enhance the quality of life and heterogeneity in the selection criteria and the treatments
prevent cognitive decline. 9,13,14 applied, these studies presented promising results, causing
a heightened research interest in this field and a dramatic
A combination of the ICIs ipilimumab and nivolumab
is recommended for non-symptomatic patients with accumulation of relevant evidence. Meta-analyses and
multiple small lesions, regardless of BRAF gene status. 3,9-10 systematic reviews are the best avenues to comprehensively
Long et al. reported an intracranial response rate (IRR) assess the true medical value of combined treatments, given
15
of 46% versus 20% in 60 patients treated with ipilimumab the nature of the available evidence. Since 2019, several
plus nivolumab versus those with nivolumab alone. An meta-analyses and systematic reviews have explored the
overall response rate (ORR) of 50% and a progression-free efficacy and safety of radiotherapy associated with ICIs for
survival (PFS) of >50% at 18 months favoring the combo the treatment of BM, some of which specifically focus on
have been reported. Steroid use has been found to have a melanoma BM (Table 1).
16
negative impact on the outcome of immunotherapy. For Combined treatment has consistently been shown to
17
the patients carrying BRAF v600 mutations, which account improve some clinical outcomes compared to either of the

Volume 2 Issue 2 (2024) 2 doi: 10.36922/arnm.3499