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Combination of radiotherapy and targeted therapy for melanoma brain metastases: a systematic review

Ge, Yia,,b,,c; Che, Xuanlina,,b,,c; Gao, Xina,,b,,c; Zhao, Shuanga,,b,,c; Su, Juana,,b,,c

Author Information
doi: 10.1097/CMR.0000000000000761
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Abstract

Introduction

The incidence of cutaneous melanoma has steadily increased over the last decades. Approximately half of the patients with melanoma either present with brain metastases (MBM) or develop MBM during the course of their treatment [1,2], which is often devastating, resulting in significant neurological symptoms and reduction in quality of life. Historically, survival varies according to many factors including the local treatment received; 8.9 months for surgery plus whole-brain radiation therapy (WBRT), 8.7 months for surgery alone, 3.4 months for WBRT alone and 2.1 months for supportive care alone [3,4,5].

In recent years, the landscape for metastatic melanoma patients has changed significantly with novel therapeutic agents such as immunotherapy consisting of anti-CTLA-4 and/or anti-PD-1 therapy and targeted therapies, consisting of BRAF and MEK inhibitors.

These modern systemic therapies have been approved by the Food and Drug Administration in the USA because of their significant survival benefit, and have emerged as new standard therapies. As of 2016, the median survival duration of patients with unresectable or metastatic melanoma approaches nearly 2 years with these novel drug therapies [6,7,8,9], compared to 6–9 months with traditional cytotoxic chemotherapy [6,10,11,12]. Although immunotherapy and targeted therapy have shown improvements in extracranial efficacy, their benefit intracranially has been limited [13,14,15]. As a result, these agents are often utilized with radiation to maximize intracranial control. Although WBRT is the historical standard of care [13], two concerns for melanoma patients have arisen with this therapy: (a) as melanoma patients are living longer because of improvements in systemic therapy, neurocognitive toxicities from WBRT are more significant [16] and (b) melanoma is a radioresistant tumor; low dose per fraction WBRT may not provide adequate local control [17]. Meanwhile, stereotactic radiosurgery (SRS) overcomes the radioresistance usually exhibited by melanoma by allowing the delivery of higher radiation doses to the tumor with a dramatically sharp radiation dose falloff, thereby minimizing the radiation to the surrounding normal tissue [18,19]. SRS is an effective treatment option when compared to WBRT with an excellent local control rate of up to 90% and an associated median survival of 5–11 months [3,20,21]. As a result, systemic agents, including targeted therapy, are commonly being combined with (SRS) for melanoma brain metastases (MBM) patients.

Recent studies, however, report potential concerns from treatment with radiation and targeted therapy such as the optimal sequence of radiotherapy and targeted therapy, the relevant prognostic factor, the safety of the use of targeted therapy concurrently with radiotherapy. In this review, we sought to report these clinically relevant issues which are still controversial in patients with MBM who received radiotherapy and targeted therapy.

Methods

We undertook a search of the PubMed, Embase, Web of Science and the Cochrane library database on 13 April 2020, for any articles on targeted therapy, when used in combination with radiotherapy, in patients with MBM published online. We excluded conference reports/abstracts, news items, case reports and articles published in languages other than English.

One author reviewed the search results and chose potential articles on the basis of the title and abstracts. Articles were rejected from the review if they were not specific to acquired targeted therapy (i.e. the focus was on immunotherapy) in cutaneous melanoma (i.e. excluding ocular or mucosal melanoma).

From this group of articles, those most likely to contain pertinent information about the combination of radiotherapy and targeted therapy for brain metastases from cutaneous melanoma were extracted for discussion. Due to nonstandard endpoints, data were just tabularized and summarized narratively.

Results

Figure 1 shows the study PRISMA diagram. There were 2096 studies identified, of which 472 were duplicates. Sixty-six articles underwent full-text review and 11 met the inclusion criteria. These 11 articles reported data relating to 316 patients and more than 911 brain metastases.

Fig. 1
Fig. 1:
Overview of trials search and selection.

Table 1 provides a summary of the study characteristics for included studies. All studies included were retrospective studies. In studies with data available (n = 11), 6 studies were conducted in the USA while others were in Switzerland, France and Australia. More men than women are involved in two of these studies. The median age was over 48.5 years old (range 48.5–65). Only three studies reported the median size of 6.5, 9.6 and 17.0 mm, respectively. Table 1 also visually summarizes the primary and secondary endpoints. For some studies, results on OS, LC and DIC could not be reported as no subgroup analyses were presented. About half the studies reported the median OS from radiotherapy (range 6.2–7.8 months). Almost all of the studies (90.9%) reported the 1-year OS (range 40–65.0%) and only fifty percent of the study reported the 2-year OS (range 10–26.7%) at the same time. As for LC, five studies were showing the 1-year LC (range 72–96.7%) and 2-year LC (range 62.7–70.0%) respectively. Only four studies reported the DIC, which at 1-year ranged from 10–34.9% and at 2-year ranged from 0–10%. The implementation outcomes were less numerous but also quite diverse.

Table 1 - Endpoints of included studies
Author/year Country N of patients (%) M/F Median
age
N of brain metastases Size
(median)
Median OS
from radiotherapy
(months)
1–2 year
OS (%)
1–2 year
LC (%)
1–2 year DIC (%) Reference number
Filipe et al. (2020) Switzerland 11 (13.1) 0.28 55.0 60 NA 9.1–NA NA NA NA 61
Susanne et al. (2019) Switzerland 18 (37.5) NA NA NA NA NA 40–NA NA NA 44
Rauschenberg et al. (2019) France 67 (32.5) NA NA NA NA NA SRS: 65–NA
WBRT: 18–NA
NA NA 62
Mastorakos et al. (2019) America 67 (33.8) NA 53 268 NA 13 52.2–20.9 74.7–62.7 74–53.3 35
Gaudy-Marqueste et al. (2017) France 34 (19.0) NA NA NA NA 7.3 35.3–8.8 NA NA 64
Choong et al. (2017) Australia 39 (36.1) NA NA NA NA 17.8 46.2–12.8 NA NA 3
Acharya et al. (2017) America 16 (22.2) 0.6 NA 64 NA NA NA 72–NA 10–NA 1
Ahmed et al. (2016) America 30 (31.2) NA NA 37 NA NA NA NA 12.8–NA 63
Patel et al. (2016) America 15 (17.2) 2.8 ≤65.0 32 (21.4) 9.6 17.3 64.3–26.7 96.7–NA 34.9–NA 13
Ly et al. (2015) America 17 (32.7) 3.3 50.1 96 NA NA 50.2–NA 85–70 NA 48
Ahmed et al. (2015) America 24 (100) 3.8 58.5 80 6.5 7.2 49–NA 75–NA 23–10 58
Gaudy-Marqueste et al. (2014) France 30 (100) 1.1 NA 263 NA 6.2 56–10 NA NA 47
Narayana et al. (2013) America 12 (100) NA 48.5 48 17.0 NA 50–25 NA 33.3–0 65
M/F, male/female; N, number; BM, brain metastases; DIC, distant intracranial control; LC, local control; OS, overall survival; SRS, stereotactic radiosurgery; WBRT, whole-brain radiotherapy.

Table 2 summarizes some important information about these studies. Radiotherapy included SRS in all series, WBRT in n = 4 publications. The median dose in most studies was 20 or 21 Gy. Targeted therapy was given before radiotherapy in 22–56% in n = 9 studies, concurrently with radiotherapy in 16% of cases in n = 4 studies, and after radiotherapy in 7–42% of cases in n = 8 studies. Targeted therapy was given before radiotherapy in 22–56% in n = 9 studies, concurrently with radiotherapy in 16% of cases in n = 4 studies, and after radiotherapy in 7–42% of cases in n = 8 studies. Drugs used were dabrafenib in n = 5 studies, vemurafenib in n = 6 studies and trametinib in n = 1 studies. Finally, the analysis of G1-3 toxicity was described in 9 of 11 studies (n = 266 patients). Fatigue was reported in n = 1 study (25%). Dermatologic toxicity was dermatitis 7–48%, cutaneous rash 10%, and Stevens–Johnson syndrome 5%. The negative impact of radiotherapy on CNS led to cognitive changes in 5–41% of cases, bleeding in 18–28%, radionecrosis 1–27.6%, headache 4–26% and ataxia 4.2%. Finally were reported gastrointestinal effects like diarrhea (10–31%), nausea (5–9%) and anorexia (4–5%). Dermatologic toxicity was rash 16.7–19.4%, oral sores 8.3%, hyperkeratotic reaction 6.9%, squamous cell carcinoma of the skin 1.5% and Pruritus. The negative impact of radiotherapy on CNS led to cognitive changes in most cases, radionecrosis 4.2–38.9, bleeding in 5.6–60.7%, intracranial hypertension 3.3–16.7%, seizures 6.3%, headache 5.6%, confusion 3.3%, paresthesia 3.3%, hemiplegia 3.3%, convulsion on meningitis 3.3% and aphasia 3.3%. Finally were reported other effects like hepatotoxicity 6.0–16.7%, diminished appetite 7.5%, arthralgia 6.0–33.3%, myalgia 6.0%, leucopenia 5.6%, abdominal pain 3.0% and colitis.

Table 2 - Characteristics of included studies
Author/year Radiotherapy type (%) Dose median
(Gy)
Timing radiotherapy (%) Targeted therapy drug (%) Main toxicities (%) Reference number
Filipe et al. (2020) SRS (100) 24 Before or after: 100 NA NA 61
Susanne et al. (2019) SRS (100) NA Before: 83.3
After: 16.7
Not specified Radionecrosis G1-2:38.9; G3:5.6
Intracerebral bleeding G1-2:5.6
Headache G1-2:5.6
Leucopenia G1-2:5.6
44
Rauschenberg et al. (2019) SRS (40.3)
WBRT (59.7)
SRS: 20
WBRT: 30
Before
After
Before+after
NA Hepatitis
Pruritus
Colitis
62
Mastorakos et al. (2019) SRS (100)
WBRT (Prior to SRS: 21
Salvage after SRS: 12)
Craniotomy and resection prior to SRS (18)
NA Before: 17.9 concurrent: 28.4
After: 53.7
DAB: 37.3
VMF: 53.7
Both: 9.0
Elevation of alanine transaminase: 6.0
Arthralgia: 6.0
Squamous cell carcinoma of the skin: 1.5
Rash: 19.4
Myalgia: 6.0
Diminished appetite: 7.5
Hyperkeratotic reaction: 6.0
Fatigue: 9.0
Abdominal pain: 3.0
Intracranial hemorrhage: 10.4
35
Gaudy-Marqueste et al. (2017) SRS 0028100) NA After: 100 NA NA 64
Choong et al. (2017) SRS (100) NA Before or after: 100 NA NA 3
Acharya et al. (2017) SRS (100)
WBRT (Prior to SRS: 18.8)
18 NA BRAFi: VMF
BRAFi+MEKi: DAB+TRA
Seizures: 6.3 1
Ahmed et al. (2016) SRS (100) BRAFi+MEKi: 31
BRAFi: 24
Before: 24.3
Concurrent or after: 75.7
VMF
BRAFi+MEKi: DAB+TRA
NA 63
Patel et al. (2016) SRS (100) 21 Before: 20.0
Concurrent: 13.3
After: 66.7
VMF: 93.3 DAB: 6.7 Radiation necrosis: 34.4 13
Ly et al. (2015) SRS (100) 20 Before: 21.9
Before+after: 35.4
After: 42.7
DAB: 52.9
VMF: 41.2
Unknown: 5.9
Intratumoral hemorrhage: 60.7 48
Ahmed et al. (2015) SRS (100) 21 Concurrent: 100 VMF: 100 Radiation necrosis: 4.2
Headache G1: 4.2
Fatigue and vertigo G1:4.2
58
Gaudy-Marqueste et al. (2014) SRS (100) NA Before: 80.0
After: 20.0
DAB: 86.7
VMF: 13.3
Confusion : 3.3
Paresthesia: 3.3
Hemiplegia: 3.3
Intracranial hypertension : 3.3
Convulsion on meningitis : 3.3
Aphasia: 3.3
47
Narayana et al. (2013) SRS (50)
partial brain or WBRT (41.7)
partial brain radiation and SRS (8.3)
SRS: 20
WBRT: 30
Before: 58.3
Concurrent: 41.7
VMF: 100 Intracranial edema: 16.7
Radiation necrosis: 8.3
Arthralgia: 33.3
Fatigue: 25
Rash : 16.7
Oral sores: 8.3
Hepatotoxicity16.7
65
BRAFi, BRAF inhibitor; DAB, dabrafenib; G, grade; MEKi, MEK inhibitor; SRS, stereotactic radiosurgery; VMF, vemurafenib; WBRT, whole-brain radiotherapy.

Discussion

There is a strong preclinical and clinical rationale for combining radiotherapy with targeted therapy for the treatment of brain metastases, to achieve both local and extracranial disease control, possibly leading to an improvement of OS.

However, safety and efficacy data on this strategy are still limited. We have performed a systematic review of studies exploring the efficacy and safety of radiotherapy associated with targeted therapy for the treatment of brain metastases. To our knowledge, this is the first systematic review explicitly assessing this topic. However, publications included in this systematic review reported solely data of patients with brain metastases from melanoma (100%); therefore, the results cannot be directly translated to patients with other primary tumors.

We found several main key results: prolonged OS with the combination of the two modalities, a good local control that correlates with OS, an effect of timing of this association. Overall, a median OS of about 6.2–17.8 months from radiotherapy was observed. Weighted survival and local control at 1 and 2 years were correlated (50.1 and 17.8%, 90.7 and 14.7% at 1 and 2 year, respectively). Finally, the sequencing of radiotherapy and targeted therapy seems important, with radiotherapy given before or concurrently to immunotherapy providing the best effect on the outcome.

BRAFi has shown encouraging extracranial and intracranial responses in advanced melanoma. However, acquired resistance is a substantial barrier to targeted therapy. It may result from reactivation of the MAPK signaling pathway, making BRAFi inhibitor therapy ineffective after 6–8 months. Combination of BRAFi with MEKi has been reported to delay resistance to BRAFi. A phase 3 trial by Long et al. showed that the combination of dabrafenib and trametinib improves progression-free survival and OS compared with dabrafenib monotherapy. The median OS was 25.1 months in the dabrafenib and trametinib group versus 18.7 months in the dabrafenib-only group [22,23]. But, our median OS was calculated from radiotherapy rather than targeted therapy, not comparable with a previous report the data reported above. Gabani et al. found the median OS was 6.2 months in radiotherapy alone [24]. A retrospective study by Bian et al. reported the median OS was 7.7 months in patients with MBM treated with SRS between 1994 and 2015 (95% CI, 6.7–8.3 months) [25]. In this review, the median OS of 6.2–17.8 months favorably compares with that previously reported for patients receiving radiotherapy alone for brain metastases from melanoma. The difference in OS is probably due to the widely heterogeneous prognosis of patients with brain metastases, which highly depends on several prognostic factors, including both clinical and molecular variables. Among them, significant prognostic factors included WBRT, BRAF status and the presence of extracerebral metastases.

Evidence for the role of WBRT in predicting the prognosis of brain metastases from melanoma are less consistent. Many studies report no benefit to overall survival [26,27,28,29]. Frinton et al. reported the majority of patients treated with WBRT alone died within 2 months of treatment and recommended if WBRT alone is the only treatment option available for a particular patient this should be offered only after careful consideration and discussion with the patient as there is a very poor outlook in this group of patients [26]. But others suggest that certain circumstances, such as stable extracranial disease or adjuvant treatment with SRS or neurosurgery, may enable WBRT to control the intracranial disease for a limited period [30].

Meanwhile, the literature provides conflicting data on the significance of the BRAF status as a prognostic factor [31,32,33,34]. Previous studies have demonstrated that BRAF mutation is associated with an unfavorable prognosis in patients with melanoma [35,36,37]. Other reports have suggested that the presence of a BRAF mutation correlates with worse local metastasis control and survival [35,38,39]. Rutter et al. showed no difference in survival or recurrence following SRS for brain metastasis depending on BRAF status [40]. Nevertheless, Sperduto et al. reported higher median OS rates for BRAFmut patients compared with BRAFwt patients in contrast to Ly et al. Elham et al. also found BRAFmut patients have a prolonged survival [31]. Further studies found that the presence of the BRAF mutation was an independent positive prognostic factor in patients with melanoma brain metastasis [35]. However, Rupesh et al. considered BRAF mutational status alone was not prognostic of patient outcome. These conflicts may have the following explanations: (a) while most studies examined the relationship between tumor mutation status and clinical outcomes in patients with MBMs, molecular testing was performed on primary tumors or extracranial metastases, not on MBMs, for many patients. Of the patients for whom molecular testing was performed on MBMs, all the specimens had identical BRAF and NRAS mutation profiles as the primary tumors. While previous studies have suggested very high concordance for BRAF and NRAS mutations between primary tumors and extracranial metastases, a recent study reported that analysis of 20 matching pairs of primary tumors and brain metastases identified discordance for BRAF mutation status in one patient, and NRAS in four patients. Thus, it is possible that the mutation status of the extracranial and intracranial metastases could have differed in some cases. (b) In the setting of widespread use of BRAFi, the presence of a BRAF mutation offers a better prognosis. (c) It is likely affected by the genomic profile of the MBMs [35]. Namely, the gene expression profile associated with BRAF mutations may contribute to multiple pathways including enhanced immune responsiveness, cell motility and melanosome processing [41,42,43].

Interestingly, the presence of extracerebral metastases was associated with superior OS [44,45]. Furthermore, the recent preclinical study in a melanoma tumor transplantation model with intracranial plus extracranial tumor, mimicking the clinically observed coexistence of metastases inside and outside the brain [44,46]. The data indicate that in the context of extracranial disease, anti-PD-1/anti-CTLA-4 treatment increases intratumoral CD8+ T cells in the brain through peripheral expansion of effector CD8+ T cells and potentiation of their trafficking to intracranial tumors via upregulation of T cell entry receptors on the tumor vasculature. Therefore, the coexistence of metastases inside and outside the brain may be a survival advantage which probably depends on the tumor burden and localization [47]. This phenomenon was also observed in MBM treated with targeted therapy in other studies suggesting immunologic effects of BRAFi±MEKi as well [44].

Other known prognostic factors for the shorter OS including male sex, cerebellar involvement, a higher number of metastatic brain tumors or concurrent presence of adrenal metastasis [6].

Our study shows a weighted local control rate of about 90.7% in 1 year. This rate is consistent with those from previous studies, which have estimated 1-year local control rates after SRS of between 49 and 94.3%. In our review, patients with melanoma who underwent SRS and targeted therapy had improved local control. At 1 year, the local control rates in patients with SRS alone were 60–90.3%. Radiotherapy has been shown to increase permeability in the blood–brain barrier. The enhanced permeability of BRAF inhibitors by radiation can increase radiosensitivity and may improve local control. However, the weighted distant intracranial control rate was 10–34.9%, not satisfactory. This may be because vemurafenib and dabrafenib do not cross the blood–brain barrier in high concentrations. In previous studies in which the role of BRAFi was examined, distant intracranial control was not specifically studied [48,49,50]. Because SRS is a targeted treatment, it can likely focally improve the blood–brain barrier penetration of a BRAF inhibitor. We hypothesize that BRAF inhibitors failed to impact distant brain control because the blood–brain barrier remains intact at other sites not treated with SRS. In addition, acquired resistance from BRAF therapy may affect distant brain control [51]. Overcoming resistance may necessitate focusing on molecular targets, such as MEK [52]. The use of combined BRAF and MEK inhibitors has resulted in improved progression-free survival [53]. This highlights the importance of developing therapies that can overcome the blood–brain barrier or be delivered intrathecally. However, although tumor-related outcomes such as LC rate or DIC rate may be important to evaluate treatment effectiveness, this outcome may be less important for a patient. For example, the tumor may respond well, but if a patient is experiencing considerable treatment toxicity, this treatment may be less meaningful for that patient.

The present review suggests that radiotherapy given before or concurrently with immunotherapy may provide better results than the inverse sequencing. In previous studies, given the inconsistent data, sequencing of targeted therapy and radiotherapy is always the subject of investigations. Hecht et al. reported that interrupting treatment with the BRAFi vemurafenib before radiotherapy was associated with longer survival compared with concurrent treatment [54]. David et al. found no association with local control when BRAF inhibitor therapy was initiated before SRS [48]. Further evidence is provided by recent studies showing that a better outcome in patients receiving targeted therapy after SRS [44]. Panagiotis et al. confirmed that the administration of BRAFi has an optimal effect when treatment is initiated at least 1 week following SRS [35]. Stera et al. reported a significant median OSRT benefit for patients who received targeted therapy after radiotherapy or who started targeted therapy before radiotherapy and continued thereafter (5.1 versus 9.8 and 12.2 months, respectively) irrespective of SRS and WBRT [44]. Overall, the available evidence is mostly indicative of a better outcome in patients receiving targeted therapy after radiotherapy or targeted therapy accompanied by radiotherapy. This phenomenon may be attributed to the development of resistance to BRAFi over time [55,56]. Additionally, the physiochemical properties of vemurafenib allow only limited distribution in the brain [57]. The improved effect of BRAFi following SRS may be attributed in part to increased permeability of the blood–brain barrier by SRS.

Finally, toxicity is also one of the most pervasive concerns of clinicians. Several studies have questioned the safety of the use of BRAFi concurrently with radiotherapy, due to the occurrence of liver and skin toxicity as well as radiation necrosis and intracranial hemorrhage. In the initial studies, safety reports on patients receiving BRAFi while undergoing SRS have primarily focused on cutaneous toxicities. However, in a study of 24 patients undergoing SRS with concurrent vemurafenib, no significant adverse skin complications were observed [58]. Hepatotoxicity is common in most studies. Intratumoral hemorrhage and radiation necrosis seem to be associated with the use of BRAFi [35]. Ly et al. reported an increased hemorrhagic risk in patients treated with BRAFi compared with those treated with SRS alone (60 vs. 23% at 12 months) [48]. However, a study by Wolf et al. did not demonstrate a similar effect. As is well-known, radionecrosis may occur several months or years after SRS. The majority of retrospective analyses suggest that combining SRS with ST does not increase toxicity including radionecrosis. However, patients receiving ST concurrent with radiotherapy may have an increased risk of radionecrosis. Panagiotis et al. reported radionecrosis after SRS and ST was documented in 2% of patients in their study [35]. Rupesh et al. considered the use of targeted agents within 4 weeks of SRS to be safe for clinical practice and optimal for tumor control [59]. This is also supported by recent consensus guidelines, which have recommended that BRAFi be withheld ≥1 day before and after SRS [60]. Of studies evaluated, the evidence of grade 3 or greater toxicity is infrequent1,15,17, 28. The most common toxicity included rash 16.7–19.4%, arthralgia 6.0–33.3%, radionecrosis 4.2–38.9 and bleeding in 5.6–60.7% [30]. Because of the smaller sample size, the rate of toxicity in some studies was high relatively. But, all treatment-emergent toxicities were acceptable.

Limitations and future directions

All studies evaluated were retrospective, noncomparative clinical trials. It means them has some intrinsic limitations, including unavoidable selection and referral bias. Again, these retrospective series varied in terms of endpoints, patient characteristics, medications, radiation protocols, sequencing, SRS and immunotherapy protocols, and timing of radiotherapy plus ST making a direct comparison difficult. Thus, prospective studies are required to answer the questions that remain unanswered here and the management of patients under the combination of targeted therapy and radiotherapy needs to be standardized in future clinical trials. At the same time, more studies in developing therapies that can overcome the blood–brain barrier or be delivered intrathecally are needed to overcome resistance to targeted therapy.

Conclusion

Based on this systematic review, the combination of targeted therapy and radiotherapy for the treatment of patients with brain metastases from melanoma has acceptable toxicity and prolongs OS. Radiotherapy given before or concurrently with targeted therapy seems to be the sequence with the best effect on the outcome. Radiotherapy modality, dose, fractioning and combinations with novel radiotherapy agents should be further investigated in specifically designed, prospective clinical trials.

Acknowledgements

This work was supported by the National Natural Science Foundation of China [grant numbers 81974478].

Conflict of interest

There are no conflicts of interest.

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    Keywords:

    radiotherapy; targeted therapy; brain metastases; sequence; survival

    Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.