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Systemic treatments for brain metastases from breast cancer, non-small cell lung cancer, melanoma and renal cell carcinoma: An overview of the literature
Cancer Treatment Reviews
- HER targeted therapies showed interesting results in brain metastases from breast cancer.
- EGFR inhibitors showed activity in brain metastases from adenocarcinoma lung cancer.
- Antiangiogenic drugs showed activity in brain metastases from renal carcinoma and adenocarcinoma lung cancer.
- Immunostimulatory agents showed efficacy in brain metastases from melanoma.
The frequency of metastatic brain tumors has increased over recent years; the primary tumors most involved are breast cancer, lung cancer, melanoma and renal cell carcinoma. While radiation therapy and surgery remain the mainstay treatment in selected patients, new molecular drugs have been developed for brain metastases. Studies so far report interesting results.
This review focuses on systemic cytotoxic drugs and, in particular, on new targeted therapies and their clinically relevant activities in brain metastases from solid tumors in adults.
Keywords: Brain metastases, Melanoma, Lung cancer, Breast cancer, Renal cell carcinoma.
Metastatic brain tumors are the most common intracranial neoplasms in adults and are a significant cause of deleterious effects on many critical neurological functions. Moreover, morbidity and mortality rates are higher for patients who develop brain metastasis (BM); over the last few years, the frequency of BM has increased due to longer survival of patients through more effective systemic treatment and earlier BM detection by improved neuro-imaging.
Estimates of BM incidence vary from 20% to 50%  ; analyses of patient data from the Metropolitan Detroit Cancer Surveillance System showed a total incidence proportion of BM of 9.6%  ; the incidence proportion of BM was highest for lung cancer (19.9%), followed by 6.9% for melanoma, 6.5% for renal cancer, 5.1% for breast cancer. However, as described in various studies, the incidence of BM may be higher than observed, due to asymptomatic BM  .
Radiation therapy and surgery remain the cornerstone of treatment in selected patients, while cytotoxic drugs have a limited impact. On the other hand, in recent years, advances in the understanding of the biology of BM have led to the development of new targeted therapies and interesting results have been obtained so far.
In this review, we analyzed systemic treatments, both cytotoxic and, in particular, new molecular drugs for BM from solid tumors in adults, such as breast cancer, lung cancer, renal cancer and melanoma.
Recent improvements in systemic therapy have increased the overall survival of breast cancer (BC) patients, including metastatic patients. In the context of controlled systemic disease, the prevalence of BM from BC is increasing. BC is the second leading cause of BM after lung cancer and accounts for 17–20% of all cases. BM treatment options currently include whole-brain radiotherapy (WBRT), surgery, stereotactic radiosurgery (SRS), chemotherapy and a combination of these methods (see Table 1 ).
|Author||PTS||Regimen||RR (%)||PFS (ms)||OS (ms)|
|Freedman et al. ||15||Sagopilone||13.3||1.4||5.3|
|Siena et al. ||51||Temozolomide||4||1.9||NR|
|Cassier et al. ||25||Cisplatin + vinorelbine + RT||76||3.7||6.5|
|Rivera et al. ||24||Capecitabine + temozolomide||18||12 wks||NA|
|Franciosi et al. ||56||Cisplatin + etoposide||38||4||8|
|Brufsky et al. ||258||Trastuzumab vs. no use||NA||NA||17.5 vs. 3.9|
|Lin et al. ||39||Lapatinib||2.6||3||NR|
|Lin et al. ||(50)||(Lapatinib + capecitabine)||(20)||(3.6)|
|Lin et al. ||22||Lapatinib + capecitabine vs. lapatinib + topotecan||38 vs. 0||NA||NA|
|Bachelot et al. ||44||Lapatinib + capecitabine||66||5.5||17|
|Lin et al. ||35||Lapatinib + RT||79||4.8||19|
PTS: patients; RR: response rate; PFS: progression free survival; OS: overall survival; RT: radiation therapy; NR: not reached; NA: not available.
In the setting of newly or recurrent BM from BC, few prospective trials have evaluated the benefit of cytotoxic agent administration. At the onset of BM, in combination with radiotherapy, the use of cisplatin and vinorelbine was associated with 76% of objective brain response rate (RR) for 25 pts. However, median progression free survival (PFS) remained modest (3.7 months) while median overall survival (OS) was 6.5 months, and half of patients presented with non-hematological grade 3–4 toxicities  . In another phase II trial  , combination of cisplatin and etoposide with radiation therapy (RT) for 56 patients with BM was associated with 13% of complete response and 14 partial responses (25%); however, mPFS and mOS remained modest (4 and 8 months, respectively). In these first-line studies, despite encouraging response rates, effect of combination of RT and cytotoxic agents remained modest.
In another phase II study  , the authors evaluated temozolomide activity with alternating weekly, dose-dense temozolomide, in pretreated patients with BM, stratified by primary tumor type. In this study, 51 BC patients presented with a mPFS of 1.9 months while mOS was not reached. The disease control rate (responses + stable disease) was 20% while ORR was 4%.
In a phase I trial  , 24 newly or recurrent patients with BM from BC, were treated with temozolomide plus capecitabine. This regimen was associated with 18% of ORR, an mPFS of 12 weeks and was correlated to improvement or stabilization of neurocognitive function and quality of life.
Sagopilone, an epothilone B analogue that crosses the blood–brain barrier, was evaluated in a phase II trial  for 15 patients with recurrent BM from BC. ORR was 13.3%, mPFS and mOS were 1.4 and 5.3 months, respectively; these modest results led to premature stopping of enrollment.
Finally, no prospective trial has evaluated the potential benefit of hormonal therapy for patients with BM from BC.
Human epidermal growth factor receptor (HER) targeted therapies
HER2 is overexpressed in approximately 20% of breast cancer tissue and it represents one of the main molecular targets in the development of new therapies.). Trastuzumab, a monoclonal antibody targeting HER2, was approved for metastatic breast cancer in 1998. Lapatinib is a dual tyrosine kinase inhibitor of both HER1 and HER2, approved by the FDA in 2007. Finally, pertuzumab, a monoclonal antibody that blocks dimerisation of HER2 with HER1, 3 and 4, was approved in 2012.
Overexpression of HER2 is an independent factor for development of BM, which may likely be due to a more aggressive subtype of HER2-positive breast cancer, or to the fact that these patients treated with HER2-targeted therapies live longer. Moreover, these targeted drugs have limited potential to cross the blood–brain-barrier. Hence, in the setting of well-controlled extracranial disease and BM, the best treatment is still unknown and several clinical trials to determine the optimal treatment of BM are ongoing.
In the treatment of BM, several studies have suggested activity of trastuzumab for treatment of BM from BC. However, all studies, except one  , were retrospective and even in the prospective study, data concerning BM were retrospectively collected. In this study  , use of trastuzumab was associated with better OS (17.5 vs. 3.8 months). Despite the absence of a prospective and randomized trial, use of trastuzumab at the time of BM could represent an interesting option. Trastuzumab was used in intrathecal treatment in several case reports in association with intrathecal methotrexate or cytarabine. This strategy was associated with stabilization of multiple BM in one case  and . However, the absence of a larger cohort or prospective trial did not allow any conclusion about the potential benefit of the use of intrathecal trastuzumab.
Several studies have evaluated the activity of lapatinib for BM in BC and 5 of these were prospective trials. Lin et al. in 2008  first reported on lapatinib for recurrent BM from BC. In this single-arm phase II study, 39 patients were enrolled. By “Response Evaluation Criteria In Solid Tumors” (RECIST) assessment, the ORR was only 2.6%; but by volumetric analysis, 10 pts (26%) achieved at least 10% of volumetric reduction. In this study, mPFS was 3.0 months  . In 2009, Lin et al. published a second phase II trial evaluating lapatinib for patients with BC and BM progressing after RT  . In this study, lapatinib refractory-patients were treated with lapatinib plus capecitabine. Overall response or volumetric reduction of lesions was observed in 6% and 21% of patients, respectively. In patients with the extension of lapatinib + capecitabine, ORR and volumetric reduction were seen in 20% and 40% of patients, respectively, leading to the preferential use of this association. For patients with lapatinib alone or lapatinib plus capecitabine, mPFS were 2.4 and 3.6 months, respectively, while mOS for the entire cohort was 6.4 months  .
In a recent randomized phase II trial, the combination of lapatinib and capecitabine versus lapatinib plus topotecan was analyzed  . However, this trial was prematurely stopped due to excess toxicity and lack of efficacy in the lapatinib plus topotecan arm (ORR = 0%). In the LANDSCAPE trial  , the combination of lapatinib plus capecitabine for the treatment of untreated brain metastases from HER2-positive breast cancer was evaluated. Sixty-six percent of patients had objective brain partial response, delaying the initiation of radiotherapy. In this trial, mPFS was 5.5 months and mOS was 17 months.
At the onset of BM, another phase I trial  evaluated the association of lapatinib and RT for newly BM from BC in 35 pts. ORR was 79% by volumetric criteria. In this study, mPFS was 4.8 months and mOS was 19 months. However, this study did not meet the primary objective of feasibility because of toxicity.
Moreover, combination of lapatinib and trastuzumab for BM from BC was only evaluated in retrospective studies. Use of both anti-HER2 agents could be associated to an interesting effect on patient survival  and .
Finally, no study is available to date on the evaluation of pertuzumab for BM from BC.
Non-small cell lung cancer
In patients with non-small cell lung cancer (NSCLC), brain metastases develop in approximately 30% of cases  . In the literature, BM from NSCLC was treated with various cytotoxic drugs or new molecular drugs with or without RT.
Recently, many chemotherapeutic regimens have been tested in phase II or phase III trials for the treatment of brain metastases from NSCLC (see Table 2 ).
|Author||PTS||Regimen||RR (%)||mPFS (ms)||OS (ms)|
|Franciosi et al. ||43||Cisplatin–etoposide||30||4||8|
|Cortes et al. ||26||Cisplatin–taxol||38||3.2||5.3|
|Cotto et al. ||31||Cisplatin–fotemustine||23||5||4|
|Fujita et al. ||30||Cisplatine–ifosfamide–CPT11||50||4.6||12|
|Dinglin et al. ||42||Pemetrexed–cisplatin||68||10.6||12.6|
|Kleisbauer et al. ||24||Cisplatin||30||NA||NA|
|Siena et al. ||53||TMZ||NA||66 days||172 days|
|Giorgio et al. ||30||TMZ||10||3.6 ms||6 ms|
|Quantin et al. ||23||RT + vinorelbine–ifosfamide–cisplatin||30||NA||7.6|
PTS: patients; RR: response rate; PFS: progression free survival; OS: overall survival; RT: radiation therapy; NR: not reached; NA: not available; TMZ: temozolomide; CPT11: irinotecan.
Franciosi et al.  analyzed 116 patients receiving cisplatin 100 mg/m2 on day 1 and Etoposide 100 mg/m2 on days 1, 3, and 5 or on days 4, 6, and 8 every 3 weeks. The distribution of primary tumor site was breast cancer in 56 patients (52%) and NSCLC in 43 (40%). Among 43 patients with NSCLC, 3 achieved CR (7%), 10 achieved PR, 15 had SD, 7 had PD, and 8 had insufficient treatment or response was not assessed. The median survival was 32 weeks for patients with NSCLC.
Another trial  evaluated the efficacy and safety of pemetrexed–cisplatin plus concurrent WBRT in patients with BM from lung adenocarcinoma. Forty-two patients were enrolled in this study. Patients with newly diagnosed NSCLC with BM and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2 received up to six cycles of cisplatin and pemetrexed (75 and 500 mg/m2, respectively) every 3 weeks in association with WBRT 30 Gy during the first cycle. Concerning brain lesions, RR was 68.3%, PFS was 10.6 months and OS was 12.6 months. A Spanish study  evaluated the activity of paclitaxel–cisplatin with vinorelbine or gemcitabine as front-line therapy in BM from NSCLC. Whole-brain irradiation was offered early in case of progression and later as consolidation treatment. The median OS for all patients was 21.4 weeks and the median PFS was 12.8 weeks. Paclitaxel and cisplatin combined with vinorelbine or gemcitabine as front-line therapy in brain metastases seem to achieve a response similar to that for extracranial disease; intracranial RR was observed in 38% of the patients. Kleisbauer et al.  analyzed the response to high dose cisplatin. Twenty-four consecutive patients with BM of lung carcinoma were included in this study. The total dose of cisplatin (200 mg/m2) was divided into 5 equal daily fractions, infused over 6 h. Failure was observed in 17 cases, ORR in 7 cases (2 cases without injection contrast in the tumor, 3 partial regressions, 2 complete regressions). In conclusion, 30% of patients exhibited an ORR with low toxicity.
In the study by Quantin et al.  , 23 previously untreated patients suffering from NSCLC BM were prospectively included in this feasibility study. Treatment consisted of three cycles of WBRT (18 Gy in 10 fractions) and vinorelbine, 30 mg/m2 on days 1 and 8, ifosfamide 1.5 g/m2 daily from day 1 through day 3, and cisplatin 100 mg/m2 on day 2. A cycle restarted every 28 days. Specific evaluation of brain response demonstrated complete response for 7 patients, and partial response in 6 (ORR 56%). Median OS from start of protocol was 7.6 months.
In a multicentric phase III trial, Neuhaus et al.  analyzed OS, local response and PFS of patients with BM from NSCLC and small cell lung cancer treated with RT alone or RT plus topotecan. The data showed no significant advantage for concurrent radiochemotherapy; however, the recruited number of patients was too low to exhibit advantage of combined treatment.
Temozolomide is an orally administered prodrug that is converted spontaneously to the active alkylating agent. In patients with newly-diagnosed BM or with progression after RT, temozolomide demonstrated an interesting activity.
A phase II study  , evaluated the efficacy of alternating weekly, dose-dense temozolomide in pretreated patients with BM prospectively stratified by primary tumor type. This study analyzed 53 patients with NSCLC. PFS was 66 days and OS was 172 days. Thrombocytopenia was the most common adverse event causing dose modification or treatment discontinuation.
Giorgio et al.  evaluated in a phase II study the efficacy and safety of temozolomide in 30 NSCLC patients pre-treated with WBRT and at least one previous line of chemotherapy for metastatic brain disease. Three patients (10%) achieved an objective response of BM with 2 complete remissions. Stable disease and progressive disease were achieved in 3 (10%) and 24 patients (80%), respectively.
Epidermal growth factor receptor (EGFR) inhibitors
Targeted therapies are undergoing active development as a means to improve treatment efficacy in selected patient populations. Novel agents, such as EGFR tyrosine kinase inhibitors (TKI), have now been included in standard non-small-cell lung cancer treatments. In a small subset of patients harboring EGFR-activating mutations, erlotinib and gefitinib administration was followed by RR and a longer PFS and OS than that obtained with standard chemotherapeutic regimens. In recent years however, several authors have reported a growing number of cases of partial and complete response in BM patients treated with EGFR TKIs (see Table 3 ). Data from retrospective series and phase II studies also suggest that a response can be obtained using EGFR tyrosine kinase inhibitors treatment for patients with BM, especially those harboring EGFR mutations.
|Author||PTS||Regimen||RR (%)||mPFS (ms)||OS (ms)|
|Ceresoli et al. ||41||Gefitinib||10||3||5|
|Chiu et al. ||21||Gefitinib||76||5||9.9|
|Wu et al. ||44||Gefitinib||38||9||13|
|Kim et al ||23||Gefitinib/erlotinib||69||7.1||18.8|
|Welsh et al. ||40||Erlotinib + RT||86||NA||19.1|
PTS: patients; RR: response rate; PFS: progression free survival; OS: overall survival; RT: radiation therapy; NA: not available.
Kim et al.  analyzed the response of 23 never-smoking Korean patients with adenocarcinoma of the lung with BM treated with EGFR TKI therapy until disease progression. RR was 69.6% and disease control rate 82.6%. Intracranial RR was observed in 17 patients.
Gefinitib is an orally active and reversible inhibitor of EGFR tyrosine kinase. Chiu et al., conducted a prospective study with 76 patients with NSCLC and presence of BM treated with gefitinib showing a RR of 33%. PFS and OS were 5 and 9.9 months, respectively. Severity of skin toxicity was associated with tumor response and patient survival  .
Moreover, EGFR inhibitors can be safely administered concurrently with WBRT; in fact, a recent phase II randomized study  in BM from NSCLC compared WBRT plus gefitinib vs. WBRT plus temozolomide. In this randomised phase II trial, patients with BM from NSCLC were randomly assigned to 30 Gy WBRT with either concomitant gefitinib 250 mg/day continuously or temozolomide 75 mg/m2 for 21 days every 28 days. The primary end-point was OS but the study failed to show any advantage for gefitinib: 6.3 months in the gefinitib arm and 4.9 months in the temozolomide arm (p not significant).
Ma et al.  analyzed the efficacy and toxicity of the treatment with WBRT and gefinitib. In this study, 21 patients were enrolled. Gefitinib was administrated at dosage of 250 mg/day. The primary end points were safety and OS. Concomitant treatment was well tolerated, 4 and 13 patients had a complete and partial response, respectively; 3 patients had stable disease. The concomitant treatment seems to be well tolerated with a significant improvement of quality of life in this Chinese population.
In a recent study, Hsiao et al.  analyzed the predictive role of EGFR mutations in BM treatment. In this study, 180 of 505 lung adenocarcinoma patients developed BM during their disease and 139 patients including 89 EGFR-mutant and 50 EGFR wild-type patients were identified for analysis. Among patients eligible for evaluation of treatment response, up to 85% received RT and the remaining took EGFR TKIs. EGFR-mutant patients compared with EGFR wild-type patients had significantly greater intracranial RR of BM and a longer median OS after BM diagnosis.
Erlotinib is a low-molecular weight, orally bio-available drug that selectively and reversibly inhibits the tyrosine kinase activity of EGFR. Welsh et al.  analyzed in a phase II trial the median OS of patients with BM from NSCLC treated with erlotinib plus WBRT. Eligible patients had BM from NSCLC, regardless of EGFR status. 40 patients completed erlotinib + WBRT. Median OS of 17 patients with known EGFR status was 9.3 months and 19.1 months for EGFR wild-type and EGFR mutated, respectively.
In another retrospective study  , 40 NSCLC patients with BM were treated with erlotinib until disease progression, death, or intolerable side effects. For intracranial diseases, partial response was observed in 4 patients (10%), stable disease in 21 (52.5%), and progressive disease in 15 (37.5%), with an RR of 10% and a disease control rate of 62.5%. PFS and OS were 3.0 months and 9.2 months, respectively.
Ceresoli et al.  evaluated the activity and safety of gefitinib in 41 NSCLC patients with BM. Thirty-seven patients had received prior chemotherapy and 18 patients had been treated previously with WBRT, completed at least 3 months before entering the trial. Partial response was observed in 4 patients (10%), and stable disease in 7 cases, for a disease control rate of 27%. Median duration of partial response was 13.5 months. PFS was 3 months. Toxicity was mild and consisted of grade 1–2 skin toxicity and diarrhea, occurring in 24% and 10% of patients, respectively.
Wu et al.  evaluated the activity of gefitinib in 44 NSCLC patients with BM. Of these patients, 30 were previously treated with WBRT. Partial response was observed in 14 patients (31.8%) and stable disease in 21 (47.7%). PFS and OS were 9 and 13 months, respectively. The difference in disease control rate between the patients who had previous WBRT and those without was not significant (p not significant).
Antiangiogenic drug bevacizumab
One of the targeted approaches most widely studied in the treatment of NSCLC is the inhibition of angiogenesis. Angiogenesis is essential for the development and progression of cancer, and vascular endothelial growth factor (VEGF) is a critical mediator of tumor angiogenesis. Bevacizumab, an anti-VEGF recombinant humanized monoclonal antibody, is the first targeted agent which, when combined with chemotherapy, has shown superior efficacy versus chemotherapy alone as first-line treatment of advanced non-squamous NSCLC patients. Patients with BM have initially been excluded from bevacizumab trials for the risk of cerebral hemorrhage as a result of the treatment. Nevertheless, the available data suggest an equal risk of intracranial bleeding in patients with CNS metastases treated with or without bevacizumab therapy  .
A phase II trial (PASSPORT)  specifically addressed bevacizumab safety in patients with NSCLC and previously treated BM. This open-label multicenter trial for first- and second-line treatment of nonsquamous NSCLC enrolled patients with BM. First-line patients received bevacizumab (15 mg/kg) every 3 weeks with platinum-based doublet therapy or erlotinib, and second-line patients received bevacizumab with single-agent chemotherapy or erlotinib, until disease progression or death. The study showed that addition of bevacizumab to various chemotherapy agents or erlotinib in patients with NSCLC and BM is safe and is associated with a low incidence of CNS hemorrhage.
A Japanese study retrospectively identified patients treated with bevacizumab and chemotherapy for BM from NSCLC, including 17 patients with lung adenocarcinoma. In 14 pts with evaluable BM, the response rate for intracranial metastases was 78.6%. In these patients, 2 bleeding events were reported: one was grade 1 intracranial hemorrhage, the other was grade 1 bronchopulmonary hemorrhage. This study showed that chemotherapy and bevacizumab is effective for patients with BM and is a well-tolerated regimen with a favorable toxicity profile  .
Zustovich et al.  analyzed 18 patients with BM mostly from lung and renal adenocarcinoma and the majority of patients had a treatment-naïve brain disease: 82% of patients had a partial response and 18% had stable disease. PFS was 14 months and OS was 15 months. Toxicity was the same as that in clinical practice and no cerebral hemorrhagic events were reported.
Noroxe et al.  analyzed OS, PFS, RR and toxicity in patients who received bevacizumb plus chemotherapy. Median OS and PFS were 8.8 and 4.5 months in patients with ECOG PS of 0–1, while 2.6 and 1.2 months for those with PS 2. Therefore, these data suggest that patients with PS 2 should not receive this treatment.
Melanoma BM are common since at least one patient out of three with advanced melanoma will ultimately develop BM. Survival remains dismal with an expected median OS of 16–22 weeks, probably because of the poor efficacy of conventional treatments due to radioresistency of melanoma cells and the low blood–brain barrier penetrance of systemic cytotoxic agents commonly used in metastatic melanoma. More recently, new therapeutic agents have proven their efficacy in progressing metastatic melanoma and in particular on the basis on molecular status of primary disease (see Table 4 ).
|Author||PTS||Regimen||RR (%)||mPFS (wks)||mOS (wks)|
|Jacquillat et al. ||36||Fotemustine||25||NA||NA|
|Avril et al. ||22||Fotemustine||5.9||NA||NA|
|Mornex et al. ||37||Fotemustine + RT||10||8||15|
|Margolin et al. ||31||Temozolomide + RT||9||8||24|
|Atkins et al. ||39||Temozolomide + RT + Talidomide||7.6||7||16|
|Margolin et al. ||51||Ipilimumab||16||10.7||28|
|Queirolo et al. ||146||Ipilimumab||11||11.2||17.2|
|Falchook et al. ||10||Dabrafenib||90||16.8||32|
|Dummer et al. ||24||Vemurafenib||52||16||30|
PTS: patients; RR: response rate; PFS: progression free survival; OS: overall survival; RT: radiation therapy; NA: not available.
These recent advantages achieved by small molecules and personalized therapy give rise to the issue of the best sequencing of therapeutical interventions and the need for stratification of patient prognostic factors.
Cytotoxic chemotherapy with nitrosoureas, such as fotemustine and temozolomide, have been tested in melanoma brain metastasis patients because of their ability to penetrate the blood–brain barrier. Response rate of 5.9% was observed for fotemustine and 6% for temozolomide without any added benefit to RT, and with increased toxicity , , , , and .
Recently, two systemic agents showed encouraging results in control of melanoma brain metastasis alone or in association with brain irradiation. These preliminary data are very encouraging even if still investigational.
The first is the human CTLA4-antibody, ipilimumab, which inhibits immunologic checkpoints. The mechanism of action involves the blockade of negative signaling in cytotoxic T cells that occurs normally following cytotoxic activation.
Ipilimumab was approved in 2011 for patients with metastatic melanoma based on a survival advantage over a melanoma vaccine, corticosteroid therapy and single agent dacarbazine.
Up to 15% objective response and 25% of stabilization 12 weeks following the initiation of therapy were observed in a phase II open study ipilimumab (10 mg/kg intravenously every 3 weeks for 4 cycles followed by the same dose every 12 weeks) versus corticosteroid therapy. Furthermore, median OS of 1 year was obtained in a phase II trial testing ipilimumab in addition to fotemustine. These results encouraged “proof of principle” that the benefıt of CTLA4 blockade extends to central nervous system (CNS) disease with peculiar concordant response in the control of brain and extracranial disease in metastatic melanoma. Ipilimumab is currently undergoing testing as adjuvant therapy after resection of high-risk melanoma, either compared with placebo or compared with interferon. In the short-term, combinations with less toxic agents such as temozolomide as well as other new checkpoint-blocking antibodies and RT need to be explored , , , , , , , and .
As other immunostimulatory agents, promising antibodies that block negative signaling through the PD-1/PD-L1 axis continue to be studied and represent a potential tool for the management of CNS disease.
The second systemic agent is BRAF inhibitor. BRAF mutations occur in approximately 50% of melanomas, resulting in constitutive up-regulated signaling through the MAPK pathway, independent of receptor–ligand interactions, that can be targeted by selective small-molecule inhibitors  and .
The first report of activity of BRAF inhibitors for patients with melanoma BM was in 10 patients with V600E (9 patients) and V600K (1 patient) melanoma  . Nine patients had a size reduction of BM and four had a complete response.
These results led to the largest trial ever conducted in active melanoma BM: 172 patients with V600E or V600K mutation-positive melanoma were treated with 150 mg twice daily of dabrafenib (BREAK-MB); all patients were divided into two cohorts according to prior local therapy with surgery, WBRT, or stereotactic radiosurgery at progression. Responses were seen in both cohorts, and in both V600E and V600K BRAF mutation positive melanoma. Overall intracranial RR were up to 39% with median PFS of 16 weeks and OS of 31 and 33 weeks (according to prior treatment at progression)  .
Interestingly, the brain is not always the first site of progression: 30% of progression at an extracranial site alone and 40% progression both at intra and extra cranial sites were observed  .
After the encouraging results of the phase I/II study of dabrafenib, vemurafenib (960 mg twice daily) was studied in 24 patients with V600E BRAF mutation-positive melanoma and symptomatic, progressing and untreated BM. The authors had a median PFS of 4 months and a median OS of 5 months. Only 3 patients (16%) had a confırmed partial response in the brain, whereas 13/21 patients (62%) had extra-cranial responses  .
Another encouraging observation is the dramatic symptomatic relief of neurological symptoms in patients with active brain metastases treated with dabrafenib  .
However, it is not clear whether a difference in activity exists between dabrafenib and vemurafenib in BM although, a recent preclinical study suggests that dabrafenib may have a higher concentration and longer acting lipophilic metabolites crossing the BBB in murine model  . Regarding safety, liver toxicity, arthralgia, and photosensitivity appear more common with vemurafenib; fever is more frequent with dabrafenib  .
Development of resistance to treatment occurs in most patients and a new strategy could be the association with other inhibitors of MAPK cascade. In fact, a phase 2 study compared single-agent dabrafenib with the combination of dabrafenib and trametinib showing a superior RR (76% vs. 54%), superior progression-free survival (9.4 vs. 5.8 months), and superior progression free survival at 12 months (41% vs. 9%) for the combination regimen  .
Interestingly, an “abscopal effect” has been described in a patient receiving RT after discontinuation of vemurafenib because of subsequent progression of metastatic melanoma and appearance of a brain metastasis, which was treated by radiosurgery  . After radiosurgery, he showed regression of metastatic disease and also appearance of white hair and vitiligo of the skin suggesting an immune response against normal and neoplastic melanocytes activated after radiosurgery without concomitant vemurafenib, which was stopped before radiosurgery at second melanoma progression. At 18 months after the completion of radiosurgery, the patient showed no evidence of recurrence or regression of other metastasis. The term “abscopal effect” (from the Latin “ab”-position away from- and “scopus”-target- has been used to denote this phenomenon of tumor regression at sites that are remote from an irradiated target). The pathophysiology of the abscopal effect seen in this patient is not completely understood; one hypothesis is that BRAF inhibition could result in increased immunogenicity in melanoma cells with increased expression of melanoma antigens and enhanced reactivity to antigen-specific T lymphocytes which ultimately contribute to the systemic response to stereotactic radiosurgery. The response seen in this patient provides insight into how local ablative strategies can augment a systemic response to targeted therapy  .
In conclusion, the successful results recently obtained in the treatment of patients with BM from melanoma are an example of the need to redesign the therapeutical attitude and to design new clinical trials in this setting of dismal prognosis. The extended survivals obtained by new therapeutic agents justify consideration of aggressive local therapy for patients with melanoma BM. At the moment, the main remaining issue is to find the optimal sequences and combinations of new molecular drugs and to find other molecular alterations that may candidate patients to personalized target therapy.
Renal cell carcinoma
Brain metastasis from renal cell carcinoma (RCC) occurs in approximately 5–10% of cases; data from Maastricht Cancer Registry showed that the 5-year cumulative incidence of brain metastases from RCC was 9.8%  and .
The median survival of patients with untreated RCC BM averages from 3 to 4 months  ; the outcome for these patients is poor, with median OS of only 4–11 months after diagnosis even after surgical resection, WBRT, or stereotactic radiosurgery  . Moreover, metastatic RCC is generally resistant to chemotherapy and thus, immunologic therapy with interferon or interleukin-2 has been the most commonly used treatment, despite low response rates. The advent of TKIs and other targeted therapies has drastically altered the management of metastatic RCC, and some published data suggest that these agents may be effective on BM as well (see Table 5 ).
|Authors||PTS||Regimen||RR (%)||mPFS (ms)||mOS (ms)|
|Gore et al. ||213||Sunitinib||12||5.6||9.2|
|Stadler et al. ||70||Sorafenib||4||NA||NA|
|Zustovich et al. ||4||Bevacizumab||75||26.3||33.2|
The maximum reported value among the four patients.
PTS: patients; RR: response rate; PFS: progression free survival; OS: overall survival; NA: not available.
Sunitinib is a small, oral, multi-targeted receptor TKI with antitumor and antiangiogenic activity. It has been shown that brain penetration of sunitinib may reach 31%, a higher penetration than other TKIs  . Gore et al.  reported results from an open-label, expanded access program with sunitinib (50 mg once daily, in repeated 6-week cycles of 4 weeks on treatment, followed by 2 week off) for more than 4500 patients with metastatic RCC. Among these, 213 patients with BM were evaluable for tumor response: 12% had partial response and 1% achieved a complete response, yielding an ORR of 12% compared with an ORR of 17% in the overall population  . PFS was 5.6 months (95% CI, 5.2–6.1) and 10.9 months (95% CI. 10.3–11.2) in patients with and without BM, respectively. Similarly, median OS was 9.2 months (95% CI, 7.8–10.9) in patients with BM, compared with 18.4 months (95% CI, 17.4–19.2) in the overall population. However, the median OS observed in patients with BM compares favorably with historical survival data for untreated patients with BM  . Regarding toxicity, the incidence of severe adverse events and treatment-related adverse events was not different between the two groups of patients. The most common adverse events were diarrhea and fatigue. Cerebral hemorrhage was reported in only one patient. Moreover, the tolerability of sunitinib in patients with BM was similar to that reported in the prior phase II/III trials.
Sorafenib is a multikinase inhibitor of receptor tyrosine kinases VEGF receptors 1, 2, and 3 and platelet-derived growth factor receptors α and β as well as the Raf/MEK/ERK pathway at the level of Raf kinase. In the sorafenib expanded access program  , of the 1891 evaluable patients with metastatic RCC, 70 had BM. Among these, 4% out of patients obtained a partial response; no patient achieved a complete response, yielding an ORR of 4%. No data on PFS and OS was reported for patients with BM. Toxicity was comparable to that observed with sunitinib.
Massard et al.  retrospectively analyzed the incidence of BM in 139 patients treated with sorafenib compared with that in the placebo group in a subgroup of patients from TARGET trial (Treatment Approaches in Renal Cancer Global Evaluation Trial); this study was a randomized phase III trial, involving 903 patients with metastatic RCC, 451 treated with sorafenib and 452 received placebo. The overall incidence of BM was 3% and 12% in patients treated with sorafenib and placebo, respectively (p = 0.04). The incidence of BM was also significantly lower in the sorafenib group after one and two years of treatment compared with placebo group (p = 0.045). On univariate analyses, the administration of sorafenib therapy was the only predictive factor to affect the occurrence of BM in patients with metastatic RCC. However, some patients in the TKI group were also treated with other targeted agents: erlotinib, temsirolimus and bevacizumab; these agents likely had a protective role with regard to BM as well.
Another retrospective study  , evaluated the impact of sunitinib and sorafenib on incidence of BM and OS in patients with metastatic RCC. Among 338 patients who were identified (patients were included in the TKI group only if they had received the agent before BM was diagnosed), 154 (46%) were treated with a TKI before brain metastases and 184 (54%) were not. No significant differences in prognostic factors between the two groups were observed. Median OS was longer in the TKI-treated group (25 vs. 12.1 months, p < 0.0001). In multivariate analysis, TKI therapy was associated with improved OS (HR 0.53; 95% CI, 0.38–0.74; p < 0.001). The 5-year actuarial rate of BM was 40% vs. 17% (p < 0.001); on multivariate analysis, TKI treatment was associated with lower incidence of BM (HR, 0.39; 95% CI, 0.21–0.73; p = 0.003). This retrospective study found sunitinib and sorafenib to be protective with regard to BM development.
Bastos et al.  analyzed 65 patients treated with targeted therapy after BM diagnosis; 52 patients (80) were treated with anti-angiogenic agents and 13 (20%) with mTOR inhibitors. Median OS from start of TKI was 12.2 months (95% CI 8–15.5); median PFS was 3.4 months for first line TKI therapy and 1.9 months for second line TKI.
Larkin et al.  retrospectively identified 21 patients (7%) out of 294 patients with RCC developing symptomatic BM while on treatment with sorafenib or sunitinib; the median time from starting TKI to BM was 4 months (range 1–44); the median OS from starting TKI was 11 months (95% CI, 5–17 months). Verma et al.  , in another retrospective study, confirmed that the development of symptomatic BM is rare but a significant problem in advanced RCC during therapy with sorafenib or sunitinib; in fact, they analyzed 81 patients with BM: 41 patients never received TKI and the remaining 40 received TKI therapy; the median OS from BM diagnosis was 5.4 months for the whole group: 4.4 vs. 6.7 months (p = 0.07) in the never-TKI versus TKI groups, respectively. However, patients who received TKI therapy post BM development had a median OS of 23.6 months vs. 2.08 and 4.41 months for the patients who received TKIs pre-BM or never-TKI, respectively (p = 0.0001).
A few case reports described the efficacy of other targeted agents on BM from RCC; pazopanib, a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit, demonstrated efficacy in a patient who developed more than 20 brain metastases plus multiple bone, lymph node, and soft tissue metastases, and who survived 23 months  .
Vickers et al.  , in a retrospective study, analyzed prognostic factors of survival for patients with BM from RCC treated with targeted therapy; they studied 106 patients: 77 treated with sunitinib, 23 with sorafenib, 5 with bevacizumab and 1 patient with temsirolimus. On multivariate analysis, Karnofsky performance status <80% (HR 2.07; 95% CI, 1.2–3.6), RCC diagnosis to treatment with targeted therapy <1 year (HR 2.6; 95% CI, 1.5–4.5) and higher number (>4) of BM (HR 3.1; 95% CI, 1.3–7.5) were associated with worse survival from the time of BM diagnosis. Moreover, patients treated with targeted therapy after BM diagnosis had survived longer than patients who developed BM while receiving targeted therapy, 19.1 vs. 6.3 months, respectively.
Finally, Zustovich et al.  described 4 cases of RCC patients with BM treated with bevacizumab with or without α-interferon. They reported a maximum PFS of 26.3 months and a maximum OS of 33.2 months from start of bevacizumab treatment.
In recent years, the frequency of metastatic brain tumors has been increasing and primitive lung cancer is the most common cause. Radiation therapy and surgery can be used in selected patients but can be responsible for acute or delayed neurological deficits. Recently, new targeted drugs have been developed and employed either on established brain metastases or in a preventive setting. Interestingly, these new molecular drugs reported interesting activity and safety in selected cases and in retrospective or prospective studies, with or without radiation therapy in BM from common solid tumors in adults. However, a multidisciplinary collaboration is always required to obtain the appropriate treatment that balances a good quality of life with the prolongation of survival in these patients.
Conflict of interest
We thank Ms. Christina Drace for English support.
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a Medical Oncology 1 Unit, Veneto Institute of Oncology IOV – IRCCS, Padua, Italy
b AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2, Paris 75013, France
c National Neurological Institute C. Mondino, University of Pavia, Italy
d APHM, Timone Hospital, Neuro-Oncology, Marseille, France
e Aix-Marseille University, CRO2, UMR911, Marseille, France
1 All authors contributed equally to the writing of the paper.
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