Abstract
Background: Melanoma is among the top three cancers to present with brain metastasis. The risk of brain metastases in advanced melanoma increases with disease duration. Cytotoxic chemotherapy does not have a significant role in the management of melanoma patients with brain metastases, neither alone nor in conjunction with radiation therapy. Patients and Methods: We herein discuss a case of a 66-year-old male diagnosed initially with stage III-B melanoma and underwent a wide local excision with a split thickness graft and sentinel lymph node biopsy, followed by adjuvant treatment with high-dose interferon. Results: On subsequent follow up he was found to have a brain lesion, which later on resolved after starting ipilumumab. Five to twenty percent of patients with melanoma of any stage develop cerebral metastases. Conclusion: Immunotherapy modalities, ipilimumab has been shown to have activity against brain metastases.
Melanoma is the third most likely cancer to be complicated by brain metastasis (BM) (1) after lung and breast cancer. The incidence of brain metastases increases with advanced disease (13% in advanced regional melanoma) (2). The risk of brain metastases in advanced melanoma also increases with disease duration (3). The primary approach to treat brain metastasis continues to be surgical resection, stereotactic radiosurgery (SRS) and/or whole-brain radiation therapy (WBRT). Cytotoxic chemotherapy does not have a significant role in the management of melanoma patients with brain metastases, neither alone nor in conjunction with radiation therapy (RT) (4).
There is growing interest in the use of systemic agents, such as BRAF and MEK inhibitors or checkpoint inhibitors in place of WBRT for selected patients with small and non-threatening metastases. Targeted agents like BRAF inhibitors have shown activity in patients with asymptomatic brain metastases containing either the V600E or V600K mutation (5, 6). Among immunotherapy modalities, ipilimumab has been shown to have activity against brain metastases (7).
The anti-programmed death-1 (anti-PD1) and anti-programmed death ligand-1 (anti-PD-L1) checkpoint inhibitors nivolumab and pembrolizumab, respectively, are immunotherapy drugs demonstrated to have a higher response rate and more favorable side-effect profile than ipilimumab in patients with systemic disease. Their effectiveness of treatment for brain metastasis, however, remains yet to be determined.
Case Presentation
We present a case of a 66-year-old male diagnosed initially with stage III-B melanoma (T3a N1b M0) with a lesion on his left upper back. He was initially diagnosed in June 2013. He originally presented with a pruritic lesion with some changes in color. He underwent a wide local excision with a split thickness graft and sentinel lymph node biopsy. The final surgical pathology showed that one out of 4 lymph nodes was positive for melanoma. He underwent a staging positron emission tomography-computed tomography (PET-CT) scan with positive uptake in the cluster of the right external iliac lymph nodes. CT-guided right external iliac lymph node biopsy was consistent with foreign body granuloma with no evidence of metastases. He was started on high-dose interferon with 20 million units/m2 intravenously (i.v.) daily for 4 weeks followed by 10 million units/m2 subcutaneously (s.c.) 3 times weekly for 48 weeks but ended up requiring a dose reduction for cytopenia.
On a subsequent follow-up 6 months from completion of adjuvant interferon, he was noted to have some tenderness in the left axilla with a small 1 cm lymph node located deep; it was followed-up with a PET scan. The left axillary lymph nodes and left anterior subcutaneous soft tissue densities within the lateral chest wall/breast showed increased metabolic activity consistent with recurrent metastatic melanoma. He also underwent a brain magnetic resonance imaging (MRI) that showed a 4-mm enhancing lesion along the surface of the lateral right frontal lobe consistent with metastatic disease. Based on these findings a gamma knife treatment to the brain metastasis was scheduled. He was then immediately started on nivolumab (Opdivo®) administered once every 2-week cycle. When gamma knife was attempted after just 2 cycles of nivolumab, the procedure had to be aborted as the lesion could no longer be visualized. Restaging PET-CT scan following 6 cycles of nivolumab demonstrated significant decrease in the size and activity of the left axillary lymph node and left breast mass. Brain MRI was also repeated 2 months after the initial one showing no evidence of the previously noted lesion in the right frontal lobe. He has since completed 8 cycles of nivolumab, with only side-effects being a mild rash and intermittent diarrhea.
Discussion
Five to twenty percent of patients with melanoma of any stage develop cerebral metastases (8). Five-year cumulative incidence of brain metastases was noted to be 7% for patients with all stages of melanoma. Approximately 20% of patients have brain metastases at initial diagnosis of distant metastatic melanoma (9). Additionally, up to 45% of patients with metastatic melanoma develop clinically-documented brain metastases during their lifetime, with a prevalence of brain metastasis being 50-75% in autopsy series. Patients with advanced melanoma and active brain metastases (BMs) have dismal prognosis with a median overall survival (OS) of 3.8-5.2 months (10). They significantly affect patients' quality of life as they are associated with pain and neurological deterioration.
Clinicopathological characteristics associated with the increased risk of brain metastases among patients with melanoma include male gender, melanomas arising on mucosal surfaces or on the skin of the trunk or head and neck, thick or ulcerated primary lesions and acral lentiginous or nodular histology. Involvement of more than three regional lymph nodes either at diagnosis or relapse, unresectable stage III or IV melanoma, elevated lactate dehydrogenase (LDH) and stage M1b or M1c have been independent predictors for the risk of brain metastasis (11, 12).
Molecular changes found in melanoma brain metastases include increased vascular endothelial growth factor (VEGF) secretion, increase in phosphorylated signal transducer and activator of transcription 3 (STAT3) leading to up-regulation in invasive and angiogenesis genes, as well as increased activity of heparanase (13). The development of brain metastasis is observed in all melanoma mutational subgroups, most frequently, however, in those harboring rat sarcoma mutations (14). Moreover, patients with melanomas containing BRAF or NRAS mutations were more likely than patients with wild-type tumors to have brain metastasis at the time they were diagnosed with distant metastatic disease (15). Loss of phosphatase and tensin homolog (PTEN) expression has been associated with shorter time to brain metastases development.
Brain metastases are devastating and challenging to manage. Management depends on three modalities: surgery, radiotherapy and systemic therapy. With the advent of improved target localization and radiation delivery techniques, RT is often the first choice for local control of brain disease in patients with metastatic melanoma.
Historically, cytotoxic agents, such as temozolomide or fotemustine, with or without WBRT, were used; but have marginal impact on progression-free survival (PFS) and OS in patients with melanoma BMs (16). The survival impact of temozolomide was marginal with a median PFS of approximately 1 month and median OS of 3.2 months (17). The combination of extended-dose temozolomide and thalidomide in melanoma patients with BMs was also studied but was found to have more toxicity than clinical benefit (18).
Beginning in 2011, targeted therapies and immune activating checkpoint inhibitors showing durable responses have led to a treatment paradigm change. Several clinical studies utilizing immunotherapy in patients with metastatic melanoma have demonstrated improved survival compared to chemotherapy. There is renewed excitement due to the development of these drugs over the last six years with novel targeted and immunotherapeutic agents, namely ipilimumab, vemurafenib, dabrafenib, trametinib, pembrolizumab and nivolumab.
Vemurafenib and dabrafenib are used to treat metastatic melanoma harboring BRAFV600E and V600L mutations. These targeted agents have been shown to produce meaningful intracranial responses and expand the systemic treatment options available for patients with melanoma BMs (19). Trametinib, another MEK inhibitor, has been used in combination with BRAF inhibitors with good results.
Immunotherapy drugs include ipilimumab, which is an antibody against cytotoxic T lymphocyte associated protein 4 (CTLA-4), and antibodies targeting PD-1 like pembrolizumab and nivolumab or combination of both ipilimumab and nivulomab; all being treatment options.
Nivolumab and pembrolizumab, the two anti-PD-1 monoclonal antibodies, have demonstrated robust and durable clinical response in patients with advanced melanoma. Thus, they were approved in 2014 as second- or third-line therapy for patients with advanced disease refractory to ipilimumab and BRAF inhibitors.
The underlying mechanism of action of immunotherapy with PD-1 inhibitors is that the PD-1 receptor, expressed on activated T and B cells, NK cells and monocytes, acts as the negative regulator of the immune system. Engagement of PD-1 to its primary ligand, PD-1 ligand 1 (PD-L1 or B7-H1), inhibits T-cell effector function, ultimately inducing T-cell exhaustion and deletion. Up-regulation of PD-L1 expression has been demonstrated in the tumor microenvironment of many human cancers, including melanoma.
Ipilimumab did show activity in melanoma patients with stable asymptomatic brain metastase (20, 21). To a less extent, pembrolizumab was also studied in patients with asymptomatic brain metastases, with half the patients achieving partial response or stable disease (21).
Since nivolumab is an antibody that shares a similar target to pembrolizumab, it was hypothesized to have similar activity in brain metastasis. Yet to date, there had been no case reports showing that to be the case. Our case report, therefore, represents one example that may help advance the field forward in further testing as part of a larger prospective trial.
Footnotes
Conflicts of Interest
None.
- Received July 2, 2016.
- Revision received July 27, 2016.
- Accepted August 5, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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