UC San Diego Health Department of Radiology, 200 W. Arbor Drive MC 0834, San Diego, CA, 92103-0834, USA.
UC San Diego Health Department of Radiation Medicine and Applied Sciences, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
BMC Cancer. 2018 May 9;18(1):549. doi: 10.1186/s12885-018-4470-y.
While data from several studies over the last decade has demonstrated that introduction of immunologic checkpoint blockage therapy with anti-CTLA-4/PD-1 drugs leads to improved survival in metastatic melanoma patients, relatively little is known about brain-specific therapeutic response and adverse events in the context of immunotherapeutic treatment of intracranial disease. Here we report two independent cases of new intracranial metastases presenting after initiation of combined checkpoint blockade Ipilimumab and Nivolumab for recurrent metastatic melanoma in the context of positive systemic disease response.
Case #1: A 43-year-old Caucasian male with Stage III melanoma of the left knee had subsequent nodal, hepatic and osseous metastases and was started on ipilimumab/nivolumab. He developed an intractable headache one week later. MRI revealed new enhancing and hemorrhagic brain metastases. After 6 weeks of immunotherapy, there was interval hemorrhage of a dominant intracranial lesion but substantial improvement in systemic metastatic disease. Durable, near complete intracranial and systemic response was achieved after completion of both induction and maintenance immunotherapy. Case #2: A 58-year old Caucasian woman with stage II melanoma of the right index finger developed cutaneous, pulmonary and hepatic metastases within 4 months of adjuvant radiation. Although combined checkpoint blockade resulted in improvement in both cutaneous and systemic disease, brain MR performed for eye discomfort demonstrated new enhancing and hemorrhagic brain metastases. Serial MR imaging five months later revealed only a solitary focus of brain enhancement with continued improved systemic disease.
These cases raise the question of whether the initial immune activation and modulation of the blood brain barrier by Ipilimumab/Nivolumab somehow "unmasks" previously clinically silent metastatic disease, rather than representing new or progressive metastatic disease. An overview of currently available literature discussing the role of immune checkpoint blockade in the treatment of intracranial metastatic melanoma will be provided, as well as discussion highlighting the need for future work elucidating the response of brain metastases to anti-CTLA/PD-1 drugs and documentation of brain-specific adverse events.
尽管过去十年的几项研究数据表明，采用抗 CTLA-4/PD-1 药物的免疫检查点阻断疗法可提高转移性黑色素瘤患者的生存率，但对于免疫治疗颅内疾病时的脑特异性治疗反应和不良事件相对知之甚少。在此，我们报告了两例新的颅内转移病例，这些病例是在复发性转移性黑色素瘤患者接受伊匹单抗和纳武单抗联合检查点阻断治疗时出现的，这些患者的全身疾病反应呈阳性。
病例 1：一名 43 岁的白种男性，左膝患有 III 期黑色素瘤，随后出现淋巴结、肝和骨转移，开始接受伊匹单抗/纳武单抗治疗。一周后，他出现了难以控制的头痛。MRI 显示新的增强和出血性脑转移。免疫治疗 6 周后，一个主要的颅内病变发生了间隔性出血，但全身转移性疾病有了实质性的改善。在完成诱导和维持免疫治疗后，实现了持久的、几乎完全的颅内和全身反应。病例 2：一名 58 岁的白种女性，右手食指患有 II 期黑色素瘤，在辅助放疗后 4 个月内出现皮肤、肺部和肝脏转移。尽管联合检查点阻断导致皮肤和全身疾病的改善，但因眼部不适而行的脑部 MRI 显示新的增强和出血性脑转移。五个月后的连续 MRI 成像显示仅存在一个单一的脑增强焦点，同时全身疾病继续改善。
这些病例提出了一个问题，即伊匹单抗/纳武单抗最初的免疫激活和血脑屏障的调节是否以某种方式“揭示”了先前临床上无症状的转移性疾病，而不是代表新的或进展性的转移性疾病。将提供对目前讨论免疫检查点阻断在治疗颅内转移性黑色素瘤中的作用的文献综述，以及强调需要进一步阐明抗 CTLA/PD-1 药物对脑转移瘤的反应并记录脑特异性不良事件的必要性的讨论。
