2019, Vol. 46
索拉菲尼(Sorafenib)是一种口服的联芳脲, 半衰期为25~48 h[1], 为小分子多激酶抑制剂, 通过选择性抑制丝氨酸/苏氨酸激酶Raf以及受体酪氨酸激酶, 包括血管内皮生长因子受体(vascular endothelial growth factor receptor, VEGFR) 2和3、血小板衍生生长因子β受体(platelet-derived growth factor beta receptor, PDGFRB)、fms样酪氨酸激酶3(fms-like tyrosine kinase 3, FLT3)和c-kit等的活性[2], 可有效抑制肿瘤细胞增殖和血管生成[3]。目前索拉菲尼已被FDA批准用于晚期肾细胞癌和肝细胞癌治疗, 对于甲状腺癌也具有良好的临床疗效[4]。皮肤不良反应是索拉菲尼最常见的不良反应[5], 多数并不严重, 大部分患者可以耐受; 但是皮肤不良反应对患者的健康相关生活质量造成一定的影响[6], 必要时需予以辅助治疗, 甚至调整药物剂量。美国国家癌症研究所通用不良事件术语标准4.0版(Common Terminology Criteria for Adverse Events version 4.0, CTCAE v4.0)是评价肿瘤药物治疗安全性的常用标准, 其中包括皮肤不良反应评估。依据CTCAE v4.0, 皮肤不良反应的严重程度可分为5级, 索拉菲尼常见皮损的严重程度分级见表 1 [7]。
| Adverse event | CTCAE v4.0 | Grade 1 | Grade 2 | Grade 3 | Grade 4 | Grade 5 |
| HFSR | Palmar-plantar erythro-dysesthesia syndrome | Minimal skin changes or dermatitis (e.g., erythema, edema, hyperkeratosis) without pain |
Skin changes (e.g., peeling, blisters, bleeding, edema, hyperkeratosis) with pain; limiting instrumental ADL |
Severe skin changes (e.g., peeling, blisters, bleeding, edema, hyperkeratosis) with pain; limiting self-care ADL |
- | - |
| Exanthematous drug eruption |
Rash maculo- papular |
Macules/papules covering＜10% BSA with or without symptoms (e.g., pruritus, burning, tightness) |
Macules/papules covering 10%-30% BSA with or without symptoms (e.g., pruritus, burning, tightness); limiting instrumental ADL |
Macules/papules covering＞30% BSA with or without associated symptoms; limiting self-care ADL |
- | - |
| Facial erythema | Rash maculo- papular |
Macules/papules covering＜10% BSA with or without symptoms (e.g., pruritus, burning, tightness) |
Macules/papules covering 10%-30% BSA with or without symptoms (e.g., pruritus, burning, tightness); limiting instrumental ADL |
Macules/papules covering＞30% BSA with or without associated symptoms; limiting self-care ADL |
- | - |
| Oral mucositis | Oral mucositis | Asymptomatic or mild symptoms; intervention not indicated |
Moderate pain; not interfering with oral intake modified diet indicated |
Severe pain; interfering with oral intake |
Life-threatening consequences; urgent intervention indicated | Death |
| Alopecia | Alopecia | Hair loss of＜50% of normal for individual that is not obvious from distance but only on close inspection; different hair style may be required to cover hair loss but it does not require wig or hairpiece to camouflage | Hair loss of≥50% normal for individual that is readily apparent to others; wig or hairpiece is necessary if patient desires to completely camouflage hair loss; associated with psychosocial impact |
- | - | - |
| Subungual hemorrhage |
Bruising | Localized or independent area |
Generalized | - | - | - |
| Pruritus | Pruritus | Mild or localized; topical intervention indicated |
Intense or widespread; intermittent; skin changes from scratching (e.g., edema, papulation, excoriations, lichenification, oozing/crusts); oral intervention indicated; limiting instrumental ADL |
Intense or widespread; constant; limiting self-care ADL or sleep; oral corticosteroid or immunosuppressive therapy indicated | - | - |
| Neoplasm | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated |
Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental ADL |
Severe or medically significant but not immediately life threatening; hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-care ADL |
Life-threatening consequences; urgent intervention indicated | Death |
| Semicolon indicates “or” within description of grade.A single dash (-) indicates a grade is not available.Not all Grades are appropriate for all AEs.Therefore, some AEs are listed with fewer than five options for Grade selection.ADL:Activities of daily living.Instrumental ADL refers to a higher functioning level such as preparing meals, shopping for groceries or clothes, using telephone, or managing money.Self-care ADL refers to basic daily functions such as bathing, dressing and undressing, feeding self, using toilet, or taking medications.BSA:Body surface area. | ||||||
手足皮肤反应 手足皮肤反应(hand-foot skin reaction, HFSR)见于26.9%~63.3%的患者[8], 是索拉菲尼最常见的皮肤不良反应[9-10]。HFSR常在治疗开始后2~4周出现, 好发于手足易受摩擦部位, 如足跟、足侧缘和手部的虎口区域, 表现为局限性角化、发硬, 周围偶有红晕, 并逐渐进展为角化斑块, 可出现张力性水疱/大疱, 伴感觉异常以及疼痛[11]。HFSR的严重程度与用药剂量相关[12], 多数皮损并不严重[13], 但仍有部分会限制患者的手足活动, 需要减量或停用索拉菲尼才能缓解。HFSR与传统化疗药引起的手足综合征(hand-foot syndrome, HFS)不同, 后者是掌跖部位的水肿性红斑, 对称发生, 边界不清, 表面可发生水疱和溃疡, 常由阿糖胞苷、卡培他滨、5-氟尿嘧啶或多柔比星引起[10, 14]。HFSR的病理表现为角化不全和角化不良, 真皮层病变无特异性[11]。免疫组织化学染色见表皮角蛋白10(Keratin-10)的表达减少, 而Keratin-14增加[15]。
HFSR的发生机制不详, 过去认为HFSR的发生可能与掌跖部位汗腺数量较多, 而药物通过汗液排泄有关, 但在汗液中并未检测到索拉菲尼相关成分[16]。目前认为HFSR的发生与血管内皮细胞VEGFR的抑制有关。与索拉菲尼相似, 舒尼替尼(Sunitinib)也可引起HFSR, 它与索拉菲尼共同的靶点包括VEGFR、PDGFR、c-kit和Flt-3。而伊马替尼(Imatinib)可以抑制PDGFR和c-kit, 而不会导致HFSR, 这意味着HFSR的发生可能与VEGFR和(或)Flt-3相关。然而表皮和外泌汗腺缺乏VEGFR和Flt-3的表达, 所以推测HFSR与血管内皮细胞VEGFR的抑制相关[17]。掌跖作为反复受力部位, 容易产生微小血管损伤, 而VEGFR的抑制致使血管修复障碍, 微小的损伤即可诱发显著的炎症, 即HFSR。在HFSR的发病中, 血管内皮细胞的抑制属于索拉菲尼的靶效应, 与抗癌疗效具有一致性, 而多项研究也表明HFSR的发生可以预测索拉菲尼疗效[7]。尽管舒尼替尼和索拉菲尼均可抑制VEGFR, 但HFSR的发生率明显低于索拉菲尼, 说明VEGF并不是唯一参与HFSR形成的因素。体外试验发现索拉菲尼可通过有机阴离子转运子6(organic anion transporter 6, OAT6)向角质形成细胞内转运, 作用于转化生长因子活化激酶1(transforming growth factor beta-activated kinase 1, TAK1)[18]。TAK1在维持角质形成细胞稳态中具有重要作用, 表皮TAK1基因缺陷的小鼠可出现广泛的皮肤硬化[19]。
HFSR发病率高, 困扰患者生活。有研究表明, 在好发部位涂抹尿素霜可以预防HFSR[20]。对于已经发生的HFSR, 需根据皮损的严重程度分级给予相应的处理。依据CTCAE v4.0标准, HFSR可分为3级[21](表 1)。对于1级皮肤反应, 可在做好基础防护, 如戴手套、修脚、穿着合脚鞋子[22]的同时, 局部使用角质溶解剂, 如20%~40%尿素霜或6%水杨酸制剂。对于2级皮肤反应, 即限制了功能性日常生活活动(activities of daily living, ADL)的疼痛性皮损, 可予普瑞巴林(Pregabalin)或非甾体类药物治疗, 以缓解疼痛, 局部应用0.05%丙酸氯倍他索(Clobetasol Propionate)或/和2%利多卡因(Lidocaine)制剂, 必要时将索拉菲尼减量50%, 维持1~4周, 直至评分降至0~1级, 再恢复至原剂量。3级反应指严重的伴ADL受限的皮肤病变, 至少中断治疗1周, 直至CTCAE v4.0评分降为0~1级, 才能以原剂量的50%重新开始治疗[23]。
然而, HFSR在治疗的第2~4周出现, 可以作为药物疗效的早期指征, 即发生HFSR的患者更可能从索拉菲尼的治疗中获益[24]。
发疹型药疹 发疹型药疹大多是由过敏反应所致, 表现为泛发的斑疹、斑丘疹, 常伴瘙痒, 部分患者有发热等全身症状[25-26]。服用索拉菲尼几天或几周内, 高达20%的患者可出现类似表现, 口服抗组胺药及局部外用类固醇激素可以减轻症状, 一般无需调整索拉菲尼用药方案[9, 27]。
面部红斑 43例接受索拉菲尼治疗的患者中, 有27例发生面部红斑[11]。面部红斑常在治疗开始后的1~2周内出现, 类似于脂溢性皮炎的表现, 为面中部的红斑, 表面覆有鳞屑, 眶周区域常不受累。舒尼替尼和伊马替尼所致的面部红斑少见, 表明该皮损的发生可能与索拉菲尼抑制RAF有关, 而非VEGFR或PDGFR[10]。尽管面部红斑具有自限性, 一般在2个月内自愈, 外用润肤剂、抗真菌或类固醇药物可缓解症状[21]。
口腔炎 口腔炎是索拉菲尼治疗中常见的皮肤反应, 见于26%~42%的患者[11, 28]。口腔病变常出现在治疗早期, 与HFSR严重程度有一定的相关性。口腔炎症的处理包括保持良好的口腔卫生和局部使用类固醇、局部麻醉剂和抗菌药物等[28-29]。
脱发 在接受索拉菲尼治疗的第3~15周, 有27%~44%的患者可出现脱发[11, 21], 表现为斑片状损害。大多数患者脱发不严重, CTCAE v4.0评分最高为2级, 无需调整用药剂量[11, 30]。部分患者在治疗期间毛发可再生, 新生的毛发颜色更深, 并且通常是脆性和卷曲的[21]。脱发与HFSR具有一定相关性, 3级HFSR患者发生脱发高达50%, 而不伴HSFR的患者发生脱发不足5%[18]。
甲下出血 服用索拉菲尼1~2周后, 超过60%的患者可发生无痛性甲下裂片状出血[11], 呈黑色或红色线条, 随着指甲的生长向远端推移, 直至消失。裂片状甲下出血通常无症状, 无需特殊处理。
服用舒尼替尼的患者中, 有25%可发生甲下裂片状出血[31], 而很少有关于伊马替尼导致的甲下裂片状出血的报道[10]。VEGFR是索拉菲尼和舒尼替尼的共同靶点, 提示甲下裂片状出血可能由选择性阻断VEGFR所致。VEGFR参与手指末端螺旋毛细血管的持续更新, 阻断VEGFR可能会阻止频繁微损伤的甲床毛细血管的生理性修复, 导致甲下裂片状出血[10]。
瘙痒 接受索拉菲尼治疗的患者中约18.2%发生瘙痒, 具体的发病机制尚不清楚, 可能涉及皮肤中无髓鞘的C纤维和某些神经递质, 也可能与索拉菲尼导致的皮肤干燥相关。治疗包括外用润肤剂以及口服抗组胺药等[32-33]。
皮肤肿瘤 口服索拉菲尼的患者中约10%可发生鳞状上皮不典型增生, 包括角化棘皮瘤和典型的鳞癌, 而服用舒尼替尼的患者少见[34]。两者均可抑制VEGFR, 与舒尼替尼不同的是, 索拉菲尼是一种泛RAF抑制剂。威罗替尼(Vemurafenib)是一种选择性的BRAF抑制剂, 部分应用威罗替尼治疗黑色素瘤的患者可发生角化棘皮瘤和鳞癌[35]。以上证据提示皮肤肿瘤的发生与RAF的抑制相关。此外, 这些皮损中可检测到HRAS、TGFBR1和TP53等紫外线诱导的基因突变, 提示在这些突变的基础上, 进一步RAF的抑制导致了鳞状上皮不典型增生[36]。皮肤肿瘤可采用常规切除术, 其中角化棘皮瘤可见自发性消退[36-37]。
其他皮肤反应 索拉菲尼的其他皮肤不良反应包括面部的表皮样囊肿[9]、痤疮[39]、毛周角化症[40]、获得性穿通性皮肤病[41]、多形红斑[42]、结节性红斑[27]、急性泛发性发疹性脓疱病[43]、银屑病[44]等, 严重的甚至发生Stevens-Johnson综合征[45]以及药物超敏反应综合征[46]。
结语 索拉菲尼作为肝癌、肾癌治疗的常用靶向药, 其皮肤不良反应不容忽视。索拉菲尼所致的皮肤不良反应往往不严重, 但是困扰患者的生活, 且对症处理后收效有限, 部分皮疹在药物减量后可好转。随着索拉菲尼的临床适应证的不断扩大, 未来也亟需对其产生机制及针对性应对策略进行深入研究。
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