Department of Endocrinology, Christie Hospital NHS Foundation Trust, Manchester, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
Department of Reproductive Medicine, Manchester University NHS Foundation Trust, Manchester, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
Eur J Cancer. 2020 Jun;132:207-210. doi: 10.1016/j.ejca.2020.03.016. Epub 2020 May 5.
Adjuvant therapy with PD-1 inhibitors for resected Stage III/IV melanoma reduces the risk of recurrence by 40-50% and is now a standard of care. Immune-related adverse events occurred in approximately 37% of patients in the pivotal trials, 10-15% were severe (grade III-IV). Endocrine toxicities were common and mostly irreversible. Thyroid toxicity occurred in 15-20% of patients, hypophysitis (2.2%), insulin-dependent diabetes mellitus (1%) and adrenalitis (1%). Revision of the American Joint Committee on Cancer staging system (version 8) has resulted in a significant improvement in prognosis for patients with Stage III disease. As a result, clinicians may now offer adjuvant immunotherapy to patients with a lower risk of recurrence than those in the pivotal trials. There is a need to balance the relatively small reduction of absolute risk of recurrence against the risk and impact of toxicity. Five-ten percent of biochemically euthyroid patients on levothyroxine report symptoms of depression. Hypogonadism can result from toxicity to the hypothalamic-pituitary axis, and can lead to sexual dysfunction and subfertility. Secondary hypogonadism can be treated by the administration of Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH) which induce spermatogenesis/ovulation in a functioning gonad but is not always successful. Insulin-dependent diabetes mellitus often presents with rapid onset of hyperglycemia and potentially life-threatening diabetic ketoacidosis. Long-term adverse outcomes are likely to mimic Type 1 DM with a 6-fold increase in cardiovascular disease related mortality and 3-fold in all-cause mortality. These survivorship issues are relevant to all melanoma patients but are particularly pertinent where the absolute benefit is modest.
辅助治疗用 PD-1 抑制剂治疗 III/IV 期黑色素瘤可降低 40-50%的复发风险,现已成为标准治疗方法。关键性试验中约有 37%的患者出现免疫相关不良反应,10-15%为严重(III-IV 级)。内分泌毒性很常见,且大多不可逆转。甲状腺毒性发生在 15-20%的患者中,垂体炎(2.2%)、胰岛素依赖型糖尿病(1%)和肾上腺炎(1%)。美国癌症联合委员会分期系统(第 8 版)的修订显著改善了 III 期疾病患者的预后。因此,临床医生现在可能会向复发风险低于关键性试验的患者提供辅助免疫治疗。需要平衡复发风险降低的绝对风险与毒性的风险和影响。5-10%服用左甲状腺素的生化甲状腺功能正常的患者报告有抑郁症状。性腺毒性可导致下丘脑-垂体轴功能减退,导致性功能障碍和不孕。继发性性腺功能减退可通过给予促卵泡生成素(FSH)和黄体生成素(LH)治疗,这可诱导功能性腺的精子发生/排卵,但并不总是成功。胰岛素依赖型糖尿病常表现为高血糖迅速发作,且可能危及生命的糖尿病酮症酸中毒。长期不良结局可能与 1 型糖尿病相似,心血管疾病相关死亡率增加 6 倍,总死亡率增加 3 倍。这些生存问题与所有黑色素瘤患者有关,但在绝对获益较小的情况下尤其相关。