Kirkwood John M, Moschos Stergios, Wang Wenjun
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213-2584, USA.
Clin Cancer Res. 2006 Apr 1;12(7 Pt 2):2331s-2336s. doi: 10.1158/1078-0432.CCR-05-2538.
Adjuvant trials have evaluated the influence of multiple agents on relapse and mortality for patients with intermediate-risk (stage IIA, American Joint Committee on Cancer staging manual, 6th ed.), high-risk (stage IIB-III), or very high-risk (stage IIIB-IV) operable melanoma. A 25% to 33% reduction of relative relapse risk with high-dose IFN-alpha2b therapy has been documented in stage groups overall, with survival prolongation in two of these trials. In contrast, no large cooperative group trial has ever shown a significant prolongation of survival for inoperable advanced stage IV melanoma. The basis for the failure of therapies in advanced disease may lie in differences in the immune function of patients with active metastatic stage IV disease. These observations argue for the exploration of promising new therapies in adjuvant settings. Past adjuvant studies have targeted stage IIB-III patients, focusing less on the more advanced but resectable stage IIIB and IV (M(1a-b)) disease groups. Current chemobiotherapy (S0008) and granulocyte-macrophage colony-stimulating factor plus peptide vaccination (E4697) trials have now evaluated the higher-risk disease groups where trials may soon be expected to yield results. Predictive markers that would allow us to focus treatment on those patients who are most likely to respond would accelerate our development of adjuvant therapy for melanoma. We have recently developed a neoadjuvant approach to high-dose IFN in which the molecular and immunologic effects of IFN have been correlated with clinical antitumor effects of this therapy. In addition, the Hellenic Oncology group has shown that the benefit of high-dose IFN is closely correlated with serologic and clinical manifestations of autoimmunity. These new insights will allow us to develop more efficient approaches to adjuvant therapy of melanoma, focusing on autoimmunity and antitumor immunity with new immunomodulators, such as anti-CTLA4 antibodies and vaccination.
辅助治疗试验评估了多种药物对中危（美国癌症联合委员会癌症分期手册第6版中的IIA期）、高危（IIB - III期）或极高危（IIIB - IV期）可手术切除黑色素瘤患者复发和死亡率的影响。总体而言，在各分期组中，高剂量干扰素α2b治疗已被证明可使相对复发风险降低25%至33%，其中两项试验显示生存时间延长。相比之下，尚无大型协作组试验表明不可手术切除的晚期IV期黑色素瘤患者的生存时间能显著延长。晚期疾病治疗失败的原因可能在于IV期有转移活性的患者免疫功能存在差异。这些观察结果支持在辅助治疗环境中探索有前景的新疗法。过去的辅助治疗研究主要针对IIB - III期患者，对更晚期但可切除的IIIB期和IV期（M(1a - b)）疾病组关注较少。目前的化疗（S0008）以及粒细胞巨噬细胞集落刺激因子加肽疫苗接种（E4697）试验现已对高危疾病组进行了评估，预计这些试验很快会得出结果。能够让我们将治疗重点放在最可能有反应的患者身上的预测标志物，将加速我们对黑色素瘤辅助治疗的研发。我们最近开发了一种高剂量干扰素的新辅助治疗方法，其中干扰素的分子和免疫效应已与该疗法的临床抗肿瘤效应相关联。此外，希腊肿瘤学组已表明高剂量干扰素的益处与自身免疫的血清学和临床表现密切相关。这些新见解将使我们能够开发更有效的黑色素瘤辅助治疗方法，重点关注自身免疫和抗肿瘤免疫，并使用新的免疫调节剂，如抗CTLA4抗体和疫苗接种。
