Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial
Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial
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DOI：
10.1016/s1470-2045(15)00187-4
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发表时间：
2015-09-01
期刊：
影响因子：
51.1
通讯作者：
Thompson, John F.
中科院分区：
文献类型：
--
作者：
Henderson, Michael A.;Burmeister, Bryan H.;Thompson, John F.
背景 建议对淋巴结切除术后的黑色素瘤患者进行辅助放疗。我们之前表明，这种治疗降低了复发风险高的患者重复淋巴结野癌的风险，但对总生存期没有影响。在这里，我们的目标是更新该试验的复发和生存数据，并评估生活质量和毒性反应。方法在 ANZMTG 01.02/TROG 02.01 随机对照试验中，我们在 16 家医院（澳大利亚 11 家、新西兰 3 家、荷兰 1 家、巴西 1 家）入组了因可触及淋巴结野复发而接受淋巴结切除术且复发风险较高的患者。我们将患者 (1:1) 随机分配至辅助放疗（48 Gy，分 20 次，最长 30 天）或观察组，按机构、淋巴结野面积（腮腺和颈部、腋窝或腹股沟）、受累淋巴结数量（3）、最大受累淋巴结直径（4 cm）和囊外延伸范围（无、有限或广泛）进行分层。参与者、接受治疗的人和评估结果的人都没有被治疗分配所掩盖，但参与者不知道彼此的治疗分配。在这次随访中，我们从随机分组开始的前 2 年每 3 个月评估一次结果，然后每 6 个月到 5 年评估一次，然后每年评估一次。主要终点是淋巴结野复发作为首次复发，在没有重大资格违规的患者中进行评估（由独立数据监测委员会确定）。我们根据接受治疗人群的标准标准评估了晚期不良反应（在手术或开始放疗后 90 天以上发生）。本研究已在 ClinicalTrials.gov 注册，编号为 NCT00287196。 结果 2003 年 3 月 21 日至 2007 年 11 月 15 日期间，我们随机分配 123 名患者接受辅助放疗（109 名符合疗效评估条件），127 名患者接受观察组（108 名符合资格）。最终随访日期为 2011 年 11 月 15 日。中位随访时间为 73 个月（IQR 61-91）。辅助放疗组中有 23 例（21%）出现复发，而观察组有 39 例（36%）出现复发（调整后风险比 [HR] 0.52 [95% CI 0.31-0.88]，p=0.023）。总生存期（HR 1.27 [95% CI 0.89-1.79]，p=0.21）和无复发生存期（0.89 [0.65-1.22]，p=0.51）在组间没有差异。放射治疗引起的轻微长期毒性反应（主要是疼痛、皮肤或皮下组织纤维化）很常见，90 名接受辅助放射治疗的患者中有 20 名（22%）出现了 3-4 级毒性反应。 90 名患者中有 18 名 (20%) 出现 3 级毒性反应，主要影响皮肤（9 名 [10%] 患者）和皮下组织（6 名 [7%] 患者）。 5 年来，与观察相比，辅助放疗后下肢体积显着增加（平均体积比 15.0%）（7.7%；差异 7.3% [95% CI 1.5-13.1]，p=0.014）。各组之间的上肢体积没有显着差异。解释长期随访支持了我们之前的发现。辅助放疗对于淋巴结野控制是主要问题的患者可能有用，但进入辅助全身治疗试验可能是更好的首选。或者，观察、保留手术和放疗以防止进一步复发，可能是一种可接受的策略。
Background Adjuvant radiotherapy is recommended for patients with melanoma after lymphadenectomy. We previously showed this treatment reduced risk of repeat lymph-node field cancer in patients with a high risk of recurrence but had no effect on overall survival. Here, we aim to update the relapse and survival data from that trial and assess quality of life and toxic effects.Methods In the ANZMTG 01.02/TROG 02.01 randomised controlled trial, we enrolled patients who had undergone lymphadenectomy for a palpable lymph-node field relapse and were at high risk of recurrence at 16 hospitals (11 in Australia, three in New Zealand, one in Netherlands, and one in Brazil). We randomly assigned patients (1:1) to adjuvant radiotherapy (48 Gy in 20 fractions, given over a maximum of 30 days) or observation, stratified by institution, areas of lymph-node field (parotid and cervical, axilla, or groin), number of involved nodes (3), maximum involved node diameter (4 cm), and extent of extracapsular extension (none, limited, or extensive). Participants, those giving treatment, and those assessing outcomes were not masked to treatment allocation, but participants were unaware of each other's treatment allocation. In this follow-up, we assessed outcomes every 3 months from randomisation for the first 2 years, then every 6 months up to 5 years, then annually. The primary endpoint was lymph-node field relapse as a first relapse, assessed in patients without major eligibility infringements (determined by an independent data monitoring committee). We assessed late adverse effects (occurring >90 days after surgery or start of radiotherapy) with standard criteria in the as-treated population. This study is registered with ClinicalTrials.gov, number NCT00287196.Findings Between March 21, 2003, and Nov 15, 2007, we randomly assigned 123 patients to adjuvant radiotherapy (109 eligible for efficacy assessments) and 127 to observation (108 eligible). The final follow-up date was Nov 15, 2011. Median follow-up was 73 months (IQR 61-91). 23 (21%) relapses occurred in the adjuvant radiotherapy group compared with 39 (36%) in the observation group (adjusted hazard ratio [HR] 0.52 [95% CI 0.31-0.88], p=0.023). Overall survival (HR 1.27 [95% CI 0.89-1.79], p=0.21) and relapse-free survival (0.89 [0.65-1.22], p=0.51) did not differ between groups. Minor, long-term toxic effects from radiotherapy (predominantly pain, and fibrosis of the skin or subcutaneous tissue) were common, and 20 (22%) of 90 patients receiving adjuvant radiotherapy developed grade 3-4 toxic effects. 18 (20%) of 90 patients had grade 3 toxic effects, mainly affecting skin (nine [10%] patients) and subcutaneous tissue (six [7%] patients). Over 5 years, a significant increase in lower limb volumes was noted after adjuvant radiotherapy (mean volume ratio 15.0%) compared with observation (7.7%; difference 7.3% [95% CI 1.5-13.1], p=0.014). No significant differences in upper limb volume were noted between groups.Interpretation Long-term follow-up supports our previous findings. Adjuvant radiotherapy could be useful for patients for whom lymph-node field control is a major issue, but entry to an adjuvant systemic therapy trial might be a preferable first option. Alternatively, observation, reserving surgery and radiotherapy for a further recurrence, might be an acceptable strategy.