高压氧对乳腺癌放疗后遗症甜不甜

　　乳腺癌术后放疗可以降低局部复发率并提高无病生存率，但是也可增加长期局部毒性反应的风险，包括疼痛、纤维化、水肿、运动受限、影响外观，发生率可达16%，还可影响生活质量。高压氧疗是指在2.0～2.5个大气压下呼吸100%纯氧，可使血液和组织的氧分压升高，从而诱导血管生成和组织再生，已被建议作为减少乳腺癌放疗后长期局部毒性反应的治疗方法。不过，高压氧疗简便、安全，门槛较低，中小医院比较热衷，似乎可以包治百病，有滥用趋势，且不太规范；而大医院放疗科以放疗为主，较少开展高压氧疗，放疗后坚持到大医院长期随访的患者也较少，因此现有高压氧疗证据大多来自小样本单组非对照回顾研究，缺乏说服力。

　　2024年2月8日，《美国医学会杂志》肿瘤学分册在线发表荷兰乌得勒支大学医学中心、阿姆斯特丹大学医学中心、圣安东尼医院、亚历山大门罗医院、阿尔利尼医院、特温特医院集团、鹿特丹达芬奇医院、朱利叶斯健康科学和初级医疗中心的甜蜜（HONEY）研究报告，分析了高压氧疗对乳腺癌术后放疗长期局部毒性反应的有效性。

HONEY (NCT04193722): The Effect of Hyperbaric OxygeN Therapy on brEast Cancer Patients With Late Radiation toxicitY - UMBRELLA HONEY Trial

　　该单中心双组前瞻非盲随机对照三期临床研究首先从2013年10月～2022年7月参加乌得勒支乳腺癌多重干预研究和长期评价队列（UMBRELLA）4485例早期乳腺癌患者筛选出2654例术后放疗且随访≥1年患者进行问卷调查，2029例回复问卷，其中388例报告乳腺癌放疗后≥12个月乳房、胸壁和/或肩部中重度疼痛，并伴轻中重度水肿、纤维化或运动受限，再从其中招募189例符合条件患者按1∶2随机分为两组：

• 对照组61例（随机分组时年龄36～80岁，中位60岁）
• 干预组125例（随机分组时年龄37～85岁，中位56岁）

　　2019年11月～2022年8月对对照组进行常规随访、对干预组进行连续6～8周30～40次高压氧疗。2023年5月～9月对意向治疗者和坚持治疗者平均因果效应进行数据分析。

　　主要指标为随机分组后6个月通过欧洲癌症研究治疗组织（EORTC）生活质量（QLQ）乳腺癌23项（BR23）问卷对乳房、胸壁和/或肩部疼痛的评分，次要指标为患者报告的纤维化、水肿、运动受限、总体生活质量。

　　结果，干预组125例患者其中仅31例（25%）完成高压氧疗且完成6个月时随访，94例未完成高压氧疗，最常见原因为治疗次数太多，其中10例未完成6个月时随访；对照组9例未完成6个月时随访。

　　对意向治疗者进行主要指标分析，完成6个月时随访的干预组115例女性与对照组52例女性相比，随访时报告中重度疼痛率：50%比62%（比值比：0.63，95%置信区间：0.32～1.23，P=0.18）。

　　对坚持治疗者平均因果效应进行主要指标分析，完成高压氧疗且完成6个月时随访的干预组31例女性与预期能够完成高压氧疗的对照组12.9例女性相比，随访时报告中重度疼痛率：32%比75%（校正后比值比：0.34，95%置信区间：0.15～0.80，P=0.01）。

　　对意向治疗者进行次要指标分析，完成6个月时随访的干预组107例女性与对照组49例女性相比，随访时报告中重度纤维化率：33%比51%（比值比：0.36，95%置信区间：0.15-0.81，P=0.02）。

　　对意向治疗者和坚持治疗者平均因果效应进行次要指标分析，干预组与对照组女性相比，乳房水肿、运动受限、总体生活质量相似。

　　因此，该随机对照临床研究结果表明，对于乳腺癌放疗后发生长期局部毒性反应的女性，高压氧疗虽然未能有效减少疼痛，但是可以有效减少纤维化。对于完成高压氧疗的女性亚组，可见疼痛和纤维化显著减少。长期局部毒性反应女性愿意并完成高压氧疗的比例远远低于预期。

　　对此，加拿大多伦多大学玛格丽特公主癌症中心、以色列希伯来大学医学院和哈达萨大学医学中心发表同期评论：高压氧对乳腺癌放疗后遗症甜不甜？

JAMA Oncol. 2024 Feb 8. IF: 28.4

Hyperbaric Oxygen Therapy and Late Local Toxic Effects in Patients With Irradiated Breast Cancer: A Randomized Clinical Trial.

Mink van der Molen DR, Batenburg MCT, Maarse W, van den Bongard DHJG, Doeksen A, de Lange MY, van der Pol CC, Evers DJ, Lansdorp CA, van der Laan J, van de Ven PM, van der Leij F, Verkooijen HM.

University Medical Centre Utrecht, Utrecht, the Netherlands; Amsterdam University Medical Centers, Amsterdam, the Netherlands; St Antonius Hospital, Nieuwegein, the Netherlands; Alexander Monro Hospital, Bilthoven, the Netherlands; Alrijne Hospital, Leiderdorp, the Netherlands; Hospital Group Twente, Hengelo, the Netherlands; Da Vinci Clinic, Rotterdam, the Netherlands; The Julius Center for Health Sciences and Primary Care, Utrecht, the Netherlands.

QUESTION: What is the effectiveness of hyperbaric oxygen therapy (HBOT) for late local toxic effects in patients with irradiated breast cancer?

FINDINGS: In this cohort-based randomized clinical trial in the Netherlands including 189 women with late local toxic effects, 1 in 4 patients with late local toxic effects accepted to undergo HBOT when offered. In the intention-to-treat analysis, pain was not significantly reduced in women who were offered HBOT but fibrosis was; among women who completed HBOT, pain and fibrosis were significantly reduced.

MEANING: HBOT seems effective for reducing pain and fibrosis in women with late local toxic effects after breast irradiation.

IMPORTANCE: Hyperbaric oxygen therapy (HBOT) is proposed as treatment for late local toxic effects after breast irradiation. Strong evidence of effectiveness is lacking.

OBJECTIVE: To assess effectiveness of HBOT for late local toxic effects in women who received adjuvant radiotherapy for breast cancer.

DESIGN, SETTING, AND PARTICIPANTS: This was a hospital-based, pragmatic, 2-arm, randomized clinical trial nested within the prospective UMBRELLA cohort following the trials within cohorts design in the Netherlands. Participants included 189 women with patient-reported moderate or severe breast, chest wall, and/or shoulder pain in combination with mild, moderate, or severe edema, fibrosis, or movement restriction 12 months or longer after breast irradiation. Data analysis was performed from May to September 2023.

INTERVENTION: Receipt of 30 to 40 HBOT sessions over a period of 6 to 8 consecutive weeks.

MAIN OUTCOMES AND MEASURES: Breast, chest wall, and/or shoulder pain 6 months postrandomization measured by the European Organization for Research and Treatment of Cancer QLQ-BR23 questionnaire. Secondary end points were patient-reported fibrosis, edema, movement restriction, and overall quality of life. Data were analyzed according to intention-to-treat (ITT) and complier average causal effect (CACE) principles.

RESULTS: Between November 2019 and August 2022, 125 women (median [range] age at randomization, 56 [37-85] years) with late local toxic effects were offered to undergo HBOT (intervention arm), and 61 women (median [range] age at randomization, 60 [36-80] years) were randomized to the control arm. Of those offered HBOT, 31 (25%) accepted and completed treatment. The most common reason for not accepting HBOT was high treatment intensity. In ITT, moderate or severe pain at follow-up was reported by 58 of 115 women (50%) in the intervention arm and 32 of 52 women (62%) in the control arm (odds ratio [OR], 0.63; 95% CI, 0.32-1.23; P = .18). In CACE, the proportion of women reporting moderate or severe pain at follow-up was 32% (10 of 31) among those completing HBOT and 75% (9.7 of 12.9) among control participants expected to complete HBOT if offered (adjusted OR, 0.34; 95% CI, 0.15-0.80; P = .01). In ITT, moderate or severe fibrosis was reported by 35 of 107 (33%) in the intervention arm and 25 of 49 (51%) in the control arm (OR, 0.36; 95% CI, 0.15-0.81; P = .02). There were no significant differences in breast edema, movement restriction, and quality of life between groups in ITT and CACE.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, offering HBOT to women with late local toxic effects was not effective for reducing pain, but was effective for reducing fibrosis. In the subgroup of women who completed HBOT, a significant reduction in pain and fibrosis was observed. A smaller than anticipated proportion of women with late local toxic effects was prepared to undergo HBOT.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04193722

PMID: 38329746

DOI: 10.1001/jamaoncol.2023.6776

JAMA Oncol. 2024 Feb 8. IF: 28.4

Hyperbaric Oxygen Therapy for Management of Late Radiation Toxicity-A Honey of a Trial?

Hahn E, Popovtzer A, Corn BW.

Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada; Hadassah University Medical Center, Jerusalem, Israel; Hebrew University, Faculty of Medicine, Jerusalem, Israel.

PMID: 38329763

DOI: 10.1001/jamaoncol.2023.6698

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