内分泌治疗对于激素受体阳性乳腺癌的预防或治疗具有核心作用，例如连续5年口服他莫昔芬或芳香化酶抑制剂进行内分泌治疗，可将原发乳腺癌或乳腺癌复发风险减半。不过，超过半数患者不能坚持完成5年内分泌治疗，造成乳腺癌复发和死亡风险增加。由于临床医师主要采用最高级别不良事件数据对临床研究的药物毒性进行分析和报告，为了提高治疗耐受性，美国国家癌症研究所抗癌登月计划呼吁对药物毒性的分析和报告进行改进。在抗癌登月研究计划的资助下，全国乳腺癌大肠癌术后辅助治疗研究协作组（NSABP）对B-35研究数据进行二次分析，采用新的毒性指数，同时考虑临床医师报告不良事件数据和患者报告结局问卷数据，以探讨内分泌治疗过早停药的潜在原因。
2021年9月23日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表密歇根大学罗杰尔癌症中心、洛杉矶加利福尼亚大学琼森综合癌症中心、西达赛奈（西奈雪松）医学中心、匹兹堡大学的研究报告，利用B-35研究临床医师报告不良事件数据和患者报告结局问卷数据计算的毒性指数，对阿那曲唑和他莫昔芬的过早停药原因进行了分析。
该国际多中心双盲安慰剂随机对照三期临床研究于2003年1月1日～2006年6月15日从美国和加拿大333家医院入组绝经后激素受体阳性乳腺导管原位癌保乳术后女性3104例，按1∶1的比例随机分为两组：
他莫昔芬组（1552例）连续5年每天口服他莫昔芬＋安慰剂
阿那曲唑组（1552例）连续5年每天口服阿那曲唑＋安慰剂
该二次分析主要结局为治疗停止时间。随机分组后，每6个月对全部3104例患者收集一次不良事件数据，并采用毒性指数进行汇总。其中，1194例患者在随机分组前以及参加研究期间每6个月完成患者报告结局问卷。通过比例风险回归模型对治疗停止时间进行单因素和多因素分析，将毒性指数和患者报告结局作为时间相关因素。
结果，其中58例患者未开始内分泌治疗，其余3046例患者开始内分泌治疗，869例（28.5%）过早停止治疗。
中位随访9年后，阿那曲唑组与他莫昔芬组相比，无乳腺癌间隔时间延长27%，尤其对于60岁以下女性。
如果仅考虑药物不良事件数据，阿那曲唑组与他莫昔芬组相比，不良事件发生率和治疗过早停止率相似。
当同时考虑随机分组前患者报告结局和药物不良事件数据时，根据多因素分析，他莫昔芬和阿那曲唑停药的共同相关因素：血栓形成、关节疼痛。停药相关其他不良事件因药而异。
随机分组前疼痛、潮热、不悦与他莫昔芬停药显著相关（589例；总体哈勒尔一致性指数：0.686，95%置信区间：0.640～0.732），随机分组前患者报告结局均与阿那曲唑停药无关（589例；总体哈勒尔一致性指数：0.656，95%置信区间：0.630～0.681）。
当仅分析随机分组前患者报告结局时，疼痛、潮热、不悦与他莫昔芬停药较快显著相关；仅潮热与阿那曲唑停药显著相关。
因此，该研究二次分析结果表明，毒性指数通过增加随机分组前患者报告结局和治疗期间出现症状，对不良事件进行加强分析，确定了内分泌治疗停药相关的预期和非预期毒性，与仅分析最高级别不良事件数据相比，对内分泌治疗停药原因产生了更深入的了解，这些结果可能有助于临床医师预先确定难以耐受特定内分泌治疗的患者，例如对于治疗前已有疼痛、潮热、不悦的患者，那么就不适合服用他莫昔芬。此外，采用毒性指数可以分析以前开展的临床研究数据，对治疗耐受性进行详细深入评估。
J Clin Oncol. 2021 Sep 23. Online ahead of print.
Toxicity Index, Patient-Reported Outcomes, and Early Discontinuation of Endocrine Therapy for Breast Cancer Risk Reduction in NRG Oncology/NSABP B-35.
Henry NL, Kim S, Hays RD, Diniz MA, Luu M, Cecchini RS, Yothers G, Rogatko A, Ganz PA.
University of Michigan Rogel Cancer Center, Ann Arbor, MI; Cedars Sinai Medical Center, Los Angeles, CA; University of California Los Angeles, Los Angeles, CA; University of Pittsburgh, Pittsburgh, PA; University of California Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles, CA.
PURPOSE: The US National Cancer Institute Moonshot initiative calls for improving analysis and reporting of toxicity to inform treatment tolerability. We used existing clinician-reported adverse event (AE) and patient-reported outcome (PRO) questionnaire data from the randomized, double-blind NSABP B-35 clinical trial to explore reasons for anastrozole and tamoxifen discontinuation.
METHODS: Postmenopausal women with ductal carcinoma in situ treated with breast-conserving therapy were randomly assigned to anastrozole or tamoxifen for 5 years. The primary outcome for this analysis was time to treatment discontinuation. AEs were collected every 6 months post-random assignment from all 3,104 participants and summarized using the Toxicity Index (TI). PRO data were collected at baseline and every 6 months from 1,194 participants. Univariate and multivariable analyses of time to treatment discontinuation were performed using Cox regression models with TIs and PROs as time-dependent covariates.
RESULTS: Of 3,046 analyzed participants, 869 (28.5%) discontinued treatment prematurely. In multivariable analysis, when both baseline PROs and on-treatment AEs were considered, thrombosis and arthralgia AEs were associated with discontinuation of both tamoxifen and anastrozole; additional AEs associated with discontinuation varied by drug. In addition, baseline pain interference, hot flashes, and unhappiness were associated with tamoxifen discontinuation (n = 589; overall Harrell's C-statistic 0.686 [95% CI, 0.640 to 0.732]); no baseline PROs were associated with anastrozole discontinuation (n = 589; overall Harrell's C-statistic 0.656 [95% CI, 0.630 to 0.681]). When only baseline PROs were examined, pain interference, hot flashes, and unhappiness were associated with shorter time to discontinuation of tamoxifen; only hot flashes were associated with discontinuation of anastrozole.
CONCLUSION: Analysis of AEs using the TI yielded important insights into reasons for discontinuation of endocrine therapy that was enhanced by the addition of PRO baseline and treatment-emergent symptoms.
KEY OBJECTIVE: Maximum-grade adverse event data are widely used to report toxicity of therapies in clinical trials. This secondary analysis of toxicity and patient-reported symptom data from a previously conducted clinical trial was performed using the Toxicity Index (TI), a novel summary measure, to explore reasons for early discontinuation of endocrine therapy (ET).
KNOWLEDGE GENERATED: The TI identified both anticipated and unanticipated toxicities associated with ET discontinuation and yielded greater insights about treatment discontinuation than examining maximum-grade adverse event data alone. The addition of patient-reported symptom data from before treatment initiation and during therapy further enhanced understanding of reasons for treatment discontinuation.
RELEVANCE: These findings may be clinically useful for a priori identification of patients who will have difficulty tolerating a specific ET. In addition, use of the TI can enrich the assessment of treatment tolerability through examination of data from previously conducted clinical trials.
PMID: 34554865
DOI: 10.1200/JCO.21.00910
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