乳腺癌激素治疗可能影响认知功能

旧金山——美国临床肿瘤学学会主办的乳腺癌研讨会上公布的一项入组81例患者的前瞻性研究显示，在校正其他因素后，接受激素治疗的乳腺癌患者出现认知功能下降的风险是未接受治疗的患者的7倍以上。此外，神经心理测试的客观结果支持患者的认知功能障碍主诉。研究者表示，激素治疗可能是认知功能障碍的危险因素，应设计干预研究对该组患者进行重点研究。


Hope Rugo医生

这项研究加州大学旧金山分校乳腺肿瘤学临床试验项目主任Hope S. Rugo医生及其同事进行，研究对象是35~80岁的早期乳腺癌女性患者。接受辅助治疗的患者接受3~4个月的单纯化疗、5年单纯激素治疗或两者兼有。患者无既往化疗或中枢神经系统放疗史，并且无重性精神病、严重头部外伤、神经疾病、药物或酒精滥用和重大疾病史。中位年龄为54岁，78%的患者为白人。各组患者的特征相似。研究者在治疗前和开始激素治疗(22例)、化疗(14例)或化疗继以激素治疗(33例)后的几个时间点，收集各治疗组患者和对照组12例未接受治疗的患者的神经心理测试结果和患者报告。

神经心理测试结果显示，5个月后近25%的患者的认知功能与基线相比有所下降(在接受治疗的患者中，这种情况在停止化疗后1个月或开始激素治疗后5个月发生)。近35%在随访9个月时出现认知功能下降，30%在18个月后出现认知功能下降。研究者表示，认知功能下降常见于接受辅助治疗的早期乳腺癌患者。进行中的激素治疗是认知功能恶化的危险因素。

多因素分析显示，不能预测认知功能下降的其他因素包括年龄、教育水平、随时间推移的平均雌二醇水平、以及基线时的估计言语智商。

单因素条件logistic回归分析发现，激素治疗可预测认知功能下降(比值比为5)，但化疗、放疗、随时间推移的平均疲劳和随时间推移的平均抑郁均不能预测任何时间点的认知功能下降。

新墨西哥高地大学心理学客座教授Lara Heflin医生及其同事进行的一项探讨主观患者报告与神经心理测试客观指标之间关联的独立分析发现，患者报告的认知问题与心理困扰和疲劳存在显著横截面关联。然而，在研究者校正抑郁和疲劳的影响后，患者感知的认知功能与基线(治疗前)至首次随访间可测的认知功能下降之间仍存在显著关联。记忆评分下降的患者更可能感知记忆问题，并且言语流畅性评分下降的患者更可能感知言语流畅性问题。Heflin医生总结指出，自我报告认知问题的患者可能确实正在发生认知功能下降，不应将这种自我报告简单归因于疲劳或焦虑和抑郁等心理因素。

该研究获美国国立卫生研究院资助。Rugo医生声明与默沙东、诺华和辉瑞公司存在利益关系。

专家点评：区分困扰和干预的影响


Julia White医生

俄亥俄州立大学乳腺放射肿瘤科主任Julia White医生表示，虽然化疗与神经认知改变之间的关系已日益被阐明，但乳腺癌激素治疗与认知功能改变之间的关系仍有点复杂。化疗可使这点进一步复杂化。目前存在一些问题，一是在使用不同药物、使用选择性雌激素受体调节剂和芳香化酶抑制剂的情况下，观察到的转归不同；而是尚不清楚绝经期状态、既往卵巢切除术、以及激素治疗等所有这些因素是如何影响女性认知功能变化的。

上述研究的重点是在基线、1个月和18个月时进行了纵向测定。此外，每个时间点均收集了综合神经心理测试和患者报告的转归结果。在该研究中，在校正抑郁和疲劳后，发现记忆测试评分下降可预测感知的认知问题。同样，言语流畅性评分下降可预测感知的言语流畅性问题。这一结果证实了既往一项对189例接受激素治疗的患者进行的前瞻性纵向研究的结果(J. Natl. Cancer Inst. 2013;105:791-801)。

困扰常被称为癌症治疗的“第6个生命体征”。重要的是，如果我们识别了患者工作或学习功能上的困扰或情感或记忆问题，我们目前有能力通过神经心理测试和进一步评估来界定困扰究竟是归因于抑郁情绪还是疲劳还是干预。White医生声明无经济利益冲突。

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By: SHERRY BOSCHERT, Internal Medicine News Digital Network

SAN FRANCISCO – Patients with breast cancer who received hormone therapy were over seven times more likely to show cognitive decline as were untreated patients after controlling for other factors, based on a prospective study of 81 patients.

Further, objective results on neuropsychological testing tended to back up patients’ complaints of cognitive difficulties.

Hormone therapy may be a risk factor for cognitive deficits, and interventional studies should be designed to focus on this group of patients, Dr. Hope S. Rugo and her associates recommended in a poster presentation at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

The study collected neuropsychological test results and patient reports before treatment and at several points after starting hormone therapy (22 patients), chemotherapy (14), or chemotherapy followed by hormone therapy (33), and in a control group of 12 untreated patients.

Compared with baseline results, nearly 25% of patients had cognitive decline on neuropsychological testing after 5 months. (Among treated patients, this occurred 1 month after ending chemotherapy or 5 months after starting hormone therapy.) Nearly 35% had cognitive declines at 9 months of follow-up, and 30% had cognitive declines after 18 months.

"Decline in cognitive function is common in patients receiving adjuvant therapy for early-stage breast cancer," concluded Dr. Rugo, director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco. "Ongoing hormone therapy appears to be a risk factor for worse cognitive function."

Other factors that did not predict cognitive decline in the multivariate analysis included age, education level, average estradiol level over time, and estimated verbal IQ at baseline.

Separate univariate conditional logistic regression analyses found that hormone therapy predicted cognitive decline with an odds ratio of 5, but chemotherapy, radiation therapy, average fatigue over time, and average depression over time were not predictive of cognitive decline at any point.

The study enrolled women aged 35-80 years with early-stage breast cancer. Those who underwent adjuvant therapy received 3-4 months of chemotherapy alone, 5 years of hormone therapy alone, or both.

A separate analysis in the same study looked at how well subjective patient reports correlated with objective measures on neuropsychological tests. Dr. Lara Heflin and her associates found significant cross-section correlations between patient-reported cognitive problems and psychological distress and fatigue.

After researchers controlled for the influence of depression and fatigue, however, significant relationships remained between patients’ perceived cognitive functioning and measurable cognitive decline from baseline (pretreatment) to the first follow-up. Patients whose scores indicated memory decline were more likely to perceive memory problems, and patients whose scores on letter fluency declined were more likely to perceive problems with verbal fluency.

"Patients who self-report cognitive problems may indeed be experiencing cognitive decline, and their self-report should not simply be attributed to fatigue or to psychological factors such as anxiety and depression," concluded Dr. Heflin, a visiting professor of psychology at New Mexico Highlands University, Las Vegas.

Patients in the study had no prior chemotherapy or central nervous system radiation and no history of major psychiatric illness, serious head injury, neurologic disease, drug or alcohol abuse, or significant medical illness. The median age was 54 years, and 78% of patients were white. Patient characteristics were similar between groups.

The symposium was cosponsored by the American Society of Breast Disease, the American Society of Breast Surgeons, the National Consortium of Breast Centers, the Society of Surgical Oncology, and the American Society for Radiation Oncology.

The National Institutes of Health funded the study. Dr. Rugo reported having financial associations with Merck, Novartis, and Pfizer.

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Differentiating the impacts of distress and interventions

While the relationship between chemotherapy and neurocognitive changes is increasingly well described, cognitive changes associated with hormone therapy for breast cancer has proven to be somewhat complex. Chemotherapy can confound this. There are questions about different reports of outcomes for different drugs, for selective estrogen-receptor modulators and aromatase inhibitors, as well as how menopausal status, prior oophorectomy, and hormone therapy all affect cognitive changes in women.

The important points of this study are that there are measurements at baseline, 1 month, and 18 months for a longitudinal picture. In addition, both comprehensive neuropsychological testing and patient-reported outcomes are available at each of those time points.

Previous studies have assessed these relationships, including a small study of memory impairment with anastrozole vs. tamoxifen in 31 patients treated for a minimum of 3 months. There was no difference between groups in depression, anxiety and fatigue, but researchers found that those on anastrozole had significantly poorer performance on learning and memory measures than those taking tamoxifen (Menopause 2007;14:995-8).

Another small substudy compared 94 patients enrolled in the ATAC (Arimidex, Tamoxifen Alone or in Combination) study to 35 noncancer controls. There were no differences in working memory, attention and visual memory, but those on endocrine therapy had poorer performance on tests of verbal memory and processing speed compared with controls.

The IBIS II (International Breast Cancer Intervention II) prevention study comparing anastrozole vs. placebo showed no overall difference in cognitive function with the addition of anastrozole. At 6 months, those on anastrozole had poorer memory, but this finding resolved by 24 months.

In a subset of 179 patients in the TEAM (Tamoxifen Exemestane Adjuvant Multinational) phase III adjuvant study, comparing exemestane with tamoxifen then exemestane, there was little change from baseline to 1 year in all domains of cognitive function with the addition of exemestane.

A substudy done from the BIG 1-98 (Breast International Group 1-98) trial indicated significant improvement in cognitive function from year 5 of therapy to year 6 after cessation of hormone therapies. Interestingly, perceived cognition did not change in the patients.

The current study looked at the relationship between perceived and measurable cognitive deficits in the same group of patients. Prior reports showed that patient-reported cognitive complaints post breast cancer treatment are common and are associated with persistent fatigue and depressive symptoms. It’s often difficult to sort out the etiology of those complaints.

In the current study, after controlling for depression and fatigue, decline on memory tests predicted perceived cognitive problems. Similarly, decline in verbal fluency predicted perceived verbal fluency problems.

This finding corroborates similar results from a prospective, longitudinal study of cognitive complaints and neuropsychological testing for verbal memory, psychomotor speed, and executive functioning in 189 patients who were beginning hormone therapy at the University of California, Los Angeles. (J. Natl. Cancer Inst. 2013;105:791-801).

Evaluations at baseline, 6 months, and 12 months showed that 23% had higher memory complaints and 19% had higher cognitive complaints after starting hormone therapy, slightly lower percentages than those seen in Dr. Rugo’s study.

Distress is often called the "sixth vital sign" of cancer care. Importantly, if we identify distress in a patient’s functioning at work or school or emotional or memory problems, we now have the ability to define by neuropsychological testing and further evaluation whether it’s attributable to depressed mood or fatigue or to an intervention.

Dr. Julia White is the director of breast radiation oncology at Ohio State University, Columbus. She made her remarks as the discussant of these papers at the meeting. She reported having no financial disclosures.