诊断癌症时即开始姑息治疗可改善生存

芝加哥——阿拉巴马大学姑息治疗与支持护理中心副主任Marie Bakitas医生在美国临床肿瘤学会（ASCO）年会上报告的ENABLEⅢ研究结果表明，几乎完全通过电话实施的早期姑息治疗改善了晚期癌症患者的生存。

经过中位时间略多于1年的随访后，从诊断癌症即开始接受姑息治疗的患者和延迟接受姑息治疗的患者分别有46%和54%死亡。立即姑息治疗组与延迟姑息治疗组的中位总生存期分别为18.3个月和11.9个月（P=0.17）。在预先计划的分析中，立即姑息治疗组的1年死亡风险显著降低（危险比0.72；P=0.003），之后则呈追赶效应。

 “医疗保健水平的提高、侵入性治疗和化疗的减少、更早启动临终关怀，以及生活质量改善的生物学影响，均有可能是这种生存优势的机制所在。但是，目前我们尚无数据支持具体的某种机制，而且实际上我们正在通过二次分析探究这一问题。”

ENABLE（教育、培养、咨询、死前）Ⅲ是首个检验早期姑息治疗时机的研究，但并不是首个显示出生存优势的研究。近期一项研究显示（N. Engl. J. Med. 2010;363:733-42），从随机分组时即开始接受姑息治疗的转移性非小细胞肺癌（NSCLC）患者，比接受标准抗癌治疗者的生存期显著延长了2.7个月，而接受侵入性临终护理的比例则明显减少（33% vs. 54 %）。

在ENABLEⅢ研究中，207例晚期癌症患者及其照护者被随机分为两组，一组接受常规癌症护理并从诊断时即开始接受干预（立即姑息治疗组），另一组接受3个月常规癌症护理后再启动干预（延迟姑息治疗组）。干预包括一次传统的门诊姑息治疗咨询，以及护士教练依据指南提供的为期6周的结构化电话指导，涉及解决问题、管理症状、沟通和制定高级护理计划等话题。常规护理包括临床咨询，但不包括电话干预。

受试者的平均年龄为64岁，一半为男性，60%生活在农村地区，65%已婚或与配偶同居。肺癌是最常见的诊断，占42%。基线时，75%的患者正在接受化疗，19%正在接受放疗，43%在诊断时已完成了预先医疗指示（编者注：即患者事先声明，在罹患不治之症且昏迷时停止治疗）。

与Bakitas医生等人之前开展的一项比较姑息治疗与常规护理的临床试验不同的是，立即姑息治疗相比延迟姑息治疗并未显著改善生活质量：慢性疾病治疗-姑息治疗功能评估量表（129.9 vs. 127.2；P=0.34），流行病学研究中心抑郁量表情绪部分（11.2 vs. 10.8；P=0.33），临终生活质量症状影响亚量表（11.4 vs. 12.2；P=0.09）。

对于上述发现，一个似乎合理的解释是，两组在姑息治疗启动时间方面的差异并没有达到预设的程度：延迟姑息治疗组患者原计划在第84天开始接受姑息治疗，但实际上有40%的患者平均提前30天开始接受姑息治疗。其次，增益和降低研究效力方面的困难可能使研究者难以确定两组在主观指标上的差异，从而导致2类错误。

“即使延迟3个月，仍然处于非常早期。”Bakitas医生指出，早期干预使姑息治疗小组得以与患者接触平均1年之久（范围240~493天），而一项针对142家医院的全国调查显示，从转诊至死亡的中位时间为41~90天（JAMA 2010;303:1054-61）。

ENABLEⅢ研究中两组患者对资源和化疗的使用情况也具有可比性。立即组和延迟组的死亡患者在死亡前7~9个月内的中位住院时间分别为5天和6天，分别有8%和5%在生命的最后2周内接受了化疗。

这一结果优于全国平均水平。2014年Dartmouth医疗图集显示，全国死亡患者在生命的最后6个月内平均住院8天以上，上文提到的NSCLC研究报告称，17.5%的死亡患者接受了化疗。

Bakitas医生呼吁进行更多的早期姑息治疗研究，以确定最佳时机、人员、要素和改善生存的机制。“虽然这些方法已被证明在诊断癌症诊断后早期使用可带来获益，但在临床实践中这些潜在有益的姑息治疗服务往往很晚才被提供给患者，有时在死亡前数小时甚至数周才开始。如果不能清晰地解答‘谁来做’、‘做什么’、‘何时做’等实际问题，那么这种趋势就有可能持续下去。”

这项研究是由国立护理研究所资助的。Bakitas博士报告称无相关利益冲突。

姑息治疗可以为晚期癌症患者照顾者提供支持

ENABLEⅢ研究显示，早期姑息治疗对晚期癌症患者照顾者的支持，可改善他们的生活质量、抑郁和压力负担。阿拉巴马大学伯明翰分校的Nick Dionne-Odom博士指出：“与在患者中的情况相似，如果等到患者死亡前数周时才向照顾者提供这些服务，就可能不足以解决困扰他们的问题。”

在美国，1300万晚期癌症患者的照顾者可能每天需要花费8小时来为患者提供症状管理、情感和精神支持、备餐、预约就诊和转运等辅助。除了这一负担之外，照顾者还不得不目睹亲近的患者与病魔斗争，从而导致相当于乃至更甚于患者的精神压力。

在ENABLEⅢ研究中，122名照顾者被随机分组，在患者被诊断为癌症时或12周后接受姑息治疗干预，包括由高级护理教练进行3周的结构化患者教育电话沟通，每月通过电话了解和解决当前问题，以及给亲友去世的照顾者打电话安慰。照顾者并不仅限于家属，还可能包括好友甚至邻居。他们的平均年龄为60岁，79%为女性，75%为患者的配偶，均有至少高中教育程度。

开始干预后12周时，立即组照顾者的生活质量（照顾者生活质量指数-癌症量表）显著优于延迟组照顾者（平均50.2 vs. 56.1；P=0.02），同时抑郁症状更少[流行病学研究中心抑郁量表（CESD）评分，10.2 vs. 16.6；P=0.0006]。值得注意的是，延迟组照顾者的CESD评分超过了抑郁症的临床切点（16分）。

干预似乎并未改变照顾者对于患者要求或客观负担的感知，不过立即组表现出照顾者压力负担（Montgomery Borgatta照顾者负担量表）减轻的趋势（13.2 vs. 13.8；P=0.10）。

两组中有亲友死亡的照顾者在抑郁或悲痛评分方面无显著差异。不过研究者称，如果增加样本量，就有可能发现这方面的组间差异。既往研究显示，在患者死亡之前减轻照顾者的压力有助于改善照顾者对悲痛情绪的调整。

至于为什么照顾者似乎从姑息治疗护理干预中的获益大于患者，Bakitas医生在接受采访时解释，这可能与评估时间有关，因为其他研究显示姑息治疗在4个月时而不是3个月时显示出效果。

爱思唯尔版权所有  未经授权请勿转载

By: PATRICE WENDLING, Oncology Practice Digital Network

CHICAGO – Early palliative care delivered almost exclusively by telephone improved survival among patients with advanced cancer in the ENABLE III study.

After a median follow-up of a little more than 1 year, 46% of patients receiving palliative care from the time of cancer diagnosis and 54% of those with delayed palliative care had died.

Overall median survival was 18.3 months for the immediate group and 11.9 months for the delayed group (P = .17).

In preplanned analyses, the risk of death at 1 year was significantly lower in the immediate group (hazard ratio 0.72; P = .003), with a catch-up effect thereafter, Marie Bakitas, DNSc, reported at the annual meeting of the American Society of Clinical Oncology.

"Enhanced medical care, reduced aggressive care and chemotherapy use, longer access to hospice, and biologic impacts of improved quality of life have all been proposed as mechanisms to explain this survival advantage," Dr. Bakitas said. "However, at the present time, we do not have the data to support a particular mechanism and we are actively exploring this question through secondary analyses."

ENABLE (Educate, Nurture, Advise, Before Life Ends) III is the first study to examine the timing of early palliative care, but not the first to identify a survival advantage.

A recent study (N. Engl. J. Med. 2010:363:733-42) found that patients with metastatic non–small cell lung cancer (NSCLC) who received palliative care at the time of randomization lived a significant 2.7 months longer than did those receiving standard oncologic care, despite receiving significantly less aggressive end-of-life care (33% vs. 54%).

In ENABLE III, 207 patients with advanced cancer, and their caregivers, were randomized as a dyad to begin usual cancer care plus the intervention at the time of diagnosis (immediate group) or usual care alone for 3 months followed by the intervention (delayed group).

The intervention consisted of a traditional outpatient palliative care consult and six weekly structured telephone calls with a nurse coach using a guidebook that covers such topics as problem solving, symptom management, communication, and advanced care planning, explained Dr. Bakitas, the Marie O’Koren Endowed Chair and Professor, School of Nursing, and associate director of the Center for Palliative and Supportive Care, University of Alabama, Birmingham.

Usual care included the clinical consult, but not the telephone intervention.

The participants’ mean age was 64 years, half were male, 60% lived in a rural area, and 65% were married or living with a partner. Lung cancer was the most common diagnosis at 42%.

At baseline, 75% of patients were receiving chemotherapy, 19% were undergoing radiation, and 43% had an advanced directive completed at diagnosis.

Unlike the group’s prior trial comparing palliative care to usual care at 3 months, immediate versus delayed palliative care did not lead to significant improvements in quality of life on the Functional Assessment of Chronic Illness Therapy-Palliative care scale (129.9 vs. 127.2; P = .34), mood on the Center for Epidemiologic Studies Depression scale (11.2 vs. 10.8; P = .33), or symptom impact on the Quality of Life at the End of Life symptom impact subscale (11.4 vs. 12.2; P = .09).

One plausible reason for the findings is that there may not have been enough care differences between the two groups, with 40% of the delayed group receiving their first palliative care contact an average of 30 days before they were scheduled to do so on day 84, Dr. Bakitas said.

Second, difficulties in accrual and decreased study power may have made it difficult to pick up between-group differences on the subjective instruments, resulting in a type 2 error.

"A 3-month delay is still very early," Dr. Bakitas said.

She noted that early intervention allowed the palliative care team to have contact with patients for 1 year on average (range 240-493 days), compared with a median of 41-90 days from referral to death reported for outpatient clinics in a national survey of 142 National Cancer Institute and non-NCI cancer centers (JAMA 2010;303:1054-61).

Resource and chemotherapy use in ENABLE III was also comparable in both groups. Decedents in the immediate and delayed groups spent a median of 5 and 6 days, respectively, in hospital in the 7-9 months preceding death, while 8% and 5% received chemotherapy in the last 2 weeks of life.

This compares favorably with a national average of more than 8 hospital days in the last 6 months of life observed in the 2014 Dartmouth Atlas of Health Care, and a chemotherapy rate of 17.5% reported in the previously noted NSCLC study, Dr. Bakitas said.

She called for more studies of early palliative care to determine the optimal timing, personnel, essential elements, and mechanisms of improved survival.

"While the benefits of these approaches have been demonstrated when provided early after a cancer diagnosis, in practice these potentially beneficial palliative care services are often provided very late, sometimes hours or weeks before death," Dr. Bakitas said. "This trend is likely to continue in the absence of clear direction on the very pragmatic questions of who, what, and when."

The study was funded by National Institute for Nursing Research. Dr. Bakitas reported having no relevant disclosures.

Palliative care support buoys caregivers of advanced cancer patients

Providing early palliative care support to caregivers of advanced cancer patients improves their quality of life, depression, and stress burden, the ENABLE III study found.

"Similar to patients, waiting to provide these caregiver services until patients are in their last weeks to days of life may not adequately address the distress that they experience," Nick Dionne-Odom, Ph.D., RN, said at the meeting.

Caregivers for the 13 million cancer patients in the United States living with advanced disease can spend up to 8 hours per day providing assistance in activities that include symptom management, emotional and spiritual support, meal preparation, arranging medical appointments, and transportation.

The combination of this burden and witnessing someone close to you struggle with illness can cause psychological distress equal to or sometimes greater than that experienced by the patient, said Dr. Dionne-Odom, a postdoctoral fellow at the University of Alabama at Birmingham.

In ENABLE III, 122 caregivers were randomized at the time of the patient’s cancer diagnosis or 12 weeks later to a palliative care intervention that consisted of three weekly structured educational telephone calls from an advanced practice nurse coach, monthly check-in calls to address new or ongoing issues, and a bereavement call for caregivers whose loved ones died.

Caregivers were not restricted to family members, but could include close friends and even neighbors. Their mean age was 60 years, 79% were female, 75% were spouses, and all had at least a high school education.

At 12 weeks from the start of the intervention, caregivers in the immediate versus delayed group had significantly better quality of life on the Caregiver Quality of Life Index–Cancer scale (mean 50.2 vs. 56.1; P = .02) and less depressive symptoms on the Center for Epidemiologic Studies Depression (CESD) scale (10.2 vs. 16.6; P = .0006), Dr. Dionne-Odom said. Notably, the delayed group surpassed the clinical cutoff for depression of 16 on the CESD scale, he added.

The intervention did not appear to change the perception among caregivers of what was demanded of them by the patient or their objective burden, though there was a trend among the immediate group for improved caregiver stress burden on the Montgomery Borgatta Caregiver Burden Scale (13.2 vs. 13.8; P = .10).

There was no significant difference between groups in depression or grief scores for caregivers of decedents. A difference may have been detected with a larger sample size, he said, adding that prior studies have shown that reducing caregiver stress before patients’ death is associated with better bereavement adjustment.

As for why caregivers appear to benefit more than the patients from the parallel palliative care interventions, Dr. Bakitas said in an interview it may be the timing of the assessments, adding that other studies have shown an impact of palliative care at 4 months, but not at 3 months.