转移性乳腺癌患者摘除原发肿瘤不改善生存

圣安东尼奥——在圣安东尼奥乳腺癌研讨会上报告的两项随机试验表明，在首发症状为转移性乳腺癌的患者中，手术摘除原发肿瘤及其累及的淋巴结并不能改善总生存率。

第一项试验纳入350例对初始化疗有应答的印度患者。第一作者、印度孟买塔塔纪念医院院长Rajendra Badwe博士在会上和新闻发布会上报告称，无论患者接受了手术治疗还是仅接受了更多的全身性治疗，大约20%的患者5年后仍然存活。


Rajendra Badwe博士
 
Badwe博士称，虽然手术后局部区域控制率更高，但远处进展的风险也更高，这支持了Bernard Fisher博士及其同事20多年前的临床前数据，这些数据表明完整的原发肿瘤可以抑制远处转移瘤的生长(Cancer Res. 1989;49:1996-2001 )。

Badwe博士评论道：“对于表现为转移性乳腺癌的患者，局部区域治疗原发肿瘤并不能改善总生存率，因此不应作为常规治疗手段。”

他补充道：“从生物学来看，这项研究提示手术摘除这些患者的原发肿瘤可能促进了远处转移瘤的生长……这是我们第一次在人体研究中找到证据证明局部区域治疗对远处转移瘤有明显的动力学效应。”

第二项试验纳入293例未经治疗的新发(de novo)转移性乳腺癌的土耳其患者。第一作者、Atilla Soran博士代表土耳其乳腺疾病学会联盟在会上报告称，无论患者是直接接受手术还是仅接受全身性治疗，中位生存期并没有统计学差异，大约为3.5年。

亚组分析表明，手术能延长单发骨转移患者的生存期，但却缩短了多发肝转移或肺转移患者的生存期。

手术治疗组患者的局部区域进展率只有全身性治疗组患者的1/5。Soran博士评论道：“早期随访数据显示，总生存期方面无统计学差异，但我们还需要开展更长时间的随访。有可能存在重要的亚组差异。”

特邀评论员、美国西北大学外科学教授和Bluhm Family癌症研究教授/西北大学附属Lynn Sage乳腺中心的Seema A. Khan博士称，这两项试验对于其他正在开展的试验以及患者诊疗都很有意义。“从现有数据来看，原发肿瘤的局部治疗似乎并不能产生很大的效益。因此可能需要重新评估正在进行中的试验在设计上所使用的假设。事先计划的合并分析可能需要产生足够的检验效能以检测出更小的差异。”在患者诊疗方面，“此刻很显然我们必须确保患者了解原发肿瘤的局部治疗在改善生存率方面的确没有什么优势”。 Khan博士说：“因此，我认为除非患者是在参与临床试验，否则对于无症状性肿瘤患者不应予以这种治疗。这种治疗在局部控制率方面可能具有优势，但我们需要更多的相关数据。”

印度试验

这项印度试验于2005~2013年期间开展，受试者为新发转移性乳腺癌患者，并且对单纯蒽环类药物化疗或者与紫杉类药物联合化疗完全或部分应答。受试者被平均随机分配至接受局部区域治疗(乳房肿瘤切除术或乳房切除术伴腋窝淋巴结清扫术，加胸壁或乳房和淋巴结放疗)或者不接受局部区域治疗(作为对照)。只要有指征，两组患者均可接受激素治疗。

Badwe博士称，对照组大约10%的患者因将要发生乳房真菌感染或疼痛，接受了姑息性乳房切除术，这也是研究方案所允许的。

因此，除了16%的HER2阳性患者没有接受靶向药物曲妥珠单抗(赫赛汀)之外，这些患者接受了当代治疗。

结果显示，中位总生存期大约为18个月，局部区域治疗组的5年生存率为19.2%，对照组为20.5%，差异没有统计学意义。Badwe博士报告称：“在所有患者亚组中，也都没有观察到明显的组间差异。”

Badwe博士指出，这项研究采用的是单侧优效性设计。“我们不能观察到2.5或3个月的差异，或者总生存率上4%的差异。”

局部区域治疗组出现局部无进展生存事件的风险更低(危险比[HR]，0.16；P=0.00)，但出现远处无进展生存事件的风险更高(HR，1.42；P=0.01)。

Badwe博士称，多个理论都可以解释为何摘除原发肿瘤会加快转移瘤的生长。“第一种也是最重要的一种解释是，手术本身的作用可能会促进部分生长因子，这可能促使转移性疾病生长。第二种可能性是由Fisher博士提出的(Cancer Res. 1989;49:1996-2001)，先于远处转移瘤出现的原发肿瘤可以促进部分抑制因子，但原发肿瘤一旦被摘除，这些抑制因子就不存在了，给远处转移瘤的生长创造了条件。第三种可能性是手术可能会通过播散诱导更多的转移过程并且形成新的疾病。”

与会者来自纽约州布朗克斯的肿瘤科医生Steven Vogl博士说：“确认疾病进展需要有你可以追踪的疾病。对于一名单纯骨转移的患者，如果原发肿瘤没有摘除，你就可以通过评估原发部位或淋巴结是否长大来确定癌症病情是否加重。如果已经摘除了原发肿瘤，对胸壁进行了放疗，那么评估起来就会困难得多。你是否分析过数据来确定事实就是如此，为什么会出现更多的远处转移瘤，是因为它们无法局部进展吗？这种基于医学试验的解释与Fisher的生物学假设相矛盾。”

Badwe博士回答道：“我们有固定的时间来开展全身性检查以评估远处转移瘤是否进展。”对于没有接受手术治疗的患者，对其远处转移瘤的评估也更加频繁。

与会者来自纽约纪念斯隆-凯特琳癌症中心的Tari A. King博士指出，试验中缺少HER2治疗可能产生了很大的效应。她评论道：“由乳腺癌转化治疗研究联盟发起的一项试验已经在美国完成，其提供的前瞻性登记库数据[摘要18-09，墙报展示]显示，无论患者是否接受了手术治疗，2年总生存率都远远高于你刚刚报告的数据。因此我不能确定我们是否应该把你报告的数据用于现代靶向治疗方案中，靶向治疗目前在美国已经很常用了。”

土耳其试验

这项名为“MF07-01”的土耳其试验于2008~2012年开展，受试者均未接受过治疗。受试者被平均随机分配至接受单纯全身性治疗或者原发肿瘤手术治疗(伴或不伴腋窝淋巴结清扫术)以及随后的放疗(如有指征)，加全身性治疗。

所有患者均可根据需要接受激素治疗，HER2阳性患者接受曲妥珠单抗治疗。

Soran博士报告称，中位随访18个月后，初始手术治疗组的中位总生存期为46个月，初始全身性治疗组为42个月，差异没有统计学意义。

在没有事先计划的亚组分析中，大部分亚组患者的结果都是相似的。不过，手术延长了单发骨转移患者的生存期(没有达到 vs. 42个月， P = .02)，但却缩短了多发肝转移或肺转移患者的生存期(16个月vs. 没有达到，P = .02)。

初始手术治疗组的局部区域进展率大大低于初始全身性治疗组(0.7% vs. 3.6%)。

Soran博士强调道，这项试验计划的中位随访期为36个月，所以这里报告的数据只是初步结果。生活质量和患病率分析正在进行当中。

Badwe博士和Soran博士声明无相关利益冲突。

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By: SUSAN LONDON, Internal Medicine News Digital Network

SAN ANTONIO – Surgical removal of the primary tumor and affected lymph nodes afforded no overall survival benefit in women who had metastatic breast cancer at initial presentation, according to a pair of randomized trials presented at the San Antonio Breast Cancer Symposium.

In a first trial, conducted among 350 women in India who had responded to initial chemotherapy, about 20% of the women were still alive at 5 years regardless of whether they had surgery or just received more systemic therapy, first author Dr. Rajendra Badwe, director of the Tata Memorial Hospital in Mumbai, India, reported in a session and at a press briefing.
 
Superior locoregional control conferred by surgery was canceled out by a higher risk of progression in distant sites, lending support to more than 20-year-old preclinical data by Dr. Bernard Fisher and his colleagues suggesting that an intact primary suppresses growth of distant metastases (Cancer Res. 1989;49:1996-2001).

"Locoregional treatment of the primary tumor in women presenting with metastatic breast cancer did not result in any overall survival benefit and hence should not be offered as a routine practice," Dr. Badwe commented.

"The biological fallout of this study is that surgical removal of the primary tumor in these women appears to confer a growth advantage on distant metastases. ... This is the first time that we have evidence in human studies that locoregional treatment has a great kinetic effect on distant metastases," he added.

In a second trial, conducted among 293 women in Turkey with untreated de novo metastatic breast cancer, median estimated survival was statistically indistinguishable, at about 3.5 years, regardless of whether women had up-front surgery or simply systemic therapy, first author Dr. Atilla Soran reported in a session on behalf of the Turkish Federation of Societies for Breast Diseases.

Subgroup analyses suggested that surgery conferred a survival advantage among women with solitary bone metastases but a survival disadvantage among women with multiple liver or lung metastases.

The rate of locoregional progression was one-fifth as high with surgery as with systemic therapy.

"There was no statistically significant difference in overall survival at early follow-up, but we need longer follow-up," Dr. Soran commented. "There were potentially important subgroup differences."

The two trials have implications – both for other ongoing trials and for patient care – according to invited discussant Dr. Seema A. Khan, a professor of surgery and Bluhm Family Professor of Cancer Research at Northwestern University, Chicago, and a physician at the university’s Lynn Sage Breast Center.

"A large benefit of primary site local therapy seems unlikely based on the data we saw today," she maintained. "The assumptions we have used in our ongoing trial designs will need to be reassessed. Preplanned pooled analyses may yield sufficient power to detect smaller differences."

As for patient care, "it is pretty clear that at this point in time, we have to make sure that our patients understand that there is really no proven survival advantage to primary site local therapy," Dr. Khan said. "So I don’t think this treatment should be offered to patients with asymptomatic tumors unless they are participating in a clinical trial. There may be a local control advantage; we need to see more data on that."

Indian trial

Participants in the Indian trial, conducted between 2005 and 2013, were women with de novo metastatic breast cancer who had had a complete or partial response to anthracycline chemotherapy alone or with a taxane.

They were randomized evenly to receive locoregional therapy (lumpectomy or mastectomy with axillary lymph node dissection, plus radiation therapy to the chest wall or breast and lymph nodes) or no locoregional therapy as a control. Both groups received hormonal therapy if indicated.

In the control group, about 10% of women underwent a palliative mastectomy because of impending fungation or pain in the breast, as permitted by study protocol, according to Dr. Badwe.

The patients thus received contemporary therapy, he said, except that the 16% with HER2-positive disease did not receive the targeted agent trastuzumab (Herceptin).

Results showed that median overall survival was about 18 months, and the 5-year rate was 19.2% with locoregional therapy and 20.5% without it, a nonsignificant difference. "Uniformly, there was no difference at all in any subsets," Dr. Badwe reported.

The study had a one-sided superiority design, he noted. "We wouldn’t have been able to see a 2.5- or 3-month difference, or a 4% detriment" in overall survival.

The surgery group had a lower risk of local progression-free survival events (hazard ratio, 0.16; P = .00), but a higher risk of distant progression-free survival events (HR, 1.42; P = .01).

Several theories might explain why removal of the primary would accelerate growth of metastases, according to Dr. Badwe.

"The first and the foremost is that the act of surgery itself might elaborate some growth factors which might allow metastatic disease to grow. The second possibility, which was suggested by Dr. Fisher (Cancer Res. 1989;49:1996-2001) is that the primary tumor, which predates the onset of distant metastases, elaborates some inhibitory factors, and they are not there once the primary tumor is removed, bestowing autonomy of growth on the distant metastases," he explained. "And the third possibility is the act of surgery might induce some more metastatic processes by dissemination and create new disease."

Session attendee Dr. Steven Vogl, an oncologist in the Bronx, N.Y., said, "The ascertainment of disease progression requires disease that you can follow. A woman with bone-only metastases with her cancer in place, you can tell when her cancer is getting worse because the primary site or the axillary nodes are getting bigger. It’s much more difficult if you’ve taken those off and irradiated the chest wall. Have you looked at your data to see if that’s what was going on, why you had more distant metastases, because they couldn’t progress locally? This is a medical trial explanation that contradicts Fisher’s biologic hypothesis."

"There was a fixed time duration at which systemic investigations were performed to assess whether the distant metastases progressed," Dr. Badwe replied. If anything, the patients who did not have surgery had more assessments of their distant metastases, he said.

Dr. Tari A. King, a session attendee from the Memorial Sloan-Kettering Cancer Center, New York, noted that a lack of HER2 therapy in the trial may have had a large effect.

"We do have prospective registry data here [abstract 18-09, presented in a poster session] from a trial that we completed in the United States sponsored by the Translational Breast Cancer Research Consortium, and the patients in our study, whether they received surgery or not, their 2-year overall survival is far superior to what you’ve just showed us," she commented. "So I’m not sure that we can really apply your data to the modern targeted therapy regimens that we see in the United States."

Turkish trial

The Turkish trial, known as the MF07-01 trial, was conduced between 2008 and 2012 among treatment-naïve patients.

They were randomized evenly to receive either systemic therapy alone or surgery for the primary tumor (with or without axillary dissection) followed by radiation therapy if indicated, plus systemic therapy.

All patients received hormonal therapy as needed, and those with HER2-positive disease received trastuzumab.

With a median follow-up of 18 months, the median overall survival was 46 months with initial surgery and 42 months with initial systemic therapy, a nonsignificant difference, reported Dr. Soran, who disclosed no relevant conflicts of interest.

In unplanned subgroup analyses, the findings were similar for most subgroups of patients. However, surgery yielded superior survival in patients with solitary bone metastases (not reached vs. 42 months, P = .02) and inferior survival in patients having multiple liver or pulmonary metastases (16 months vs. not reached, P = .02).

The rate of locoregional progression was much lower with initial surgery than with initial systemic therapy (0.7% vs. 3.6%).

Dr. Soran emphasized that the trial’s planned median follow-up is 36 months, so the presented results are only preliminary. Quality of life and morbidity analyses are ongoing.

Dr. Badwe and Dr. Soran disclosed no relevant conflicts of interest.