September 20, 2017
New 10-year results from a major clinical trial in breast cancer confirm that it does not compromise overall survival to leave behind minimal amounts of cancer that have spread to the underarm lymph nodes in certain patients, according to the investigators.
The long-term data are from the American College of Surgeons Oncology Group Z0011 trial and were published online September 12 in JAMA.
The study participants were women with clinical T1 or T2 invasive breast cancer, no palpable axillary nodes, and 1 or 2 sentinel lymph nodes containing metastases. In addition to lymph node management, all patients were treated with lumpectomy, tangential whole-breast irradiation, and adjuvant systemic therapy.
At a median follow-up of 9.3 years, the 10-year overall survival was 86.3% in the sentinel lymph node dissection (SLND) alone group (n = 446) and 83.6% in the axillary lymph node dissection (ALND) group (n = 445), which demonstrates the noninferiority of the less invasive SLND approach (P?=?.02).
ALND is a subsequent invasive procedure whereby all lymph nodes in the axilla are removed if nodes are found to be positive upon SLND. ALND carries a significant risk for complications, including lymphedema, numbness, and pain.
Before Z0011, "there was a general consensus that axillary dissection was necessary for better cancer control when [any] metastases were identified in sentinel lymph nodes," explain the study authors, led by Armando Giuliano, MD, from Cedars-Sinai Medical Center in Los Angeles, California.
In other words, before this trial, patients with one, two, or more positive nodes would routinely get ALND.
The 5-year Z0011 results, which were first reported in 2005, showed that SLND in patients (with one or two involved nodes) was noninferior in terms of overall survival and changed the above-mentioned consensus. In turn, axillary dissections decreased in the United States and elsewhere.
The trial has also made its way into educational curriculum. "Medical students and residents on the surgical service are being made aware of the results of this study," Dr Giuliano told Medscape Medical News.
However, the study authors point out that longer follow-up in Z0011 was crucial because of a "serious criticism" of the study- - -namely, that most study patients had estrogen receptor–positive tumors, which may recur later in the disease course.
But recurrence was not a problem in the trial.
Between year 5 and year 10, there was only one regional recurrence in the SLND-alone group vs none in the ALND group. Ten-year regional recurrence did not differ significantly between the groups and was minimal.
Still, even with the long-term follow-up currently in hand and a big criticism now addressed, Z0011 is a trial that has had "major" problems, say Edward Livingston, MD, and Hsiao Ching Li, MD, from the University of Texas Southwestern Medical Center in Dallas, in an accompanying editorial.
The trial was "plagued" by low enrollment because a lot of women were conflicted about having cancer left behind or the potential complications of axillary lymph node surgery. In the end, Dr Giuliano and his coinvestigators enrolled about 900 women but fell far short of their goal of 1900 participants. Then, there were "very few" mortality events (110 vs the expected 500) in the trial, which had a primary outcome of overall survival. The result was a "seriously underpowered study," say the editorialists.
But Dr Livingston and Dr Li believe it is necessary to look past these flaws.
"Irrespective of the statistical limitations, this was a remarkable outcome," they write.
About the SLND-alone study arm, they say: "There was the realization that 446 women who would have otherwise have undergone full axillary dissection did not have that operation" but did not have their survival compromised.
The editorialists acknowledge that breast cancer surgery has benefitted from many very important clinical trials in the last 100 years, which have had "great rigor applied to evidence generation."
But sometimes, they say, "common sense is needed to overcome statistical parochialism."
Z0011 did not meet the "predefined rigorous statistical end point," the editorialists realize. But neither did a major trial in the surgical management of appendicitis, which showed that most patients with uncomplicated disease need only antibiotics — and not surgery. That trial, known as APPAC, also changed practice, they point out.
Dr Livingston and Dr Li argue that "sometimes less than perfect clinical trials can be interpreted with common sense instead of statistical purity, resulting in changed clinical practice that improves patient care."
Medscape Medical News asked Dr Giuliano what he thought about the editorialists' line of thinking. It's "a reasonable summary," he said. "The fact is that over 10 years, without axillary dissection, we saw no increased mortality and few regional recurrences. When there are so few regional recurrences, common sense would tell you that mortality is not likely to be increased."
Still, Z0011 has ongoing critics and doubters.
In 2014, the American Society of Clinical Oncology newly recommended that that some women with early-stage breast cancer and minimal lymph node involvement (ie, the Z0011 criteria) can forgo extensive lymph node surgery (ie, ALND).
That prompted objections that were then published in the Journal of Clinical Oncology.
Two sets of critics said that the trial results are not "generalizable" to all subtypes of breast cancers, such as human epidermal growth factor receptor 2 (HER2)–positive disease. (The testing for HER2 disease was not standard at the start of Z0011.)
At the time, Dr Giuliano and colleagues responded, saying there is "no reason to believe" that various subtypes of breast cancer have increased nodal recurrences.
This week, Dr Giuliano elaborated on this criticism about the generalizability of the Z0011 results, including to younger women (Z0011 participants were mostly postmenopausal).
"Consider the randomized studies of lumpectomy," he said. "In those studies, we were not yet aware of the different biologic subtypes, nor were there many young women. Yet few now question these studies and say they are not applicable to different ages or different subtypes of breast cancer," he argued.
The study was supported by the National Cancer Institute. One study investigator reported ties to Genentech and Genomic Health. The editorialists have disclosed no relevant financial relationships.