Summary
National Comprehensive Cancer Network (NCCN) guidelines have been updated for breast cancer patients with clinically node-positive disease with suspicion of three or more nodes or larger, more extensive tumors, based on the results of clinical trials.
At the NCCN 2020 Annual Meeting, Benjamin Anderson MD, of the Fred Hutchinson Cancer Center, reviewed the updated guidelines, in particular, for node-positive disease and neoadjuvant chemotherapy.
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Original Article
Revised Guidelines for Node-Positive Disease and Large Extensive Tumors
Oncology Times
By Mark L. Fuerst
National Comprehensive Cancer Network (NCCN) guidelines have been updated for breast cancer patients with clinically node-positive disease with suspicion of three or more nodes or larger, more extensive tumors, based on the results of clinical trials.
At the NCCN 2020 Annual Meeting, Benjamin Anderson MD, of the Fred Hutchinson Cancer Center, reviewed the updated guidelines, in particular, for node-positive disease and neoadjuvant chemotherapy.
“For patients with more extensive nodal disease and not given chemotherapy, if it looks like disease goes beyond 1 or 2 positive nodes, the standard of care is to do complete axillary nodal dissection (CAND),” said Anderson.
The NCCN guidelines for invasive breast cancer clearly state after sentinel node mapping and excision which patients need further axillary surgery and which individuals who clinicians can consider doing sentinel node biopsy alone in the adjuvant setting.
From a surgical perspective, neoadjuvant chemotherapy may help avoid CAND. “This is highly motivating because we do not like to cause lymphedema if we can help it,” said Anderson.
If chemotherapy is given in more extensive nodal disease, the standard of care is axillary dissection, if there is evidence of residual disease.
“We can consider sentinel node biopsy in selected patients who are clinically node-negative after neoadjuvant chemotherapy. This was a category IIB recommendation so there was disagreement among the NCCN panelists about what allows stopping after a sentinel node when you know the patient is node-positive before starting neoadjuvant therapy,” said Anderson.
Research Trials
The SENTINA trial, a prospective, multicenter trial of sentinel node lymph biopsy in 592 patients with breast cancer before and after neoadjuvant chemotherapy, was one of the first major trials to examine this issue. In the study, Arms A and B had sentinel node biopsy upfront before neoadjuvant chemotherapy. Arm A was node-negative and no dissection was required. Arm B had a second sentinel node biopsy and CAND, which was not successful.
Arm C patients had clinically node-positive disease that converted to node-negative by virtue of chemotherapy. They were randomized to sentinel node biopsy and CAND to look at the false-negative rate. “If they were clinically node-positive before and clinically node-negative after, the patients needed CAND. This shows there is still a role for CAND,” said Anderson.
In Arm B, the false-negative rate was 50 percent. “This is the reason why we have largely abandoned sentinel node biopsy before chemotherapy. This is a shift from where the NCCN was 15 years ago,” he said.
In Arm C, the false-negative rate was 14 percent. The threshold in clinical trials for cross-over is 10 percent. “So 14 percent is not good enough. These patients still need CAND,” said Anderson, who noted that those with one positive node had a 24 percent false-negative rate.
He pointed out in Arm C the false-negative rate goes below 10 percent once patients had 3 or more positive sentinel nodes.
“The more sentinel nodes we are able to find, the more we can believe sentinel node data,” said Anderson. Use of dual tracer radiotrackers also led to a false-negative rate below 10 percent. “This gives us relevant data on how we can get below a 10 percent false-negative rate, either if 3 or more sentinel nodes are removed or with the dual-tracking method. Putting these two together is a strong argument that we can do well by doing sentinel nodes after neoadjuvant chemotherapy when there appears to be clinically complete resolution of disease,” said Anderson.
A subsequent trial, Z1071, provides supportive data. The 756 patients had N1 or N2 breast cancer and received neoadjuvant chemotherapy. A subgroup had a clip placed on the nodes at the time of surgery.
“The clip provides good evidence that we are looking at the sentinel node that had disease. For those who had at least two sentinel nodes removed, the false-negative rate was 9.1 percent, and with clipped nodes it was 6.8 percent. This subset analysis shows us we can get to appropriate selection,” said Anderson.
A third trial, the 153-patient SN FAC trial, also shows the overall false-negative rate with more positive nodes. “The false-negative rate is less than 10 percent once patients get to three or more positive nodes. Our practices are considered adequate for leaving the rest of the node dissection alone,” said Anderson.
More Extensive Nodal Disease
According to the NCCN guidelines, patients with more extensive nodal disease (N3) either have level 3 axillary node involvement or positive internal mammary nodes or supraclavicular lymph nodes. N3 patients were excluded from randomized trials evaluating CAND in neoadjuvant setting, pointed out Anderson.
This leads to the clinical question: does N3 disease before neoadjuvant chemotherapy require CAND after chemotherapy? “This is a data-free zone. The false-negative rate of sentinel node biopsy is unknown in N3 disease. We can only infer from other areas if we are going to apply it,” said Anderson. “The axillary recurrence rate following sentinel node biopsy might be higher than expected. On the other hand, CAND has no bearing on removal of supraclavicular or internal mammary nodes. We have been managing it this way for some time using radiation therapy. Prior studies of radical node extirpation, such as extended radical mastectomy, have never shown superior regional disease control.”
Anderson said NCCN centers were polled when this debate became clear and found a spectrum of answers. The centers were asked: Does N3 disease before neoadjuvant chemotherapy demand CAND after chemotherapy?
One center said it was not ready to go to CAND from sentinel node biopsy. It acknowledged the potential of selection bias and would like to see a higher level of data, he said. Another center said the definition of N2 and N3 disease is problematic since nodes are not sampled. It said, if a patient has extensive nodal disease, the real concern is distant metastases, and axillary disease is less relevant.
A third center said it performed CAND, but had low axillary recurrence rates. A fourth center said it leaves out CAND altogether.
“As you can see, while we are in transition away from CAND, we do not have uniformity. There’s a clear need for more data as we move forward,” said Anderson.
Janice Lyons, MD, of the Case Comprehensive Cancer Center, emphasized the importance of shared decision-making with the breast cancer patient. “Know what the patient’s goals are for therapy. Is the patient willing to accept the potentially higher risk of local regional recurrence as compared to a higher risk of toxicity from lymphedema and with respect to arm involvement?” she said.
For post-mastectomy patients with clinically stage III disease, the risk of local regional recurrence without radiation can be high. “Off trial, we would not recommend holding off radiation for patients with clinically stage III disease,” said Lyons.
She posed some pertinent questions for clinicians. If we remove an internal mammary node, do we really need to add radiation? As systemic therapy improves how much local regional treatment do we need? Are there subgroups of patients who do not need treatment of nodal areas?
“Off study, if internal mammary nodes are not involved, enroll the patient in the NSABP B-51 trial, which has randomized patients to radiation to the breast alone versus comprehensive nodal irradiation. We hope we can maximize the systemic therapy and minimize the toxicity of local therapy,” said Lyons.
Mark L. Fuerst is a contributing writer.