Carlson, Robert H.
SAN FRANCISCO—Can radiotherapy be tailored for breast cancer patients who have positive nodes at presentation but convert to negative nodes after neoadjuvant chemotherapy?
The question is very topical in view of the increasing use of neoadjuvant chemotherapy.
Two experts here at the Breast Cancer Symposium debated the pros and cons of postmastectomy and regional nodal irradiation following a pathological complete response (pCR) to neoadjuvant therapy in patients presenting with node-positive breast cancer.
Each had viable arguments, but in the end they both agreed that a randomized controlled clinical trial is needed to settle the question.
And just such a trial is opening, they noted, to be conducted by the NRG Oncology Group, the clinical trials group formed by the scientific merger of the National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group.
The study, NRG 9353, will include patients with T1-3 disease, N1, M0 breast cancer who receive neoadjuvant chemotherapy and have pathologically negative nodes at surgery, who will be randomly selected to have or not have regional nodal radiotherapy. The trial endpoint is invasive breast cancer disease-free survival.
Yes, Radiotherapy is Necessary
THOMAS A. BUCHHOLZ, MD
Thomas A. Buchholz, MD, said there is a need for high-quality prospective studies to allow clinicians to tailor radiation decisions on the basis of response to neoadjuvant chemotherapy because to date there have not been enough data to forego a potentially curative treatment like radiation— “but now there is an open national protocol to address this very important question,” he said, referring to the NRG Trial.
He said that while he is an advocate of radiotherapy, he is not overly dogmatic about this issue, and he described a case in which he would probably not recommend postmastectomy radiotherapy—that of a 58-year-old woman with T1, N1, ER+, HER2+ disease with a pCR after mastectomy.
But for patients with more aggressive disease, triple-negative breast cancers, larger tumors, or ER- status, he said he would definitely recommend postmastectomy radiotherapy: “I would treat those patients, because radiation decreases distant metastases and improves survival in patients with positive lymph nodes.”
And, arguably, patients with pathologic complete response, the topic of this debate, are the most important group to treat because they have the best chance for being cured, he said.
More than 8,500 mastectomy patients have been treated with or without radiotherapy on randomized trials, according to an Oxford Overview, which showed a 72 percent reduction in the locoregional recurrence rate with radiotherapy — from 29 to eight percent. “And that translates into an overall survival advantage,” he said.
He also cited the Canadian MA.20 trial of 1,832 patients, which compared whole-breast irradiation with or without regional lymph node irradiation. There was only a modest decrease of two percent in regional recurrence, Buchholz said, but that led to a five percent reduction in distant metastases.
Buchholz dismissed some of the data his opponent would be presenting: The B-18 and B-27 trials that would be cited, while overall including more than 3,000 patients, actually included very few patients relevant to this debate, he said.
“Are these data solid enough to forego a potentially curative treatment? No! Are these data solid enough to enroll patients on a well-designed Phase III comparator trial? Yes!”
He said he hopes the upcoming NRG trial will put the issue to rest, and he applauded Mamounas for being principal investigator of the trial.
No, Observation Can Be Sufficient
TERRY MAMOUNAS, MD
Terry Mamounas, MD, said that patients who have positive nodes require adjuvant radiotherapy by all the guidelines, but patients whose disease converts to node-negative status after neoadjuvant chemotherapy may behave more like node-negative patients in terms of risk for locoregional recurrence. He said he is a proponent of observation for those patients, based on the results of the NSABP B-18 and B-27 trials.
He said there is abundant information on rates and predictors of locoregional recurrence with or without adjuvant systemic therapy for patients with early-stage breast cancer who receive surgery first. And there would be no debate that postmastectomy and regional node radiotherapy are generally recommended for patients with involved axillary nodes at surgery, he said.
“The question is not whether we can improve the patient's local recurrence, it is whether the local recurrence risk is high enough to make us obtain a survival benefit versus potentially a survival detriment. Radiotherapy is not a totally indolent treatment; there is a price to pay.”
Neoadjuvant chemotherapy is the standard of care for patients with locally advanced breast cancer, Mamounas said, and it is a reasonable alternative to adjuvant chemotherapy for those with large operable disease.
With the increasing use of neoadjuvant chemotherapy, a commonly encountered scenario involves patients who present with involved axillary nodes, receive neoadjuvant chemotherapy, and are found pathologically node negative at the time of definitive surgery.
Mamounas agreed with Buchholz that for patients with aggressive disease and extensive stage, radiotherapy should be given even if their disease is downstaged. “But for a patient who presents with T2, N1 disease and eventually goes to pathological complete response, we found in our combined analysis of the NSABP B-18 and B-27 trials that these patients behave more like node negative and not like node positive, so their locoregional recurrence is not as high as you would think,” he said, referring to a study published last year in the Journal of Clinical Oncology (2012;30:3960-3966).
He noted that those two NSABP neoadjuvant trials were conducted during a time when NSABP adjuvant and neoadjuvant breast cancer trials did not permit chest wall or regional radiotherapy after mastectomy or regional radiotherapy after breast-conserving therapy.
Therefore, the trials provide an opportunity to examine the rates and patterns of locoregional recurrence after neoadjuvant chemotherapy, and to identify independent predictors of locoregional recurrence without the confounding effects of locoregional radiotherapy, he said.
“The results indicate that node-positive patients at presentation—i.e., candidates for comprehensive radiotherapy—who become pathologically node negative after neoadjuvant chemotherapy have low rates of locoregional recurrence with no radiotherapy after mastectomy or breast radiotherapy after lumpectomy.”
But before such a strategy becomes the standard of care, randomized controlled trials are needed to demonstrate that the use of radiotherapy would not significantly improve breast cancer recurrence. “If so, this would produce a major paradigm shift in the locoregional management of early-stage breast cancer,” Mamounas predicted.
In the meantime, he said, clinicians can use the available data to discuss with patients the benefits versus risks of radiotherapy, particularly for those who have undergone mastectomy with reconstruction where radiotherapy has some morbidity associated with cosmetic result.