Research Efforts Continue With Radiation Therapy in Breast Cancer

Eileen Connolly, MD, PhD

The role of radiation therapy continues to be refined in breast cancer, especially as investigators go on exploring the optimal use of regional radiation and how to select the best patients to receive it, according to Eileen Connolly, MD, PhD.

“The important thing for patients is that we are offering regional radiation. This therapy not only gives you a local control benefit, but some studies have demonstrated a survival benefit and a disease-free survival (DFS) benefit,” said Connolly, an assistant professor of radiation oncology at Columbia University Medical Center. “If you prevent one local occurrence, then you are going to prevent a distant recurrence.”

Additionally, the ongoing TAILOR RT trial (NCT03488693) is poised to determine whether patients with low-risk, node-positive breast cancer might be able to avoid regional radiation. Moreover, efforts are ongoing to maintain quality of life (QOL) for patients as well as to lower the risk of lymphedema, Connolly added.

In an interview during the 2020 OncLive^® State of the Science Summit™ on Breast Cancer, Connolly reflected on novel radiation techniques, as well as ongoing research and challenges with radiation therapy in breast cancer.

OncLive: Could you share insight on the optimal uses of radiation and mastectomy in breast cancer?

Connolly: Basically, postmastectomy radiation or regional radiation have traditionally been used in the up-front setting for patients who have 4 or more positive lymph nodes, inflammatory breast cancer, or large primary tumors in the breast.

That has expanded with the publication of several large trials in 2015, as well as a meta-analysis from the Early Breast Cancer Trialist Group that came out in 2014. We carefully looked at the benefit of treating regional lymph nodes for patients with node-positive disease. The meta-analysis looked at prior clinical trials, such as the National Cancer Institute of Canada MA.20 and the EORTC 22922-10925 trial, which were specifically designed to answer the question of whether or not there is a benefit to resume nodular radiation.

[In these analyses], any patient who had 1 to 3 positive lymph nodes, or had high-risk, node-negative disease, was randomized to receive regional lymph node radiation or to not undergo the treatment.

What regional lymph node radiation means is treating the axillary and internal mammary lymph nodes. A woman who has had a mastectomy and has node-negative disease would not receive radiation. If she had a lumpectomy or breast-conserving surgery, she would only undergo breast-conserving surgery versus the surgery plus receiving comprehensive nodular radiation.

The MA.20 and EORTC 22922-10925 studies were trying to show the benefit in overall survival with comprehensive radiation compared with either no radiation in the mastectomy setting or breast-conserving surgery alone. While neither study met its primary outcome of survival, both showed a meaningful local control benefit as well as a DFS benefit.

The subsequent meta-analysis demonstrated a survival benefit. In the analysis, part of the issue was that the researchers underpowered the original studies because therapy evolved. However, the compelling data of it really changed the practice in radiation oncology. We went from routinely never treating women who were node-positive with regional radiation to making it routine practice.

Now, the landscape has changed because patients are frequently treated with chemotherapy first. We have moved to a new form of adjuvant therapy for node-positive disease upfront. We are in an unknown area because there may or may not be a pathologic complete response (pCR).

Retrospective analyses of early neoadjuvant chemotherapy trials looked back at locoregional recurrence risk. [They compared] patients with node-positive disease who converted to node-negative disease with patients who started out with node-positive disease and remained node-positive. For patients who remain node-positive, [neoadjuvant chemotherapy has] a clear benefit. For those who convert to a pCR, it is questionable on whether or not we are overtreating. An ongoing trial is close to accrual, so hopefully we can actually answer that question [in the future].

The other controversial area is for hormone receptor (HR)—positive women with a low Oncotype DX score. In the TAILORx trial, we saw that [some] patients can possibly avoid chemotherapy. In node-positive women, we are waiting for the results of the RxPONDER trial [to determine] whether there is benefit with chemotherapy or not.

A similar study is now open for radiation, called the TAILOR RT trial. Essentially, in this trial, women who are HR-positive and node-positive, and have a recurrent score <18 are randomized to regional radiation versus no regional radiation. This is another area where we need more information.

Right now, as a physician, I give a balanced overview [of options], but the standard of care is to treat. We try our best to make it nuanced, but there are a lot of unknowns. The way that we handle that is knowing when patients can enter a trial to help us answer those questions in the future.

Could you discuss the toxicity profile of radiation therapy?

Regarding toxicity, [physicians and patients are concerned about] what this will do to patients' QOL. There are an abundance of data now looking at cardiac and pulmonary toxicities. Historically, people were concerned about heart toxicity, and we have shown that we do not see increased cardiac toxicity with radiation.

However, we do see an increased risk of secondary lung cancer in active smokers. [Patients who quit smoking] can make a difference during therapy and significantly reduce their lifetime risk [of lung cancer] because the radiation therapy does add to the risk.

Regarding lymphedema, both the MA.20 and EORTC 22922-10925 trials did a good job of looking at this [concern]. Historical data were not great. Researchers went back and looked at the event rate of lymphedema in their studies, and they showed that regional radiation increased patients’ probability of about 3% over the baseline of what they already had, based on surgery and number of nodes removed. In 2019, the MA.20 group published a nomogram that helps us to predict the risk of lymphedema. They demonstrated that the biggest risk factor is surgery, and radiation increases that risk. The nomogram includes other information like body mass index, age, type of surgery, etc, to help predict risks.

A huge amount of work looking at lymphedema has been done by Alphonse Taghian, MD, of [Massachusetts General Hospital]. [His group] has recently shown risk factors displaying that if you measured lymphedema before and after surgery, you see a slight risk increase just from surgery. Now we have better numbers to quote and, in terms of regional radiation, how much more the risk increases.

Surgery is the biggest place where we will make a difference. Studies are looking to reduce the probability of getting an axillary lymph node dissection. This is important because if you do not do a full dissection, you will avoid the toxicity more significantly.

How has surgery impacted the risk of lymphedema risk?

We have newer exploratory surgical techniques, such as lymphatic bypass. [This approach] may be able to potentially reverse or help eliminate lymphedema. What is important for patients [who undergo surgery] is physical therapy. A lot of data are looking at how much QOL is improved by referring patients to go for physical therapy. It is standard in my practice and how much [physical therapy] they need depends on the patient.

What is your take-home message on the state of radiation in breast cancer?

It is important for physicians to know what the toxicities are and how best to manage them and also to help alleviate some of the concerns patients have. As more data come out, we can potentially de-escalate surgery and radiation.

If we get positive results from NSABP B-51 or TAILOR RT, a lot of patients will not need to be treated. That is great, but we need to know whether or not that is the right thing for their disease.