Expert Reinforces Importance of Regional Nodal Irradiation in Breast Cancer

Wendy A. Woodward, MD, PhD

The EORTC 22922 trial reported a significant reduction in breast cancer mortality and recurrence in patients with stage I to III disease, but also underscored the need for a predictive assay to qualify who will benefit the most from regional node irradiation, said Wendy A. Woodward, MD, PhD.

In the trial presented at the 2018 ASCO Annual Meeting, women with node-positive disease and central or medial tumors were randomized to regional nodal irradiation. At 15 years, overall survival (OS) was 73.1% in the nodal irradiation group and 70.9% in the control group (HR, 0.95 95% CI, 0.84-1.06; P = .358).

The rates of disease-free survival were 60.8% and 59.9% in the study and control arms, respectively (HR, 0.93; 95% CI, 0.84-1.03; P = .1789). The rates of distant metastases—free survival were 70.0% and 68.2% in the experimental and control arms, respectively (HR, 0.93; 95% CI, 0.83-1.04; P = .1782). The rates of breast cancer mortality were 16.0% in the irradiation arm and 19.8% in the control arm (HR, 0.81; 95% CI, 0.70-0.94; P = .0055).

The trial has redefined the way physicians think about radiotherapy, explained Woodward. “This trial...really demonstrates that radiotherapy has a systemic effect in these early-stage [patients].”

OncLive: What are some of the most important trials in radiotherapy for breast cancer that recently read out?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Breast Cancer, Woodward, professor and chief, Clinical Breast Radiotherapy Service, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, highlighted encouraging advances and ongoing developments with radiotherapy in breast cancer.Woodward: The most important radiotherapy trial that was presented at the 2018 ASCO Annual Meeting was EORTC 22922. This was a randomized trial of regional nodal irradiation. It was for stage I to III patients who were node positive and had central or medial tumors. The primary endpoint was OS; the secondary endpoints were all of the other typical tumor outcomes.

At 15 years, the primary findings showed that breast cancer mortality was improved 3.8% in the patients who had regional nodal irradiation. That's an exciting finding. This in combination with another trial asking the same question demonstrating that radiotherapy has a systemic effect in these early-stage [patients]. That's a new way of thinking about radiotherapy for this group. That was a significant piece of information.

One of the challenges of regional nodal irradiation is that you would expect it to increase the dose to the heart. [In the trial] they did not see worse cardiac outcomes, but they did have an increased number of deaths in the regional nodal irradiation arm from unknown causes. One of things that they highlighted was how important it is to go back and identify what those causes were. The time frame of that study [was] in a time where you might have expected higher heart doses than we see now.

There's a lot of effort that goes into contemporary radiotherapy practice to reduce the dose to the heart. That can be done with [a deep inspiration] breath hold (DIBH). It's standardly done in left-sided patients. There are more advanced technologies for when you are struggling to get those heart doses down. In our current practice, we would expect the risk of a heart event to be less than 1%, even with regional nodal irradiation. It should be safe.

That leaves us with the question of whether everybody who was eligible for that trial should get regional nodal irradiation. Most people think that's too much. Forty percent of the patients on trial had no positive lymph nodes, so that's a low-risk population. It is a trial that largely predated sentinel lymph node biopsies. Many of the node-positive patients that you meet today who have had a positive sentinel node might have actually been node negative on that trial, so you have to weigh that into it.

For most of us, the real effort now is to try to determine who has enough risk of distant recurrence or overall recurrence to benefit [from the treatment] and really outweigh the toxicity. In our practice, we're not offering it to everyone who is node negative, but we're certainly advising patients of the results of the trial. We’re trying to work with them to look at their individual risk factors and offer it to people who have reasonable risk and might benefit from it.

Is DIBH standard practice?

The thing that it highlights is how desperately we need a predictive assay, so that we can really identify patients who will benefit from radiotherapy. [Hopefully we can] get to a place where we can determine what the best dose is for that individual, so we're not giving everyone the same dose. There's been a lot of progress on that front, both from a scientific standpoint and from a clinical trial standpoint, but there's still room to go. It probably depends on the practice. In our practice, every left-sided patient, whether they're getting regional nodes treated or not will get DIBH as long as they can manage it. There's a proportion of the right-sided patients as well [who receive it]. You do still see some benefit. It lengthens the lung some, so you can improve your lung dose constraints. We use it in most of our practice. We're going to see that more across the country as most places will do something to reduce the heart dose.

Is proton therapy available to all patients?

There's an upfront cost to the institution to buy the software and camera [for DIBH], but it's relatively modest considering the kinds of equipment we use in radiotherapy. Once you do that, it doesn't add to the cost of what we are providing to the patient for them to hold their breath while we give radiotherapy. It's relatively simple; it's sort of a video game. You have goggles and you can watch your breathing. The machine says breath in and hold your breath. If you can't and it falls out of the bar, the machine turns off. It’s kind of a no-brainer. There are clearly patients for whom [the financial cost] is worth it. There are situations where I'm treating somebody who has either complicated disease or anatomy and I simply can't cover what I feel needs to be covered and maintain the normal tissue constraints below what they need to be. That is, by no means, the majority of patients. It's a small fraction of patients, but in those cases I would love it if it cost the same and it wasn't an insurance battle.

Can you speak to the ongoing TAILOR RT trial?

The onus is on the randomized trial to ask the question of whether it is worth it to go from a standard heart dose of around 3.5 Gy down to almost 0 Gy. There's no question if, I said to a patient, “You could have this therapy with almost no radiation or you could have this with 3.5 Gy [that they would] all want 0 Gy.” Whether they need [the lower dose] is what that trial will show. Kudos to those investigators for getting that up and going.TAILOR RT is a fascinating trial. It’s following this question of whether there are patients who appear to be low risk but are getting a mortality benefit from regional nodal irradiation. [It’s also examining] whether we can predict who those patients are with a genomic predictor. The recurrence score from Genomic Health is a well-established [modality] that gives you a score of high, medium, or low risk. That is going to be the determinant for who gets on that trial.

We are really seeing some differences in getting radiation sensitizers up and going. One of the other things that we talked about is the new SWOG trial that will open for olaparib (Lynparza) in combination with radiation. The trial will look at the other end of the spectrum: patients who are higher risk with a higher risk of recurrence. This is largely for patients with inflammatory breast cancer to see whether we can do better for patients with high-risk disease.

Poortmans P, Collette S, Struikmans H, et al. Fifteen-year results of the randomized EORTC trial 22922/10925 investigating internal mammary and medial supraclavicular (IM-MS) lymph node irradiation in stage I-III breast cancer. J Clin Oncol. 2018;36 (suppl; abstr 504).