Jagsi Holds a Magnifying Glass to Radiation Oncology: Uncovering Key Disparities and When to Omit Radiation in Breast Cancer

Reshma Jagsi, MD, DPhil

The decision to omit radiation therapy for patients with favorable characteristics is at the center of many studies seeking to evaluate which groups of patients could be eligible for therapy omission, such as older women with early-stage hormone receptor–positive, node-negative disease after breast-conserving surgery, according to Reshma Jagsi, MD, DPhil. Accordingly, it is important to keep in mind that advances in radiation therapy continue to occur, with data from several key trials and studies having been presented over the course of 2023.

Studies diving into regional nodal irradiation and disparities encompass those that are currently underway, of which Jagsi detailed new research findings in an interview with OncologyLive. Jagsi is the Lawrence W. Davis Professor and chair of the Department of Radiation Oncology at Emory University School of Medicine in Atlanta, Georgia.

Searching for Disparities and Ways to Counteract Them

Jagsi and fellow investigators examined cardiac radiation doses in a large cohort of patients with breast cancer, as previous research has not explored the implications of dose disparities or looked at cardiac radiation doses by race.

“When you take a deep breath in, you push your heart out of the way of the radiation beam—it’s the best way to get away from a normal tissue. It’s not hard to have someone hold their breath reproducibly during treatment and yet we now have evidence that the access to that simple, important advance is not equitable in our society,” Jagsi said. “This gives us ideas of ways that we can intervene at every level, no matter where we come in [during] the treatment continuum.”

In the study, when investigators generated laterality- and fractionation-specific models of mean heart dose among patients (n = 8750) who received whole breast therapy from 2012 to 2018 and generated patient- and facility-level models to estimate race-specific cardiac doses, they found that depending on laterality and fractionation, Asian and Black women received higher cardiac doses than White women. Compared with findings among White women, there was an estimated excess of up to 2.6 cardiac events and 1.3 deaths per 1000 Black women and 0.7 cardiac events and 0.3 deaths per 1000 Asian women as a result of cardiac dose disparities.¹

The study also demonstrated that when controlling for radiation technique, including deep inspiration breath hold, the dose disparity for Black women was reduced by 30%. However, among patients treated with conventional fractionation for left-sided disease, 14% of Black patients received deep inspiration breath hold compared with approximately 30% to 45% of Asian and White patients.

“African American patients are receiving care in centers that don’t have access to breath hold devices,” Jagsi explained. “If your hospital doesn’t buy you the equipment that you need [as a radiation oncologist,] that’s problematic; and if you’re serving an underserved community, and you face the challenge of being under-resourced that is a societal problem.”

An additional factor that may have influenced cardiac dose levels in the study was intensity-modulated radiotherapy (IMRT), which was associated with an increased cardiac dose and used in Black patients more often—70.1% of Black women received IMRT compared with 35.8% of Asian women and 42.1% of White women. Facility-level practice variation was also found to produce cardiac dose disparities.¹

Further, investigators of another study noted that shorter courses of radiation therapy may aid in reducing disparities as African American patients are 48% more likely to have radiation therapy omitted during treatment, 40% less likely to complete radiation therapy, and significantly more likely to experience radiation treatment delays than White patients.² Level 1 evidence has also indicated that treatment with standard fractionation and hypofractionated regimens results in equivalent outcomes and adverse effect profiles. As overall treatment time with hypofractionation is reduced by 30% to 40%, acute toxicities are in turn reduced.

“We finally have a more efficient way of delivering radiation that creates less toxicity, and we’re less likely to use it in the patients we know are more likely to have acute toxicity and more likely to have financial toxicity. It’s shocking and it also gives us a little window into something that is entirely within the control of a treating radiation oncologist. Offering hypofractionated courses is something that we have direct control over and can help improve the equity of cancer care,” Jagsi said.

De-Escalation/Omission Approaches in Favorable Subgroups Requires Careful Examination

In addition to being mindful of disparities, omission of radiation in certain patient populations also is top of mind, with data from many studies presented throughout 2023 exploring the de-escalation as well as omission of radiation for patients with favorable characteristics. Jagsi noted that careful consideration of these recent data is warranted because meaningful advances in radiation treatment delivery have also occurred.

“PRIME II [ISRCTN95889329] is the best trial to point to because it was a randomized trial whose data showed there is a benefit from radiation treatment for pretty much any group of patients, even [those with] highly favorable select [characteristics]. But in some subgroups of patients, the risk of recurrence even without radiation is reasonably low enough that some women might want to choose to omit radiation.”

Ten-year outcomes of the phase 2 PRIME II trial revealed that local recurrence rates increased when radiation therapy was omitted vs given for patients 65 years or older with node-negative, hormone receptor–positive, T1 or T2 primary breast cancer who received breast-conserving surgery with clear excision margins and adjuvant endocrine therapy.³ However, no significant impact was observed regarding breast cancer–specific survival or overall survival (OS) rates.

“We now would feel comfortable offering patients, if they’re 65 and older, the option of omitting radiation treatment with the caveat that the risk of recurrence at 10 years is approximately 10% without radiation and only 1% or 2% with radiation, even in that highly selected subgroup of patients,” Jagsi explained.

The cumulative incidence of local recurrence among patients who did not receive radiotherapy (n = 668) was 9.5% (95% CI, 6.8%-12.3%) compared with 0.9% (95% CI, 0.1%-1.7%) for those who did receive radiotherapy (n = 658). Ten-year distant recurrence–free survival rates were 1.6% (95% CI, 0.4%-2.8%) vs 3.0% (95% CI, 1.4%-4.5%), respectively, and the breast cancer–specific survival rate was 97.4% (95% CI, 96.0%-98.8%) for patients who did not receive radiotherapy compared with 97.9% (95% CI, 96.5%-99.2%) for those who did. The 10-year OS rates were 80.8% (95% CI, 77.2%-84.3%) vs 80.7% (95% CI, 76.9%-84.3%), respectively (Table).³

Table. Outcomes in the PRIME II Trial

“Many patients can also avail themselves of the advances of ultrahypofractionated whole breast radiation, which has somewhat shorter follow-up, as well as accelerated partial breast irradiation, which has good long-term follow-up. We can probably get treatment done in 5 fractions [with either approach],” Jagsi noted.

In addition to PRIME II, data from the IDEA study (NCT02400190) revealed that the 5-year OS and breast cancer–specific survival rates were 100% among postmenopausal patients (n = 186) who omitted radiotherapy treatment and received at least 5 years of endocrine therapy.⁴ Patients who were prospectively enrolled were 50 to 69 years old and had estrogen receptor–positive, progesterone receptor–positive, HER2-negative, pT1N0 unifocal invasive breast cancer with margins of 2 mm or greater after breast-conserving surgery and an Oncotype DX 21–gene recurrence score of 18 or less. Further, the 5-year rate of freedom from any recurrence was 99% (95% CI, 96%-100%).

Study authors, led by Jagsi herself, noted that due to the low risk of recurrence observed under these circumstances in IDEA, long-term follow-up of the study in conjunction with additional studies will aid in determining whether initial radiotherapy treatment is avoidable in a broader group of patients than guidelines currently recommend.⁴

“But we have to be very careful when presenting these results to patients to make sure they understand both the risks and the benefits of radiation treatment,” Jagsi noted on study findings on the omission of radiotherapy. “Radiation [oncology] is the only specialty that has a ‘danger: radiation’ sign that comes immediately to mind when you think about the treatment modality that we use. Patients are scared of radiation, and we don’t want patients who don’t fall into these favorable groups where there’s clearly a substantial benefit from radiation to be scared about radiation. Nor do we want patients who are in patient populations where there is some benefit from radiation treatment to dismiss that benefit without understanding the current experience of radiation treatment.”

Examining Regional Nodal Irradiation

A portion of radiation treatment that has remained under debate, according to Jagsi, includes regional nodal irradiation, which encompasses areas that are typically left undissected. As many patients receive sentinel lymph node biopsy alone, levels 1 and 2 of the axilla as well as level 3 (the infraclavicular region), the supraclavicular region, and the internal mammary nodal region—may be included.

“These are areas where there has been long-standing debate over whether our treatment fields should encompass those areas—there is not zero toxicity from encompassing those regions; there is a slight increase, for example, in the rates of radiation pneumonitis or lymphedema that come from including those regional nodal basins. However, when we treat with radiation, we are not only trying to prevent local regional recurrence, which of course can be morbid, but also the persistence of an isolated reservoir of disease that might remain after surgery and systemic therapy that could serve as a source for distant metastases. Regional nodal irradiation may be particularly important in improving overall disease control because of that latter mechanism,” Jagsi said.

Pointing to a landmark publication from November 2023, Jagsi noted that a metanalysis from the Early Breast Cancer Trialists’ Collaborative Group examining 8 modern trials from 1989 to 2008 found that regional nodal irradiation significantly reduced recurrence in 12,167 patients (rate ratio [RR], 0.88; 95% CI, 0.81-0.95; P = .0008) (Figure). Mortality was also significantly reduced with radiotherapy (RR, 0.87; 95% CI, 0.80-0.94; P = .0010) with no significant effect on non–breast cancer mortality observed (RR, 0.97; 0.84-1.11; P = .63); this resulted in a significant reduction in all-cause mortality (RR, 0.90; 0.84-0.96; P = .0022).⁵

Figure. Metanalysis From 8 Modern Trials

Although regional nodal radiotherapy significantly reduced the rates of breast cancer mortality and all-cause mortality in trials completed following the 1980s, it did not in those prior to the 1980s which could be a result of radiotherapy improvements, according to the study authors.

“Data from studies [such as this one] emphasized the potential for long-term gains from relatively minor adaptations of our radiation treatment fields,” Jagsi said. “We’ve learned a lot about patient selection [and] how to administer treatment more efficiently with lower doses to normal tissues. That’s a key takeaway from this regional nodal irradiation meta-analysis—we have made truly meaningful advances, and we have seen transformation of the most worrisome potential complications of radiation therapy as a result. 2023 was quite a year for radiation oncology and for breast cancer [with so many key analyses and trial data published].”

Unpacking Burgeoning Advances in Radiation Oncology at The Miami Breast Cancer Conference

Discussions centered around disparities, the new American Society for Radiation Oncology (ASTRO) guidelines, and more will be among those of interest at the Miami Breast Cancer Conference^® taking place March 7 to 10, 2024.⁶ “I am excited about this year’s Miami Breast Cancer Conference because it’s the first time that radiation oncology has had its own full track,” Jagsi, who is cochairing the conference, said. Topics such as “Radiation Therapy for Oligometastases” and “Considerations in Concurrent Use of Radiation Therapy and Systemic Agents” will also be highlighted at the conference.

The new ASTRO guidelines that now recommend partial breast rather than whole breast irradiation for patients with favorable characteristics and early-stage node-negative invasive disease or ductal carcinoma in situ will also be discussed.⁷ The guidelines, which were based on a systemic literature and comparative effectiveness evidence review, mark the first ASTRO recommendations for partial breast radiation since 2017. The review conducted by the Agency for Healthcare Research and Quality found comparable outcomes for partial breast and whole breast radiation.

“The wonderful thing about the Miami Breast meeting is that the world experts who led these trials and initiatives [will present on them],” Jagsi said. “We’ll have Eleftherios P. Mamounas, MD, MPH, and Julia R. White, MD, speaking about the landmark phase 3 NSABP B-51/RTOG 1304 trial [NCT01872975] that looked at whether we can get away without regional nodal irradiation in patients who had neoadjuvant chemotherapy and a pathologic complete response. We’re going to have a chance to hear from the experts who led that trial, their perspectives, and how the findings should be applied in practice.”

The trial data revealed that omitting adjuvant regional nodal irradiation treatment did not increase the risk of disease recurrence or death 5 years after surgery in select patients. Patients with biopsy-proven axillary node involvement whose axillary nodes convert to ypN0 after neoadjuvant chemotherapy did not experience improvements in 5-year invasive breast cancer recurrence–free interval or OS following treatment with chest wall plus regional nodal irradiation after mastectomy or whole breast plus regional nodal irradiation after lumpectomy.⁸

Regarding the trial’s primary end point of invasive breast cancer recurrence–free interval, there were 59 events in those who did not receive regional nodal irradiation (n = 784) and 50 events in those who did receive regional nodal irradiation (n = 772; HR, 0.88; 95% CI, 0.60-1.29; P = .51).

Additionally, Jagsi noted she is “going to present a series of studies conducted whose findings have demonstrated that not only are there unacceptable disparities in mortality and financial toxicity, but also in pain experiences and acute toxicities [for patients when] receiving radiation treatment. Not only are there disparities in those acute toxicities but there are disparities in providers’ recognition of those toxicities, which in part might explain why we’re seeing uncontrolled toxicities that are more frequent in our patients of color.”

References

1. Chapman CH, Jagsi R, Griffith KA, et al. Mediators of racial disparities in heart dose among whole breast radiotherapy patients. J Natl Cancer Inst. 2022;114(12):1646-1655. doi:10.1093/jnci/djac120
2. McClelland S 3rd, Harris EE, Spratt DE, et al. Navigator-assisted hypofractionation (NAVAH) to address radiation therapy access disparities facing African-Americans with breast cancer. Rep Pract Oncol Radiother. 2022;27(3):583-588. doi:10.5603/RPOR.a2022.0064
3. Kunkler IH, Williams LJ, Jack WJL, Cameron DA, Dixon JM. Breast-conserving surgery with or without irradiation in early breast cancer. N Engl J Med. 2023;388(7):585-594. doi:10.1056/NEJMoa2207586
4. Jagsi R, Griffith KA, Harris EE, et al. Omission of radiotherapy after breast-conserving surgery for women with breast cancer with low clinical and genomic risk: 5-year outcomes of IDEA. J Clin Oncol. 2024;42(4):390-398. doi:10.1200/JCO.23.02270
5. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Radiotherapy to regional nodes in early breast cancer: an individual patient data meta-analysis of 14 324 women in 16 trials. Lancet. 2023;402(10416):1991-2003. doi:10.1016/S0140-6736(23)01082-6
6. 41st Annual Miami Breast Cancer Conference Agenda. Physicians’ Education Resource®. Accessed January 25, 2024. bit.ly/3vOyhel
7. ASTRO issues patient-centered clinical guideline on partial breast irradiation for early-stage invasive breast cancer and DCIS. News release. ASTRO. November 15, 2023. Accessed January 25, 2024. bit.ly/48DdQ2t
8. Mamounas E, Bandos H, White J, et al. Loco-regional irradiation in patients with biopsy-proven axillary node involvement at presentation who become pathologically node-negative after neoadjuvant chemotherapy: primary outcomes of NRG Oncology/NSABP B-51/RTOG 1304. Presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Abstract GS02-07.