Three Critical Decisions in Breast Cancer Radiotherapy

Roxanne Nelson, BSN, RN

Disclosures

January 22, 2016

Back to the Future

Editor's Note: Radiation therapy has become an integral part of breast cancer treatment, but skipping radiation in select low-risk breast cancer patients may be a viable option. During a plenary session at the 2015 San Antonio Breast Cancer Symposium, Jay R. Harris, MD, a radiation oncologist at the Dana-Farber Cancer Institute and professor of radiation oncology at Harvard Medical School, addressed three critical decisions that radiation oncologists face when selecting the optimal treatment for patients. He began his presentation by describing how recent developments in breast cancer radiotherapy have given rise to these three questions in clinical practice, and then presented evidenced-based recommendations for each.

The 'Survival Mantra' Proven Wrong

"Prior to 2005, particularly in the United States, it was widely thought that radiation influenced local recurrence but did not influence survival," said Dr Harris. "It was kind of a mantra."

That all changed in 2005, when the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) published a meta-analysis in the Lancet,[1] showing that radiation therapy after mastectomy or breast-conserving surgery reduced local recurrence and, for the first time, demonstrated that it improved survival.

However, the EBCTCG erroneously postulated that for every four local recurrences that were avoided at 5 years, there was an additional survivor at 5 years. "And I really think they've backtracked on that postulation," said Dr Harris.

EBCTCG subsequently adopted any first recurrence, local or distant, as the primary endpoint for the effect of radiation therapy. This was based on a number of factors, one being that in 2005, it was shown for the first time that radiation had a proven systemic effect on distant metastases as well as local recurrence.[2]

The time to local recurrence, which we calculate all the time, is not strictly valid.

"One thing that has become more apparent is that the time to local recurrence, which we calculate all the time, is not strictly valid," said Dr Harris. "Actuarial calculation requires statistical independence, which is fine for survival. But with time to local recurrence, there is the competing risk of distant disease, which invalidates the true time to local recurrence."

"Third, when they looked at that 4-to-1 ratio, it didn't hold up," he noted.

In the latest EBTCG meta-analysis,[3] which looked at the original trials plus new ones that included low-risk patient trials, the use of radiation therapy proportionally reduced any first recurrence by about one half and reduced breast cancer mortality by about one sixth. "That benefit seems to be pretty substantial, but it's important to point out that in many subsets, which are critical to look at, the absolute benefit was quite small," Dr Harris emphasized.

It has now also become quite clear that the survival benefit of radiation is not just mediated by its reduction in local recurrence. The new EBCTCG "ratio" is that for every 1.5 first recurrences avoided at 10 years, there is an added survivor at 20 years.

These findings were also illustrated in the results of the MA20 trial,[4] which was conducted in patients with node-positive or high-risk, node-negative breast cancer who were treated with breast-conserving surgery and adjuvant systemic therapy. They were randomly assigned to either whole-breast irradiation plus regional nodal irradiation (including internal mammary, supraclavicular, and axillary lymph nodes) or whole-breast irradiation alone.[4] At 10 years, the addition of regional nodal irradiation to whole-breast irradiation did not improve overall survival but reduced the rate of breast cancer recurrence, from 6.8% to 4.3% (HR 0.59; P = .009). It was statistically significant and there was also a reduction in distant disease, from 12.9% to 10.9% (HR 0.76; P = .03)

Ironically, as we've perfected breast-conserving therapy, with very low recurrence rates, more patients are electing mastectomy.

Dr Harris noted that when he first entered the field in the 1970s, patients treated with breast-conserving therapy had a 5-year local recurrence rate of about 10%. That has now dropped to about 2%. "And ironically, as we've perfected breast-conserving therapy, with very low recurrence rates, more patients are electing mastectomy," he said.

So what are the reasons for this reduced rate of local recurrence?

One reason is improved mammographic evaluation, and another is improvements in pathologic evaluation. But "probably most important is the benefit seen with the addition of adjuvant systemic therapy," explained Dr Harris. "This was developed to address micrometastases, but serendipitously it had a large benefit in reducing local recurrence."

The interaction between radiation and systemic therapy was observed in two National Surgical Adjuvant Breast and Bowel Project (NSABP) trials.[5] In the B-13 trial, patients with ER-negative, node-negative disease who did not receive chemotherapy had a 10-year local recurrence of 13.3%. In contrast, those who received chemotherapy reduced that rate to 3.5%.[5]

In the companion B-14 study, patients who were ER positive and node negative were randomly assigned to tamoxifen or placebo. "Local recurrence went from 11% to 3.6%.[5] Subsequent studies involving increasingly improved systemic therapy showed further reductions in local recurrence," said Dr Harris.[5]

In 2008, Dr Harris and colleagues were the first to show that local recurrence is linked primarily to the biologic subtype of tumors, rather than treatment approaches.[6] "Five-year local recurrence is 6% for triple-negative cancers and only about 1% for luminal A cancers," he noted.

They found that HER2 and basal tumor subtypes were the only factors associated with increased local recurrence, and neither margin status, tumor size, age, nor nodal status was significant.[6]

"In 2011, with more follow-up and events,[7] we showed that age was also a risk factor," said Dr Harris. "But it was a much lesser risk factor, with older patients having a lower risk for recurrence and younger patients having a higher risk."

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