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Three Critical Decisions in Breast Cancer Radiotherapy

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The ‘Survival Mantra’ Proven Wrong

Three Critical Decisions in Breast Cancer Radiotherapy“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.

“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,¬†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.”

Do All Patients Receiving Breast-Conserving Surgery Need Radiation Therapy?

Three Critical Decisions in Breast Cancer Radiotherapy“We know that radiation reduces first recurrence and mortality, but the absolute benefit is small in some subgroups,” he said. “It is now time, or past time, to find ways in which we can safely omit radiation in some patients.”

The proof of principle comes from the CALGB 9343 trial, which demonstrated that the omission of radiation therapy after breast-conserving surgery was reasonable in patients who had favorable ER-positive breast cancer, were aged 70 years or older, and were treated with tamoxifen.[8]

“In this trial the distant metastasis rate was 5%, so it’s very likely that these patients were all luminal A patients, and some have wondered whether these results are generalizable to all older patients with less favorable breast cancer,” he said.

There may be other patient populations that can be spared from radiation therapy, but for right now, the focus is on this particular subset. “Multiple groups, including our own, are looking at older patients with small ER+/ HER2- luminal A cancers,” he said.

In one study conducted in women aged 50-75 years who were T1, N0, ER+/PR+/HER 2-, with grade 1 or 2 tumors, the local recurrence at 5 years was less than 1% and any first recurrence was less than 2%. [Personal communication; Lior Zvi Braunstein; June 6, 2015]

Dr Harris noted that a trial will soon be opening at Dana-Farber that will offer hormone therapy alone to women age 50-75 with small, low-grade, node-negative luminal A breast cancers. “They will be offered and encouraged to choose the option of hormonal therapy alone,” he said. “I think that we will be comfortable omitting radiation in a significant portion of patients.”

Which Patients Can Be Treated With Hypofractionation?

radioterapia_tumoreHypofractionation has many benefits for the patient. It reduces treatment time from 6 weeks to between 3 and 4 weeks, making it more convenient and more cost-effective than standard radiotherapy regimen. But it is also related to major improvements in the delivery of radiation therapy, such as greater 3-D dose homogeneity and more refined radiobiologic estimates of dose equivalence.

The two Standardisation of Breast Radiotherapy (START-A and START-B) trials [9] provide justification for increased use of hypofractionation. “The results are statistically better with hypofractionation than with conventional fractionation, and although not statistically significant, the rate of local tumor relapse was also better,” said Dr Harris.

Hypofractionation resulted in fewer distant metastases, fewer common effects to normal tissue (breast shrinkage, telangiectasia, and breast edema), and improved overall survival (HR 1.00 vs 0.80; P = .04).

However, Dr Harris cautioned that it’s not clear whether “these results are real or spurious,” and a team in the United Kingdom is working on a model to determine whether these results are related to declines in local recurrence. More important, the same model was replicated in Denmark, so those results should become available in a few years.

“If this survival difference had gone the other way, I’m sure it would have killed hypofractionation for radiation oncologists, but instead, it provides more comfort,” Dr Harris said.

In 2011, the American Society for Radiation Oncology amended their guidelines regarding hypofractionation for certain patients.[10] Dr Harris explained that at his institution, the use of hypofractionation has been greatly expanded on the basis of START-B results. “We restrict it to patients getting tangents only because we still have concerns about nodal radiation with these larger fraction sizes and the possible effects on the brachial plexus,” he said. “We have also used it with patients who are getting chemotherapy and haven’t seen any deleterious effects.” But he concluded that the evidence is strong for the use of hypofractionation.

Who Should Get Nodal Radiation Therapy?

20110211-4“This is a controversial issue, and I don’t think there is a clear consensus among experts,” Dr. Harris emphasized. “What it boils down to is: How does one reconcile the results from the MA20 trial, which showed a benefit, and the Z11 trials, which did not use nodal radiation?”

The American College of Surgery Oncology Group Z0011 trial (ACOSOG Z11)[11] was a prospective, randomized trial of axillary node dissection (ALND) vs sentinel lymph node dissection (SLND) and no further axillary surgery in women undergoing breast-conserving surgery and whole-breast radiation who were found to have three or fewer positive sentinel nodes. Nearly all patients also had received adjuvant systemic therapy of choice (97%). The standard tangents treat a substantial portion of level I/II of the axilla, but the superior border of the tangents was raised (high tangents) to treat even more axilla, explained Dr Harris.

The 5-year survival results were similar between the two study arms (92% for the ALND vs 95% for SLND alone), as were the results for disease-free survival (82% vs 84%).

Almost half (46%) of the positive sentinel nodes were micrometastases, and importantly, only 27.4% of patients who underwent axillary node dissection had additional positive nodes removed beyond the sentinel node, he explained. “And that’s a low percentage compared with unselected patients. These were a highly selected group, and surgeons were very careful to enter only low-risk patients.”

The MA20[4] and EORTC[12] trials addressed the value of ipsilateral internal mammary/supraclavicular and axillary lymph node radiation therapy in women who received axillary node dissection. These patients all had macrometastases and showed a small improvement (5%) in disease-free survival at 10 years.

“But as radiation oncologists, we have to recognize that radiation has its complications,” he said. “In MA20, grade 2-3 lymphedema increased from 4.5% to 8.4%. It increased the dose to the lung and heart, and there will likely be more second cancers.” The issue is whether nodal radiation is optimal for a patient with one to two positive sentinel nodes. “If the patient looks like a Z11, then no,” he said.

The above post is reprinted from materials provided by: MedScape
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