Local control matters for long-term breast cancer survival

Oct 18, 2007

No one knows exactly who coined the phrase, "think globally, act locally," but it has been shorthand for "start from where you are" since at least the 1970s. It's catchy, but the principle is easier said than done: When faced with a systemic catastrophe, it can be difficult to focus on the local manifestation of the problem.

When it comes to breast cancer, whether local treatment improves a woman's long-term survival rates has been a point of debate for decades, according to Dr. Jay Harris, chair of radiation oncology at the Dana-Farber/Brigham and Women's Cancer Center, and professor of radiation oncology at Harvard Medical School, both in Boston. Harris made the case that local control does matter at the 2007 Breast Cancer Symposium in San Francisco.

Three different clinical paradigms have developed to answer the question of whether local-regional control (LRC) affects a woman's mortality, Harris said:

The Halstedian theory holds that breast cancer spreads in an orderly fashion; that "adequate" local treatment offers a chance of cure only during a particular moment of opportunity in overall treatment; and that improved LRC will impact a woman's chance of cure.
The systemic theory divides breast cancer into two groups: those that may spread distantly and those that won't; holds that tumors with metastatic potential show this characteristic early, and assumes that LRC has little or no effect on a woman's chance of cure.
The intermediate theory states that for many breast cancers there is a point in which they haven't spread; that it is impossible to determine whether this point has passed at diagnosis; and that not achieving LRC allows some cancers to spread and reduces a woman's chance of cure.

To thoroughly establish the link between local control of cancers and a woman's mortality risk would require a randomized study that would need to include more than 3,400 patients, Harris said. In past attempts to settle the question, researchers have used the negative results from two trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) in an attempt to show that LRC had no effect on survival. But these trials are too small, according to Harris.

What's proved most helpful in connecting LRC with long-term mortality rates is clinical evidence from the 2005 Early Breast Cancer Trialists' Collaborative Group (EBCTCG) study, Harris said, as the group collects updated data on each woman randomized into all trials of operable breast cancer (Lancet, December 17, 2005, Vol. 366, pp. 2087-2106).

EBCTCG's data suggest that women live longer when they receive effective local treatment (meaning to the breast, chest wall, and draining lymph nodes). Study data came from meta-analyses of 78 randomized clinical trials that assessed the extent of surgery and the use of radiotherapy (RT) in 42,000 women from the 1960s to 1995. Researchers looked at data from women who had more extensive versus less extensive surgery, RT versus no RT, and extensive surgery versus RT to determine long-term survival rates. Data were gathered for each patient on initial characteristics, treatment, and time to outcomes as they related to breast cancer recurrence, cause-specific and overall mortality, and incidence of second primary cancers before recurrence. Contralateral breast cancer was not considered local recurrence.

What they found, according to Harris, was that improved local control of recurring cancer at five years from initial treatment resulted in considerable improvement in both breast cancer-specific mortality and overall survival at 15 years.

Women enrolled in trials with more than 10% differences in five-year local recurrence risk had a 19% absolute reduction in five-year local-regional recurrence and decreased cancer mortality of 1.6%, 3.7% at 10 years, and 5.0% at 15 years -- whether improvements had been realized through more extensive surgery or through the addition of RT. And the effect was proportional, with a 4-to-1 ratio, Harris said.

"The greater the reduction of local-regional recurrence at five years, the greater the improvements were in 15-year mortality rates," he said.

There were side effects to the RT, Harris cautioned: at 15 years, 9.3% of women treated with RT had developed contralateral breast cancer versus 7.5% of those who had not had RT, and nonbreast cancer mortality increased from 14.6% to 15.9%; the key factor was increased cardiac mortality -- which is now avoidable, he said.

The bottom line? There's now evidence that treatments that improve LRC positively affect 15-year breast cancer mortality rates: In other words, local control matters. But it may take time for the medical community to catch up with the data.

"The systemic theory has been so ingrained in the U.S. that it will take some time for us to realize implications of this finding," Harris said.

Going forward, local therapy's impact on a woman's long-term survival should be considered vis-à-vis the use of systemic therapy as well, as systemic therapy decreases the risk of both local and distant recurrence, Harris said. Clinicians need to adopt cardiac-sparing RT techniques, and research is needed to establish better estimates of baseline local recurrence rates and updated estimates of ratio in the presence of systemic therapy, he noted.

By Kate Madden Yee
AuntMinnie.com staff writer
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