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Older Breast Cancer Patients Also Benefit from Added Radiation

Fromer, Margot J.

doi: 10.1097/01.COT.0000293385.49371.43
Large Retrospective Study

A large study has now confirmed that for women over age 70 with small estrogen receptor (ER)-positive, node-negative tumors, the standard of care should be lumpectomy followed by radiation.

The study, published in the May 17th issue of the Journal of the National Cancer Institute (2006;98:681–690), was led by Benjamin D. Smith, MD, Chief Resident in the Department of Therapeutic Radiation at Yale School of Medicine

Although radiation therapy following lumpectomy for early breast cancer has long been the standard, the 2004 Cancer and Leukemia Group B C9343 study had cast doubt on that idea because it found that the absolute risk reduction was only three events per 100 people at five years of follow-up. Given this small benefit, combined with the high cost and side effects, it was suggested that radiation therapy (RT) might be omitted.

However, said Dr. Smith, “while there may be meaningful differences between patients in clinical trials and those in the general population, the efficacy of breast RT in the community has not been investigated. Identification of those who are most—and least—likely to benefit from RT would help clinicians tailor their treatment recommendations appropriately.”

Hence, the retrospective study to determine whether added radiation is indeed associated with a lower risk of recurrence.

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SEER Database

Patients were chosen from the NCI's Surveillance, Epidemiology, and End Results (SEER)-Medicare database that links tumor-specific variables to Medicare claims. The study lasted from 1992 until 1999.

Originally, a total of 60,717 women over age 70 were identified with breast cancer, but many were eliminated because they would not have met the criteria for the study—that is, having a tumor larger than 2.0 cm, invasive disease, advanced stage or distant metastases, among other factors.

The final cohort was 8,724 women who had been treated with conservative surgery for small lymph node-negative, ER-positive (or unknown ER status) breast cancer. Their median age was 77, and 90% of patients were white, with a median tumor size of 1.0 cm.

Comorbidity, a factor known to influence recurrence and survival, was absent in 65% of patients, mild in 22%, and moderate to severe in 10%. Seventy-three percent of the women received breast radiation, and 3% had chemotherapy.

After a median follow-up of five years, 1% of patients had a second ipsilateral breast cancer and 1.9% had subsequent mastectomy. Radiation therapy was associated with a reduced risk of recurrence, subsequent mastectomy, or both.

At five years, the risk of recurrence was 5% in patients receiving no radiation and 1% for those so treated. At eight years, the risks were 8% and 2%, respectively. Of the total number of patients, 9% had repeat breast-conserving surgery, but irradiation was not associated with this outcome.

Other variables associated with recurrence included being black, widowed, and progesterone receptor (PR)-negative. Asked why these three variables made a difference, Dr. Smith said, “We have to interpret them cautiously and speculate about reasons. But it may be that older widows don't receive adequate follow-up care, they may have fewer mammograms, and less social support than other women.

“As for black women, they may risk recurrence because of the nature of the tumor itself. We're not sure of any of this, and it all merits further study.”

Asked for his opinion, Thomas Buchholz, MD, Director of the Breast Cancer Radiation Oncology Program at the University of Texas M. D. Anderson Cancer Center, noted that widowhood probably doesn't increase the risk of recurrence—“I think it's a fluke,” he said.

And regarding black women, he added: “They may have higher grade tumors, and they are more likely to be ER- and PR-negative.”

PR-negative tumors may be more aggressive than PR-positive ones, Dr. Smith explained. “We think that the combination of ER-positive/PR-negative tumors behave biologically differently from ER-positive/PR-positive ones, and they may derive less benefit from tamoxifen,” said Dr. Smith. “But this is by no means a sure thing.”



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In the C9343 study, Kevin S. Hughes, MD, Co-Director of the Avon Foundation Comprehensive Breast Evaluation Center at Massachusetts General Hospital, and colleagues sought to determine whether older women with early breast cancer can derive benefit from radiation therapy following lumpectomy plus tamoxifen compared with the surgery and tamoxifen alone.

The study of 636 women was conducted from 1994 to 1999 and randomly assigned patients to one of the two treatments. Primary endpoints were time to local or regional recurrence, frequency of mastectomy, breast cancer-specific survival, time to distant metastases, and overall survival.

The only significant difference between the two groups was the rate of local or regional recurrence at five years: 1% in the group given radiation and 4% in the tamoxifen-alone group. However, physicians and patients agreed that in terms of cosmetic results and adverse events, tamoxifen alone was preferable.

The authors thus concluded that lumpectomy plus tamoxifen is a “realistic choice” for women age 70 and over who have early ER-positive breast cancer. They did not say, though, that it is a better choice.

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What the Results Mean

Dr. Smith noted that even though the results from C9343 and the JCO study are similar, the results from his study indicate that important, readily identifiable characteristics can determine which patients are most likely to benefit from radiation therapy.

For example: healthy women age 70 to 79 tend to do better than women over 79 and those with moderate to severe comorbidity. “Identification of patients unlikely to benefit from radiation therapy will minimize the number of older women unnecessarily exposed to its morbidity, cost, and inconvenience,” he said.

Should these patients be offered radiation therapy anyway? “When talking about treatment decisions with patients, it's helpful to frame the discussion in a way that highlights problems that supersede the breast cancer, such as other illness,” he said. “Many women are relieved to know that they may not derive much benefit from RT and choose not to go through a fairly onerous course of therapy.”

Dr. Buchholz said that although he didn't consider six weeks of radiation therapy to be overly troublesome, it is still reasonable to discuss the pros and cons of the therapy with all women under age 80.

A major contrast between the two studies is the role of radiation therapy in preventing subsequent mastectomy. In the population-based study, radiation lowered the risk of mastectomy, but it did not in C9343. This suggests that women who do not receive radiation therapy and who subsequently develop a recurrence may be more likely to lose that breast in the community setting than in a clinical trial.

Why is that? “C9343 was a much smaller study and therefore had less statistical power,” Dr. Smith explained. “But a more compelling reason is that patients in a clinical trial get the best quality follow-up. Thus, subsequent cancers are discovered earlier when they can be treated with more conservative therapy.”

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Public Health Implications

One of the most important results of the study is a public health one, he added. By 2030 the elderly population will double, and about 50,000 women over age 70 will get breast cancer each year. It is thus critical to identify who will and will not benefit from various treatments.

“We need to be able to tailor therapy so as not to over- or undertreat,” he said. “We set out to validate C9343, but when we developed a comparison cohort—women with criteria somewhat outside the bounds of the clinical trial—we found that slightly younger women—those age 66 to 69—had a higher risk of recurrence than did those age 70-plus, as did those with a tumor that was 2.1 to 5 cm or ER-negative. But for them, the benefit of RT is somewhat better.”

He added, “Both studies contain real findings, and I believe that radiation therapy reduces the risk of subsequent mastectomy and should be the treatment of choice for older women.”

Dr. Buchholz shared his enthusiasm. “These are two major studies—one setting out to corroborate the other but coming up with important well-analyzed information on its own. Although the follow-up is relatively short, Dr. Smith made some important insights about the risk of recurrence without radiation.”

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Accompanying Editorial

In an accompanying editorial, Bruce E. Hillner, MD, Professor of Internal Medicine, Genetic Medicine, and Primary Care at Virginia Commonwealth University, and Jeanne Mandelblatt, MD, MPH, Director of Cancer and Aging and Cancer Outcomes Research at Lombardi Cancer Center, said that the study is important because of the projected increase in breast cancer in older women, as well as the lack of clinical trials specific to this age group. The editorial also cited the uncertainty of balancing treatment toxicity and benefits and the potential for therapy to exacerbate existing medical conditions.

Since only about 1.5% of older women participate in clinical trials—and they are healthier than most breast cancer patients—the results can't be generalized to community practice.

This study, the editorial noted, provides an unprecedented opportunity to compare clinical trial and community-based data. “Most importantly, Smith et al show that a well-designed observational study can not only reproduce estimates of the impact of treatment seen in the trial setting but, given its larger size, also provide new or complementary insights—for example, that the maximum benefit of radiation therapy was in younger women with no or minimal comorbidity.”

This finding is critical. Moreover, because RT does not affect overall survival, women make decisions about using it for other reasons.

The study highlights the power of observational data, Drs. Hillner and Mandelblatt said, because:

  • ▪ The clinically relevant database has sufficient prognostic factors.
  • ▪ The starting point in the disease trajectory is easily defined.
  • ▪ The quality of intervention does not differ markedly between academic and community settings, and the sample represents the real world.
  • ▪ The study was considerably less expensive than a clinical trial.

Such studies can indeed provide information for shared decision-making between older women and their physicians, the editorial concluded.

© 2006 Lippincott Williams & Wilkins, Inc.
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