From the ONI archives: Specialists contend with modest evidence on the value of adjuvant therapy

Physicians must take into account toxicity, comorbidity, and competing mortality when considering adjuvant therapy for elderly breast cancer patients.

The American Society of Clinical Oncology recently released updated guidelines on the use of adjuvant endocrine therapy in hormone-receptor-positive breast cancer (see Fact box). While the guidelines focus on all postmenopausal women, those who are age 75 and older require special consideration. Unfortunately, meaningful data to help healthcare providers make treatment decisions for these patients are scarce, according to Peter Ravdin, MD, PhD, director of the Breast Health Clinic at the Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio.

"This population of women is large and will continue to increase in the next few decades. There is a great need to treat these women with individualized therapy," said Dr. Ravdin, who also serves as an executive committee member and scientific program planning member for SABCS 2010. He outlined some of the principles of treatment that oncologists should keep in mind when deciding if their older patients are candidates for adjuvant therapy.

Assessing patient suitability
When considering adjuvant therapy for older patients, the same overall questions as for all patients need to be answered: Do the positives of the therapy outweigh the negatives of therapy? Does the physician have the right information to determine the efficacy and safety of adjuvant treatment for his or her patients? Finally, how does adjuvant therapy fit with the patient’s general health and life expectancy?

The latter question is particularly important when consulting with older patients.

"Many of these patients…have tumors that have very fatal prognoses," Dr. Ravdin said. "The benefit that adjuvant therapy might provide these patients becomes more modest. This benefit will be weighed against the toxicity, and you have to ask the question: Will there be more toxicity in older patients? And will comorbidity and competing mortality dwarf the relative benefit of adjuvant therapy taken by older patients?"He described one simplified way to estimate therapeutic benefit: Take the baseline risk of negative outcome and multiply it by the proportional risk reduction due to an adjuvant therapy. But Dr. Ravdin cautioned that this formula ignores the negative effects of competing mortality and comorbidity. "Obviously the remaining life expectancy of the average woman in the U.S. decreases as she gets older. By the time she’s 80 years old, her remaining life expectancy on average is only about 10 years," he said. In addition, "comorbid illnesses are more common in older patients and that does have a strong impact on remaining life expectancy."

For instance, a 70-year-old cancer patient has 15 years of life expectancy, and the probability that she will die of that cancer before she dies of a competing illness is high. "The amount of benefit attained [from adjuvant therapy] is not strongly attenuated by the competing mortality," he said. But "where you have a 10-year life expectancy, there’s a very good chance that [an 80-year-old] will die of something else before there’s a chance for the breast cancer to recur. That will cut the actual benefit from an adjuvant therapy by almost 50%."

In addition to comorbidity, tumor size and disease stage can be used to assess mortality risk. Dr. Ravdin referred to life expectancy tables developed by Louise C. Walter, MD, and Kenneth E. Covinsky, MD, MPH, as well as by Sei J. Lee, MD, and Karla Lindquist, MS (JAMA 285:2750-2756, 2001; 295:801-808, 2006).

"So a patient with a tumor that is node negative, T1a-b, and 10 mm or smaller has a 3% risk of [breast cancer] mortality," he explained. "For node-negative T1c patients, the risk of 10-year [breast cancer] mortality, if they’re estrogen-receptor positive [ER-positive], is only about 8%. And then as you take a look at patients with T2 lesions, or lesions that are node positive, their risk actually begins to go up substantially."

This means that for stage I patients, adjuvant therapy delivers a relatively small benefit, he said. And in the face of competing mortality and older age, the benefit becomes even more modest, even if the patient is stage I.

Therapy breakdown
Dr. Ravdin highlighted current research in the different adjuvant treatment options, starting with radiation therapy. A recent CALGB study randomized stage I, ER-positive patients, 70 and older, to either a tamoxifen-only arm or a tamoxifen plus radiation arm. At eight years’ follow up, no survival advantage was seen with radiation, with the majority of deaths in the study occurring from competing mortalities (American Society of Clinical Oncology [ASCO] 2010 abstract 507).

"The risk of ipsilateral breast tumor recurrence was 6% in the tamoxifen-only group and 1% in the tamoxifen plus radiation therapy group," he said. "So there’s a 5% advantage. In terms of the number of patients who…underwent a mastectomy, the difference was 3% vs 1%, so a 2% advantage," he said. Physicians and patients could interpret these data and see an advantage to radiotherapy, but the overall benefit would still be small, Dr. Ravdin added.

Moving on to hormone therapy, Dr. Ravdin cited a 2005 meta­-analysis showing proportional risk reductions for five years of tamoxifen in ER-positive patients. Only 5% of the patients entered in the trials were age 70 and up, and while the meta-analysis did show a trend toward benefit, it was a small one (Lancet 365:1687-1717, 2005).

"We treat patients in all age categories with tamoxifen with the expectation that they’ll have a reduction in risk of recurrence and may have an improvement in mortality," he said.

Information about toxicity is better gleaned from the results of a 10,000-patient NSABP P-1 prevention trial, which found that women (ages 70-79) on tamoxifen vs placebo had a 7% greater risk for endometrial cancer. Also, there were more instances of pulmonary embolism and stroke in this patient population. The results might give one pause as to the use of tamoxifen in these older patients even in the adjuvant setting, Dr. Ravdin said (J Natl Cancer Inst 91:1829-1846, 1999 and 97:1652-1662, 2005).

As for endocrine therapy, the IMPACT study tested aromatase inhibitors (AIs) against tamoxifen and found that for five years of use, patients benefited from AIs regardless of age. Dr. Ravdin pointed out that 23% of the patients overall in this study were 70 years or older, "so it looks like aromatase inhibitors, at least in terms of efficacy, would be better to use in older age groups" (J Clin Oncol 23:5108-5116, 2005; see Did You Know box).

In order to assess toxicity associated with AIs, Dr. Ravdin turned to results from the BIG 1-98 trial, which compared tamoxifen with letrozole (Femara). Older patients on the letrozole protocol had a significantly higher incidence of any grade 3-5, protocol-specified, nonfracture adverse events compared with tamoxifen, although the differences were not significant for thromboembolic or cardiac adverse events, the authors reported (J Clin Oncol 26:1972-1979, 2008).

For chemotherapy, Dr. Ravdin turned to another meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group that assessed 194 unconfounded, randomized trials of adjuvant chemotherapy or hormonal therapy including anthracycline-based polychemotherapy and CMF-based (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy (Lancet 365:1687-1717, 2005).

"There is a trend with age for the polychemotherapy to become less effective as patients get older," Dr. Ravdin said. "For the patients who are 70 years and older, there is not a statistically significant advantage." But Dr. Ravdin also cautioned that only 4% of all the patients entered on polychemotherapy fell into the older age group and that patients were not categorized by ER status. That was done by a 2008 study in ER-negative patients and, based on that analysis, the benefit from chemotherapy did not appear to be age-dependent. Again, there were no data in this study from age 70-plus patients, Dr. Ravdin said, and chemotherapy seemed to be less effective in patients who were ER-positive and ER-negative, who are generally older (Lancet 371:29-40, 2008).

Finally, are there benefits to adjuvant trastuzumab (Herceptin)? Overall, adjuvant trastuzumab trials have either included a small subset of patient older than 60 or have excluded them altogether (Lancet 369:29-36, 2007).

HERA and other trials have turned in conflicting results, either showing a slight benefit from trastuzumab in older patients or showing no benefit and a significantly increased risk of cardiac toxicity (N Engl J Med 353:1673-1684, 2005; J Clin Oncol 23:7811-7819, 2005).

"I don’t think that there’s anything that’s absolutely compelling here," Dr. Ravdin said. "It’s not entirely reassuring. We really haven’t answered this question about the safety of trastuzumab in older patients."

Dr. Ravdin concluded that it appears that adjuvant strategies have the same relative effectiveness in healthy, older patients as they do in younger women. Toxicity is a concern for older patients, especially for older, stage I patients. Comorbidity and competing mortality, particularly in low-risk women, can limit the benefit of adjuvant therapy. He advised that "if you’re going to treat an older patient, treat the older patient with a real regimen, not something that is likely to have little or no impact on their disease and only a little toxicity."