Adverse Effects of Breast Chemotherapy Called Under-Reported

BOSTON, Aug. 16 -- Serious side effects and the cost of chemotherapy for younger breast cancer patients are greater than previously estimated, researchers reported.

Chemotherapy-related serious events -- infections, fevers, low blood counts, pulmonary embolus, deep-vein thrombosis -- may be more common than reported by large clinical trials, according to a report in the Aug. 16 issue of the Journal of the National Cancer Institute.

These adverse effects may cause more patient suffering and higher health care expenditures for women 63 or younger than generally predicted, said Michael Hassett, M.D., of the Dana-Farber Cancer Institute here, and colleagues.

Of more than 12,000 women in a claims-based study by Dr. Hassett and colleagues, 61% given chemotherapy were hospitalized or visited the emergency room for all causes versus 42% of non-chemotherapy women (mean difference =19%, 95% confidence interval 16.7% to 21.3%, P<0.001),

This 19% absolute difference and other findings came from analysis of a database of medical claims made by individuals with employer-provided health insurance from January 1998 through December 2002. Of 12, 239 women with newly diagnosed breast cancer, 4,075 received chemotherapy during 12 months after the initial breast cancer diagnosis and 8,164 did not.

For chemotherapy-related serious adverse effects, the rates were 16% versus 5% (mean difference = 11%, CI = 9.6% to 12.4%, P<0.001), the researchers reported.

The percentages of chemotherapy recipients who were hospitalized or visited the emergency room during the year after their breast cancer diagnosis were 8.4% for fever or infection; 5.5% for neutropenia or thrombocytopenia; 2.5% for dehydration or electrolyte disorders; 2.4% for nausea, emesis, or diarrhea; 2.2% for anemia; 2% for constitutional symptoms; 1.2% for deep venous thrombosis or pulmonary embolus; and 0.9% for malnutrition, the researchers said.

Compared with the non-chemotherapy women, chemotherapy recipients incurred larger incremental expenditures for chemotherapy-related serious adverse effects (,271 per person per year) and for ambulatory care (, 617 per person per year).

There are several reasons why the rates of serious adverse effects in the general population could be greater than the rates reported by large clinical trials, Dr. Hassett said. For example:

• Clinical trials are designed to identify benefits not to characterize risks.
• There are differences in terms of age, race, disease severity, socioeconomic status, and economic status between the small fraction of women in clinical trials versus the general population.
• Some, though not all, studies suggest that participation in a clinical trial could lead to improved outcome, independent of the effects of the treatment.
• Clinical trials frequently do a poor job of reporting the frequency and severity of serious adverse effects during the trial.

Few studies have examined the economic outcome associated with serious adverse events, the researchers said. According to the study, the incremental expenditure for chemotherapy-related serious adverse effects was ,271 per recipient per year.

A further estimate found that the cost of inpatient care was ,213 per person per year higher among chemotherapy recipients than for non-recipients. For women with serious adverse events, the costs per person per year were ,907 higher than for women without adverse events. These costs, the investigators said, are higher than previous estimates of incremental costs for cancer patients, particularly those for colorectal cancer patients.

The study had certain limitations, the researchers wrote. Because the insurance claims analyzed in this study contained limited amounts of clinical data, it was not possible to control for stage or to establish a direct link between chemotherapy and a particular adverse event. Also, identifying serious medical conditions completely unrelated to chemotherapy was particularly challenging.

The findings of this study support assertions that clinical trials often lack external validity, and underscore the fact that health care providers "must carefully decide whether trial results can be applied to routine clinical practice," Dr. Hassett's team wrote.

"Improving efforts to estimate the frequencies of treatment-related serious adverse effects and presenting the information in ways that patients find meaningful would generate a more complete picture of the impact treatments have on patients' lives and facilitate informed decision making," the team concluded.

In an editorial in the same JNCI issue, John Erban, M.D., and Joseph Lau, M.D., of Tufts New England Medical Center here wrote that adding to the importance of this study is the fact that it is the first to assess toxicities in a younger population of patients. Patients younger than 63, they said, are frequently offered chemotherapy in the adjuvant setting, and though improvements in survival may be below 5%, women will often accept chemotherapy for as little as a 1% to 2% survival advantage.

Although the study's methodology may have excluded under-represented populations and racial and ethnic minorities, they called the results "important and intriguing." The study delivered several important messages about the present but also about the future. One message, they said, is the need to develop patient-specific predictive instruments to focus the use of therapeutic drugs and supportive treatments.

But perhaps the most important message, they wrote, is the need to focus on longer-term toxicity studies and late-onset adverse events, such as cardiovascular health, including heart attacks, and also on bone health, including hip fractures. "Meticulous tracking of long-term toxicity of new drugs in ongoing trials is necessary if we are to know how to advise practitioners and patients on best practices for the future," they wrote.

"As new drugs of increasing efficacy and few acute toxicities emerge, the tendency will be to push them to market, and there will be few incentives for longer-term toxicity studies," they wrote. "Without careful, long-term tracking of late adverse effects, there is a risk that very important toxicity events will occur unnoticed," they concluded.

Joseph Newhouse, M.D., a co-author of the chemotherapy study, holds stock in and is a director of Aetna.