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The Will Rogers Phenomenon: Roping the Effects of a New Cancer Staging System

Damaris Christensen

At least in some cases, historical controls may become history, thanks to the recent changes in a national set of cancer staging guidelines. A large study has shown that using the new American Joint Committee on Cancer (AJCC) staging guidelines—in place as of January 2003—results in dramatic artifactual improvements in stage-specific survival among women with locally advanced breast cancer. Although unlikely to affect treatment decisions, the findings suggest that comparing the results of current clinical trials to historical controls may result in misleading benefits.

The problem has been dubbed the "Will Rogers phenomenon," because the situation resembles that of a classic Will Rogers quote, "When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states." By taking the patients with the worst prognosis and reclassifying them as having more severe disease, the new AJCC standards raised each stage-specific survival rate, said Wendy A. Woodward, M.D., Ph.D., a radiation oncology resident at the University of Texas M. D. Anderson Cancer Center in Houston. In essence, because the prognosis of those who "migrated"—although worse than that for other members of the better-stage group—was better than that for other members of the worse-stage group, survival rates rose in each group without any change in individual outcomes.



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Dr. Wendy Woodward

 
Similar findings have already been demonstrated in lung cancer patients, therefore the results are not unexpected. Nonetheless, said Woodward, the extent of the difference was quite surprising. "We’re showing that the 10-year overall survival for stage II [breast cancer] patients can increase by more than 20% simply by using the new staging system," she said. "That’s the kind of difference that if you were looking at new clinical data on a drug you’d be bowled over."

She and her colleagues looked at records of 1,350 women with locally advanced breast cancer who had been followed for a median of 10 years, and they used the raw clinical data to stage patients according to each set of guidelines. This June, at the American Society of Clinical Oncology (ASCO) meeting in Chicago, she reported "a surprising difference" in stage-specific mortality between the 1988 and 2003 AJCC guidelines. For example, women diagnosed with stage II breast cancer according to the 1988 guidelines had 5- and 10-year survival rates of 72% and 53%, respectively; yet among those same women classified with stage II disease according to the 2003 guidelines, survival rates were 86% at 5 years and 75% at 10 years.

Changes to Staging System

The new AJCC guidelines incorporate a number of changes. Among the most important changes for breast cancer patients are the incorporation of the common practice of sentinel lymph node dissection and the incorporation of the number of affected lymph nodes to predict survival and determine staging. In 1988, T1N1 stage IIa disease included both a woman with a 1.5-centimeter primary tumor and one out of 10 positive lymph nodes and a woman with a 1.7 cm primary tumor and 15 out of 17 positive lymph nodes. Now, this second woman would be reclassified as having T1N3 stage IIIc disease (see News, Vol. 94, No. 22, p. 1664, "Updates to Staging System Reflect Advances in Imaging, Understanding").

Woodward and her colleagues showed that the AJCC changes, especially incorporating the extent of metastatic disease through positive lymph nodes, moved 31% of women with 1988-diagnosed stage IIa disease into higher stages. Likewise, 54% of women with stage IIb disease and 38% of women with stage IIIa breast cancer (according to the 1988 guidelines) were reclassified under the current system.

These findings imply that comparisons of survival data between patients staged with different systems will be inaccurate, she said. In addition, she cautioned, the results of her study suggest that outcome results reported to national cancer databases should identify the staging system used and need to include tumor characteristics.

Metastatic Disease

Another change in the AJCC guidelines may have an opposing effect, at least for patients with very early stage disease. Until now, clinicians have not consistently ranked micrometastatic disease as node positive, in part because the clinical implications of these micrometastases are unknown. The 2003 proposals clarify that micrometastatic deposits between 0.2 mm and 2 mm should be counted as node positive; isolated tumor cells measuring less than 0.2 mm will now be marked as node negative.

However, David McCready, M.D., of the departments of surgical oncology and pathology at the Princess Margaret Hospital in Toronto, Ontario, speculated that this change might affect false-negative rates for sentinel lymph node biopsies. He and his colleagues reexamined data from a series of 205 patients with sentinel lymph node biopsies and concurrent level I and II axillary dissection. The data was presented at the ASCO meeting by Wei Sean Yong, M.B.B.S., a fellow at Princess Margaret.

Of the patients, 94 (46%) had metastatic deposits in their sentinel lymph nodes. There were two patients with significant metastases in other lymph nodes but no positive sentinel nodes, meaning that the false-negative rate was 2.1%. Reclassifying metastatic deposits of less than 0.2 mm as node negative resulted in 75 patients (37%) with diagnosed positive sentinel nodes and five patients whose metastatic disease would have been unidentified using the new AJCC guidelines and a sentinel node biopsy alone. Essentially, McCready said, classifying sentinel lymph node metastatic deposits less than 0.2 mm as node negative doubled the false negative rate.

‘Falsely Downstaging’

"The concern is that, if further axillary dissection were not performed, you could be falsely downstaging patients with gross amounts of disease in other lymph nodes," McCready said.

These reports are an important reminder that along with revisions in staging guidelines comes the need to examine the effects of the changes and how it affects the comparability of data, said Lisa Newman, M.D., associate professor of surgery at the University of Michigan Comprehensive Cancer Center in Ann Arbor. "It’s clear that there will be substantial stage migration" as a result of the updated AJCC guidelines, and this should be taken into account when using historical controls, she said. Although the clinical effects of ignoring micrometastatic disease is unknown, the possibility that it might lead to downgrading the stage of some patients with early breast cancer and larger metastases in other lymph nodes is "concerning," Newman said. She suggested that the possible effects should be tracked through the revised staging system.



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Dr. Lisa Newman

 



             
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