New Staging System Predicted to Lead to Significant Improvements in Stage-Specific Survival

CHICAGO—Changes to the AJCC cancer-staging guidelines will result in widespread improvements in stage-specific survival, according to work presented at the ASCO Annual Meeting. Although unlikely to affect therapy, the findings suggest that care needs to be taken when comparing the results of current clinical trials to historical controls lest survival improvements due to changes in staging be attributed to the effects of a drug. Starting this year, physicians and tumor registrars have been using an updated system published in the sixth edition of the American Joint Committee on Cancer (AJCC) Staging Manual. The new system incorporates the common practice of using sentinel node dissection; defines the size at which micrometastases should register as a positive lymph node (between 0.2 and 2 mm; nodes with positive cells measuring less than 0.2 mm would be marked negative with isolated tumor cells); and incorporates the number of affected nodes to predict survival and determine staging of breast cancer.Figure: Wendy A. Woodward, MD, PhD: This is a reminder that it should be tumor characteristics and not stage reported to national databases.The change to incorporate the number of positive lymph nodes into breast cancer staging reflects current practice and was expected to improve stage-specific overall survival, said Wendy A. Woodward, MD, PhD, a radiation oncology resident at the University of Texas M. D. Anderson Cancer Center. The reason for the improvement is that as the staging guidelines are refined, the sickest patients in one staging category are typically moved into categories reflecting increasing cancer burden—but now end up being the least sick in the new category. “We expected there would be a difference, but we were surprised by the extent of the difference,” Dr. Woodward said. She and her colleagues reported that in women diagnosed with Stage II breast cancer, the five- and 10-year survival rates among those diagnosed according to the 1988 AJCC guidelines were 72% and 53%, respectively. With the 2003 guidelines, however, those rates were 86% and 75%, respectively. Study Details Dr. Woodward and her colleagues followed 1,350 patients with locally advanced breast cancer who had been enrolled into five consecutive prospective trials at her institution between 1975 and 1994, and using the raw data staged the women according to both 1988 and 2003 guidelines. The researchers then correlated survival data among the women, who had been followed for a median of 10 years, according to the different staging guidelines. In 1988, a woman with a 1.5 cm primary tumor and one positive lymph node in 10 was classified as having T1N1 Stage IIa cancer, just as was a woman with a 1.7 cm primary tumor and 15 out of 17 positive lymph nodes. Using the new guidelines, in 2003 this second woman would be classified as having T1N3 Stage IIIc disease. Largely because of the reclassification of women with positive lymph nodes, Dr. Woodward and her colleagues showed that 31% of women diagnosed with Stage IIa breast cancer using the 1988 guidelines would be reclassified under the current system: 95 were switched into the Stage IIa category, and 44 into Stage IIIc. Overall survival curves were significantly different among the 1988 Stage IIa patients stratified by the 2003 stage, the results showed. Among women with Stage IIb disease according to the 1988 guidelines, 54% experienced a “stage shift” under the new guidelines: 219 were reclassified as Stage IIIa, and 126 as Stage IIIc. Among women with 1988 classifications of Stage IIIa breast cancer, 38% were reclassified, predominantly into Stage IIIc. In all cases, stratification by 2003 stage showed significant differences in survival among the women with similar stages of cancer according to the 1988 guidelines. “Changing the staging system dramatically affects stage-specific survival,” at virtually all stages, without—obviously—affecting overall survival, Dr. Woodward said. That implies two things: that comparisons among patients staged with different systems will be inaccurate, and that outcome results need to indicate which staging system is used. This is a reminder that it should be tumor characteristics and not stage reported to national databases, she said. Implications “We want people to be aware that while the stage-specific populations will be doing better, the breast cancer population in general is not faring better,” said the senior researcher for the study, Thomas Buchholz, MD, Associate Professor in the Department of Radiation Oncology at M.D. Anderson. “So often manuscripts of new studies will report the percentage of survival among, say, Stage II patients,” and improvements due simply to the more accurate 2003 staging system could be misconstrued as benefits attributable to a drug. Thus, he said, oncologists need to pay careful attention to which staging system is used when reading research papers, especially those that use historical controls. “We're showing that 10-year overall survival for Stage II cancer patients can increase by more than 20% simply by using the new staging system,” Dr. Woodward. “That's the kind of improvement that if you were looking at new clinical data on a drug, you'd be bowled over.” Micrometastases May Have Opposite Effect For the study, the researchers did not have the clinical data to examine the effects of the guideline changes on micrometastases as well as the number of positive lymph nodes. The technology to detect micrometastases is relatively new and thus not available from many of the patients they followed. However, the changes in diagnosis of micrometastatic nodal disease may also affect classification, said Dr. W.S. Yong of Princess Margaret Hospital in Toronto. “The clinical significance of micrometastases is not well defined. However, sentinel nodes are being used more and more to stage breast cancer, and we wanted to see what would happen if one ignores micrometastatic nodal disease of less than 0.2 mm in sentinel lymph nodes.” A cohort of 205 patients, operated on by a single surgeon between 1997 and 2001, was reviewed to try to answer this question. All the patients underwent sentinel lymph node biopsy and concurrent level I and II axillary dissection. The lymph nodes were cut at 2–3 mm intervals, and sentinel lymph nodes were serially sectioned and examined with H&E stain and immunohistochemistry for low molecular weight keratin, and non-sentinel lymph nodes were examined with one H&E stain per block. Of 205 patients, 94 had metastatic deposits of any size in the sentinel lymph node, Dr. Yong reported. The researchers found two false negative sentinel lymph nodes, leading to a false negative rate of 2.1%. Micrometastatic disease of less than 0.2 mm was found in 19 of the 94 patients, three of whom had significant metastasis in non-sentinel lymph nodes. If these patients with micrometastatic deposits of less than 0.2 mm in the sentinel lymph nodes were reclassified as sentinel lymph node negative, than only 80 patients would be identified as having metastatic deposits in the sentinel lymph nodes, and the false negative rate would increase to 6.3% (5/80). “These findings suggest that the false-negative rate of sentinel lymph node biopsy will be increased if these small deposits are ignored,” Dr. Yong said. “Ignoring micrometastases can result in downgrading of stage.” Interdisciplinary Approach Asked for her opinion, Lisa A. Newman, MD, MPH, Director of the Breast Cancer Center and Associate Professor of Surgery at the University of Michigan Comprehensive Cancer Center, said, “These reports are excellent work. “Revisions to staging guidelines are frequently a painful process, but it is incumbent upon us to make this hurdle periodically.” But along with these revisions come the need to examine the effects of the changes, she said. Dr. Woodward's study makes it clear that there will be a substantial stage migration, Dr. Newman said, adding that the findings also suggest that the new guidelines very effectively stratify patients by their chance of survival. The changes should not affect treatment, since therapeutic decisions are typically made using the raw data that goes into the staging decision. The idea that ignoring micrometastases in sentinel lymph nodes might result in downgrading stages is “concerning,” she said, and the clinical effects of this decision can and should be something that should be tracked through the revised staging system. Finally, Dr. Newman concluded, the new guidelines will strengthen the need for an interdisciplinary approach to staging. “The task force has very accurately reflected treatment and diagnostic practices, and we are now entering an exciting and challenging period of trying to implement these changes in national databases.”

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