Journal of the National Cancer Institute Advance Access originally published online on November 27, 2007
JNCI Journal of the National Cancer Institute 2007 99(23):1748-1749; doi:10.1093/jnci/djm259
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© Oxford University Press 2007.
NEWS |
New NSCLC Staging Raises Treatment Issues
Oncologists may consider more patients for surgery and adjuvant therapy under a revised staging system for non–small-cell lung cancer (NSCLC) recommended by the International Association for the Study of Lung Cancer.
Because staging groups patients according to their prognosis, which helps determine therapy, the new system raises important questions about treatment. Some will ultimately have to be answered through additional clinical trials, said Peter Goldstraw, F.R.C.S., of Royal Brompton Hospital and Imperial College in London, who presented the proposed revisions in September at the 12th World Conference on Lung Cancer in Seoul, Korea. In the meantime, he said, "it will have an impact on the discussions in every multidisciplinary meeting about treating patients with lung cancer around the world."
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The proposed system is now under consideration by the International Union Against Cancer in Geneva and the American Joint Committee on Cancer in Chicago for the 7th edition of the TNM Classification of Malignant Tumors, due out in January 2009. The tumor–node–metastasis (TNM) staging system groups patients according to their prognosis on the basis of tumor size, lymph node involvement, and metastasis. Successive editions of the TNM Classification have been widely used for staging most cancers for the last 40 years.
NSCLC staging is derived from a much smaller database, created in the 1970s at the University of Texas M. D. Anderson Cancer Center in Houston. That database had grown to include more than 5,000 cases over the years but was still limited to cases from that institution and some cooperative group trials.
"There had been some disquiet that the previous database was relatively small, that it had been accumulated over 30 years, and that some of the staging tests used to evaluate TNM had changed over that time," Goldstraw said at a press conference in Seoul. The older database also contained mostly surgical cases.
The new dataset includes more than 67,000 cases, diagnosed between 1990 and 2000, from institutions and clinical trial groups in more than 19 countries in North America, Europe, Asia, and Australia. There are still some limitations, Goldstraw said. About half of the cases are surgical—still too many to be representative—and there are large geographical gaps, with no data from South America, Africa, or the Middle East. But the new groupings were validated both internally, by using a subset of the larger dataset, and externally, by using the SEER (Surveillance, Epidemiology, and End Results) database.
"To say that the data are robust would be an understatement," said Gerard Silvestri, M.D., of the Medical University of South Carolina in Charleston, in an editorial accompanying several reports on the revised system in the August issue of the Journal of Thoracic Oncology.
Even with the much larger dataset, much of the old system remains intact, Goldstraw noted. "One of the interesting things about this project has been how much of the existing staging system we’ve been able to validate."
Nevertheless, the new data generated four major changes in staging, two of which raise important treatment issues.
Important Stage Shifts
Most salient is the shift of node-negative patients with larger tumors from stage IB, where adjuvant chemotherapy is often not recommended, to IIA or IIB, where chemotherapy is standard treatment after complete surgical resection. Under the revised system, node-negative patients with tumors larger than 5 cm would be placed in IIA and those with tumors larger than 7 cm would be IIB. Previously, both had been lumped with smaller tumors in IB.
This shift could lead to a new clinical trial. "The biggest opportunity offered by the revised system is to define those tumors whose larger size does merit different therapy, since the previous system did not account for larger size," said Thomas D’Amico, M.D., of Duke University Medical Center in Durham, N.C., a member of the steering committee of the National Comprehensive Cancer Network and its NSCLC committee. The NCCN establishes consensus-based treatment guidelines that are widely used in the United States.
The other stage shift with a potential effect on treatment, as well as the design of clinical trials, will affect patients with additional cancerous nodules in the lung on the same side as their primary tumor. If these ipsilateral nodules are in the same lobe as the primary tumor, the cancer is currently classified as stage IIIB. Under the new system, same-lobe nodules become stage IIB if there is no lymph node involvement (N0) and IIIA if lymph node disease is limited (N1 or N2).
The downstaging could mean that more patients with ipsilateral nodules will be considered for surgery worldwide. Some patients in this category are already offered surgery in the U.S., in line with NCCN guidelines, D’Amico said, and the new grouping provides a better fit for them.
"But that is certainly not the case in the U.K., Europe, and the rest of the world," Goldstraw said. "I think there is little doubt that these changes will lead to more of these cases’ being considered for surgery."
The picture could also change for patients, worldwide and in the U.S., who have a nodule in the same side of the lung but in a different lobe. These cases move from stage IV to IIIA (lymph node status N0 or N1) or IIIB (N2 or N3) under the new system. "People may now be more open-minded about resection of these nodules," D’Amico said.
The ipsilateral-nodule revisions also highlight the need for more data, which the IASLC hopes to continue collecting. For instance, should more than one ipsilateral nodule be a different stage from just one? "It's on our wish list," Goldstraw said.
Other recommended stage shifts, though they provide more accurate prognoses, do not have treatment implications. Extensive tumors with pleural or pericardial effusion move from stage IIIB to IV, where they are grouped with other tumors that are not resectable. This change is "probably the most obvious one that had to be made," D’Amico said, because these so-called wet IIIBs have always been treated as stage IV.
Another major change without treatment implications—at least not yet—is the division of metastases into two subgroups—M1a for metastases in the other lung and M1b for distant metastases. Both remain stage IV.
"There was a lot of discussion about whether it was worth cluttering up the staging system with this division," Goldstraw said. "But the committee decided to go ahead because such a change was justified by the data, and at least this way we can collect data prospectively and get more information on whether there is a clinically meaningful difference in prognosis."
Coming Soon to Staging
In fact, prospective data collection is the next big step for the IASLC's staging project. Such studies will help address questions like this one and fill in geographic gaps.
While the IASLC looks for funding to gather prospective data—an estimated $3.5 million over the 7-year cycle of the revision process—it will begin adding follow-up data on cases in the existing database. It expects to have even more definitive retrospective data for the 8th edition of the TNM in 2016. A fully prospective database could be the basis for the 9th edition in 2023, Goldstraw said.
Also on the horizon is the issue of biological markers and how to incorporate them into lung cancer staging. Trials now under way and in the planning stages will soon provide data on whether markers, such as gene expression patterns, are useful prognostic tools. That prospect raises hope for a more detailed and accurate staging system.
"We know that even in stage I, about 30% of patients recur and die before 5 years," Silvestri said. "So as accurate as the whole staging system is, it's still pretty crude in some ways. If you knew right after surgery that you were in that 30% [on the basis of biological markers], you might consider adjuvant therapy."
How to integrate the predictive information that could become available from biological markers with the anatomical extent of disease described by the TNM system is uncertain, Goldstraw said, and it will ultimately be a policy decision for the International Union Against Cancer and the American Joint Committee on Cancer. One possibility is that T, N, and M could be joined by a B (biological) factor. Another more probable solution, Goldstraw said, would be to integrate TNM, biological information, and other factors into a composite prognostic model.
In either case, incorporating biologic markers will probably be the next major development in NSCLC staging. "I firmly believe that within 10 years we will be using molecular staging in addition to TNM," Silvestri said.
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