'Antiquated' Medullary Thyroid Cancer Staging Gets Update

Pam Harrison

June 27, 2017

A proposed new staging system for medullary thyroid cancer (MTC) dramatically shifts the stage into which many of the cancers are diagnosed compared with the current American Joint Committee on Cancer (AJCC) staging system.

Most notably, the new system would nearly double the rate of stage I diagnoses and decrease the rate of stage IV diagnoses by about sixfold. Furthermore, for metastatic disease, 5-year survival rates would be significantly worse.

"The current staging system is somewhat antiquated and mostly based on older data, and there is not very good discrimination between stages with regard to survival," lead author Julie Sosa, MD, professor of surgery and medicine oncology, Duke University Medical Center, Durham, North Carolina, told Medscape Medical News in an email.

The new system has potential implications for treatment.

"We believe that the new staging system can provide a guide for more clinically appropriate surgery and allow patients with advanced disease to start chemo-/small-molecule therapy earlier, which may provide more appropriate treatment than aggressive surgery," Dr Sosa suggested.

The proposed system arises out of a retrospective cohort analysis that was published online June 21 in JAMA Surgery.

"We hypothesized that eliminating preexisting bias and reanalyzing survival empirically and objectively using a large contemporary population of patients treated for MTC would allow for better discrimination among stages," Dr Sosa explained.

The National Cancer Database (NCDB) provided most of the data used for the current analysis. It was chosen because of its large sample size. A total of 3315 patients diagnosed with MTC between 1998 and 2012 were included in the cohort.

Sophisticated methodology was applied to the data overall to identify differences in survival among patients and to define more accurate staging groups.

A majority of the group were women (58.6%) and were white (85.6%); the median age was 54 years.

The results show important differences in the percentages of patients identified by the proposed staging system within four different stages and the current AJCC TNM staging system.

Table 1. Percentage of Patients With MTC Staged in Accordance With the Proposed vs the Current Staging System

  Stage I (T1) Stage II (T2) Stage III (T3) Stage IV (T4)
Proposed TNM staging system 54.2% 20.6% 20.2% 5.0%
Current AJCC TNM staging system 28.4% 27.4% 12.8% 31.4%

In the study, "recursive partitioning" was applied to the NCDB cohort to divide the patients with various T, N, and M categories into groups with similar overall survival, the study authors explain. Subsequent "bootstrapping" identified four distinct TNM groups: stage I (T1N0-1aM0, T2N0M0), stage II (T1N1bM0, T2N1a-bM0, and T3N0M0), stage III (T3N1a-bM0, T4N0-1bM0), and stage IV (T1-4N0-1bM1).

Ultimately, overall survival between the proposed TNM groupings differed from current survival estimates based on the AJCC TNM staging system.

Table 2. 5-Year Overall Survival for MTC Patients Using the Two Staging Systems

  Stage I Stage II Stage III Stage IV
Proposed TNM staging system 94% 86% 69% 35%
Current AJCC TNM staging system 95% 91% 89% 69%

An Explanation of the Stage IV Differences

Asked to explain the large discrepancy between the proportion of patients identified with stage IV disease when the two staging systems were applied to the same cohort, Dr Sosa said that the existing AJCC system allocates many patients to stage IV on the basis of locoregional disease only, "lumping them together with those who have distant metastatic disease.

"However, there are clear differences in survival between patients who do and those who do not have distant metastases, even though the current staging system does not make this discrimination well," Dr Sosa observed. "Combining these patients together in stage IV is likely inadequate," she added.

As a result, stage IV in the AJCC staging system is associated with a prognosis that is much too severe for patients with extensive locoregional disease but who do not have distant metastases. That is because for patients with locoregional disease, survival is longer than is typically predicted on the basis of their current AJCC stage.

In addition, the AJCC staging system overestimates survival for patients with distant metastases; in the proposed system, survival estimates for such patients are much shorter than in the AJCC system.

"By reclassifying some of these patients who have better survival into earlier-stage disease, our proposed staging model seems to provide a more realistic overall prognosis for many patients, and we were able to robustly demonstrate this is in two large national databases," Dr Sosa said.

Data from the Surveillance, Epidemiology, and End Results (SEER) program on more recently diagnosed MTC patients were used to validate the new NCDB analysis, the authors report. The investigators also performed an external validation analysis using SEER data as part of the new study.

Results of this external validation analysis showed mostly similar 5-year disease-specific survival rates for the proposed vs the current staging system.

Dr Sosa acknowledged that their results need to be further validated in other MTC cohorts and that, because the proposed staging system is relatively different from the current system, adoption of the proposed staging system may be slow.

However, if results are shown to be reproducible, "then it might be time to look at staging with a fresh eye," Dr Sosa suggested.

"We therefore encourage clinicians and researchers to keep an open mind, as we need to continue to evolve staging in other ways, such as potentially incorporating information about tumor biomarkers and molecular profiles," she observed.

"It is also possible that a similar approach to ours could be replicated for other cancers," Dr Sosa concluded.

Neuroendocrine Tumor

In an accompanying editorial, Quan-Yang Duh, MD, and Jessica Gosnell, MD, University of California, San Francisco, and UCSF-Mount Zion, noted that as a neuroendocrine tumor, MTC is considerably different from differentiated thyroid cancers, namely, papillary and follicular thyroid cancer.

The pair observed that fewer patients were classified as having disease of stages II, III, or IV when the proposed TNM groupings were applied to the NCDB cohort, but each stage was associated with a "significantly worse prognosis" than would have been the case had the tumors been staged using the current AJCC TNM staging system.

"Most significantly, the current AJCC TNM staging system assigned...32% to stage IV with a 5-year survival of 68%, whereas the proposed TNM groups assigned only...5% to stage IV, [although] they had a much worse 5-year survival of 35%," Dr Duh and Dr Gosnell observe.

"The proposed TNM groups can [therefore] potentially lower the risk of overtreatment for patients with stage I MTC and may justify more aggressive treatment for the fewer patients remaining at higher stages," they write.

The study was funded by a grant from the National Institutes of Health. Dr Sosa is a member of the data monitoring committee of the Medullary Thyroid Cancer Consortium Registry, which is supported by Novo Nordisk, GlaxoSmithKline, AstraZeneca, and Eli Lilly. Neither Dr Duh nor Dr Gosnell have reported any relevant financial relationships.

JAMA Surg. Published online June 21, 2017. Full text, Editorial

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