PREDICTORS OF POOR PROGNOSIS IN ENDOMETRIAL CANCER: 0006

It is estimated that during calendar year 2004, 40 230 new cases of endometrial cancer will be diagnosed and 7090 women will die of this disease. While this neoplasm declares itself early in its natural history and 80% of patients present with stage I disease, nearly 1 of every 3 women who die of endometrial cancer present with presumed localized disease. The majority of treatment failures and the accompaning compromised longevity are the result of the failure to recognize sites of occult extrauterine dissemination at the time of primary treatment. Furthermore, adjuvant therapy has generally been dictated by traditional preferences (modality based) rather than target-based algorithms as determine by patterns of recurrence. The natural history of epithelial corpus cancer includes 4 potential routes of metastasis: contiguous extension, hematogenous dissemination, lymphatic embolization, and exfoliation with intraperitoneal spread. The associated recurrences of each of these diverse routes of spread would presuppose different adjuvant target-based treatment surgeries. In turn, such target-based therapies are predicated on the cataloging of specific pathologic or molecular factors that identify patients at high risk for harboring occult disease disseminated via one or more of these four routes of metastasis. To identify patients at risk for hematogenous, lymphatic or peritoneal failures who might benefit from target-based therapies, 915 endometrial cancer patients managed with hysterectomy and standard adjuvant therapy were subjected to retrospective outcomes assessment. On the basis of our previous regression analyses, depth of myometrial invasion predicted the risk for hematogenous recurrences, positive lymph node and cervical stromal invasion predicted lymphatic recurrences, and stage IV disease or a combination of nonendometrioid histology, cervical stromal invasion, positive lymph nodes, and positive peritoneal cytology predicted peritoneal recurrences. Applying these criteria to the population of 915 patients having a median follow-up time of 66 months, 24% were considered at risk for hematogenous recurrence, 31% for lymphatic recurrence and 42% for peritoneal recurrence. The respective relapse rates at 5 years were 28% for patients who were at risk for hematogenous recurrence, 31% for lymphatic recurrence, and 42% for peritoneal recurrence. This contrasted with less than a 5% recurrence rate in the corresponding subgroups at risk for relapse (P < 0.001). Collectively, of the 915 patients, 324 (or 35%) were considered at risk for recurrence in 1 or more of the above 3 sites. Overall, 89% of all recurrences were identified in this at-risk group. Importantly, 190 of the 324 (46%) patients considered at risk subsequently had recurrence via 1 or more of the 3 main routes of dissemination compared with only 2% of patients not at risk for relapse (P < 0.0001). Considering approximately one-third of the population was declared at risk for post-treatment relapse and 46% of this cohort subsequently failed despite receiving traditional modality-based therapy, the need for new treatment strategies is readily apparent. We believe innovative target-based algorithms should be incorporated in the development of future prospective multimodality clinical trials predicated on the at-risk site or sites of recurrence based on definitive surgical staging and pathologic and/or molecular assessment.