Endometrial Cancer: Disease-based Treatment

It is estimated that during calendar year 2005, 40,880 new cases of endometrial cancer will be diagnosed and 7,310 women will die of this disease in the United States. The majority of treatment failures and the accompanying 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, namely modality-based therapy, rather than disease-based algorithms as determined by patterns of recurrence.

The natural history of epithelial corpus cancer includes four potential routes of metastases: contiguous extension, hematogenous dissemination, lymphatic embolization and exfoliation with intraperitoneal spread. The associated recurrences for each of these diverse routes of spread would presuppose different adjuvant treatment strategies. In addition, such disease-based therapies are predicated on the cataloguing of specific pathologic or molecular factors that identify patients at high risk for harboring occult disease disseminated via one or more of these routes.

Recently, an outcomes analysis was conducted of all consecutive surgically managed endometrial cancer patients treated at the Mayo Clinic over a 10 year interval. While all patients received “standard of care“ under the direction of a gynecologic oncologist, a recurrence rate of 23% was observed. On the basis of regression analysis, we were able to identify independent pathologic risk factors predictive of the four routes of metastatic spread. Depth of myometrial invasion predicted the risk for hematogenous dissemination, positive lymph nodes and cervical stromal invasion predicted lymphatic recurrence, and stage IV disease or combinations of non-endometrioid histology, cervical stromal invasion, positive lymph nodes and positive peritoneal cytology were predictive of peritoneal failures. In addition, grade 3 histology or lymphvascular space involvement or both were correlated with vaginal recurrence.

Applying the above criteria to a population of 915 patients with a median follow up time of 66 months, 25% were at risk for hematogenous dissemination, 18% for lymphatic recurrence and 16% for peritoneal failure. The respective relapse rates at 5 years were 28% for patients who were at risk for hematogenous dissemination, 31% for lymphatic recurrence and 42% for peritoneal failure. This contrasted with less than a 5% recurrence rate in the corresponding subgroups not at risk for relapse (p<0.001). Collectively, of the 915 patients, 324 or 36% were considered at risk for recurrence in one or more of the above three sites. Overall, 89% of all recurrences were identified in this group of at-risk patients. Importantly, 45% of the patients considered at risk subsequently experienced a recurrence in one or more of the three sites, compared with only 2% of patients not judged to be at-risk based on these criteria (p<0.001).

Considering disease-based therapy is predicated on anticipated patterns of failure based on clinicopathologic parameters, definitive surgical staging is mandatory. The latter should include hysterectomy, salpingo-oophorectomy, peritoneal cytology, and systematic pelvic and paraaortic lymphadenectomy. However, in the course of our detailed retrospective assessment of nearly 1,000 patients, a “low risk“ cohort was identified that does not require systematic lymph node dissection. The distinguishing parameters for the “low risk“ cohort include stages IA and IB, FIGO grades 1 and 2, endometrioid histology and primary tumor diameter (PTD) ≤ 2cm. In this “low risk“ population, involvement of regional lymph nodes was not detected and neither pelvic nor paraaortic failures experienced. While only 2% of this “low risk“ cohort developed vaginal recurrence, all were salvaged with radiotherapy. The 5-year survival for this “low risk“ group was 100% and accounts for approximately 20% of the entire patient population, 25% of stage I patients and 30% of patients with endometrioid histology.

With the exception of the “low risk“ patients, we suggest that a systematic lymphadenectomy up to the renal vessels should be considered standard of care for all other endometrial cancer patients. Approximately 20% of the patients requiring lymphadenectomy will have node metastasis detected on histologic review. However, in the absence of cervical stromal invasion (CSI) or lymph node metastases, the risk of pelvic sidewall failure is minute. Most important from a treatment standpoint, 47% of the patients with pelvic lymph node metastases either had paraaortic node metastasis at the time of primary surgery or subsequently failed in the paraaortic node bearing areas. In a recent prospective outcomes assessment, the greater majority of patients with paraaortic node involvement had positive nodes above the inferior mesenteric artery and hence our recommendation that the paraaortic node dissection be extended to the level of the renal vessels. Therefore, in the absence of CSI or pelvic node metastasis, adjuvant treatment to the pelvic or paraaortic node-bearing areas does appear justifiable. Conversely, the presence of pelvic node metastasis or inadequately staged patients at-risk for nodal involvement requires adjuvant therapy that addresses both the pelvic and paraaortic node bearing areas.

The optimal treatment paradigm for patients with endometrial cancer should minimize overtreatment by identifying patients not requiring lymphadenectomy, radiotherapy or chemotherapy and minimize undertreatment by identifying those patients benefiting from lymphadenectomy or radiation or chemotherapy or a combination of these modalities. As noted above, 45% of the at-risk patients (which equates to 36% of the Mayo population) experienced treatment failure. Extrapolating these percentages to the 40,880 patients expected to be diagnosed with endometrial cancer in the US during 2005, we would predict 6,625 patients would fail treatment. This estimate approaches the anticipated number of deaths that will be attributed to this disease during 2005. Therefore, approximately one-third of the patients with endometrial cancer in the US would potentially benefit from enrollment in clinical trials addressing disease-based adjuvant therapy. Innovative disease-based algorithms should be incorporated in the development of future multimodality clinical trials predicated on the site or sites of recurrence.

Mariani A, Webb MJ, Keeney GL, Haddock MG, Calori G, Podratz KC. Low-risk corpus cancer: Is lymphadenectomy or radiotherapy necessary? Am J Obstet Gynecol 2000.

Mariani A, Webb MJ, Keeney GL, Calori G, Podratz KC. Hematogenous dissemination in corpus cancer. Gynecol Oncol 2001.

Mariani A, Webb MJ, Keeney GL, Aletti G, Podratz KC. Predictors of Lymphatic failure in endometrial cancer. Gynecol Oncol 2002.

Mariani A, Webb MJ, Keeney GL, Lesnick TG, Podratz KC. Surgical stage I endometrial cancer: predictors of distant failure and death. Gynecol Oncol 2002.

Mariani A, Webb MJ, Keeney GL, Aletti G, Podratz KC. Endometrial cancer: predictors of peritoneal failure. Gynecol Oncol 2003.

Mariani A, Keeney GL, Aletti G, Webb MJ, Haddock MG, Podratz KC. Endometrial carcinoma: paraaortic dissemination. Gynecol Oncol 2004.

Mariani A, Dowdy SC, Keeney GL, Long HJ, Lesnick TG, Podratz KC. High-risk endometrial cancer subgroups: candidates for target-based adjuvant therapy. Gynecol Oncol 2004.

Mariani A, Dowdy SC, Keeney GL, Haddock MG, Lesnick TG, Podratz KC. Predictors of vaginal relapse in stage I endometrial cancer. Gynecol Oncol 2005.