Uterine Papillary Serous Carcinoma: Comparisons of Outcomes in Surgical Stage I Patients With and Without Adjuvant Therapy
Abstract & Commentary
Synopsis: In this largest reported series of surgical Stage I UPSC patients, recurrence rates were lower than those published in previous studies, suggesting a potential benefit of comprehensive surgical staging in these patients. The risk of recurrence and the mean overall survival were similar between surgical Stage I UPSC patients who were managed conservatively and those treated with adjuvant radiation therapy. These data question the benefit of radiation therapy in UPSC patients with disease confined to the uterus. Finally, given the absence of recurrences and disease-related deaths for adjuvant chemotherapy in these patients, a Phase II/III trial evaluating adjuvant chemotherapy in surgical Stage I UPSC patients should be considered.
Source: Huh WK, et al. Gynecol Oncol. 2003;91(3): 470-475.
In a collective effort from the tumor registries of 4 academic centers, Huh and colleagues accessioned cases of uterine papillary serous carcinoma (UPSC), which, following comprehensive surgical staging, were identified with disease limited to the uterine corpus—surgical stage I. The retrospective data set, conducted for a 14-year period ending in 2000, was collected to address the benefit, if any, from the use of adjuvant therapy. Surgical staging required removal of the uterus, tubes, and ovaries, peritoneal cytology, and pelvic and paraortic lymphadenectomy. Specific biopsy of other peritoneal tissue and organs were not required but were obtained in some cases. In all, 60 patients were identified, 40 of whom were simply observed following surgery. The remaining 20 received adjuvant radiation therapy (n = 12), chemotherapy (n = 9) or both (n = 1). Recurrence rates were no different between those patients receiving adjuvant therapy (16%) and those undergoing conservative observation (17%). Interestingly, no recurrences were observed in patients receiving chemotherapy—all of whom remain alive at a mean 32 months. The 5-year disease-free and overall survival rates for the observation group were 65% and 66%, respectively. This compared to the 5-year disease-free and overall survival rates of 60% and 59%, respectively, for those patients receiving radiation therapy. The small differences were not statistically different.
Huh et al conclude that performance of comprehensive surgical staging most likely contributed to the lower than expected historical recurrence rates. However, despite a noted risk for distant failure, no clear benefit from adjuvant radiation therapy was obvious. The lack of disease failure in patients receiving chemotherapy is interesting and should herald further clinical investigation.
Comment by Robert L. Coleman, MD
Since its initial description more than 20 years ago, UPSC has been a challenging clinical entity. Characterized by frequent extrauterine spread, aggressive clinical behavior, and inconsistent preoperative histology, this distinct uterine cancer is uncommon (about 4-9% of all uterine primaries) but remains poorly understood. Effective therapeutic strategies are elusive and, as appreciated in this study, even candidate selection for therapy is controversial. What is well documented and what makes management decisions so difficult is that its natural history appears to be very different from the much more common uterine endometrioid cancer. Surgical care and adjuvant therapy, which has been traditionally applied under the supposition of parity with the more common endometrioid histology has, to some degree, limited our ability to make accurate decisions about management—particularly with the retro-spectroscope. Since early stage disease represents the most curable cohort in all histologic subgroups, identifying the most effective adjuvant treatment, if any, is a premium target.
There are several notable differences between UPSC and uterine endometrioid adenocarcinoma that help to illustrate the clinical challenges faced. First, the diagnosis is variably determined by standard endometrial aspiration. Studies have noted that between 37% and 77% of preoperative biopsies are representative of the final histology in cases of UPSC. Some of this discrepancy may be explained by the occurrence of a mixed pattern in up to 40% of patients.
Unfortunately, the appearance of endometrioid features does not appear to alter the clinical course. Second, the patient demographic is generally one of an older population (median age, 68) and generally not obese or peripherally exposed to exogenous estrogen. Third, local recurrence is frequently associated with not only intra-abdominal and distant disease but also death. In a trial of endometrioid adenocarcinoma, Stage I patients who, following observation, were identified with local recurrence, treatment with radiation was associated with successful salvage in nearly 50% at 4 years. Fourth, little apparent relationship exists between myometrial invasion and the occurrence of extrauterine disease.
While the depth of myometrial invasion in UPSC patients has been determined by some to be an independent prognostic factor, up to 40% of patients with non-invasive UPSC will have evidence of extrauterine and frequently intra-abdominal metastatic disease. This latter observation is likely responsible for the seemingly improved prognosis of Stage I patients reported in this and other contemporary trials. "Stage migration" refers to the temporal reclassification of a particular cohort of patients on the basis of diagnostic precision—or in this case, on the basis of occult disease re-categorizing Stage I patients to a higher stage—a classic example of, ". . .if you look for it, you will find it." In this regard, the current recommendation for proper staging of a patient with UPSC is to obtain additional intra-abdominal biopsies similar to those performed for ovarian cancer.
The study by Huh et al attempts to shed light on the management of properly evaluated (for the most part) Stage I UPSC. The goal of the paper was to elicit the proper management of those patients in whom no extrauterine disease was identified, knowing that our clinical "track record" with this disease is poor and frequently characterized by distant failure. Although no "winning" strategy was declared in the retrospective data set, important contributions were made in the observations that adjuvant radiation therapy did not improve any of the survival parameters and in the curious absence of recurrence in patients given adjuvant chemotherapy. Although the number of patients in this subgroup was small (n = 7), the 32-month mean follow-up was consistent with the other subgroups; a plea for prospective clinical trials is certainly supported.
The role of chemotherapy in endometrial cancer has gained new import following the presentation of the results from a randomized trial in advanced-stage endometrial cancer (GOG 122). In this trial, adriamycin and cisplatin were compared against whole abdominal radiation in Stage III and IV uterine cancer patients. Significant reduction in the hazard for recurrence (0.68, 95% CI, 0.52-0.89) and death (0.66, 95% CI, 0.5-0.89) was observed with the more toxic chemotherapy regimen. Modification to both the chemotherapy and radiation protocols is currently being investigated through a randomized trial in similar cohort of patients.
Given the rarity of UPSC and the limited number of Stage I patients to study, answers to these important issues will be some time off. However, identification of the uniqueness of this histology is an important first step. In the meantime, treatment recommendations will be based on the extrapolation of active therapies in other cohorts that address the characteristic natural history of UPSC.
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