Outcomes in surgical stage I uterine papillary serous carcinoma

OBJECTIVE: The optimal management of patients with stage I uterine papillary serous carcinoma (UPSC) is unclear. We sought to determine whether outcomes of women with surgical stage I UPSC differ with and without adjuvant therapy. METHODS: Retrospective multi-institution analysis of women with stage I UPSC surgically staged from 1976 to 2006. Inclusion criteria: comprehensive staging procedure including hysterectomy, bilateral salpingo-oophorectomy, selective pelvic/aortic lymphadenectomy, peritoneal cytology. Recurrence and survival were analyzed using Kaplan-Meier method. RESULTS: Of 83 women with stage I UPSC, 36 (43%) received adjuvant therapies (23% radiotherapy, 3% chemotherapy, 15% chemotherapy and radiotherapy, 2% progestins). Three-year overall (OS) and progression-free survival (PFS) were 80% and 68%, respectively. Three-year OS and PFS by adjuvant treatment were observation (N=47) 86% and 78%, radiotherapy (N=17) 63% and 44%, chemotherapy with or without radiotherapy (N=17) 92% and 76%, respectively. Of the 18 recurrences, 9 (50%) included an extrapelvic component. Local recurrence was 2/30 (7%) following adjuvant radiotherapy and 7/53 (13%) without radiotherapy (p=0.48). Recurrence was higher in stage IB/IC (15/51, 29%) compared to stage IA (3/32, 9%). There has been one recurrence (5%) among the 22 women observed with stage IA disease. CONCLUSION: In this largest reported series of women with surgical stage I UPSC, the high recurrence (29%) among patients with stage IB/IC disease highlights the need for clinical trials to test new therapeutic approaches. Surgically staged patients with IA disease had good prognosis. These data suggest that radiotherapy alone is not effective, that systemic therapy is needed, and that observation could be considered in patients with stage IA disease.     

Improved survival in surgical stage I patients with uterine papillary serous carcinoma (UPSC) treated with adjuvant platinum-based chemotherapy

OBJECTIVE: Uterine papillary serous carcinoma (UPSC) is an aggressive form of endometrial cancer characterized by a high recurrence rate and a poor prognosis. Prior studies evaluating treatment of UPSC have been limited by small numbers of patients and inclusion of partially staged patients. The purpose of this study was to evaluate the efficacy of adjuvant platinum-based chemotherapy and vaginal cuff radiation in a large cohort of surgical stage I UPSC patients. METHODS: We retrospectively reviewed 74 stage I patients with UPSC who underwent complete surgical staging at our institution between 1987 and 2004. RESULTS: Stage IA patients were divided into two groups: patients with no cancer in the hysterectomy specimen (defined as no residual uterine disease) and patients with cancer in the hysterectomy specimen (defined as residual uterine disease). Stage IA patients with no residual uterine disease had no recurrences, regardless of adjuvant therapy (n = 12). Stage IA patients with residual uterine disease who were treated with platinum-based chemotherapy had no recurrences (n = 7). However, 6 of 14 (43%) stage IA patients with residual uterine disease who did not receive chemotherapy recurred. The 15 patients with stage IB UPSC who received platinum-based chemotherapy had no recurrences but 10 of the 13 (77%) stage IB patients who did not receive chemotherapy recurred. One of the 7 patients with stage IC UPSC who received platinum-based chemotherapy recurred and 4 of the 5 (80%) stage IC patients who did not receive chemotherapy recurred. Overall platinum-based chemotherapy was associated with improved disease-free survival (P < 0.01) and improved overall survival (P < 0.05) in patients with stage I UPSC. None of the 43 patients who received radiation to the vaginal cuff recurred locally, but 6 of the 31 (19%) patients who were not treated with vaginal radiation recurred at the cuff. CONCLUSIONS: Platinum-based chemotherapy improves the disease-free and overall survival of patients with stage I UPSC and vaginal cuff radiation provides local control. Stage IA UPSC patients with no residual uterine disease can be observed but concomitant platinum-based chemotherapy and vaginal cuff radiation (referred to as chemoradiation) should be offered to all other stage I UPSC patients.     

Comparison of outcomes in early stage uterine carcinosarcoma and uterine serous carcinoma

Objective

To assess whether contemporary adjuvant management of early stage uterine carcinosarcoma (CS) produces equal outcomes as in uterine serous carcinoma (USC).

Methods

We reviewed 172 women treated from 2000 to 2011 for stage I–II USC (n = 112, 65%) or CS (n = 60, 35%). Adjuvant therapy was initiated in 154 (90%) patients, with 111 patients receiving intravaginal radiotherapy (IVRT)/chemotherapy. Median follow up was 4.6 years for surviving patients.

Results

Characteristics for USC vs. CS did not differ significantly by age ≥ 60, pelvic or para-aortic node sampling, stage, lymphovascular invasion, chemotherapy use, RT use or omission of adjuvant therapy. Outcomes were better for USC vs. CS in 5-year actuarial rates of recurrence [17% (C.I. 10–25%) vs. 45% (C.I. 31–59%), p < 0.001],disease-related mortality (DRM) [11% (5–17%) vs. 30% (16–44%), p = 0.016], and all-cause mortality [12% (C.I. 6–18%) vs. 34% (C.I. 20–48%), p = 0.007]. In multivariable analysis, CS histology remained a significant predictor of risk for recurrence [HR 3.1 (C.I. 1.7–5.7), p < 0.001], DRM [HR 2.4 (C.I. 1.1–5.1), p = 0.024], and all-cause mortality [HR 2.4 (C.I. 1.2–4.8), p = 0.012]. On sub-group analysis of 111 patients (77 USC, 34 CS) able to receive IVRT/chemotherapy, CS no longer was associated significantly with increased recurrence (29% vs. 15%, p = 0.18), DRM (22% vs. 10%, p = 0.39), or all-cause mortality (22% vs. 10%, p = 0.45).

Conclusions

CS was associated with worse outcomes than USC. However, that difference was not maintained in patients able to receive IVRT and chemotherapy. While intriguing, this result may be due in part to selection against rapid early relapsing CS patients in this group.     

The efficacy of adjuvant platinum-based chemotherapy in Stage I uterine papillary serous carcinoma (UPSC)

OBJECTIVE: To determine the efficacy of adjuvant platinum-based chemotherapy in Stage I uterine papillary serous carcinoma (UPSC). METHODS: A retrospective multi-institutional investigation was performed to identify surgically staged patients with Stage I UPSC who were (1) treated after surgery with 3-6 courses of platinum-based chemotherapy without radiation from 1990-2003, and (2) followed for a minimum of 12 months, or until recurrence. RESULTS: Six patients (IA-2, IB-3, IC-1) were treated with carboplatin (AUC 6) or cisplatin (50 mg/m2) alone. One patient recurred to the vagina, was treated with chemo-radiation, and is alive and well at 122 months. One patient recurred to the lung, liver, and brain, and died of disease at 24 months. The remaining 4 patients are alive with no evidence of disease 15-124 months (mean 62 months) after treatment. Two patients (IB-1, IC-1) were treated with cisplatin (50 mg/m2) and cyclophosphamide (1000 mg/m2), and both are alive and well with no evidence of disease 75 and 168 months after treatment. Twenty-one patients (IA-5, IB-13, IC-3) were treated with a combination of carboplatin (AUC 6) and paclitaxel (135 mg/m2-175 mg/m2). One patient recurred to the vagina after 3 cycles of carboplatin/paclitaxel, and was treated with chemo-radiation. She is now without evidence of disease 10 months after treatment. At present, all 21 patients with Stage I UPSC treated following surgical staging with carboplatin/paclitaxel chemotherapy are alive and well with no evidence of disease 10-138 months (mean 41 months) after treatment. CONCLUSION: Combination carboplatin/paclitaxel chemotherapy following surgery is effective in the treatment of Stage I UPSC.     

Prognosis of papillary serous, clear cell, and grade 3 stage I carcinoma of the endometrium

OBJECTIVE: The purpose of this study was to evaluate patients with uterine papillary serous carcinoma (UPSC), clear cell (CC), and grade 3 endometrioid (G3) surgically stage I endometrial cancer. METHODS: The 25th Annual Report (AR) of FIGO was used to identify patients with endometrial cancers who were surgically staged. For comparison, all cancers reported were evaluated with particular interest in patients with stage I UPSC, CC, and G3. Incidence, substage, post-surgical treatment, and survival were identified. RESULTS: Of 5694 endometrial cancer patients reported to the AR, 3996 (70%) were surgically stage I. There were 148 UPSC, 59 CC, and 325 with G3 lesions. UPSC and CC represent 5.2% of all stage I cancers while 8.1% are G3. Although there were greater number of UPSC, CC, and G3 with extrauterine disease, about 50% of UPSC and CC were stage I. This compares to 81% for G1, 68% for G2, and only 42% for G3. There were more IA cancers with UPSC and CC than G3 (22%, 33%, and 17%, respectively). Survival (5 years) for UPSC and CC was 72% and 81%, respectively, compared to 76% for G3 lesions. Postoperative radiation improved survival somewhat (6-8%) but the difference was not significant. CONCLUSION: UPSC and CC histotypes when diagnosed as stage I have a better survival than commonly perceived and equal to G3 endometrioid cancers. Postoperative radiation improves survival but not significantly so. The role of chemotherapy has not been defined.     

The expression of hepatocyte growth factor (HGF) and c-Met in uterine serous carcinoma

Objective

The hepatocyte growth factor (HGF) receptor c-Met plays an important role in tumor dissemination by activating mitogenic signaling pathways. The goal of this study was to investigate immunohistochemical (IHC) staining patterns of HGF and c-Met in endometrioid endometrial cancer (EC) and uterine serous cancer (USC) and to correlate staining with patient outcomes.

Methods

A tissue microarray was created using tissue from patients with atrophic endometrium (AE), grade 1 EC, grade 3 EC, and USC. Immunohistochemistry was used to detect c-Met, phosphorylated c-Met (p-c-Met), and HGF expression. Differences between IHC staining intensity were calculated using t-tests. Correlations between staining and clinicopathologic variables were determined by Chi-square testing for categorical variables and t-tests for continuous variables. Kaplan-Meier curves were constructed to analyze survival in USC.

Results

Patients with cancer had more total c-Met and HGF expression than those with AE (p = 0.037, p < 0.001 respectively), but no difference in p-c-Met staining. Total c-Met and HGF staining was significantly different between groups (p = 0.042, p < 0.001 respectively). This difference was accounted for by greater c-MET expression in USC compared to AE (p = 0.027). Depth of invasion, stage, and lymph node status were not significantly related to staining intensity. Patients with strong c-Met and HGF staining had decreased overall survival compared to patients with weaker staining.

Conclusions

HGF and c-Met may play a role in the progression of endometrial cancer and should be studied further as prognostic and therapeutic tools.     

The impact of race on survival in uterine serous carcinoma: a hospital-based study

Objective

Although less common than endometrioid carcinoma, uterine serous carcinoma (USC) accounts for a disproportionate number of endometrial cancer-related deaths. It is relatively more common in black compared to white women. The aim of our study is to analyze the impact of race on survival in USC.

Methods

We conducted a retrospective review in women with USC managed at two large urban medical centers. Clinical and histopathologic parameters were retrieved. Recurrence and survival data were obtained from medical records and the Surveillance, Epidemiology, and End Results (SEER) registry. Differences in overall survival between African American and Caucasian women were compared using Kaplan-Meier curves and log rank test for univariate analysis. Cox regression models for multivariate analyses were built to evaluate the relative impact of the various prognostic factors.

Results

One hundred seventy-two women with USC were included in this study, including 65 Caucasian women and 107 African American women. Both groups were similar with respect to age, stage at diagnosis, angiolymphatic invasion (p = 0.79), and the depth of myometrial invasion (p = 0.36). There was no statistical difference in overall survival between African American and Caucasian patients in univariate analysis (p = 0.14). In multivariate analysis, stage at diagnosis, angiolymphatic invasion, and depth of myometrial invasion, but not race, were significantly associated with overall survival.

Conclusion

In this study, African American women with USC had a similar survival to Caucasian women. This suggests that the racial differences seen in USC at a larger population level may be diminished in hospital-based studies, where women are managed in a uniform way.     

Clinical predictors of long-term survival for stage IVB uterine papillary serous carcinoma confined to the abdomen

Objective

To identify clinical predictors of long-term survival in women with FIGO Stage IVB uterine papillary serous carcinoma (UPSC) confined to the abdomen

Methods

Records were reviewed for 48 patients with Stage IVB UPSC diagnosed from 1/1980 to 12/2011. Study inclusion required hysterectomy, salpingo-oophorectomy and negative chest imaging. Disease-free (DFS) and overall (OS) survival rates were calculated using the Kaplan–Meier method. Multivariate analysis (MVA) was performed using Cox proportional hazards.

Results

Median age at diagnosis was 70 years (range, 53–87). Optimal cytoreduction (Opt) to < 1 cm residual disease was performed in 36 patients (75%). With a median follow-up of 21 months for all patients and 99 months for survivors, 36 (75%) experienced disease progression or relapse, most commonly intraperitoneal (16, 44%). At 5 years, DFS and OS rates were 12% and 19%, respectively. Five patients (10%) were long-term survivors without relapse at a median of 124 months. All 5 had Opt and carboplatin/paclitaxel chemotherapy, and 4 received radiotherapy (2 pelvic, 1 whole-abdominal, 1 brachytherapy). On MVA in the chemotherapy-treated population, Opt (HR 0.09, 95% CI 0.02–0.35) and radiotherapy (HR 0.36, 0.15–0.80) were associated with decreased rates of recurrence or progression. Opt (HR 0.09, 0.02–0.38) was prognostic for OS when adjusted for age.

Conclusions

Clinical predictors of long-term survival for Stage IVB UPSC confined to the abdomen include optimal cytoreduction and adjuvant platinum and paclitaxel chemotherapy. Radiotherapy may decrease rates of recurrence or progression. Despite intra-abdominal involvement, disease remission and long-term survival may be achieved in some patients.     

Optimal surgical debulking in uterine papillary serous carcinoma affects survival

Objective

UPSC is similar to papillary serous ovarian carcinoma in its histology and pattern of spread. The survival advantage with optimal debulking for ovarian cancer has been demonstrated. We examined our experience with UPSC.

Methods

Seventy-eight UPSC patients were seen between 1995 and 2008 at Rush University Medical Center for surgery and/or adjuvant treatment. Information was obtained retrospectively from the Rush computer system, National Death Registry, and charts from chemotherapy, radiation, and gynecologic oncology.

Results

Mean survival was 67.1 months for all stages (95% CI 52.8-81.2), 47.6 months for stage III (95% CI 26.7-68.3), and 21.7 months for stage IV (95% CI 14.5-29.1). No deaths occurred in stages I and II. No significant survival difference was found between African-Americans and Whites (log-rank test, p = 0.62), nor between full serous and mixed pathology (log-rank test, p = 0.52).Optimally debulked stage IV patients had a mean survival of 30.9 months, compared to 10.3 months in suboptimally debulked patients (p < 0.001). Optimal debulking had no significant effect on stage III survival (p = 0.47). Although weight was not statistically significant (p = 0.059), there was a trend associated with suboptimal debulking.The mean time to recurrence for stage I was 79.9 months (95% CI 12.8-54.9), stage III was 27.4 months (95% CI 7.8-47.1), and stage IV was 20.2 months (95% CI 11.1-29.4) (p < 0.001). There were no recurrences in stage II.

Conclusion

Our results suggest that UPSC should be optimally debulked. Weight is a risk factor for suboptimal debulking, which decreases mean survival and time to recurrence.     

The importance of chemotherapy and radiation in uterine papillary serous carcinoma

Purpose

To identify prognostic and predictive factors of overall survival (OS), relapse-free survival (RFS) and toxicity for patients with uterine papillary serous carcinoma (UPSC).

Materials and methods

Patient, tumor, treatment and relapse characteristics of 135 women with Stages I-IVA UPSC treated between 1980 and 2006 at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC) were analyzed using Cox regression models to determine prognostic and predictive factors for OS, RFS and toxicity.

Results

Mean follow-up was 5.5 years (range, 0.01-25.2). Median 5-year OS was 52%, and RFS was 42% for all patients. On Cox regression analysis, increasing age, stage, and myometrial invasion were prognostic factors associated with shorter OS and RFS. A paclitaxel-platinum chemotherapy regimen was significantly associated with longer OS (hazard ratio [HR] = 0.34, 95% confidence interval [CI] 0.15-0.74, p = 0.007) and RFS (HR = 0.45, 95% CI 0.22-0.92, p = 0.03). RFS was improved for patients treated with RT (HR = 0.44, 95% CI 0.25-0.77, p = 0.004). The 5-year grade 3+ toxicity rate was 3.5% for those who received RT and was 2.9% for those who did not (p = NS).

Conclusion

Uterine papillary serous cancer can be an aggressive tumor type with a poor prognosis. RFS was improved by radiation and chemotherapy with few grade 3 or higher complications. Using radiation and paclitaxel-platinum chemotherapy should be attempted whenever feasible for patients with UPSC who do not have distant metastases at diagnosis.     

Prior breast cancer and tamoxifen exposure does not influence outcomes in women with uterine papillary serous carcinoma

Objectives

To evaluate progression-free survival (PFS) and overall survival (OS) outcomes in women diagnosed with uterine papillary serous carcinoma (UPSC) who have had (UPSCBR +) or have not had (UPSCBR ?) an antecedent history of breast cancer and to correlate their outcomes to prior tamoxifen exposure.

Inhibition of gamma-secretase activity impedes uterine serous carcinoma growth in a human xenograft model

Objective

Uterine serous carcinoma (USC) represents an aggressive subtype of endometrial cancer. We sought to understand Notch pathway activity in USC and determine if pathway inhibition has anti-tumor activity.

Methods

Patient USC tissue blocks were obtained and used to correlate clinical outcomes with Notch1 expression. Three established USC cell lines were treated with gamma-secretase inhibitor (GSI) in vitro. Mice harboring cell line derived or patient derived USC xenografts (PDXs) were treated with vehicle, GSI, paclitaxel and carboplatin (P/C), or combination GSI and P/C. Levels of cleaved Notch1 protein and Hes1 mRNA were determined in GSI treated samples. Statistical analysis was performed using the Wilcoxon rank sum and Kaplan–Meier methods.

Results

High nuclear Notch1 protein expression was observed in 58% of USC samples with no correlation with overall survival. GSI induced dose-dependent reductions in cell number and decreased levels of cleaved Notch1 protein and Hes1 mRNA in vitro. Treatment of mice with GSI led to decreased Hes1 mRNA expression in USC xenografts. In addition, GSI impeded tumor growth of cell line xenografts as well as UT1 USC PDXs. When GSI and P/C were combined, synergistic anti-tumor activity was observed in UT1 xenografts.

Conclusions

Notch1 is expressed in a large subset of USC. GSI-mediated Notch pathway inhibition led to both reduced cell numbers in vitro and decreased tumor growth of USC some xenograft models. When combined with conventional chemotherapy, GSI augmented anti-tumor activity in one USC PDX line suggesting that targeting of the Notch signaling pathway is a potential therapeutic strategy for future investigation.     

Patients with uterine papillary serous cancers may benefit from adjuvant platinum-based chemoradiation

OBJECTIVE: The coexistence of minimal uterine disease and extrauterine metastases is common in patients with uterine papillary serous carcinoma (UPSC). Only complete surgical staging accurately depicts the extent of this disease. The purpose of this study was to evaluate different therapeutic options in surgically staged patients. METHODS: We retrospectively reviewed all patients with UPSC histologically limited in the uterus to the endometrium treated at our institution between 1987 and 2002. RESULTS: Twenty-three (45%) cases were International Federation of Gynecology and Obstetrics (FIGO) stage IA, seven (15%) were stage IIIA, one (2%) was stage IIIC, and nine (18%) stage IV. Additionally, 11 of these 51 patients (21%) were diagnosed with two cancers: a stage IA UPSC and concomitant advanced stage serous cancer of the ovary, fallopian tube, or peritoneum. Stage IA patients with no cancer in the hysterectomy specimen (defined as no residual uterine disease) had no recurrences (n = 10) regardless of treatment. There was a trend toward increased survival in stage IA patients with residual uterine disease who were treated with chemoradiation (concomitant vaginal brachytherapy and platinum-based chemotherapy). There were no recurrences in patients with locoregional disease (stages IA-IIIA) who received chemoradiation. All patients with advanced stage UPSC (stage IIIC or IV or two primary cancers) did poorly regardless of treatment. CONCLUSION: Our findings suggest that stage IA patients with no residual uterine disease may be observed. Stage IA patients with residual uterine disease may benefit from chemoradiation. More effective treatment needs to be identified for advanced stage UPSC.     

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