The role of multi-modality adjuvant chemotherapy and radiation in women with advanced stage endometrial cancer

doi:10.1016/j.ygyno.2007.06.014

Gynecologic Oncology

Volume 107, Issue 2, November 2007, Pages 285-291

https://doi.org/10.1016/j.ygyno.2007.06.014 Get rights and content

Abstract

Objective.

The optimal adjuvant therapy for women with stages III and IV endometrial cancer following surgical staging and cytoreductive surgery is controversial. We sought to determine the outcome of patients with advanced stage endometrial cancer treated with postoperative chemotherapy ±radiation to determine whether there was an advantage to combining treatment modalities.

Methods.

A retrospective analysis of patients with surgical stages III and IV endometrial cancer from 1975 to 2006 was conducted at Duke University and the University of North Carolina. Inclusion criteria were comprehensive staging procedure including hysterectomy, bilateral salpingo-oophorectomy, ± selective pelvic/aortic lymphadenectomy, surgical debulking, and treatment with adjuvant chemotherapy and/or radiotherapy. Progression-free (PFS) and overall survival (OS) were analyzed using Kaplan–Meier method and Cox proportional hazards model.

Results.

356 Patients with advanced stage endometrial cancer were identified who received postoperative adjuvant therapies; 48% (n = 171) radiotherapy alone, 29% (n = 102) chemotherapy alone, 23% (n = 83) chemotherapy and radiation. The median age was 66 years; 38% had endometrioid tumors; and 83% were optimally debulked. There was a significant difference between the adjuvant treatment groups for both OS and PFS (p < 0.001), with those receiving chemotherapy alone having poorer 3-year OS (33%) and PFS (19%) compared to either radiotherapy alone (70% and 59%) or combination therapy (79% and 62%). After adjusting for stage, age, grade, and debulking status the hazard ratio (HR) for OS was 1.60 (95% CI, 0.88 to 2.89; p = 0.122) for chemotherapy alone and 2.01 (95% CI, 1.17 to 3.48; p = 0.012) for radiotherapy alone, compared to combination therapy. When the analysis was restricted to optimally debulked patients the adjusted HR for patients who were treated with either chemotherapy or radiation alone indicated a significantly higher risk for disease progression [HR = 1.84 (95% CI, 1.03 to 3.27; p = 0.038); HR = 1.80 (95% CI, 1.10 to 2.95; p = 0.020)] and death [HR = 2.33 (95% CI, 1.12 to 4.86; p = 0.024); HR = 2.64 (95% CI, 1.38 to 5.07; p = 0.004)], respectively, compared to patients who received combination therapy.

Conclusion.

Combined adjuvant chemotherapy and radiation was associated with improved survival in patients with advanced stage disease compared to either modality alone. Future clinical trials are needed to prospectively evaluate multi-modality adjuvant therapy in women with advanced staged endometrial cancer to determine the appropriate sequencing and types of chemotherapy and radiation.

Introduction

Endometrial cancer is the most common gynecologic malignancy with 41,200 new cases and 7350 deaths reported in 2006. [1] Fortunately over 70% of patients with endometrial cancers are diagnosed with stage I disease and have an excellent prognosis. However, for patients with stages III and IV disease the 5-year survival rates decrease dramatically and range from 30 to 89% [2], [3], [4] and 0 to 10% [5], respectively. The heterogeneous outcomes of patients with advanced endometrial cancer and paucity of prospective randomized trials have hindered the development of therapeutic recommendations for patients with stages III and IV endometrial cancer. Currently the optimal management of patients with advanced stage endometrial cancer has yet to be defined and there is an imperative clinical need to develop postoperative adjuvant treatment algorithms that improve survival with acceptable toxicity.

In order to reduce the high incidence of disseminated relapse within the abdomen and extra-abdominal sites many have advocated for postoperative therapy with whole abdominal irradiation, chemotherapy, or combinations of radiation and chemotherapy to reduce the risk of recurrence and prolong survival. Radiation therapy has historically been utilized in the treatment of advanced stage endometrial cancer to improve local control. Both whole abdominal irradiation (WAI) and whole pelvic with or without extended field radiation have been extensively evaluated in this disease setting in several retrospective and prospective studies. [2], [4], [6], [7] In a randomized phase III clinical trial conducted by the Gynecologic Oncology Group (GOG) WAI was directly compared to chemotherapy in patients with advanced stage endometrial cancers who had optimally debulked (< 2 cm) disease. [3] Randall and colleagues reported that combination adriamycin and cisplatin (AC) resulted in superior overall and progression-free survival rates compared to WAI in this group of patients. After adjusting for stage, patients who were treated with chemotherapy had a significantly reduced risk of disease progression (HR = 0.71; 95% CI, 0.55 to 0.91; p = 0.007) and death (HR = 0.68; 95% CI, 0.52 to 0.89; p = 0.004) compared to those who were treated with WAI.3 Chemotherapy reduced the distant extra-abdominal failure rate from 19% to 10% compared to radiotherapy. However, there was a slightly higher pelvic recurrence rate (18%) in the chemotherapy arm compared to the radiation arm (13%). Other authors have reported an even higher pelvic failure rate (40%) in patients with high-risk endometrial cancer who were treated with adjuvant chemotherapy alone. [8] Therefore, while chemotherapy is thought to control distant disease better than radiation therapy, it may not be adequate to achieve local control.

Thus it is logical to speculate that combined modality therapy with chemotherapy and radiation will result in superior clinical outcomes compared to either modality alone by controlling both distant and local disease. Several studies have been reported in the literature regarding the use of combined modality therapy in this patient population with improved clinical outcomes. [4], [9], [10], [11] Most impressive were the results reported by Onda and colleagues regarding their experience with patients with advanced stage disease who were treated with multi-modality therapy. Thirty patients with completely staged IIIC endometrial cancer received combination chemotherapy and whole pelvis + periaortic radiation and achieved a 5-year survival of 84%. [4] These intriguing findings mandate further exploration regarding multi-modality therapy in patients with advanced stage endometrial cancer.

Given the uncertainty regarding the optimal adjuvant therapy management in patients with advanced stage endometrial cancer following cytoreductive surgery we sought to examine the outcome of patients with advanced stage endometrial cancer treated with postoperative adjuvant chemotherapy alone, radiation alone, or both to see if there appeared to be a survival advantage to combining these therapeutic modalities.

Section snippets

Materials and methods

A multi-center retrospective analysis of patients with advanced surgically staged endometrial cancer was conducted following Institutional Review Board approval from Duke University and the University of North Carolina (UNC). Tumor Registries were reviewed to identify all patients with stage III or IV endometrial cancer who received primary surgical treatment followed by adjuvant therapy with chemotherapy, radiation therapy, or both modalities at the two medical centers between 1975 and 2006.

Patient characteristics

Three hundred and fifty-six patients with advanced surgically staged endometrial cancer were identified who received postoperative adjuvant therapies between 1975 and 2006. The median age was 66 years (range 35–92). The predominant histologic subtype was endometrioid (134/354; 38%). Papillary serous, mixed, and adenocarcinoma, not otherwise specified, accounted to 24%, 23%, and 10%, respectively (Table 1). Eighty-three percent (290/349) were optimally debulked, while 17% (59/349) were

Discussion

We believe our study is the largest retrospective series to date to explore the clinical outcome of patients with advanced endometrial cancer treated with adjuvant radiation, chemotherapy, or combination chemotherapy and radiation, following comprehensive surgical staging and cytoreductive surgery. Our findings suggest that combined multi-modality therapy with adjuvant chemotherapy and radiation may improve survival in patients with advanced stage disease compared to either modality alone.

Our

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The optimal adjuvant treatment for patients with locally advanced endometrial cancer (EC) remains debatable. We comparatively analyzed recurrence patterns and survival outcomes in patients with stage III–IVA EC treated with adjuvant chemotherapy (CT) exclusively or combined with radiotherapy (CRT).
We retrospectively analyzed 184 patients treated for stage III–IVA EC at 2 tertiary institutions between 2010 and 2021. All patients underwent standard primary surgery and received either CT alone (n = 89) or CRT (n = 95) as an adjuvant treatment. We compared the failure patterns, recurrence-free survival (RFS), and overall survival (OS) between the CT and CRT groups.
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This study highlights the potential benefits of adjuvant CRT in patients with stage III–IVA EC. The incorporation of molecular classification is necessary to derive optimal personalized adjuvant treatment strategies for this patient population.
Lunchbox trial: A randomized phase III trial of cisplatin and irradiation followed by carboplatin and paclitaxel versus sandwich therapy of carboplatin and paclitaxel followed by irradiation then carboplatin and paclitaxel for advanced endometrial carcinoma
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The objective was to compare sequencing strategies for treatment of advanced endometrial carcinoma.
Patients were eligible if they had FIGO 2009 Stage III or IVA endometrial carcinoma or Stage I or II serous or clear cell endometrial carcinoma and positive cytology. Patients were randomized to: Cisplatin 50 mg/m2 IV Days 1 and 29 plus radiation followed by Carboplatin AUC 5 or 6 plus Paclitaxel 175 mg/m2 q 21 days for 4 cycles (chemoRT then chemo) vs. Carboplatin AUC 6 plus Paclitaxel 175 mg/m2 q 21 days for 3 cycles followed by radiation followed by Carboplatin AUC 5 or 6 plus Paclitaxel 175 mg/m2 q 21 days for 3 cycles (sandwich therapy). Futility analysis was planned. The primary objective was to determine if chemoRT then chemo improves recurrence-free survival (RFS) compared to sandwich therapy.
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The National Cancer Database (NCDB) and Surveillance, Epidemiology, and End Results Program (SEER) registries were queried for patients with stage IV endometrial cancer from 2004 to 2017. Treatment was categorized as chemotherapy alone, chemotherapy with external beam radiation therapy (EBRT), chemotherapy with vaginal brachytherapy (VBT), or chemotherapy with EBRT+VBT. Multivariable Cox regression models assessed associations between treatment modality and overall survival (OS).
This analysis included 17,890 (NCDB: 12,812, SEER: 5078) women with stage IV endometrial cancer, including 1757 (9.8%) with IVA disease and 16,133 (90.2%) with IVB. The majority of stage IV patients received chemotherapy alone (NCDB 78.8%, SEER 77.0%). When radiation was utilized in addition to chemotherapy, EBRT was most common (NCDB 15.8%, SEER: 15.4%). In both databases, use of any radiation in addition to chemotherapy was associated with improved OS. Stage IV patients treated with chemotherapy plus EBRT had better survival than those receiving chemotherapy alone [NCDB: HR 0.75 (95% CI 0.70, 0.79), SEER: HR 0.85 (95% CI 0.77, 0.94)]. This benefit was more pronounced in patients with IVA disease [NCDB: HR 0.66 (95% CI 0.55, 0.79), SEER: HR 0.63 (95% CI 0.46, 0.85)]. In histology-stratified analyses, the addition of radiation to chemotherapy was associated with improved OS in all histologies, except clear cell.
In this analysis of the NCDB and SEER registries, the use of multimodality treatment with radiation and chemotherapy was associated with improved OS compared to chemotherapy alone in women with stage IVA and IVB endometrial cancer.
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The prognosis of patients presenting with stage IVB uterine serous carcinoma (USC) remains extremely poor, with a reported 5-year survival of <20%. Here were evaluate the survival impact of cytoreductive surgery and identify other prognostic factors in stage IVB USC.
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Original Research ReportThe role of multi-modality adjuvant chemotherapy and radiation in women with advanced stage endometrial cancer

Abstract

Objective.

Methods.

Results.

Conclusion.

Introduction

Section snippets

Materials and methods

Patient characteristics

Discussion

Int J Radiat Oncol Biol Phys

Gynecol Oncol

Int J Radiat Oncol Biol Phys

Gynecol Oncol

Int J Radiat Oncol Biol Phys

Gynecol Oncol

Gynecol Oncol

Original Research Report
The role of multi-modality adjuvant chemotherapy and radiation in women with advanced stage endometrial cancer