Association of number of positive nodes and cervical stroma invasion with outcome of advanced endometrial cancer treated with chemotherapy or whole abdominal irradiation: A Gynecologic Oncology Group study

doi:10.1016/j.ygyno.2011.12.414

Gynecologic Oncology

Volume 125, Issue 1, April 2012, Pages 87-93

https://doi.org/10.1016/j.ygyno.2011.12.414 Get rights and content

Abstract

Objective

To determine whether the number of positive pelvic nodes (PPN), cervical stromal involvement (CSI), and/or lymphovascular space involvement (LVSI) were prognostic factors among women with advanced endometrial carcinoma treated with adriamycin plus cisplatin (AP) or whole abdominal irradiation (WAI).

Methods

Data were abstracted from records of patients treated with adjuvant WAI or AP in a GOG randomized trial. Cox proportional hazards models were used to estimate the association of CSI and PPN with differences in PFS and OS while adjusting for treatment and previously studied factors.

Results

WAI was randomly allocated to 202 and AP to 194 eligible patients. CSI (n = 93 total) was associated with a 44% increase in risk of progression and a 33% increase in risk of death. There was a trend for increasing number PPN being associated with a 7% per positive node increase in risk of progression/death. For CSI, the estimated unadjusted treatment hazard ratios (HRs) were: PFS 0.85 (0.53, 1.38); OS 0.81 (0.50, 1.33). For metastatic disease limited to a single PPN (n = 25), the unadjusted HRs were: PFS 0.96 (0.34, 2.74); OS 0.73 (0.24, 2.18). The test of homogeneity of treatment effect (ie., AP vs WAI) across subgroups (CSI, number of positive pelvic nodes) was not statistically significant for either endpoint, thus supporting the superiority of chemotherapy as reported in the original manuscript.

Conclusions

The presence of CSI and increasing number of PPN were associated with poor prognosis. On average, patients with CSI experienced improved PFS and OS when treated with AP relative to WAI.

Highlights

► Chemotherapy is superior to whole abdominal irradiation for patients with advanced endometrial carcinoma with a single positive pelvic lymph node. ► Chemotherapy is superior to whole abdominal irradiation for patients with advanced endometrial carcinoma with concomitant cervical stromal involvement. ► Cervical stromal involvement confers a poor prognosis among patients with stage III–IV endometrial carcinoma.

Introduction

In 2011, there will be an estimated 46,470 new cases of endometrial cancer in the United States and 8120 deaths [1]. In a study utilizing the Surveillance, Epidemiology, and End Results database from 1988 to 2001 containing 45,510 patients, Ueda et al. reported that during this 14-year period there was an increase in the proportion of patients dying from advanced cancers, attributing the trend to an increase in the incidence rate of advanced stage disease, high-risk histologic subtypes, and lack of adequate surgical staging [2], [3]. For patients with recurrent, metastatic, or high-risk disease, the most recent National Comprehensive Cancer Network (NCCN) clinical practice guidelines list cisplatin plus doxorubicin (AP) with or without paclitaxel as category 1 regimens and also emphasize the importance of access to relevant clinical trials whenever possible [4].

In 2006, Randall et al. reported results from Gynecologic Oncology Group (GOG) Protocol 122 which was designed to compare AP to whole abdominal irradiation (WAI) for women with advanced stage endometrial carcinomas [5]. Over 400 patients with FIGO stage III or IV disease were enrolled on this phase III multi-center trial from 1992 to 2000 [5]. Importantly, the combination of AP was shown to significantly improve progression-free survival (PFS) (HR 0.67, 95% CI 0.52–0.87) and overall survival (OS) (HR 0.69, 95% CI 0.53–0.89) compared with whole abdominal irradiation [5]. Specifically, with a median follow-up of 74 months, at 5 years and adjusting for stage, 55% of patients treated with AP were predicted to be alive compared with 42% of those who received WAI [5]. Acute toxicity was observed in the chemotherapy arm with greater frequency and severity than in the radiation treatment arm.

The current study is a retrospective, exploratory analysis of data abstracted from reports prospectively collected for GOG 122. We hypothesized that certain uterine-specific surgicopathologic factors (i.e., lymphovascular space involvement (LVSI), cervical stromal involvement (CSI)) and the number of positive pelvic lymph nodes (PPN), would have a prognostic impact on PFS and OS among patients with advanced endometrial carcinoma. In addition, we also hypothesized that the superiority of AP reported in GOG 122 would be sustained among patients with LVSI, CSI, and/or a single PPN.

Section snippets

Patients and methods

Patients providing written informed consent and enrolled on GOG 122 with International Federation of Gynecology and Obstetrics (FIGO) stage III or IV endometrial carcinoma [6] of any histology were eligible for this trial. Eligibility required total abdominal hysterectomy and bilateral salpingoophorectomy, surgical staging, tumor resection, and no single site of residual tumor more than 2 cm. Nodal sampling was optional. Negative scalene node biopsies and chest computed tomography scans were

Clinical material

A total of 396 eligible patients were enrolled and treatment with either WAI (n = 202) or AP (n = 194) was randomly assigned. LVSI information was missing in 124 (31%) patients and cervical stroma data were missing in 13 (3%). For those in whom LVSI was identified, 105 were treated with WAI and 88 were treated with AP (Table 1A). For 202 women treated with WAI, 38 had CSI and 158 did not. For those who received AP, 55 had CSI and 132 did not (Table 1B).

On the WAI arm, PPN were identified in 91

Discussion

In the past, most patients with endometrial cancer received radiotherapy either pre-operatively or in the adjuvant setting following surgery. This paradigm was challenged, first with the recognition that adjuvant radiotherapy only improved local control, and secondly with the identification of recurrence risk factors in early stage disease to identify who would benefit from localized adjuvant treatment with radiation. After many years, the pendulum has swung in the opposite direction.

GOG 122,

Conflict of interest statement

The authors wish to report that they have no conflicts of interest with the exception of Dr. Nick Spirtos who wishes to disclose relevant financial relationships with Genzyme — Speaker's Bureau, Ethicon — Speaker's Bureau and Olympus — Speaker's Bureau.

References (36)

J.T. Thigpen et al.
Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent endometrial carcinoma. A Gynecologic Oncology Group study
Gynecol Oncol
(1989)
M.S. Aapro et al.
Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomized study (55872) by the EORTC Gynaecological Cancer Group
Ann Oncol
(2003)
H.D. Homesley et al.
A randomized phase III trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: a Gynecologic Oncology Group study
Gynecol Oncol
(2009)
H.D. Homesley et al.
A randomized phase III trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: a Gynecologic Oncology Group study
Gynecol Oncol
(2009)
A.H. Klopp et al.
Node-positive adenocarcinoma of the endometrium: outcome and patterns of recurrence with and without external beam irradiation
Gynecol Oncol
(2009)
G. Nelson et al.
FIGO stage III endometrial carcinoma with metastases confined to pelvic lymph nodes: analysis of treatment outcomes, prognostic variables, and failure patterns following adjuvant RT
Gynecol Oncol
(1999)
S. Gibbons et al.
Adjuvant whole abdominopelvic irradiation for high risk endometrial carcinoma
Int J Radiat Oncol Biol Phys
(1991)
R.S. Smith et al.
Treatment of high-risk uterine cancer with whole abdominopelvic RT
Int J Radiat Oncol Biol Phys
(2000)
C.V. Lutman et al.
Pelvic lymph node count is an important prognostic variable for FIGO stage I and II endometrial carcinoma with high-risk histology
Gynecol Oncol
(2006)
N. Takeshima et al.
Effectiveness of postoperative chemotherapy for para-aortic lymph node metastasis of endometrial cancer
Gynecol Oncol
(2006)

L.J. Havrilesky et al.

Resection of lymph node metastases influences survival in stage IIIC endometrial cancer

Gynecol Oncol

(2005)

L.A. Katz et al.

Survival after multimodality treatment for stage IIIC endometrial cancer

Am J Obstet Gynecol

(2001)

J.P. Orezzoli et al.

Stage II endometrioid adenocarcinoma of the endometrium. Clinical implications of cervical stromal invasion

Gynecol Oncol

(2009)

S. Schmid et al.

Adjuvant radiation therapy in stage III node-positive uterine cancer

Gynecol Oncol

(2009)

R. Siegel et al.

The impact of eliminating socioeconomic and racial disparities on premature cancer deaths

CA Cancer J Clin

(2011)

S.M. Ueda et al.

Trends in demographic and clinical characteristics in women diagnosed with corpus cancer and their potential impact on the increasing number of deaths

Am J Obstet Gynecol

(2008)

W.T. Creasman

Revised FIGO staging for carcinoma of the endometrium

Int J Gynaecol Obstet

(2009)

NCCN Practice Guidelines in Oncology — v.1.2010

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This study comprised meta-analyses of Phase 2/3 randomized, controlled trials of first-line treatments in patients with advanced primary or first-recurrent endometrial cancer identified via systematic literature review. The strength of the surrogacy relationship was assessed by correlation analyses (estimated with Spearman and Pearson correlation coefficients) and weighted linear regression.
Data from 15 studies were included. PFS and TTP (TTP was reported in one study only) were highly correlated with future OS at multiple time points (Spearman values, 0.83–0.90; Pearson values, 0.86–0.93), suggesting that a change in PFS/TTP would likely be correlated with a change in OS in the same direction. On weighted linear regression, a 10% increase in PFS/TTP probability was significantly associated with a 9.3% to 13.3% increase in the probability of future OS. The strong positive association between PFS/TTP and OS was supported by findings from sensitivity analyses based on identified sources of interstudy heterogeneity.
PFS/TTP is a good potential candidate for predicting long-term OS outcomes in trials of first-line treatment in patients with advanced/recurrent endometrial cancer. The findings from this report may help to inform health-authority and clinical decision makers that PFS/TTP improvements are likely to translate into subsequent OS improvements once data mature.
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To compare the prevalence of patient-reported lower-extremity lymphedema (LEL) with sentinel lymph node (SLN) mapping versus comprehensive lymph node dissection (LND) for the surgical management of newly diagnosed endometrial carcinoma.
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Therefore, a wide range of 2-year PFS rates (29–60%), 3-year PFS rates (35%) 5-year PFS rates (39%) and 5-year OS rates (25–41%) in patients with positive nodes have been reported among different studies [3,5,14,15]. The extent of lymph node involvement is an important prognostic factor in most solid tumors [16,17]. The ratio of positive nodes to the total number of nodes removed - i.e. the LNR - has been found to be an independent predictor for survival in endometrial, cervical, and vulvar cancer [6,8,11].
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The AGO-CaRE-1 study multicenter database was used for analysis. LNR was defined as ratio of number of positive lymph nodes (LN) to the number of resected. Previously established LNR risk groups were used to stratify patients. LNR was investigated with respect to clinical parameters. Univariate and multivariable survival analyses were performed to assess the value of LNR in order to predict overall (OS) and progression-free (PFS) survival.
In total, 1047 patients treated with surgery including inguinal lymph node resection for squamous cell carcinoma of the vulva were identified from the database. Of these, 370 (35.3%) were found to have positive inguinal LN. In total, 677 (64.7%) had a LNR of 0% (N0), 255 (24.4%) a LNR of >0% < 20%, and 115 (11%) a LNR of ≥20%. Patients with higher LNR were found to have larger tumor size (P < .001), advanced tumor stage (P < .001), high tumor grade (P < .001), and deep stromal invasion (P < .001), more frequently. Three-year PFS rates were 75.7%, 44.2%, and 23.1% and three-year OS rates were 89.7%, 65.4%, and 41.9%, in patients with LNRs 0%, >0% < 20%, and ≥20%, respectively (P < .001, P < .001). On multivariable analyses LNR (HR 7.75, 95%-CI 4.01–14.98, P < .001), FIGO stage (HR 1.41, 95%-CI 1.18–1.69, P < .001), and patient's performance status (HR 1.59, 95%-CI 1.39–1.82, P < .001), were associated with PFS. In addition, LNR (HR 12.74, 95%-CI 5.64–28.78, P < .001), and performance status (HR 1.72, 95%-CI 1.44–2.07, P < .001) were also the only two parameters independently associated with OS. LNR generally showed stronger correlation than number of affected LN when comparing the two different multivariable models.
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^☆: This study was funded by the Gynecologic Oncology Group/Abraxis Oncology Young Investigator Award given to Dr. Tewari in 2007.

^☆☆: This study was a plenary presentation at the 2010 Annual Meeting of the Society of Gynecologic Oncologists in San Francisco, CA and at the 2010 Biennial Meeting of the International Gynecologic Cancer Society in Prague.

^★: This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office (CA 27469), the GOG Tissue Bank (CA 27469 and CA 11479) and the GOG Statistical and Data Center (CA 37517).

^★★: The following GOG member institutions participated in this protocol: University of Alabama at Birmingham, Duke University Medical Center, Abington Memorial Hospital, Walter Reed Army Medical Center, Wayne State University, University of Minnesota Medical School, University of Mississippi, University of Colorado-Anschutz Cancer Pavilion, University of California at Los Angeles (UCLA), Fred Hutchinson Cancer Research Center, University of Pennsylvania Cancer Center, Penn State Milton S. Hershey Medical Center, University of Cincinnati Medical Center, University of North Carolina, University of Iowa Hospitals and Clinics, Southwestern Medical Center of Texas, Indiana University Cancer Center, Wake Forest University School of Medicine, Associates in Gynecologic Care, PC, University of California Medical Center at Irvine, Tufts-New England Medical Center, Rush University Medical Center, State University of New York at Brooklyn, Cleveland Clinic Foundation, State University of New York at Stony Brook, Washington University School of Medicine, Cooper Hospital University Medical Center, Columbus Cancer Council/Ohio State, University of Massachusetts Memorial Health Care, Fox Chase Cancer Center, Medical University of South Carolina, Women's Cancer Center of Nevada, University of Oklahoma, University of Virginia Health Sciences Center, University of Chicago, Tacoma General Hospital, Thomas Jefferson University Hospital, Mayo Clinic, University Hospitals Case Medical Center, Tampa Bay Cancer Consortium, Gynecologic Oncology Network (GON), and Ellis Fischel Cancer Center.

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Association of number of positive nodes and cervical stroma invasion with outcome of advanced endometrial cancer treated with chemotherapy or whole abdominal irradiation: A Gynecologic Oncology Group study☆,☆☆,★,★★

Abstract

Objective

Methods

Results

Conclusions

Highlights

Introduction

Section snippets

Patients and methods

Clinical material

Discussion

Conflict of interest statement

Gynecol Oncol

Ann Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Am J Obstet Gynecol

Gynecol Oncol

Gynecol Oncol

The impact of eliminating socioeconomic and racial disparities on premature cancer deaths

CA Cancer J Clin

Trends in demographic and clinical characteristics in women diagnosed with corpus cancer and their potential impact on the increasing number of deaths

Am J Obstet Gynecol

Revised FIGO staging for carcinoma of the endometrium

Int J Gynaecol Obstet

NCCN Practice Guidelines in Oncology — v.1.2010