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Figure.  Overall Survival Among Patients With Distant Metastatic Uterine Cancer Who Received Chemotherapy Alone vs Chemotherapy Plus Total Abdominal Hysterectomy (TAH)
Overall Survival Among Patients With Distant Metastatic Uterine Cancer Who Received Chemotherapy Alone vs Chemotherapy Plus Total Abdominal Hysterectomy (TAH)

Panel A shows survival curves for all 3197 patients. Panel B shows survival curves for 2298 propensity score–matched patients. HR indicates hazard ratio.

Table.  Survival Analysis for All Patients and Propensity Score–Matched Patients
Survival Analysis for All Patients and Propensity Score–Matched Patients
1.
Barlin  JN, Puri  I, Bristow  RE.  Cytoreductive surgery for advanced or recurrent endometrial cancer: a meta-analysis.   Gynecol Oncol. 2010;118(1):14-18. doi:10.1016/j.ygyno.2010.04.005PubMedGoogle ScholarCrossref
2.
Landrum  LM, Moore  KN, Myers  TK,  et al.  Stage IVB endometrial cancer: does applying an ovarian cancer treatment paradigm result in similar outcomes? a case-control analysis.   Gynecol Oncol. 2009;112(2):337-341. doi:10.1016/j.ygyno.2008.10.009PubMedGoogle ScholarCrossref
3.
Pectasides  D, Pectasides  E, Economopoulos  T.  Systemic therapy in metastatic or recurrent endometrial cancer.   Cancer Treat Rev. 2007;33(2):177-190. doi:10.1016/j.ctrv.2006.10.007PubMedGoogle ScholarCrossref
4.
Gomez  DR, Tang  C, Zhang  J,  et al.  Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study.   J Clin Oncol. 2019;37(18):1558-1565. doi:10.1200/JCO.19.00201PubMedGoogle ScholarCrossref
5.
Parker  CC, James  ND, Brawley  CD,  et al; Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) Investigators.  Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.   Lancet. 2018;392(10162):2353-2366. doi:10.1016/S0140-6736(18)32486-3PubMedGoogle ScholarCrossref
6.
Wang  Y, Farmer  M, Izaguirre  EW,  et al.  Association of definitive pelvic radiation therapy with survival among patients with newly diagnosed metastatic cervical cancer.   JAMA Oncol. 2018;4(9):1288-1291. doi:10.1001/jamaoncol.2018.2677PubMedGoogle ScholarCrossref
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    Research Letter
    Oncology
    July 28, 2021

    Comparison of Chemotherapy vs Chemotherapy Plus Total Hysterectomy for Women With Uterine Cancer With Distant Organ Metastasis

    Author Affiliations
    • 1Department of Radiation Oncology, West Cancer Center and Research Institute, Memphis, Tennessee
    • 2Department of Gynecologic Oncology, West Cancer Center and Research Institute, Memphis, Tennessee
    • 3Department of Hematology/Oncology, West Cancer Center and Research Institute, Memphis, Tennessee
    JAMA Netw Open. 2021;4(7):e2118603. doi:10.1001/jamanetworkopen.2021.18603
    Introduction

    Uterine cancer is the most common gynecologic cancer, and 9% of patients have metastatic disease at initial presentation.1 In addition to systemic therapy, total abdominal hysterectomy (TAH) with maximal cytoreduction has been shown to increase survival for patients with abdominal or pelvic metastases.1-3 However, to our knowledge, the role of TAH for uterine cancer with distant organ metastasis has not been established. In addition, there is growing evidence that definitive local therapies may increase survival for some types of metastatic cancers.4-6 In this cohort study, we evaluate the overall survival for patients with uterine cancer with distant organ metastasis treated with chemotherapy alone vs chemotherapy plus TAH.

    Methods

    This study was approved by the West Cancer Center and Research Institute institutional review board. All patient data were deidentified in the National Cancer Database (NCDB) and, therefore, informed consent was not required, in accordance with 45 CFR §46. This study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

    The NCDB was used to identify patients with newly diagnosed uterine cancer with metastasis to the brain, lung, liver, bone, or distant lymph node. All patients received chemotherapy with or without TAH. Patients who received no treatments, definitive pelvic radiotherapy (dose ≥45 Gy), or those missing baseline variables were excluded (eFigure in the Supplement). Overall survival was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, landmark analysis, and propensity score–matched analyses. In all these analyses, 16 variables were used, including TAH, age, year of diagnosis, race, comorbidity score, grade, clinical T/N stage, facility type, insurance, histology, metastatic site, number of metastatic sites, hormone therapy, urban vs rural residence, education, and annual income. Race and ethnicity were analyzed in this study because they are associated with differences in cancer survival. Race and ethnicity reported in the NCDB were extracted from patients’ medical records. Subgroup survival analyses were done by age, comorbidity score, T/N stage, grade, histology, metastatic site, and number of sites. Statistical significance was calculated with 2-sided χ2 tests and was defined as P < .05. All statistical analyses were done using SAS statistical software version 9.4 (SAS Institute). This study was performed from January to June 2018.

    Results

    From 2010 to 2014, we identified 3197 patients (mean [SD] age, 61.9 [11.2] years; all women [100%]) with uterine cancer with distant organ metastasis in the NCDB. Most of these patients had lung metastasis (1544 patients), followed by liver metastasis (851 patients), lymph node metastasis (497 patients), bone metastasis (249 patients), and brain metastasis (56 patients). Among these patients, 1809 received chemotherapy alone and 1388 received chemotherapy plus TAH. At a median (interquartile range [IQR]) follow-up of 13.4 (1.9-54.9) months, TAH plus chemotherapy was associated with improved survival by both univariable (hazard ratio [HR], 0.57; 95% CI, 0.53-0.62) and multivariable (HR, 0.59; 95% CI, 0.54-0.65) analysis compared with chemotherapy alone (Figure and Table). Propensity score–matched analysis demonstrated superior survival (median [IQR], 19.8 [18.3-22.3] months vs 11.0 [10.0-12.2] months; HR, 0.59; 95% CI, 0.53-0.65) for TAH plus chemotherapy. Sequential landmark analysis demonstrated significant improvement in survival for long-term survivors at greater than or equal to 0.5 year (HR, 0.69; 95% CI, 0.63-0.75), greater than or equal to 1 year (HR, 0.78; 95% CI, 0.69-0.88), and greater than or equal to 2 years (HR, 0.73; 95% CI, 0.59-0.91). On subgroup analyses, TAH plus chemotherapy was associated with significantly improved survival vs chemotherapy alone for all subgroups except patients with leiomyosarcoma (HR, 0.72; 95% CI, 0.51-1.02) or metastasis to brain (HR, 0.47; 95% CI, 0.07-3.16). Among surgical patients, 79% (1091 of 1388 patients) underwent TAH followed by chemotherapy and had significantly better survival than patients receiving chemotherapy alone (median [IQR] survival, 18.8 [17.0-20.4] months vs 10.3 [9.7-11.2] months) (Table). In the NCDB, we identified 228 patients who received definitive pelvic radiotherapy and 143 patients who underwent TAH and radiotherapy, in addition to chemotherapy (Table). Both groups of patients also had improved survival over chemotherapy alone (HR, 0.60; 95% CI, 0.51-0.71 and HR, 0.34; 95% CI, 0.26-0.44).

    Discussion

    Palliative TAH was included in the 2021 NCCN guideline for uterine cancer with distant organ metastasis. However, the role of TAH as a definitive treatment approach has not been established. To our knowledge, this analysis represents the largest reported cohort of patients with metastatic uterine cancer treated by local therapies.

    To account for potential selection biases between responders and nonresponders (ie, immortal time bias), sequential landmark analysis demonstrated significant improvement in survival for long-term survivors, which suggests that the benefit of TAH in the study is not just associated with bias. In addition, by using the time of treatments initiation, we found that most (79%) surgical patients underwent TAH followed by chemotherapy and had significantly better survival than patients receiving chemotherapy alone, which helped to rule out the selection bias that TAH was only delivered to patients who had good response from neoadjuvant chemotherapy.

    The median survival for patients with stage IVB uterine cancer receiving systemic therapy is less than 1 year.3 In this study, definitive local therapy (TAH) was associated with significantly improved survival compared with chemotherapy alone. We identified patients who received definitive pelvic radiotherapy and patients who underwent TAH and radiotherapy, in addition to chemotherapy, and both groups of patients also had improved survival over chemotherapy alone, which supports that definitive local therapies may benefit distant metastatic uterine cancer.

    This study has several limitations. The information for number of metastatic lesions, specific chemotherapy agents, salvage therapies, performance status, and disease-specific survival is not available in the NCDB. Despite these limitations, the results in this analysis are intriguing.

    In this cohort study, patients with newly diagnosed uterine cancer with distant organ metastasis receiving TAH plus chemotherapy lived substantially longer than patients receiving chemotherapy alone. Randomized clinical trials to evaluate the effect of TAH on distant metastatic uterine cancer appear to be warranted.

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    Article Information

    Accepted for Publication: May 3, 2021.

    Published: July 28, 2021. doi:10.1001/jamanetworkopen.2021.18603

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Wang Y et al. JAMA Network Open.

    Corresponding Author: Yuefeng Wang, MD, PhD, Department of Radiation Oncology, West Cancer Center and Research Institute, 7945 Wolf River Blvd, Memphis, TN 38138 (ywang@westclinic.com).

    Author Contributions: Dr Wang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Wang, Tillmanns, A. VanderWalde, Ballo.

    Acquisition, analysis, or interpretation of data: Wang, N. VanderWalde, Somer, Schwartzberg.

    Drafting of the manuscript: Wang, Tillmanns, Ballo.

    Critical revision of the manuscript for important intellectual content: Wang, N. VanderWalde, Somer, A. VanderWalde, Schwartzberg.

    Statistical analysis: Wang.

    Administrative, technical, or material support: Wang, A. VanderWalde.

    Supervision: Tillmanns, N. VanderWalde, A. VanderWalde, Schwartzberg, Ballo.

    Conflict of Interest Disclosures: Dr Tillmanns reported serving on the speaker bureau for Astra Zeneca and on the advisory board for EISAI during the conduct of the study. Dr A. VanderWalde reported serving as the Medical Director for Precision Oncology; serving as a consultant for Bristol-Myers Squibb, AstraZeneca, Caris Life Sciences Consulting, George Clinical Consulting, Compugen, Concerto Health, and Immunocore; and receiving research funding from Amgen and OneOncology. Dr Ballo reported serving as a consultant for Novocure. No other disclosures were reported.

    Meeting Presentations: This article was presented at the 2019 Meeting of the American Society of Clinical Oncology; May 31-June 4, 2019; Chicago, IL.

    References
    1.
    Barlin  JN, Puri  I, Bristow  RE.  Cytoreductive surgery for advanced or recurrent endometrial cancer: a meta-analysis.   Gynecol Oncol. 2010;118(1):14-18. doi:10.1016/j.ygyno.2010.04.005PubMedGoogle ScholarCrossref
    2.
    Landrum  LM, Moore  KN, Myers  TK,  et al.  Stage IVB endometrial cancer: does applying an ovarian cancer treatment paradigm result in similar outcomes? a case-control analysis.   Gynecol Oncol. 2009;112(2):337-341. doi:10.1016/j.ygyno.2008.10.009PubMedGoogle ScholarCrossref
    3.
    Pectasides  D, Pectasides  E, Economopoulos  T.  Systemic therapy in metastatic or recurrent endometrial cancer.   Cancer Treat Rev. 2007;33(2):177-190. doi:10.1016/j.ctrv.2006.10.007PubMedGoogle ScholarCrossref
    4.
    Gomez  DR, Tang  C, Zhang  J,  et al.  Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study.   J Clin Oncol. 2019;37(18):1558-1565. doi:10.1200/JCO.19.00201PubMedGoogle ScholarCrossref
    5.
    Parker  CC, James  ND, Brawley  CD,  et al; Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) Investigators.  Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.   Lancet. 2018;392(10162):2353-2366. doi:10.1016/S0140-6736(18)32486-3PubMedGoogle ScholarCrossref
    6.
    Wang  Y, Farmer  M, Izaguirre  EW,  et al.  Association of definitive pelvic radiation therapy with survival among patients with newly diagnosed metastatic cervical cancer.   JAMA Oncol. 2018;4(9):1288-1291. doi:10.1001/jamaoncol.2018.2677PubMedGoogle ScholarCrossref
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