Total abdominal hysterectomy (TAH), in addition to chemotherapy, significantly improved overall survival (OS) in patients with newly diagnosed uterine cancer and distant metastases, a large retrospective analysis showed.
Writing in MedPage Today, Charles Bankhead said the analysis showed the survival hazard decreased by more than 40% with the addition of TAH, and a propensity score-matched analysis showed almost a nine-month gain in median overall survival. Landmark analyses for one- and two-year OS also yielded significant advantages for patients who had TAH.
TAH plus chemotherapy improved survival for all subgroups except patients with leiomyosarcoma and those with brain metastases, reported Dr Yuefeng Wang of West Cancer Center and Research Institute in Memphis, and co-authors.
"Palliative TAH was included in the 2021 NCCN [National Comprehensive Cancer Network] guideline for uterine cancer with distant-organ metastasis," the authors wrote in the study online in JAMA Open Network. "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.”
Their conclusion was that randomised clinical trials to evaluate the effect of TAH on distant metastatic uterine cancer appear to be warranted.
The study provided intriguing data for a difficult diagnosis that is associated with an overall survival of about a year, said Dr Claire Hoppenot of Baylor College of Medicine and Dan L. Duncan Comprehensive Cancer Center in Houston, who was not involved with the research.
"Chemotherapy is the first-line treatment. These findings suggest that there may be a role for hysterectomy, either at diagnosis, if feasible, or after neoadjuvant chemotherapy," she told MedPage Today.
"These large database studies are always limited by the data collected; however they do a good job in their statistical analysis to address the concern that only patients who have a good response to chemotherapy would be taken for surgery. The addition of radiation in select patients may also be beneficial, although there may be a reverse causality in that patients who live longer get more treatments, and I do not believe that this has been adjusted specifically for radiation. This data is certainly very intriguing and I would discuss the findings with patients in making treatment decisions."
Several studies have shown that TAH with maximal cytoreduction in addition to chemotherapy increases survival for patients with newly diagnosed uterine cancer and associated abdominal or pelvic metastases.
The role of TAH in uterine cancer with distant metastasis has yet to be established, Wang and co-authors noted. Evidence from studies of other cancer types has suggested a potential survival improvement with definitive local therapy in the setting of distant metastasis, including prostate, lung, and cervical cancers.
To address the impact of TAH in uterine cancer and distant metastasis, the researchers queried the National Cancer Database for the years 2010 to 2014 to identify patients with newly diagnosed uterine cancer and metastasis to the brain, lung, liver, bone, or distant lymph nodes. All patients included in the analysis received chemotherapy, with or without TAH.
The analysis included 3,197 patients, and mean age was 62. The most common site of metastasis was the lung (1,544 patients), followed by liver (851), lymph nodes (497), bone (249), and brain (56). The authors found that 1,809 patients received chemotherapy alone and 1,388 received chemotherapy plus TAH. The cohort had a median follow-up of 13.4 months.
The results showed that the addition of TAH resulted in a survival hazard ratio of 0.57 by univariate analysis (95% CI 0.53-0.62) and 0.59 by multivariable analysis, compared with chemotherapy alone. The propensity score-matched analysis yielded median OS values of 19.8 months with TAH and 11.0 months with chemotherapy alone, representing a 41% reduction in the survival hazard (95% CI 0.53-0.65).
Subgroup analysis showed that only patients with leiomyosarcoma (HR 0.72, 95% CI 0.51-1.02) and those with brain metastases (HR 0.47, 95% CI 0.07-3.16) did not derive significant benefit from TAH.
In the TAH group, 79% of patients received chemotherapy after surgery. That subgroup also had statistically significant improvement in media OS as compared with chemotherapy alone (18.8 vs 10.3 months).
In a separate analysis, the authors compared survival in 228 patients who received definitive pelvic radiotherapy and 143 who underwent TAH plus radiotherapy, in addition to chemotherapy. Both groups had significant reductions in the survival hazard versus chemotherapy alone (HR 0.60 and HR 0.34, respectively).
Study details
Comparison of Chemotherapy vs Chemotherapy Plus Total Hysterectomy for Women With Uterine Cancer With Distant Organ Metastasis
Yuefeng Wang, Todd Tillmanns, Noam VanderWalde, Bradley Somer, Ari VanDerWalde, Lee Schwartzberg, Matthew Ballo
Published in JAMA Open Network 28 July 2021
Introduction
Uterine cancer is the most common gynaecologic cancer, and 9% of patients have metastatic disease at initial presentation. 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.
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.
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 identified in the National Cancer Database (NCDB) and, therefore, informed consent was not required. The 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.
Overall survival was analysed 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 versus rural residence, education, and annual income.
Race and ethnicity were analysed 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 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.
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 non-responders (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 one year. 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. Randomised clinical trials to evaluate the effect of TAH on distant metastatic uterine cancer appear to be warranted.
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