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Abstract
Objective To investigate the prognostic significance of comprehensive lymphadenectomy at the time of primary debulking surgery for patients with rare histologic sub-types of epithelial ovarian carcinoma and clinically advanced stage disease who underwent complete gross resection.
Methods The National Cancer Database was accessed and patients diagnosed between January 2010 and December 2015 with stage III–IV clear cell, endometrioid, mucinous, and low-grade serous carcinoma who underwent primary debulking surgery and achieved complete gross resection were identified. Patients who did not undergo lymphadenectomy and those who underwent comprehensive lymphadenectomy (defined as at least 20 lymph nodes removed) were selected for further analysis. Overall survival was compared with the log-rank test and a Cox model was constructed to control for confounders.
Results A total of 381 patients were identified; 133 (34.9%) patients underwent comprehensive lymphadenectomy while 248 (65.1%) patients did not. There were no differences between the two groups in terms of patient race, age, presence of co-morbidities, type of treatment facility, disease stage, histology, and extent of intra-abdominal disease (p>0.05). There was no difference in overall survival between patients who did and did not undergo comprehensive lymphadenectomy (p=0.42); median overall survival was 51.48 and 47.38 months, respectively. After controlling for patient age, race, insurance status, presence of co-morbidities, intra-abdominal tumor spread, stage and histology, performance of systematic lymphadenectomy was not associated with better survival (HR 0.96, 95% CI 0.69 to 1.35).
Conclusion Comprehensive lymphadenectomy is not associated with a survival benefit for patients with rare histologic sub-types of epithelial ovarian carcinoma and advanced stage disease who underwent primary debulking surgery and complete gross resection.
- ovarian cancer
- cystadenocarcinoma
- mucinous
- surgery
Data availability statement
Data may be obtained from a third party and are not publicly available. Data available from the American College of Surgeons.
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HIGHLIGHTS
Systematic lymphadenectomy for advanced stage ovarian carcinoma is not supported.
In a cohort of patients with rare histotypes, 34.9% underwent lymphadenectomy.
No survival benefit was found in a large cohort of patients.
Introduction
Ovarian cancer is a heterogenous group of different histologic sub-types, each characterized by unique clinico-pathological characteristics and biologic behavior.1 Compared with the most prevalent high-grade serous ovarian carcinomas, low-grade serous, mucinous, and clear cell carcinomas are more chemoresistant to standard platinum-based chemotherapy, and patients with advanced stage disease face a poorer prognosis.1–3 As such, achieving complete gross resection for these patients is of paramount importance.1
Performance of comprehensive lymphadenectomy would remove lymph nodes that harbor microscopic metastases, present in >40% of patients with advanced stage disease.4 5 Removal of these lymph nodes would theoretically include complete resection of retroperitoneal disease, thus achieving a true complete gross resection.6 On the other hand, lymphadenectomy can be associated with increased operative time, blood loss, post-operative complications, and a higher incidence of lower extremity lymphedema.6 7 A recent landmark randomized trial investigated the role of comprehensive lymphadenectomy for patients with advanced stage ovarian cancer who achieved complete gross resection following primary cytoreductive surgery.7 Median survival was comparable between patients who underwent comprehensive lymphadenectomy and those who did not (median overall survival 65.5 and 69.2 months, respectively), while higher peri-operative morbidity was observed in the comprehensive lymphadenectomy group (serious post-operative complications 12.4% vs 6.5% (p=0.01) and 60-day mortality 3.1% vs 0.9%, (p=0.049)).7 However, the majority (73.1% and 70.7%) of patients in both arms were diagnosed with high-grade serous ovarian carcinoma and a sub-group analysis based on histologic sub-type was not performed.7 To date there have been only a few studies investigating the role of comprehensive lymphadenectomy for rare histologic sub-types of epithelial ovarian carcinoma such as clear cell and low-grade serous ovarian carcinoma, with heterogeneous results.8–10
The aim of this study was to investigate the impact of comprehensive lymphadenectomy on the survival of patients with advanced stage epithelial ovarian carcinoma and rare histologies who underwent primary debulking surgery and complete gross resection.
Methods
The National Cancer Database was accessed and cases diagnosed between 2010 and 2015 of low-grade serous, mucinous, endometrioid, and clear cell tumors with a pathologically confirmed primary ovarian carcinoma and no history of another tumor (as grouped by the International Agency for Research on Cancer) were identified. The National Cancer Database has been established jointly by the American Cancer Society and Commission on Cancer of the American College of Surgeons as a hospital-based database capturing data of patients with newly diagnosed cancer in the USA. Patient data are prospectively collected from participating commission-accredited cancer programs and are regularly audited. All data are de-identified and available for research purposes. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytical or statistical methodology employed, or the conclusions drawn from these data. The present study was deemed exempt from the Penn Institutional Review Board.
Histologic assignments were identified based on International Classification of Diseases-3 histology codes for low-grade serous, mucinous, endometrioid, and clear cell tumors.11 Those with advanced stage disease (stage III–IV) who underwent primary debulking surgery, had complete gross resection and received adjuvant chemotherapy within 6 months from surgery were selected for further analysis. Performance of lymph node dissection and the number of lymph nodes removed was evaluated from the pathology report while potentially misclassified cases were excluded. Two groups were formed for analysis purposes: no lymphadenectomy and comprehensive lymphadenectomy (defined as at least 20 lymph nodes removed). We selected a 20 lymph node cut-off to avoid including patients who had resection only of grossly abnormal lymph nodes.
The primary outcome was overall survival while secondary outcomes were 90-day mortality rate, 30-day unplanned re-admission rate, median inpatient hospital stay, time to chemotherapy, and rate of prolonged hospital stay (defined as >10 days). Demographic and clinico-pathological data were extracted from the de-identified dataset. Categorical and continuous variables were compared with the χ2 or Fisher’s exact test and Mann–Whitney U tests, respectively. Kaplan–Meier curves were generated to determine median overall survival and univariate comparisons were performed with the log-rank test. Stratified analyses by histology were performed. A Cox multivariate model was constructed to control for confounders known to be associated with overall survival. All statistical analyses were performed with the Statistical Package for the Social Sciences v.27 statistical package (IBM Corp, Armonk, New York, USA), and the alpha level of statistical significance was set at 0.05.
Results
A total of 381 patients who met the inclusion criteria were identified. The median age of diagnosis was 57 years (range 17–89). The majority of patients were white (84.3%), had no co-morbidities (85.3%), and had private insurance (56.2%). Approximately half had bulky intra-abdominal disease (50.1%). The most common histologic sub-types were clear cell (n=120, 31.5%) and endometrioid (n=108, 28.3%), followed by low-grade serous (n=90, 23.6%) and mucinous (n=63, 16.5%).
In the present cohort, 133 (34.9%) patients underwent comprehensive lymphadenectomy while 248 (65.1%) patients did not. Patients who underwent comprehensive lymphadenectomy were more likely to have private insurance (67.7% vs 50%, p=0.002). There were no differences between the two groups in terms of patient race, age, presence of co-morbidities, type of treatment facility, disease stage, and intra-abdominal disease extent (T3A, T3B, T3C) (p>0.05). Rate of comprehensive lymphadenectomy was 43.3% for patients with clear cell carcinoma compared with 33.3%, 33.3%, and 23.8% for those with low-grade serous, endometrioid, and mucinous carcinoma (p=0.061). Table 1 summarizes the clinico-pathological characteristics of the patient population. For patients who underwent comprehensive lymphadenectomy, a median of 27 lymph nodes were removed (range 20–81). Approximately half (55.6%, n=74) of patients had lymph node metastasis while the median number of positive lymph nodes removed was 3 (range 1–49). The proportions of patients with lymph node metastases by histology were 66.7%, 55.6%, 51.9%, and 46.7% for low-grade serous, endometrioid, clear cell, and mucinous ovarian carcinoma, respectively (p=0.52).
Clinico-pathological characteristics stratified by performance of comprehensive lymphadenectomy (LND)
Based on the reverse Kaplan–Meier method, median follow-up for patients who did and did not undergo comprehensive lymphadenectomy was 43.63 and 53.75 months, respectively. There was no difference in overall survival between patients who did and did not undergo comprehensive lymphadenectomy (p=0.42); median overall survival was 51.48 (95% CI 37.26 to 65.70) months and 47.38 (95% CI 35.91 to 58.86) months, respectively (Figure 1). After controlling for patient age, race, insurance status, presence of co-morbidities, intra-abdominal tumor spread, stage and histology, performance of systematic lymphadenectomy was not associated with better survival (HR 0.96, 95% CI 0.69 to 1.35). Median overall survival for patients with low-grade serous, endometrioid, clear cell, and mucinous ovarian carcinoma was 90.32, 63.51, 36.76, and 16.85 months, respectively (p<0.001). Following stratification by histology, comprehensive lymphadenectomy was not associated with a survival benefit for patients with low-grade serous (p=0.82) (Figure 2), mucinous (p=0.57), endometrioid (p=0.90) or clear cell (p=0.78) (Figure 3) carcinoma.
Overall survival of patients with stage III–IV low-grade serous, endometrioid, mucinous, and clear cell ovarian carcinoma who did and did not undergo systematic lymphadenectomy (LND) at the time of primary debulking surgery and achieved complete gross resection. LN, lymph node.
Overall survival of patients with stage III low-grade serous ovarian carcinoma who did (n=30) and did not (n=60) undergo systematic lymphadenectomy (LND) at the time of primary debulking surgery and achieved complete gross resection. LN, lymph node.
Overall survival of patients with stage III clear cell ovarian carcinoma who did (n=52) and did not (n=68) undergo systematic lymphadenectomy (LND) at the time of primary debulking surgery and achieved complete gross resection. LN, lymph node.
With regard to secondary outcomes between patients who did and did not undergo comprehensive lymphadenectomy, inpatient hospital stay (median 5 days for both groups, p=0.77), prolonged hospitalization (7.3% vs 11%, p=0.35), 90-day mortality (0.8% vs 3.3%, p=0.17), 30-day unplanned re-admission (6.1% vs 7.7%, p=0.56), and time to chemotherapy (median 36 vs 38 days, p=0.12) were comparable between the two groups.
Discussion
Summary of Main Results
In a large cohort of patients with advanced stage rare histotypes of epithelial ovarian carcinoma who underwent primary debulking surgery and achieved complete gross resection, approximately one-third of patients underwent comprehensive lymphadenectomy. A relatively high prevalence of lymph node metastasis was observed; however, the performance of comprehensive lymphadenectomy was not associated with a survival benefit even after controlling for confounders and stratifying by tumor histology. We did not find increased peri-operative morbidity in the comprehensive lymphadenectomy group.
Results in the Context of Published Literature
Several studies have demonstrated a high prevalence of lymph node metastasis among patients with advanced stage epithelial ovarian carcinoma.4 5 Similarly, in our cohort the incidence of lymph node metastasis was 54.2% and was not significantly different between histologic sub-types. It has been hypothesized that removal of lymph nodes harboring micrometases may improve survival of patients with ovarian cancer since these tumor cells may be more resistant to chemotherapy secondary to diminished blood supply (pharmacologic sanctuary hypothesis).12 In the era of second look surgery, a relatively high prevalence of lymph node metastasis was found following chemotherapy administration.13 Retrospective studies have suggested a potential benefit of comprehensive lymphadenectomy in advanced stage ovarian cancer.6 14–16 In an exploratory analysis of three randomized trials that included 1924 patients, performance of lymphadenectomy was associated with better overall survival after controlling for confounders (HR 0.74, 95% CI 0.59 to 0.94).6 In a prior analysis of the Surveillance Epidemiology and End Results database that included 13 918 patients diagnosed with advanced stage (III–IV) epithelial ovarian carcinoma between 1988 and 2001, the authors reported improved 5-year disease-free specific survival with more extensive lymph node dissection.16 A benefit was seen even after stratification by histologic sub-type.16 However, contrary to our study, the majority of patients had high-grade serous carcinoma while a major limitation was the absence of data on the administration of adjuvant chemotherapy or status of residual disease.
Two prospective randomized trials have investigated the role of comprehensive lymphadenectomy for patients with advanced stage ovarian cancer at the time of primary debulking surgery.7 ,17 Panici et al 17 randomly assigned patients with optimally debulked (residual disease ≤1 cm) stage IIIB–C/IV ovarian carcinoma to systematic pelvic and para-aortic lymphadenectomy (n=216) or removal only of bulky lymph nodes (n=211). The majority of patients had serous histology (62.6%) while, as expected, endometrioid (13.3%), clear cell (5.7%), and mucinous (2.8%) tumors were rare. Patients who underwent comprehensive lymphadenectomy had better progression-free survival (HR 0.75, 95% CI 0.59 to 0.94) and there was no difference in overall survival (HR 0.97, 95% CI 0.74 to 1.29). However, patients who underwent comprehensive lymphadenectomy had longer operative time (median 300 vs 210 min, p<0.001), higher blood loss (median 1000 vs 650 mL, p<0.001), and incidence of blood transfusion (72% vs 59%, p=0.006). Only 37% of patients enrolled in the aforementioned trial achieved complete gross resection. The LION randomized trial enrolled 647 patients with stage IIB–IV epithelial ovarian carcinoma who achieved complete gross resection at the time of primary debulking surgery. The systematic lymphadenectomy group had a median of 57 lymph nodes resected with an incidence of lymph node metastasis of 55.7%. 7 There was no difference in overall (median 65.5 vs 69.2 months, p=0.65) or progression-free survival (median 25.5 months in both groups, p=0.29) between patients who did and did not undergo comprehensive lymphadenectomy. However, patients who underwent systematic lymphadenectomy faced significant peri-operative morbidity. They experienced longer operative time (median 340 vs 280 min, p<0.001), larger blood loss (median 650 vs 500 mL, p<0.001), higher transfusion rate (63.7% vs 56%, p=0.005), admission to intensive care unit (77.6% vs 69%, p=0.01), as well as repeat laparotomy and 60-day mortality.
To date only a few studies have focused on the role of systematic lymphadenectomy for rare histologic sub-types such as low-grade serous, endometrioid, mucinous, and clear cell carcinoma. Kajiyama et al searched a Japanese multi-institutional database and identified 166 patients with stage IIB–IV ovarian clear cell carcinoma who underwent primary debulking surgery and achieved optimal cytoreduction (<1 cm residual tumor).10 A total of 112 patients underwent comprehensive lymphadenectomy (complete pelvic lymph node dissection and para-aortic lymphadenectomy to the level of the renal vessels).10 Similar to our results, following propensity score matching, there was no significant difference in progression-free survival (5-year 44% vs 46.2%, p=0.54) and overall survival (5-year 64.9% and 58.8%, p=0.45) between patients who did and did not undergo comprehensive lymphadenectomy.10 In an analysis of the Multicenter Italian Trials in Ovarian Cancer cohort that identified 97 patients with advanced stage ovarian clear cell carcinoma, lymphadenectomy was performed in 39.2% of these and was associated with better disease-free and overall survival.9 Stratified analysis by residual disease status was not performed but, by multivariate analysis, residual disease status, tumor stage, and performance of lymphadenectomy were associated with survival.9 Another multi-center study that included 126 patients with low-grade serous ovarian carcinoma (86.1% with stage III/IV disease) who underwent primary or interval debulking surgery reported no benefit of lymphadenectomy (performed in 74.6% of patients) even following stratification status of residual disease and timing of debulking surgery.8
Strengths and Weaknesses
Several limitations of the present study should be mentioned. First, given the absence of central pathology review, possible histology and staging misclassifications could not be excluded. In addition, the National Cancer Database does not collect data on tumor relapse, precluding us from analyzing differences in progression-free survival and patterns of tumor recurrence. Moreover, data on the status of lymph nodes based on pre-operative imaging and intra-operative assessment were not available. As such, we could not determine how many patients in the comprehensive lymphadenectomy group had lymph nodes suspicious for metastases based on imaging or intra-operative evaluation. Also, we could not verify the upper limit of the lymphadenectomy performed (inferior mesenteric artery vs renal vessels). While all patients received adjuvant chemotherapy within 6 months from debulking surgery, details on the exact regimen used were not available. Last, even though the two study groups were comparable in terms of age and co-morbidities, patient performance status and other factors that could potentially influence surgeons’ decisions to perform a comprehensive lymphadenectomy are not reported.
Implications for Practice and Future research
The results of our study suggest that removal of grossly normal appearing lymph nodes at the time of primary debulking surgery may not be beneficial regardless of histologic sub-type. Future research on rare histologic sub-types that includes data on relapse is warranted.
Conclusions
In a large cohort of patients with rare histologic sub-types of epithelial ovarian carcinoma and advanced stage disease who achieved complete gross resection at the time of primary debulking surgery, performance of comprehensive lymphadenectomy was not associated with a survival benefit. In the absence of any evidence supporting this practice, removal of grossly normal appearing lymph nodes at the time of primary debulking surgery may not be beneficial regardless of histologic sub-type.
Data availability statement
Data may be obtained from a third party and are not publicly available. Data available from the American College of Surgeons.
Ethics statements
References
Footnotes
Contributors DN: conception, data acquisition, data management, statistical analysis, critical analysis, drafting/final editing. NL, AFH, SK, RLG: critical analysis, drafting/final editing. EMK: supervision, critical analysis, drafting/final editing.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.