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Original research
Clinical outcome of recurrent endometrial cancer: analysis of post-relapse survival by pattern of recurrence and secondary treatment
  1. Francesco Legge1,
  2. Stefano Restaino2,
  3. Luca Leone1,
  4. Vito Carone1,
  5. Carlo Ronsini3,
  6. Giacomo Lorenzo Maria Di Fiore2,
  7. Tina Pasciuto4,
  8. Silvia Pelligra5,
  9. Francesca Ciccarone2,
  10. Giovanni Scambia2,5 and
  11. Francesco Fanfani2,5
  1. 1 Gynecologic Oncology Unit, “F. Miulli” General Regional Hospital, Acquaviva delle Fonti, Bari, Italy
  2. 2 Dipartimento per la Tutela della Salute della Donna e della Vita Nascente, UOC di Ginecologia Oncologica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
  3. 3 Gynecologic and Obstetrics Unit, Università “G. d’Annunzio, Chieti, Italy
  4. 4 Statistics Technology Archiving Research (STAR) Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
  5. 5 Gynecologic Oncology, Catholic University of the Sacred Heart, Rome, Italy
  1. Correspondence to Dr Francesco Fanfani, Gynecologic Oncology, Catholic University of the Sacred Heart, Rome, Italy; francesco.fanfani74{at}gmail.com

Abstract

Introduction Recurrence of endometrial cancer is an important clinical challenge, with median survival rarely exceeding 12 months. The aim of this study was to analyze patterns of endometrial cancer recurrence and associations of these patterns with clinical outcome.

Methods The study included patients with endometrial cancer who underwent primary surgical treatment with or without adjuvant treatment between July 2004 and June 2017 at the Gynaecologic Oncology Unit of one of three tertiary hospitals of the Catholic University Network in Italy with complete follow-up data available. Information on the date and pattern of recurrence was retrieved for each relapse. Post-relapse survival was recorded as the time from the date of recurrence to the date of death or last follow-up. Survival probabilities were compared using log rank tests, and associations of clinico-pathological characteristics with post-relapse survival were tested using Cox’s regression models.

Results A total of 1503 patients were included in the analysis. We identified 210 recurrences (14.0%) and 105 deaths (7.0%) at a median follow-up of 34 months (range 1–162). One hundred and fifty-eight recurrences (78.1%) occurred during the first two years of follow-up. Most recurrences were multifocal (n=121, 57.6%) and involved extrapelvic sites (n=38, 65.7%). Parameters associated with post-relapse survival in the univariate analysis included histotype, grade, time to recurrence, pattern of recurrence, number of relapsing lesions, and secondary radical surgery. Only the pattern of recurrence and secondary radical surgery were independent predictors of post-relapse survival in the multivariate analysis (p=0.025 and p=0.0001, respectively).

Conclusion Lymph node recurrence and the feasibility of secondary radical surgery were independent predictors of post-relapse survival in patients with recurrent endometrial cancer.

  • uterine neoplasms
  • endometrial neoplasms

https://doi.org/10.1136/ijgc-2019-000822

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    HIGHLIGHTS

    • We have analysed the pattern of endometrial cancer recurrence and associations of these patterns with clinical outcome.

    • 80% of recurrences were recorded within 2 years after primary surgical treatment. For this reason, clinical and imaging examinations are important during early follow-up.

    • Lymphatic pattern of lesion recurrence and the feasibility of secondary radical surgery were positive independent predictors of post-relapse survival.

    Introduction

    Endometrial cancer is the most common gynecological tumor in developed countries. The prevalence of endometrial cancer continues to increase alongside the increasing prevalence of its risk factors including obesity and metabolic syndrome and as the result of a growing aging population.1 Standard treatment consists of surgery (total hysterectomy, bilateral salpingo-oophorectomy with or without pelvic and aortic lymphadenectomy or sentinel lymph node mapping) followed by adjuvant therapy tailored on the basis of histologically-defined risk factors. The complexity of endometrial cancer management has increased in the past decade as a result of modifications in the indications and modalities of lymphadenectomy, the introduction of the sentinel node algorithm, the de-escalation of adjuvant therapy based on data from randomized clinical trials, and differences between the various risk factor classifications for recurrence.2 These changes have led international scientific societies to publish more specific recommendations based on the review of emerging data, although important questions about the management of endometrial cancer still remain unanswered.3 4

    Despite the widespread utility of hysteroscopy for early diagnosis and improved surgical and adjuvant treatment, the rate of endometrial cancer recurrence has been relatively unchanged in recent decades: relapse and eventual mortality occur in 20% of endometrioid (type I) and 50% of non-endometrioid (type II) cases.2 Recurrence represents the most important clinical challenge in patients with endometrial cancer, with median survival rarely exceeding 12 months.5 6 Treatment of recurrent endometrial cancer is often palliative and is primarily dependent on previous therapy and secondarily on the site of recurrence and the patient’s performance status.2–4 Few previous studies have investigated the relationship between clinical patterns of relapse and the clinico-pathologic characteristics of primary disease.5 Moreover, data regarding the clinical outcomes of recurrent endometrial cancer in terms of patterns of presentation and secondary treatment are inconclusive.7–12 A more detailed understanding of the prognoses associated with various recurrences of endometrial cancer is necessary to improve primary as well as secondary treatment.

    The principal aim of this study was to investigate the prognostic value of clinico-pathological characteristics, patterns of recurrence, and secondary treatment in a cohort of women with recurrent endometrial cancer.

    Methods

    Study sample

    The study dataset included 1988 consecutive patients with a histologically-confirmed diagnosis of endometrial cancer between July 2004 and June 2017 at the Gynaecologic Oncology Unit of three tertiary hospitals in Italy: “Fondazione Policlinico Universitario A. Gemelli, IRCCS” in Rome, “S.S. Annunziata” in Chieti, and “Miulli General Regional Hospital” in Acquaviva delle Fonti, Bari. All patients underwent total hysterectomy with salpingo-ophorectomy and pelvic±aortic lymphadenectomy in accordance with the Mayo Clinic pathological risk categories.13 Since 2015 sentinel node mapping with indocyanine green was introduced.

    High-risk cases, defined according to the Gynecologic Oncology Group criteria, were treated with adjuvant platinum-based chemotherapy with or without pelvic irradiation or brachytherapy.4 Follow-up examination included chest-abdominopelvic computed tomography (CT) or abdominopelvic magnetic resonance imaging (MRI) plus thoracic radiography, a physical examination, complete blood counts and chemistry including serum CA125. All patients were followed every 4 months for the first 2 years and twice per year thereafter; additional diagnostic procedures were performed on the basis of specific clinical suspicion. Recurrence was diagnosed by imaging with histological confirmation when biopsy was feasible and useful to tailor secondary treatments. Relapsing patients were triaged to salvage therapy and represent the object of this analysis.

    Classification of recurrence

    Patterns of recurrence were classified in accordance with the dissemination pathway of disease: loco-regional for centro-pelvic recurrence (vagina and/or bladder and/or rectum with or without contiguous pelvic lymph node involvement); lymphatic for isolated nodal recurrences; hematogeneous for visceral recurrences; and mesothelial for peritoneal, pleuric, and pericardic recurrences. Patients with multiple dissemination pathways were classified as mixed recurrences.

    Statistical analysis

    Chi-squared tests or Fisher’s exact tests were used to analyze the distributions of clinico-pathological variables in different subgroups. Time to recurrence was calculated as the date of surgery to relapse, and post-relapse survival was calculated as the date of relapse diagnosis to death or last follow-up. Median survival was computed as product limit estimates using the Kaplan–Meier method and log-rank tests were used to assess statistically significant differences in survival. All clinico-pathological characteristics for primary and recurrent disease were analyzed in the post-relapse survival analysis. Cox’s regression models were used to perform a multivariate analysis of prognostic factors (only factors with p<0.05 in the univariate analysis). The threshold for statistical significance was p<0.05 for all analyses. All analyses were performed using STATA version 13.1 (Stata Corp, College Station, Texas, USA).

    Results

    Complete clinico-pathological and follow-up data for primary and recurrent disease were available for 1503 of the 1988 patients (online supplementary Figure S1); these were distributed by initial stage as follows: 68.0% stage I, 8.1% stage II, 18.7% stage III, 5.2% stage IV. A total of 210 recurrences (14.0%) and 105 deaths (7.0%) were recorded during a median follow-up period of 34 months (range 1–162). The clinico-pathological characteristics of patients with recurrent endometrial cancer are reported in Table 1. Minimally invasive surgery was performed in 39% of patients, and pelvic and para-aortic lymphadenectomy were performed in 57.1% and 18.6% of patients, respectively. Adjuvant treatment was administered to 73.3% of patients.

    Supplemental material

    View this table:
    Table 1

    Recurrent endometrial cancer: clinico-pathological characteristics of the primary tumor (n=210)

    Characteristics of recurrent disease and secondary treatment are reported in Table 2. The median time to recurrence was 12 months (range 1–151), and 78.1% of recurrences were recorded within 24 months. With regard to the pattern of relapse, most recurrences were multifocal (n=121, 57.6%) and involved extra-pelvic sites (n=91, 43.3%).

    View this table:
    Table 2

    Clinico-pathological characteristics of recurrent tumors and secondary treatments (n=210)

    Forty-seven (22.4%) patients presented with multiple pathways of dissemination (ie, mixed recurrence), whereas the most frequently observed pattern of recurrence confined to a single anatomical site (n=163) was loco-regional (n=50, 30.7%, of which 21 (10%) were vaginal), followed by lymphatic (n=48, 29.4%), hematogeneous (n=36, 22.1%), and mesothelial (n=29, 17.8%). Most of the relapses were treated with chemotherapy alone (n=99, 47.4%), while radical surgery with or without chemotherapy was performed in 80 patients (38.1%). The distributions of single-site recurrent lesions and secondary surgical treatment are summarized in Figure 1. Fifty per cent of patients with a recurrence (n=105) died within a median of 10 months (range 1–157) from the date of recurrence (5-year post-relapse survival 25%; median post-relapse survival 21 months).

    Figure 1
    Figure 1

    Graphic representation of the relapse sites reported for patients with a single pattern of recurrence (n=163). Data shown are number (%) of patients who underwent secondary radical surgery for each site of relapse. LN, lymph node; LND, lymph node dissection.

    In the multivariate analysis, only the presence of mixed or multiple recurrences was associated with inability to perform secondary radical surgery (p=0.010 and p=0.049, respectively; see online supplementary Table S2). Multiple recurrences is a negative predictive factor for successful secondary radical surgery also in the sub-group analysis of patients with single-site recurrence (see online supplementary Table S3).

    Supplemental material

    Univariate and multivariate analyses of post-relapse survival according to the clinico-pathological features of primary or recurrent disease and type of secondary treatment are reported in Table 3. In the univariate analysis, post-relapse survival was associated with histotype (p=0.00001), grading (p=0.001), time to recurrence (p=0.005), number of relapsing lesions (p=0.00001), pattern of recurrence (p=0.00001; Figure 2A), and secondary radical surgery (p=0.00001; Figure 2B). Only lymphatic pattern of recurrence and the feasibility of secondary radical surgery were significant independent predictors of post-relapse survival in the multivariate analysis (p=0.005 and p=0.0001, respectively). Sub-group analyses confirmed that secondary radical surgery was the strongest predictor of post-relapse survival in endometrioid cases (n=154, p=0.001; online supplementary Table S4), non-endometriod cases (n=56, p=0.00001; online supplementary Table S5), and cases with single-site recurrence (n=163, p=0.0001), although in the latter sub-group lymphatic recurrence and endometrioid histotype were also positive independent predictors of post-relapse survival (p=0.005 and p=0.018, respectively; online supplementary Table S6).

    Figure 2
    Figure 2

    Post-relapse survival (PRS) curves by pattern of recurrence (A) and the modality of secondary treatment (B). CT, chemotherapy; HT, hormonal therapy; RS, radical surgery; RT, radiotherapy.

    View this table:
    Table 3

    Univariate and multivariate analysis for post-relapse survival according to clinico-pathological features of primary or recurrent tumor and type of secondary treatment (only factors with p value <0.05 at univariate analysis are shown; n=210, median post-relapse survival (PRS) 21 months)

    Discussion

    In our study we found that the overall rate of recurrence was 14% and that nearly 80% of recurrences occurred within 2 years from treatment. In addition, most recurrences were multifocal and in extra-pelvic sites. The rate of recurrence is comparable to a rate of 18% recently reported in a multi-center study of 1230 patients in France.12 The recurrence rate was 12.7% for type I and 19.2% for type II endometrial cancer. It is notable that both of these rates were lower than those previously reported (20% and 50%, respectively).2 The discrepancy between our study and previous reports may be related to the study population selection, as we included only patients who underwent primary surgery and excluded non-epithelial histotypes. Patients in our cohort may have also benefited from the use of newer treatment strategies including recently developed surgical approaches,14–16 adjuvant chemotherapy, and radiotherapy protocols.17 18

    In our cohort, approximately 80% of recurrences were within 2 years after primary surgical treatment. This finding highlights the importance of frequent clinical and imaging examinations during early follow-up.6 12 19 The surveillance algorithm in endometrial cancer is controversial: whereas the European Society for Medical Oncology/European Society of Gynecological Oncology/European Society for Radiotherapy and Oncology (ESMO-ESGO-ESTRO) guidelines do not recommend any specific scheme,3 the Society of Gynecologic Oncology and National Comprehensive Cancer Network guidelines recommend a physical examination every 3–6 months for 2–3 years and thereafter every 6 months or annually in asymptomatic patients.4 Other research suggests that more intensive follow-up including CT evaluation can improve the detection of asymptomatic (mostly extra-pelvic) recurrences and offers a survival benefit associated with the early initiation of treatment.20 21 Interestingly, our analysis of relapse patterns indicated that most recurrences were multifocal and involved extra-pelvic sites. In particular, the most frequently observed recurrence among those confined to a single anatomical site was loco-regional (30.7%), followed by lymphatic (29.4%) and visceral (22.1%), with frequent involvement of the lungs and liver. These results further corroborate the utility of intensive follow-up (eg, every 4 months) in the first 2 years after surgical treatment and special consideration of the abovementioned regions through thoraco-abdomino-pelvic CT and CA125 assessments to facilitate early detection of the most common and potentially lethal recurrences.6 12 19–22 Furthermore, imaging may assist in identifying recurrence while still surgically resectable.

    Median survival after endometrial cancer recurrence in this study was 21 months, consistent with previous descriptions of the dismal prognosis of recurrent endometrial cancer.5 7–10 12 23 Yet, post-relapse survival was significantly influenced by the pattern of recurrence, with the best prognoses found in patients with lymphatic recurrences and the worst in those with mesothelial or mixed recurrence. Bricou et al12 similarly reported that patients with peritoneal carcinosis had the poorest prognoses compared with other single-pathway recurrent endometrial cancer, while women with multiple pathway recurrences had poorer post-relapse survival than those with single-site recurrences (other than carcinosis). Most notably, our study demonstrates that, among the various characteristics of primary and recurrent disease, lymphatic recurrence independently predicted better survival in the overall population and in patients with single-site recurrent endometrial cancer. This finding is consistent with observations in other gynecological tumors24 25 and is potentially explained by: (a) the intrinsic nature of endometrial cancer cells with lymphotrophic capacity, characterized by a low rate of proliferation and inability to initially express molecules associated with peritoneal or hematogeneous metastasis; (b) the peculiar microenvironment of the lymph node, which may promote the dormancy of tumor cells; and (c) patients with lymph nodal recurrences are likely candidates for secondary radical surgery as these sites are typically accessible for surgical treatment (especially in the absence of previous retroperitoneal surgery). Additionally, our results may indirectly confirm previous findings regarding the lack of a therapeutic role of staging lymphadenectomy in primary endometrial cancer,26 27 although lymphadenectomy may have a role in debulking macroscopic retroperitoneal disease.14–16 Indeed, recent sentinel lymph node studies showed that the detection of isolated tumor cells in the lymph nodes has no prognostic value,28 and a trend for longer time to recurrence was found in patients with endometrial cancer and isolated tumor cells or micrometastases compared with node-negative cases.29

    The current study also demonstrated that resection of the recurrent lesion was a critical prognostic factor for post-relapse survival, in line with previous findings.9 11 Interestingly, we found that, while radical surgery was primarily performed in patients with recurrent pelvic or nodal disease, it was also performed in approximately one-third of patients with visceral or mesothelial recurrences. Feasibility of secondary radical surgery in our cohort was independently associated with single-site recurrence. While the study was not powered to compare secondary radical surgery to other non-surgical options, it is important and clinically relevant that the survival benefit of secondary radical surgery was independent of other confounding factors, as confirmed in patients with a single pattern of recurrence and in both type I and type II endometrial cancer sub-groups. The high percentage (38.1%) of patients who underwent secondary radical surgery as opposed to radiotherapy (7.6%) may be due to: (a) the high rate of primary adjuvant radiotherapy (41.9%); (b) the high rate of recurrences presenting with multiple lesions (57.6%); and (c) the enrolment of patients from three tertiary hospitals particularly focused on gynecologic oncology surgery.

    In addition to the benefits of pelvic and abdominal secondary radical surgery, which have previously been reported to yield a survival benefit in recurrent endometrial cancer,9 11 16 30–33 we also identified a survival benefit associated with the resection of metastatic lesions confined to specific anatomical regions such as the lungs and brain. This issue has rarely been the subject of investigation and pertinent results have only been described in a few case series, generally with a focus on lung metastases.34

    Finally, it is notable that, among all clinico-pathological characteristics of primary disease, only endometrioid histotype and grade 1–2 were positively associated with post-relapse survival in the univariate analysis, whereas crucial prognostic factors for primary endometrial cancer such as stage, node status, and adjuvant therapy were not. Possible reasons for this finding are as follows. First, the biology of the tumor may be more important than the initial spread of disease. Second, previous large-scale clinical trials have demonstrated that long-term survival is not improved by adjuvant radiotherapy,35 primarily due to a higher probability of success in treating non-irradiated local recurrences compared with irradiated recurrences and a higher rate of non-local recurrences in irradiated subjects.35 Of note, histotype and grading were not significant predictors of post-relapse survival in the multivariate analysis, suggesting that recurrent endometrial cancer should be considered de novo for prognostic stratification. The predictive significance of histotype was, however, retained in the multivariate sub-group analysis of patients with single-site recurrences. This finding indicates that single pathway recurrent endometrial cancer may be less deregulated and more biologically similar to the primary tumor than multiple pathway recurrent endometrial cancer. In this context it is important to highlight the controversial prognostic role of time to recurrence: few studies have suggested that a time to recurrence longer than 6–12 months is associated with better post-relapse survival.7 8 In our multivariate analysis, time to recurrence was not a significant predictor of post-relapse survival in the overall population or in sub-group analyses, suggesting that, unlike ovarian cancer, a short time to recurrence in endometrial cancer does not necessarily indicate treatment resistance, but may be related to the persistence of microscopic disease after primary treatment. Differently from ovarian cancer in which chemotherapy has a prominent role in the primary treatment, only a minority of patients with endometrial cancer benefit from medical treatment. From a clinical standpoint, this finding may suggest that a short time to recurrence should not be used as an absolute criterion for excluding secondary radical surgery.

    The present study had some limitations: as a retrospective study, the analysis was subject to selection bias. For example, most patients who underwent secondary radical surgery had a single lesion whereas those who received other salvage treatments generally had multiple lesions. As previously mentioned, it is also noteworthy that the study was not powered to compare secondary radical surgery to other non-surgical options; nonetheless, our analysis yielded several clinically useful findings that can assist the prognosis of recurrent endometrial cancer and inform treatment selection.

    Conclusion

    A lymphatic pattern of recurrence and the feasibility of secondary radical surgery were independent predictors of post-relapse survival in patients with recurrent endometrial cancer. Practitioners should consider these factors in the prognostic stratification of women with recurrent endometrial cancer, especially when evaluating the potential utility of secondary surgery.

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    Footnotes

    • Twitter @frafanfani

    • Correction notice Since this article was first published online, the affiliation for Dr Pelligra has been changed from number 3 to 5.

    • Contributors All authors have provided a substantial contribution to the manuscript.

    • 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.

    • Patient consent for publication Not required.

    • Ethics approval The study was approved by the Institutional Review Board of each participating center.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.