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Original Article
Oncological outcome of surgical management in patients with recurrent uterine cancer—a multicenter retrospective cohort study—CEEGOG EX01 Trial
  1. Anna Germanova1,
  2. Francesco Raspagliesi2,
  3. Luis Chiva3,
  4. Ladislav Dusek4,
  5. Macit Arvas5,
  6. Eric Leblanc6,
  7. Tibor Lengeyl7,
  8. Violante Di Donato8,
  9. Afra Zaal9,
  10. Polat Dursun10,
  11. Ignacio Zapardiel11,
  12. Taner Turan12,
  13. Sergio Augusto Triginelli13,
  14. Sang Wun Kim14,
  15. Matias Jurado15,
  16. Jalid Sehouli16,
  17. Borek Sehnal17,
  18. Ladislav Masak18,
  19. Nicolae Ioanid19,
  20. Greta Dreyer20,
  21. Robert Jach21,
  22. Miloš Mlynček22,
  23. Valentina Chiappa2,
  24. Fabio Martinelli2,
  25. Jiri Slama1,
  26. Roman Kocian1,
  27. Giorgio Bogani2 and
  28. David Cibula1
  1. 1 Department of Obstetrics and Gynecology, Gynecologic Oncology Center, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic
  2. 2 Fondazione IRCCS, IstitutoNazionale dei Tumori, Milan, Italy
  3. 3 Department of Gynecologic Oncology, MD Anderson Cancer Center, Madrid, Spain
  4. 4 Institute for Biostatistics and Analyses, Masaryk University, Brno, Czech Republic
  5. 5 Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey
  6. 6 Département de Cancérologie Gynécologique, Oscar Lambret Center, Lille, France
  7. 7 Department of Gynecologic Oncology, National Cancer Institute, Bratislava, Slovakia
  8. 8 Department of Gynecology,Obstetrics and Urology, Sapienza University of Rome, Rome, Italy
  9. 9 Department of Gynecological Oncology, University Medical Center Utrecht, Utrecht, Netherlands
  10. 10 Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Baskent University Schoolof Medicine, Ankara, Turkey
  11. 11 Gynecologic Oncology, La Paz University Hospital, Madrid, Spain
  12. 12 Division of Gynecologic Oncology, Department ofObstetrics and Gynecology, Etlik Zubeyde Hanim Womens Health Research and Teaching Hospital, Ankara, Turkey
  13. 13 Division of Women's Health, Federal University of Minas Gerais, Belo Horizonte, Brazil
  14. 14 Department of Obstetrics and Gynecology, Institute of Women'sLife Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
  15. 15 Department of Obstetrics and Gynecology, Clínica Universidad de Navarra, Pamplona, Spain
  16. 16 Department of Gynecology with Center for Oncological Surgery, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Medical University of Berlin, Berlin, Germany
  17. 17 First Faculty of Medicine, Charles University in Prague and Hospital Na Bulovce in Prague, Prague, Czech Republic
  18. 18 St. Elizabeth Cancer Institute, Bratislava, Slovak Republic
  19. 19 First Department of Oncologic Surgery, Gynecologic Oncology Unit, Regional Institute of Oncology, Iasi, Romania
  20. 20 Department Obstetrics and Gynaecology, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South Africa
  21. 21 Department of Gynecology and Obstetrics, Jagiellonian University Medical College, Krakow, Poland
  22. 22 Department of Obstetrics and Gynecology, Faculty Hospital, Constantine the Philosopher University, Nitra, Slovakia
  1. Correspondence to Dr Anna Germanova, Department of Obstetrics and Gynecology, Gynecologic Oncology Center, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague 120 18, Czech Republic; ena.german{at}gmail.com

Abstract

Objectives To assess the survival of patients who have received an operation for recurrent cervical and endometrial cancer and to determine prognostic variables for improved oncologic outcome.

Methods A retrospective multicenter analysis of the medical records of 518 patients with cervical (N = 288) or endometrial cancer (N = 230) who underwent surgery for disease recurrence and who had completed at least 1 year of follow-up.

Results The median survival reached 57 months for patients with cervical cancer and 113 months for patients with endometrial cancer after surgical treatment of recurrence (p = 0.036). Histological sub-type had a significant impact on overall survival, with the best outcome in endometrial endometrioid cancer (121 months), followed by cervical squamous cell carcinoma, cervical adenocarcinoma, or other types of endometrial cancer (81 vs 35 vs 35 months; p<0.001). The site of recurrence did not significantly influence survival in cervical or in endometrial cancer. Cancer stage at first diagnosis, tumor grade, lymph node status at recurrence, progression-free interval after first diagnosis, and free resection margins were associated with improved overall survival on univariate analysis. On multivariate analysis, the stage at first diagnosis and resection margins were significant independent predictive parameters of an improved oncologic outcome.

Conclusion Long-term survival can be achieved via secondary cytoreductive surgery in selected patients with recurrent cervical and endometrial cancer. An excellent outcome is possible even if the recurrence site is located in the lymph nodes. The possibility of achieving complete resection should be the main criterion for patient selection.

  • uterine cancer
  • secondary cytoreductive surgery

https://doi.org/10.1136/ijgc-2019-000292

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    HIGHLIGHTS

    • Extra-pelvic recurrences did not show shorter overall survival after salvage surgery.

    • Long survival was shown after lymph node recurrence debulking in endometrial cancer.

    • Microscopically clear resection margins are the most important factor for oncologic outcome.

    INTRODUCTION

    A surgical approach to the treatment of primary cervical and endometrial cancer is accepted worldwide. In cervical cancer, surgery is generally reserved for patients with early-stage disease with negative lymph nodes, while, for endometrial cancer, several studies have shown that optimal debulking provides a survival benefit even for patients with advanced-stage disease, especially when complete debulking can be achieved.1 2

    However, for recurrent cervical and endometrial cancer treatment, the role of surgery is much less established. Most of the available data are on patients after pelvic exenteration, which is used preferably for solitary pelvic central or lateral recurrence of cervical cancer after primary chemoradiotherapy, where it represents the only possibly curative choice. The oncologic outcome of pelvic exenteration for cervical or endometrial cancer recurrences is well documented, although studies show a broad range of 5-year overall survival of between 20% and 70%, depending on patient selection criteria.3–9 The procedure is associated with morbidity of up to 60% and reported mortality up to 10%.5–8

    Data for pelvic exenteration and the factors influencing survival are substantial, but evidence for other types of secondary cytoreductive surgery is poor, and mostly obtained from small single-institution cohorts. Only a few studies have reported the outcome after other types of secondary cytoreductive surgery. In their 2009 paper,10 Benedetti et al showed 5-year overall survival in up to 59% in a cohort of 29 patients after vaginectomy, with minimal associated morbidity. In another group of 76 patients with recurrent cervical cancer after resection of pulmonary metastases, 5-year overall survival reached 46%.11 A median overall survival of 18 months was reported in a small cohort of 15 cases after the resection of liver metastases.12 Other reports suggesting the possible benefit of salvage surgery were mostly case reports.13

    So far, only seven studies14–20 with a maximum of 75 patients have reported outcomes after different types of secondary cytoreductive surgery for recurrent endometrial cancer. All studies suggested increased survival after optimal surgical resection.

    This study aimed to assess the role of secondary cytoreductive surgery in the management of recurrent cervical and endometrial cancer in a larger cohort of patients. The primary objective was to assess the oncologic outcome of the two uterine cancer types and identify prognostic factors that could be used for the selection of the best candidates for secondary cytoreductive surgery.

    METHODS

    The patients enrolled in the study had undergone surgery for recurrent cervical or endometrial cancer with the aim of complete debulking and had at least 1 year post-surgery follow-up data. Cases were eligible irrespective of surgical approach, surgery type, or treatment type before or after secondary cytoreductive surgery. The presence of distant metastases was not an exclusion criterion.

    In total, 34 centers contributed to the study with data from 620 patients with recurrent cervical or endometrial cancer. Of these, 14 centers entered data from ≤10 patients, 14 centers 11–25 patients, and six centers >25 patients.

    All salvage surgeries were performed between January 1997 and April 2013.

    Data were collected via a web-based data capture system. The application was secured and accessible only to authorized users who were issued unique login information. Each center could access only its own data; patients' data were anonymized.

    The database was designed to capture data for patients and tumor characteristics; type of primary treatment; progression-free interval after primary treatment; site of recurrence; type of secondary cytoreductive surgery; type of therapy before and after secondary cytoreductive surgery, if any; progression-free interval after secondary cytoreductive surgery; and disease status of patients.

    All data were reviewed by a study monitor. Any discrepancies in data were corrected through communication between the study monitor and the individual center. Owing to missing essential data, 51 patients were excluded from the database. Additionally, further 51 patients with sarcomas or carcinosarcomas were excluded owing to the different biological behavior of these tumors. Finally, data from 518 patients were analyzed.

    Progression-free survival and overall survival were calculated from the date of secondary cytoreductive surgery to the date of diagnosis of next recurrence or date of death.

    Post-operative residuum R0 was defined as no macroscopic tumor residuum with microscopically negative resection margins, R1 as no macroscopic tumor residuum with microscopically positive resection margins, and R2 as macroscopic tumor residuum.

    Standard measures of summary statistics were used to describe primary data: relative and absolute frequencies, median, and 5–95th centile range. The ML-χ2 test was applied for statistical comparison of experimental variants in categorical variables. Patient survival was visualized using Kaplan-Meier methodology, and the statistical significance of differences in survival between groups of patients was tested by a log-rank test. A co-proportional hazard regression model was applied to assess the predictive significance of the potential predictor of overall survival and progression-free survival. Both univariate and multivariate-adjusted estimates of HR and 95% CI estimates were obtained. Analysis was computed using SPSS 22.0.0.1 (IBM Corporation, 2014).

    The ethical committee of the First Medical Faculty of Charles University in Prague approved the study.

    RESULTS

    Patient Characteristics

    From the cohort, 204 patients were diagnosed with cervical squamous cell carcinoma, 64 patients with cervical adenocarcinoma, 18 patients had other cervical cancer histological sub-types, 177 patients had endometrioid endometrial cancer, and 24 patients non-endometrioid endometrial cancer. The initial tumor stage and tumor grade and primary treatment of the cohort are shown in Table 1.

    View this table:
    Table 1

    Clinical characteristics

    The median progression-free interval to first recurrence was 18 (6–115) and 26 (6–133) months for patients with cervical and endometrial cancer, respectively.

    The type of secondary cytoreductive surgery included pelvic exenteration, removal of bulky lymph nodes, and vaginectomy in 41%, 32%, and 30% of patients with cervical cancer, respectively, and removal of bulky lymph nodes, vaginectomy, and excision of tumor in 34%, 32%, and 32% of patients with endometrial cancer. Only 7% of patients with endometrial cancer recurrence underwent pelvic exenteration.

    The median follow-up after secondary cytoreductive surgery and other detailed clinical characteristics are shown in Table 1.

    Oncological Outcome: Overall Survival and Progression-free Survival

    Overall survival differed significantly between cervical and endometrial cancer in favor of the latter. A similar trend appeared in progression-free interval after secondary cytoreductive surgery; however, the difference did not reach statistical significance (Figure 1).

    Figure 1
    Figure 1

    Overall survival and progression-free survival after secondary cytoreductive surgery according to type of cancer and histological sub-types.

    Overall survival differed significantly when patients were stratified according to histological sub-types. The best survival was shown for patients with endometrial endometrioid cancer (median overall survival 121 months), followed by cervical squamous histotype (81 months), and cervical adenocarcinoma (35 months) (p<0.001). The worst outcome was found in patients with non-endometrioid endometrial histotypes (Figure 1). The progression-free interval after secondary cytoreductive surgery disclosed a similar trend with the best outcome for endometrial endometrioid cancer (median progression-free interval of 50 months), followed by cervical squamous cell carcinoma (35 months), cervical adenocarcinoma (18 months), and endometrial non-endometrioid cancer (19 months) (p=0.001).

    The group was subsequently stratified into five subgroups according to the site of recurrence (vagina, pelvis, lymphatic nodes, abdomen, and other). Neither overall survival nor progression-free interval differed significantly between sites, although patients with vaginal recurrences tended to have better outcomes (Figure 2). Patients with pelvic recurrence who underwent pelvic exenteration or laterally extended endopelvic resection had similar oncologic outcomes to those of patients with recurrence in other sites. A notable finding was that patients who experienced recurrence in lymph nodes had similar 5-year overall survival and 5-year progression-free interval as the rest of the study cohort. Moreover, the oncologic outcome did not differ between patients with affected pelvic and para-aortic lymph nodes (3-year overall survival 62.4% and 62.1%; 5-year overall survival 56.7% and 53.1% for pelvic and para-aortic lymph node recurrences, respectively). The outcome was particularly good in patients with endometrial cancer (Figure 2).

    Figure 2
    Figure 2

    Overall survival and progression-free survival after secondary cytoreductive surgery according to site of recurrence.

    Prognostic Factors

    For potential prognostic factors, the study cohort was stratified according to the initial stage. Patients with recurrent cervical cancer and initial stage I had a significantly better prognosis than those with initial stage II and III/IV (p=0.011). A similar trend was found for patients with endometrial cancer, with a significantly longer median overall survival of 113 months in stage I compared with patients with initial stage II and III/IV (p=0.020) (Figure 3).

    Figure 3
    Figure 3

    Overall survival and progression-free survival after secondary cytoreductive surgery according to risk factors.

    Tumor grade did not affect overall survival or progression-free interval of patients with cervical cancer, whereas tumor grade was significantly related to outcome for patients with endometrial cancer (Figure 3).

    Surprisingly, no prognostic significance was shown for the progression-free interval to the first recurrence in any cancer type (Figure 3).

    R0 (no macroscopic tumor residuum with microscopically negative margin) was associated with a significantly better median overall survival as well as median progression-free interval in both tumor types (Figure 3).

    Oncological Outcome: Univariate and Multivariate Analysis

    To search for prognostic factors associated with prolonged overall survival or progression-free interval, univariate and multivariate analyses were conducted of initial stage at diagnosis, tumor grade, lymph node status at recurrence, progression-free interval to the first recurrence, site of recurrence, residual disease after salvage surgery, and therapy before and after secondary cytoreductive surgery. The results are shown in Table 2.

    View this table:
    Table 2

    Factors influencing survival and progression-free interval after secondary cytoreductive surgery

    DISCUSSION

    Our study analyzed data from 288 patients with cervical cancer and 230 with endometrial cancer. Data from patients after secondary cytoreductive surgery for recurrence were retrospectively gathered from 34 centers worldwide. Long survival was achieved in patients with recurrent cervical cancer, with a median overall survival of 57 months (5-year overall survival 49%) and even longer in patients with recurrent endometrial cancer, who had a median overall survival of 113 months (5-year overall survival 58%).

    The main limitations of the study are its retrospective design and center-specific selection criteria for secondary cytoreductive surgery. It would, however, be difficult to apply a prospective design to such a study, owing to the limited number of eligible cases and their heterogeneity. The main advantage of this study is the cohort size, which enabled comparison of the two types of uterine tumors and an analysis of prognostic factors, which may aid in the selection of appropriate candidates for secondary cytoreductive surgery.

    Published reports show that the 5-year survival rate after secondary cytoreductive surgery for predominantly central recurrence of cervical cancer is 20–70%.3–9 The 66% 5-year overall survival related to pelvic exenteration for advanced and recurrent endometrial cancer was reported separately on only a small group of 24 patients.21 Other than cohorts with central recurrence who received pelvic exenterations, only seven studies14–20 have focused on other types of secondary cytoreductive surgery in recurrent endometrial cancer, presenting a maximum of 75 cases. In their 2015 paper,19 Turan and colleagues reported 54-month median overall survival for a small group of 34 patients. An Italian study20 with 64 patients who underwent secondary cytoreductive surgery showed a 5-year survival of 51%. It is uncertain why the median survival in our study was so long. It might be due to selection or reporting bias, to the larger patient group (230 vs 34 vs 64 cases) or to the proportions of patients with various recurrence sites.

    The literature reveals only inconsistent data on the prognostic significance of histological sub-type. In the largest published cohort of 282 patients with cervical cancer, the 5-year survival was 31% in patients with cervical adenocarcinoma and 41% in those with squamous cancers; however, the difference was insignificant.22 Interestingly, in a Brazilian study23 on 77 patients, adenous histotype was a positive prognostic factor after pelvic exenteration, with 5-year overall survival of 13.6% for patients with squamous cell carcinoma (N=56) and 51.6% for adenocarcinoma (N=21). In general, cervical adenocarcinoma is considered to be associated with worse prognosis, 24 which is consistent with our results. Patients with cervical adenocarcinoma had median overall survival of 35 months (5-year overall survival 44%) compared with median overall survival of 81 months for patients with cervical squamous cell carcinoma (5-year overall survival 51%) (p <0.001).

    In our study, patients with endometrial endometrioid cancer showed a substantially better oncologic outcome, with median overall survival of 121 months (5-year overall survival 66%), compared with patients with non-endometrioid types, who had median overall survival of 35 months (5-year overall survival 20%). The tendency for better survival of patients with endometrioid cancer was seen in different studies.17 18 20 The difference in our study was significant, irrespective of whether or not patients with high-risk endometrioid cancer were included.

    As mentioned, the best-documented population after secondary cytoreductive surgery is patients who received post-pelvic exenteration. Local pelvic recurrences are considered to have a better prognosis, especially if lymph nodes are not involved. The other types of secondary cytoreductive surgery for distant recurrences in cervical or endometrial cancer are often neglected owing to expected poor prognosis,25 so only limited data are available for these. In our study, patients were stratified into five groups according to the sites of recurrence. Our expectation was that patients with recurrence in lymph nodes, abdominal cavity, and other distant sites would have a worse oncologic outcome. Surprisingly, we did not prove any significant difference in survival among these groups. Patients with lymph node recurrence had a 5-year overall survival of 42% for cervical cancer and 63% for endometrial cancer.

    Local vaginal recurrences are usually associated with a good prognosis and lower morbidity after a simple vaginectomy. Benedetti10 presented a 5-year overall survival of 71% in 29 patients after vaginectomy for recurrent cervical cancer. Similar data on the better outcome of vaginal recurrence are available for recurrent endometrial cancer.15 Our results were consistent with available sources that reported 5-year overall survival of 55% and 67% after secondary cytoreductive surgery for vaginal recurrence in patients with cervical and endometrial cancer. Moreover, univariate analysis showed that vaginal recurrence of endometrial cancer is a positive prognostic factor for overall survival.

    The 5-year cumulative survival rate after pelvic exenteration varies greatly in the literature, between 20% and 70%.5–9 Our results are in accordance with this range, showing a similar 5-year overall survival of 45% for patients with cervical cancer and 48% for those with endometrial cancer. The pelvic site of recurrence of endometrial cancer was a negative prognostic factor for progression-free interval but did not influence overall survival in either the univariate or multivariate model.

    Several studies, including ours, confirmed that the most important independent prognostic factor for better oncologic outcome is the achievement of a negative resection margin. The most detailed data for cervical cancer are available for pelvic exenteration studies, where the resection margin is considered the key prognostic factor. The studies showed that none of the patients with a microscopically positive margin lived for 3 years.26 27 Published data show similar prognostic significance of free margins after laterally extended endopelvic resection.28 Studies of endometrial cancer confirmed the similar importance of optimal debulking for prognosis, although the optimal cytoreductive surgery was mostly defined by macroscopic evaluation and not as pathologic free margins.15 18–20 In our study, patients with cervical cancer and a negative resection margin had a 5-year overall survival of 55% (compared with a 5-year overall survival of 28% for those with R1 or R2) and patients with endometrial cancer and R0 had a 5-year overall survival of 66% (median overall survival 121 months) (in comparison with a 5-year overall survival of 45% for those with R1 and 37% with R2), which is the best reported survival after secondary cytoreductive surgery for endometrial cancer so far.

    The interval between primary treatment and recurrence reflects, in the majority of tumors, their biological behavior. Although some smaller studies did not find a prognostic significance of the progression-free interval from the primary treatment in patients after pelvic exenteration,29 most authors reported a substantially better prognosis in cases with a long interval from the initial treatment.3 30 Marnitz reported a 17% 5-year survival in patients who experienced recurrence in <2 years after the initial treatment, 28% for patients with disease recurring between 2 and 5 years, and 83% if recurrence was later than 5 years.3 Our results did not confirm the progression-free interval after primary treatment as a significant prognostic factor. The 5-year overall survival tended to differ in patients with cervical cancer after stratification according to the progression-free interval; however, the difference was not significant, and the progression-free interval was not a significant prognostic factor in univariate or multivariate models. Five-year overall survival in patients with endometrial cancer did not differ significantly when analyzed according to the progression-free interval after primary treatment; however, in univariate analysis, a progression-free interval >36 months was a positive prognostic factor influencing overall survival.

    CONCLUSION

    Our study showed that long survival can be achieved by secondary cytoreductive surgery in appropriately selected patients with recurrent cervical and endometrial cancer. The most significant prognostic factor for both cancer types is the achievement of free resection margins. Interestingly, extrapelvic recurrences were not associated with a significantly worse prognosis and particularly long survival was achieved in patients with endometrial cancer after debulking of lymph node recurrence.

    Acknowledgments

    We thank Matias Jurado (Clínica Universidad de Navarra, Pamplona, Spain), Jalid Sehouli (Medical University of Berlin, Germany), Borek Sehnal (Charles University in Prague and Hospital Na Bulovce in Prague, Czech Republic), Ladislav Masak (St. Elizabeth Cancer Institute, Bratislava, Slovak Republic), Nicolae Ioanid (Regional Institute of Oncology, Iasi, Romania), Greta Dreyer (University of Pretoria, South Africa), Robert Jach (Jagiellonian University Medical College, Krakow, Poland), Miloš Mlynček (Constantine the Philosopher University, Nitra,Slovakia), Robert Tóth (VOÚ, Košice, Slovak Republic), Libor Ševčík (University Hospital Ostrava, Czech Republic), Marcin Jedryka (Wroclaw Medical University, Poland), Ivo Blšťák (Masarykova nemocnice, Ústí nad Labem, Czech Republic), Frederic Goffin (Hospital of la Citadelle, Liège, Belgium), Murat Kairbayev (Kazakh Research Institute of Oncology and Radiology, Kazakhstan), Zdeněk Adamík (Hospital Zlín, Czech Republic), Rhonda Farrell (University of New South Wales, Australia), Alejandro Soderini (Oncologic Hospital of Buenos Aires "Marie Curie", Argentina), Dariusz Wydra (Medical University of Gdańsk, Poland), Radek Chvátal (Znojmo Hospital, Czech Republic), Radovan Pilka (Faculty Hospital, Olomouc, Czech Republic) and Joong Sub Choi (Hanyang University College of Medicine, Republic of Korea) for their contributions to the study.

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    Footnotes

    • Correction notice Since this paper was first published online, further authors have been added to this manuscript.

    • Contributors AG: data collection, data clarification, manuscript preparation. FR, LC, MA, EL, TL, VDD, AZ, PD, IZ, TT, SAT, SWK, VC, FM, JS, GB, RK: data collection, participation in manuscript preparation. LD: statistical analyses, participation in manuscript preparation. DC: author of study design, consultant, manuscript preparation.

    • 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.

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