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Original research
Impact of pattern of recurrence on post-relapse survival according to surgical timing in patients with advanced ovarian cancer
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  1. Martina Aida Angeles1,
  2. Emanuela Spagnolo2,
  3. Bastien Cabarrou3,
  4. Assumpció Pérez-Benavente4,
  5. Antonio Gil Moreno5,6,
  6. Frederic Guyon7,
  7. Agnieszka Rychlik8,
  8. Federico Migliorelli9,
  9. Guillaume Bataillon10,
  10. Anne-Sophie Navarro1,
  11. Sarah Betrian11,
  12. Gwenael Ferron1,
  13. Alicia Hernández2 and
  14. Alejandra Martinez1
  1. 1 Department of Surgical Oncology, Institut Claudius Regaud, Toulouse, Occitanie, France
  2. 2 Gynecologic Oncology Unit, La Paz University Hospital, Madrid, Spain
  3. 3 Biostatistics Unit, Institut Claudius Regaud, Toulouse, Occitanie, France
  4. 4 Gynecologic Oncology Unit, Gynecology Department, Hospital Vall d'Hebron, Barcelona, Catalunya, Spain
  5. 5 Gynecology, Vall d'Hebron Hospital, SANT CUGAT DEL VALLÉS, Barcelona, Spain
  6. 6 Universitat Autònoma de Barcelona, Barcelona, Spain
  7. 7 Institut Bergonié, Bordeaux, Aquitaine, France
  8. 8 Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Warszawa, Poland
  9. 9 Institut Clínic de Ginecologia, Obstetrícia i Neonatologia, BCNatal, Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), Barcelona, Spain
  10. 10 Department of Anatomopathology, Institut Claudius Regaud, Toulouse, Occitanie, France
  11. 11 Department of Medical Oncology, Institut Claudius Regaud, Toulouse University Cancer 32 Institute (IUCT), Oncopole, Toulouse, France
  1. Correspondence to Dr Martina Aida Angeles, Department of Surgical Oncology, Institut Claudius Regaud, Toulouse, Occitanie, France; martinangeles22{at}hotmail.com

Abstract

Objective Our study aimed to evaluate the association between timing of cytoreductive surgery and pattern of presentation of the first recurrence in patients with advanced ovarian cancer. We also aimed to assess the impact of the pattern of recurrence on post-relapse overall survival according to surgical timing.

Methods This retrospective multicenter study evaluated patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC-IV ovarian cancer. Patients had undergone either primary debulking surgery, early interval debulking surgery after 3–4 cycles of neoadjuvant chemotherapy, or delayed debulking surgery after 6 cycles, with minimal or no residual disease, between January 2008 and December 2015. Survival analyses were conducted using the Log-rank test and the Cox model. Cumulative incidences of the different patterns of recurrence were estimated using a competing risks methodology.

Results A total of 549 patients were included: 175 (31.9%) patients had primary, 224 (40.8%) early interval, and 150 (27.3%) delayed debulking surgery. The cumulative incidence of peritoneal recurrences at 2 years was higher with increasing neoadjuvant cycles (24.4%, 30.9% and 39.2%; p=0.019). For pleural or pulmonary recurrences, it was higher after early interval surgery (9.9%, 13.0% and 4.1%; p=0.022). Median post-relapse overall survival was 33.5 months (95% confidence interval (CI) (24.3 to 44.2)), 26.8 months (95% CI (22.8 to 32.6)), and 24.5 months (95% CI (18.6 to 29.4)) for primary, early interval, and delayed debulking surgery groups, respectively (p=0.025). The pattern of recurrence in a lymph node (hazard ratio (HR) 0.42, 95% CI (0.27 to 0.64)), delayed surgery (HR 1.53, 95% CI (1.11 to 2.13)) and time to first recurrence (HR 0.95, 95% CI (0.93 to 0.96)) were associated with post-relapse overall survival. For primary and early interval surgery, lymph node recurrences were associated with significantly longer post-relapse overall survival.

Conclusions The pattern of first recurrence was associated with timing of surgery, with peritoneal recurrences being more frequent with the increasing number of cycles of neoadjuvant chemotherapy. Lymph node recurrences were associated with better prognosis, having higher post-relapse overall survival. This improved prognosis of lymphatic recurrences was not observed in patients who underwent delayed surgery.

  • gynecologic surgical procedures
  • ovarian cancer
  • surgical oncology
  • surgical procedures, operative
  • neoplasm recurrence, local

Data availability statement

Data are available upon reasonable request.

http://dx.doi.org/10.1136/ijgc-2022-003985

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Despite being adequately treated, most patients with advanced ovarian cancer will experience recurrence. However, the influence of the timing of cytoreductive surgery on the natural history of recurrent ovarian cancer remains unknown.

    WHAT THIS STUDY ADDS

    • We found that the pattern of presentation of the first recurrence was associated with timing of surgery, with peritoneal recurrences being more frequent after neoadjuvant chemotherapy. Lymph node recurrences were those with the best prognosis with a longer survival after the first relapse. This better prognosis was not observed in patients who had delayed surgery.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • The findings of this study help us to better understand the natural history of recurrent ovarian cancer. The prognosis of recurrence depends not only on the pattern of recurrence but also on the timing of cytoreductive surgery. The pattern of recurrence may also be a marker of disease biology.

    Introduction

    Primary debulking surgery followed by adjuvant chemotherapy is the standard of care for advanced ovarian cancer in patients with completely resectable disease and good performance status.1 2 An alternative strategy for medically non-operable patients or with unresectable disease is neoadjuvant chemotherapy followed by interval debulking surgery, which has shown similar survival outcomes.3–5 Nonetheless, despite maximal surgical effort and improved survival with the addition of maintenance treatment strategies, most patients with advanced ovarian cancer experience recurrence, irrespective of the timing of surgical cytoreduction.6

    It has been hypothesized that chemo-resistant clonal cells can be selected with neoadjuvant chemotherapy,2 meaning that surgery after neoadjuvant treatment would be less effective than upfront surgery, leading to a higher rate of recurrences. Post-relapse survival can be affected by the length of the interval between the end of treatment and recurrence, and also by the pattern of recurrence.7 However, there is little robust data in the literature assessing the influence of the timing of surgical cytoreduction on the natural history of recurrent ovarian cancer. We aimed to evaluate if the timing of cytoreductive surgery was associated with the pattern of presentation of first recurrence and to assess the impact of the pattern of recurrence on post-relapse overall survival, according to the timing of surgery.

    Methods

    Patients and Study Design

    We performed a computer-generated search of the patient databases of four institutions recognized as referral centers in the treatment of ovarian cancer in France and Spain. Our search captured all patients who had upfront or interval debulking surgery with minimal (CC-1) or no residual (CC-0) disease. This was according to Completeness of Cytoreduction score8 for the International Federation of Gynecology & Obstetrics (FIGO) stage IIIC-IV epithelial ovarian cancer and dated between January 2008 and December 2015. National and institutional review board approvals were obtained (SLN/MFI/AR193997 and HULP code PI-3432).

    Preoperative Assessment, Surgical and Chemotherapy Treatment

    At diagnosis, all patients underwent an imaging workup including a thoraco-abdomino-pelvic CT. In the case of suspected extra-abdominal disease, positron emission tomography/computed tomography (PET/CT) was performed. An exploratory laparoscopy was performed to assess resectability and histology.9 Surgical procedures were performed according to Surgarbaker’s principles of peritonectomy.10 The abdominal tumorous load was assessed with the peritoneal cancer index and the main goal of the surgery was to obtain complete cytoreduction.8 Surgical complexity was quantified using the Aletti score, with a cut-off value ≥8 corresponding to high complexity (23).

    Patients with deep infiltration of the mesentery, diffuse carcinomatosis involving large parts of the small bowel or the stomach, infiltration of the duodenum or the pancreas (not limited to the pancreatic tail) were considered non-resectable and were selected for neoadjuvant chemotherapy. Neoadjuvant strategy was also indicated in patients who were not fit to withstand multivisceral resection, owing to medical comorbidities or poor performance status, or when the surgery needed to achieve complete cytoreduction was too extensive (more than three bowel or visceral resections).11 After three to four cycles of neoadjuvant chemotherapy, a clinical, biological, and imaging assessment was performed before interval debulking surgery. In the event of poor response or poor performance status, three additional cycles of neoadjuvant chemotherapy were administered before delayed debulking surgery after discussion at tumor board. In selected patients with stable disease on CT after neoadjuvant chemotherapy, an exploratory laparoscopy was performed before interval surgery to assess resectability.

    Adjuvant chemotherapy with carboplatin and paclitaxel was delivered, when feasible, within 1–2 months of debulking surgery, for 6 cycles. In the event of high tumor burden, CC-1, or poor response to neoadjuvant chemotherapy, antiangiogenic maintenance treatment with bevacizumab was added after discussion at tumor board. When surgery was performed after 6 cycles of neoadjuvant chemotherapy, two to three additional cycles of chemotherapy were added to the antiangiogenic maintenance treatment with bevacizumab. No maintenance treatment with PARP inhibitors was administered during the study period.11

    Patients were divided into three groups according to the surgical timing: primary surgery and 6 cycles of adjuvant chemotherapy (group 1); early interval surgery after 3–4 cycles of neoadjuvant chemotherapy, then 2–3 cycles of adjuvant chemotherapy to achieve a total of 6 cycles (group 2); and delayed debulking surgery after 6 cycles of neoadjuvant chemotherapy (group 3).

    Follow-up was conducted according to each center’s protocol. Globally, this included clinical examination, cancer antigen-125 (CA-125) dosage with or without a chest, abdominal, and pelvic CT scan every 4 to 6 months for 5 years. Thereafter, follow-up visits were scheduled annually. All recurrences were confirmed by imaging and localization was classified into four subgroups: lymph node involvement; peritoneal; pleural or pulmonary; and other (metastatic localization). We defined recurrence as unique or as multiple if disease was identified in only one or in more than one of the four defined localizations, respectively. The date of recurrence was defined as the date when recurrence was confirmed by CT scan or PET/CT. We defined an early relapse as a recurrence within 6 months after last cycle of carboplatin (platinum resistance).

    Study Data

    Medical databases were carefully examined to collect all relevant information. Patients’ demographic data, World Health Organization performance status, CA-125 dosage, ascites at diagnosis, surgical timing, peritoneal cancer index recorded during debulking surgery, Aletti score, histological data, adjuvant treatment, and follow-up data (date and pattern of recurrence) were retrieved from medical records. In accordance with the journal’s guidelines, we will provide our data for independent analysis or for reproducibility of this study in other centers if such is requested.

    Statistical Analysis

    Data were summarized by frequency and percentage for categorical variables and by median and range for continuous variables. Comparisons between groups were performed using the Chi-squared or Fisher’s exact test for categorical variables and the Kruskal-Wallis test for continuous variables. Disease-free survival was defined as the time between the date of diagnosis and the date of recurrence or death from any cause; patients alive and disease-free were censored at last follow-up. Overall survival was defined as the time between the date of diagnosis and the date of death from any cause; patients alive were censored at last follow-up. Post-relapse overall survival was defined as the time between the date of diagnosis of the first recurrence and the date of death from any cause; patients alive were censored at last follow-up. Survival data were estimated using the Kaplan-Meier method. Univariable and multivariable analyses were performed using the Log-rank test and the Cox proportional hazards model. Multivariable analysis was performed including those variables with a significant association with the outcome as well as those considered clinically relevant. Hazard ratios (HR) were estimated with their 95% confidence intervals (95% CI). Cumulative incidences of the different patterns of recurrence were estimated using competing risks methodology with other patterns of recurrence and death from any cause considered as competing events. In the case of multiple first recurrences, the pattern of the recurrence was defined as the worst one according to the following order: other (metastatic), pleural or pulmonary, peritoneal and lymph node. Comparisons between groups were performed using the Gray test. All statistical tests were two-sided and p-values <0.05 were considered statistically significant. Statistical analyses were conducted using STATA v16 (StataCorp, College Station, TX, USA) software.

    Results

    A total of 549 women were included, 175 (31.9%) in group 1, 224 (40.8%) in group 2, and 150 (27.3%) in group 3. Baseline characteristics, surgical, and treatment data are shown in Table 1.

    View this table:
    Table 1

    Baseline characteristics, surgical and treatment data according to surgical timing

    The median follow-up was 68.1 months (95% CI (62.9; 73.3)). During the study period, 438/549 patients (79.8%) relapsed, 128/175 (73.1%) in group 1, 188/224 (83.9%) in group 2, and 122/150 (81.3%) in group 3. Median disease-free survival was 19.4 months (95% CI (18.0; 20.6)). It was 23.0 months (95% CI (20.0; 29.3)), 18.0 months (95% CI (15.7 20.0)), and 17.0 months (95% CI (15.0; 20.9)) for primary, early interval, and delayed debulking surgery, respectively (p<0.001).

    The pattern of first recurrence at any time during follow-up is shown in Table 2. The cumulative incidence of peritoneal recurrences at 2 years was 31.1%, 9.6% for pleural or pulmonary recurrences, 6.5% for lymph node recurrences, and 10.9% for other metastatic recurrences (Figure 1A). Cumulative incidence of peritoneal recurrences at 2 years was 24.4% (95% CI (18.2; 31.0)) in primary surgery, 30.9% (95% CI (24.9; 37.0)) in early interval, and 39.2% (95% CI (31.2; 47.1)) in delayed surgery, p=0.019. Cumulative incidence of pleural or pulmonary recurrences at 2 years was 9.9% (95% CI (6.0; 14.9)) in upfront surgery group, 13.0% (95% CI (8.9; 17.7)) in early interval and 4.1% (95% CI (1.7; 8.3)) in delayed surgery, p=0.022 (Figure 1B). Remarkably, the rate of diaphragmatic stripping was significantly different between the three groups (61.7%, 67.9%, vs 46.7%; p<0.001). There was no significant difference in the rate of early relapse between group 1 (19.5%), group 2 (22.9%), and group 3 (23.1%) (p=0.671).

    Figure 1
    Figure 1

    (A.) cumulative incidence of the pattern of recurrence by tumor location in the overall cohort. (B.) cumulative incidence of recurrences according to surgical timing for the four patterns of recurrence: peritoneal (p=0.019); lymph node (p=0.922); pleural or pulmonary (p=0.022); other (metastatic) (p=0.683).

    View this table:
    Table 2

    Pattern of recurrence during follow-up in the 549 patients included in the study

    There were 293 (53.4%) deaths, 73/175 (41.7%) in the upfront surgery group, 124/224 (55.4%) in the early interval group, and 96/150 (64.0%) in the delayed surgery group. Median overall survival was 56.7 months (95% CI (50.2; 65.8)). It was 84.0 months (95% CI (67.4; 111.0)), 50.7 months (95% CI (44.6; 59.5)), and 47.5 months (95% CI (39.3; 52.9)) in groups 1, 2 and 3, respectively (p<0.001). Median post-relapse overall survival was 26.5 months (95% CI (24.0; 31.3)), with 33.5 months (95% CI (24.3; 44.2)), 26.8 months (95% CI (22.8; 32.6)), and 24.5 months (95% CI (18.6; 29.4)) for primary, early interval, and delayed debulking surgery groups, respectively (p=0.025).

    Median post-relapse overall survival for patients with peritoneal, lymph node, pleural or pulmonary, and other recurrences was 26.5 months (95% CI (23.2; 31.2)), 68.1 months (95% CI (39.3; 88.8)), 20.5 months (95% CI (14.3; 23.5)), and 23.2 months (95% CI (18.1; 31.3)), respectively (p<0.001) (Figure 2). In multivariable analysis, the pattern of recurrence (lymph node: HR 0.42, 95% CI (0.27; 0.64), p<0.001), surgical timing (delayed surgery: HR 1.53, 95% CI (1.11; 2.13), p=0.010), and time to recurrence (HR 0.95, 95% CI (0.93; 0.96), p<0.001) remained significantly associated with post-relapse overall survival (Table 3).

    Figure 2
    Figure 2

    Post-relapse overall survival according to the pattern of recurrence (p<0.001).

    View this table:
    Table 3

    Multivariable analysis for overall survival after first relapse in the overall cohort.

    In subgroup analyses, lymph node recurrences (HR adjusted for time to first relapse (adj)=0.34, 95% CI (0.14; 0.83), p=0.018) and multiple recurrences (HRadj 1.66, 95% CI (1.03; 2.69), p=0.037) were significantly associated with post-relapse overall survival in the upfront surgery group. In early interval surgery, lymph node recurrences were associated with improved post-relapse overall survival (HRadj 0.34, 95% CI (0.16; 0.73), p=0.005), but not in the delayed surgery group (HRadj 0.54, 95% CI (0.29; 1.04), p=0.064).

    Discussion

    Summary of Main Results

    We found an increasing rate of peritoneal recurrences with the increasing number of cycles of neoadjuvant chemotherapy (primary: 24%, early interval: 31%, and delayed surgery: 39%), and a higher rate of pleural or pulmonary recurrences after early interval debulking surgery (13%) compared with primary (10%) and delayed surgery (4%). The second main finding was that lymph node recurrences were associated with a longer post-relapse overall survival. Survival benefit of lymphatic recurrences was not observed in women who underwent delayed surgery.

    Results in the Context of Published Literature

    Surgical Timing and Pattern of First Recurrence

    It is known that most patients with advanced ovarian cancer will experience disease recurrence, independently of the timing of surgery.6 Reports in the literature on the impact of the number of cycles of neoadjuvant chemotherapy on the type of recurrences are scarce.6 12 13 Gadducci et al found a non-significantly higher rate of abdominal and pelvic recurrences after interval surgery compared with primary surgery (26% vs 20% and 19% vs 16%).6 Likewise, Petrillo et al reported more aggressive behavior of recurrent disease in patients receiving neoadjuvant chemotherapy, with an increased proportion of patients presenting with peritoneal carcinomatosis compared with patients who underwent upfront surgery (57% vs 20%).13

    Himoto et al also showed that the distribution of disease at the time of the first recurrence varied with the choice of primary treatment. Neoadjuvant chemotherapy followed by interval debulking surgery was associated with a higher rate of overlapping locations between baseline and first recurrence and with a lower rate of new disease locations compared with primary debulking surgery.12 One possible explanation for the increased rate of peritoneal recurrences after neoadjuvant treatment in our study is that microscopic tumor regions might be more difficult to identify during interval surgery due to their more benign visual appearance and due to tumor scarring following chemotherapy. Therefore, a neoadjuvant strategy may interfere with the perioperative visual evaluation of tumor spread and lead to incomplete resection of tumor in potentially resectable areas.14 Another hypothesis is that microscopic non-visible disease, likely remaining after any cytoreductive surgery, could contain selected chemo-resistant clonal cells after neoadjuvant chemotherapy,2 leading to a higher rate of abdominal recurrences after interval surgery. However, this higher rate of peritoneal recurrences in our study may also be partially explained by the fact that patients who underwent neoadjuvant chemotherapy had a higher intra-abdominal tumor burden or unresectable diffuse carcinomatosis at diagnosis, or by the fact that the group of patients who underwent upfront surgery received more frequently intraperitoneal chemotherapy.

    In our study, early interval surgery was associated with a higher rate of pleural or pulmonary recurrences. This subgroup of patients had a significantly higher rate of diaphragmatic stripping, meaning that these patients had a higher rate of pleural disease at diagnosis, which could explain the higher rate of recurrences at this site.

    Impact of the Pattern of Recurrence on Post-relapse Survival

    It is known that exclusive lymph node involvement at diagnosis has a more indolent course of disease with better survival than peritoneal carcinomatosis.15 However, studies comparing survival outcomes of different types of recurrence have reported controversial results.16–18 Delangle et al did not show a better prognosis of patients with isolated nodal recurrences compared with peritoneal carcinomatosis,16 and Gadducci et al did not find that the pattern of recurrence (pelvis vs retroperitoneal lymph nodes) was an independent prognostic factor.17 Conversely, Levy et al showed better survival for patients with retroperitoneal lymph node recurrences compared with patients with peritoneal carcinomatosis or combined recurrences,18 which is concordant with our findings. Moreover, we specifically assessed post-relapse survival and found that once the recurrence is diagnosed, posterior survival will vary according to the type of recurrence. It would be interesting to evaluate if certain patterns of recurrence are markers of tumor biology and if they are associated with genetic or molecular factors.

    Our data also showed that the impact of the recurrence pattern on post-relapse survival was present in patients who underwent primary or early interval surgery, but was not significant in those who had delayed surgery. This could be explained by the fact that delayed surgery was per se associated with a higher risk of death after the first relapse. The negative impact of performing delayed surgery is maintained over time and goes beyond the first recurrence, erasing the benefit of having a more indolent recurrence that is found with exclusive lymph node involvement. To the best of our knowledge, the impact on survival of the recurrence pattern according to surgical timing has not previously been reported.

    Finally, our results showed that shorter time to first relapse was associated with an increased risk of death. This has been reported by Ferrandina et al who showed that post-relapse survival was affected not only by the type of recurrence, but also by the length of the interval between the end of primary treatment and the occurrence of first recurrence.7 This interval is widely considered the most relevant factor in determining the natural history of recurrent ovarian cancer.19

    Strengths and Weaknesses

    To our knowledge, this is the largest series of advanced ovarian cancer patients evaluating the association between the pattern of recurrence and oncological outcome according to the timing of surgical cytoreduction. We included a cohort of more than 500 women who underwent cytoreductive surgery with minimal or no residual disease and who had a long median follow-up of almost 6 years. Among the limitations of our study, we highlight its retrospective design and the associated inherent risk of selection bias. Medically non-operable patients and those with non-resectable disease at diagnosis were included in early interval and delayed surgery groups. Therefore, the poorer prognosis of these patients compared with those who underwent primary surgery might have influenced the results of our study. Moreover, patients in the delayed surgery group may also have an inherent worse prognosis compared with the early interval group, as they were not candidates for surgery after 3–4 cycles of chemotherapy. All patients without a good response after 3 or 4 cycles of neoadjuvant chemotherapy and non-resectable at delayed debulking surgery, and all those with ≥CC-2 at cytoreductive surgery were excluded from our study, which undoubtedly improved the overall survival of our cohort.

    Implications for Practice and Future Research

    Our findings suggest that the type of recurrence may vary depending on the timing of surgical cytoreduction, and that the better survival outcome of patients with lymphatic recurrences may be erased by delayed surgery. Further prospective multicenter studies need to confirm our results.

    Conclusions

    We found that the pattern of presentation of the first recurrence was associated with the timing of surgery, with peritoneal recurrences being more frequent after neoadjuvant chemotherapy. Lymph node recurrences showed a better prognosis, with increased overall survival after relapse. This improved outcome of lymphatic recurrences was more evident after primary and early interval surgery. Shorter time to first relapse and delayed debulking surgery were significantly associated with decreased overall survival after relapse. Further prospective studies are needed to confirm our findings regarding the impact on oncological outcome of the pattern of the first recurrence in ovarian cancer patients.

    Data availability statement

    Data are available upon reasonable request.

    Ethics statements

    Patient consent for publication

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    Footnotes

    • AH and AM are joint senior authors.

    • Twitter @AngelesFite, @Alejandra

    • AH and AM contributed equally.

    • Contributors All authors made the appropriate contributions, carefully compiling and analyzing data, reading the manuscript and giving their full approval.

    • 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.