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The impact of varying levels of residual disease following cytoreductive surgery on survival outcomes in patients with ovarian cancer: a meta-analysis

BMC Women's Health volume 24, Article number: 179 (2024) Cite this article

Abstract

Background

Residual disease following cytoreductive surgery in patients with ovarian cancer has been associated with poorer survival outcomes compared with no residual disease. We performed a meta-analysis to assess the impact of varying levels of residual disease status on survival outcomes in patients with ovarian cancer who have undergone primary cytoreductive surgery or interval cytoreductive surgery in the setting of new therapies for this disease.

Methods

Medline, Embase, and Cochrane databases (January 2011 – July 2020) and grey literature, bibliographic and key conference proceedings, were searched for eligible studies. Fixed and random-effects meta-analyses compared progression and survival by residual disease level across studies. Heterogeneity between comparisons was explored via type of surgery, disease stage, and type of adjuvant chemotherapy.

Results

Of 2832 database and 16 supplementary search articles screened, 50 studies were selected; most were observational studies. The meta-analysis showed that median progression-free survival and overall survival decreased progressively with increasing residual disease (residual disease categories of 0 cm, > 0–1 cm and > 1 cm). Compared with no residual disease, hazard ratios (HR) for disease progression increased with increasing residual disease category (1.75 [95% confidence interval: 1.42, 2.16] for residual disease > 0–1 cm and 2.14 [1.34, 3.39] for residual disease > 1 cm), and also for reduced survival (HR versus no residual disease, 1.75 [ 1.62, 1.90] for residual disease > 0–1 cm and 2.32 [1.97, 2.72] for residual disease > 1 cm). All comparisons were significant (p < 0.05). Subgroup analyses showed an association between residual disease and disease progression/reduced survival irrespective of type of surgery, disease stage, or type of adjuvant chemotherapy.

Conclusions

This meta-analysis provided an update on the impact of residual disease following primary or interval cytoreductive surgery, and demonstrated that residual disease was still highly predictive of progression-free survival and overall survival in adults with ovarian cancer despite changes in ovarian cancer therapy over the last decade. Higher numerical categories of residual disease were associated with reduced survival than lower categories.

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Background

Ovarian cancer is the fifth leading cause of cancer-related death among women in the USA [1]. Most cases of ovarian cancer are diagnosed at an advanced stage, for which the 5-year survival rate for patients with advanced disease is around 30% [2, 3]. Currently, the standard of care for treatment of advanced ovarian cancer includes surgery and platinum-based chemotherapy, followed by maintenance therapy [4]. Treatment regimens consist of either primary cytoreductive surgery with adjuvant platinum-based chemotherapy, or neoadjuvant chemotherapy with interval cytoreductive surgery and postoperative chemotherapy [4]. Both treatment options have similar outcomes and are typically selected based on patient and disease characteristics, with the latter being recommended for patients with bulky Stage III–IV disease who are poor surgical candidates or for whom there is a low likelihood of optimal cytoreduction [4, 5]. To achieve optimal outcomes, surgery for advanced ovarian cancer aims for tumour cytoreduction with no residual disease wherever possible [2], and chemotherapy aims to eradicate any microscopic disease remaining after surgery [6]. In the neoadjuvant chemotherapy setting, responsiveness to platinum-based chemotherapy may be known at the time of interval surgery and reflect disease status; while platinum sensitivity may alone be a prognostic factor, in the case of primary surgical debulking, the level of platinum sensitivity or resistance is unknown at the time of the procedure [7, 8]. Residual disease status after cytoreductive surgery for advanced-stage ovarian cancer is defined by the diameter of the residual tumour and is one of the most important prognostic factors for disease progression [7, 9, 10]. Residual disease status is commonly categorised as complete tumour resection or ‘no residual disease’ (residual disease 0 cm [R0]); ‘optimal cytoreduction’ (residual disease > 0–1 cm [R1]); or ‘suboptimal cytoreduction’ (residual disease > 1 cm [R2]) [9, 11,12,13].

Prior meta-analyses have shown that residual disease following primary cytoreductive surgery is associated with poorer survival outcomes in ovarian cancer compared with no residual disease, with a continuum of benefit observed across residual disease levels, R0–R2 [14,15,16]. Better overall survival was reported in patients with residual disease 0 cm versus ≤ 1 cm [14], in those with residual disease 0 cm or ≤ 2 cm versus those with residual disease > 2 cm [15], and in patients with residual disease < 1 cm versus residual disease > 1 cm following primary cytoreductive surgery [16]. However, with advancements in ovarian cancer management and treatment options in recent years [2], including utilisation of targeted treatments, a meta-analysis of studies published since 2011 is warranted to assess the impact of residual disease on patient outcomes.

The aim of this meta-analysis was to reassess the impact of varying levels of residual disease status on progression-free survival and overall survival specifically in patients with ovarian cancer who have undergone primary cytoreductive surgery or interval cytoreductive surgery in the setting of new therapies for ovarian cancer. This meta-analysis used data from publications previously identified in a recently published systematic literature review [17].

Results

Studies

Of 2832 screened articles from the original database search plus 16 from supplementary searches, 52 publications reporting on 50 primary studies were included (Supplementary Table 1) [10, 18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65]. This comprised 43 observational studies (41 retrospective [10, 18,19,20,21,22,23,24,25,26,27,28, 30, 31, 33,34,35, 37,38,39, 41, 42, 44,45,46,47,48,49,50,51,52, 54, 56,57,58, 60, 62,63,64,65], 2 prospective [32, 61]), 4 retrospective analyses of RCTs [40, 43, 53, 55], and 3 RCTs [29, 36, 59]. Included studies were conducted either solely or partly (for multinational studies) in Australia, Austria, Belgium, Canada, China, Denmark, Finland, France, Germany, Italy, Japan, the Netherlands, New Zealand, Norway, Republic of Korea, Spain, Sweden, United Kingdom, and the United States. Data on progression-free survival per residual disease status were available from 21 studies (2 randomised controlled trials [29, 36], 15 observational studies [23,24,25, 27, 31,32,33,34,35, 44, 45, 49, 51, 56, 58, 61], and 4 retrospective analyses of randomised controlled trials [40, 43, 53, 55]) and data on overall survival per residual disease status were available from 48 studies (3 randomised controlled trials [29, 36, 59], 4 retrospective analyses of randomised controlled trials [40, 43, 53, 55], and 41 observational studies [10, 18,19,20,21,22,23,24,25,26,27,28, 30, 31, 33,34,35, 37,38,39, 41, 42, 44,45,46,47,48,49,50,51,52, 54, 56,57,58, 61,62,63,64,65]). There was substantial heterogeneity in patient baseline characteristics and reported variables across the studies. The PRISMA flow chart of included publications and key characteristics of each publication included in the systemic literature review have been described previously [17].

Briefly, over half (n = 29) of the studies included in this analysis were published between 2016 and 2020, with the remaining studies published between 2011 and 2015. Nearly a third of all studies (n = 18, 36%) included patients who had undergone combination surgery (either primary and interval cytoreductive surgery [n = 16], or primary and interval cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy [n = 2]) [22, 25, 27, 28, 30, 32,33,34,35, 42, 45, 47, 48, 57, 60,61,62,63]; 15 and 4 studies included patients who had primary cytoreductive surgery [10, 18,19,20,21, 23, 31, 36, 37, 39, 41, 44, 49, 55, 57] or interval cytoreductive surgery [26, 50, 58, 64] only, respectively; and 13 reported cytoreductive surgery without specifying surgery type [24, 25, 29, 38, 40, 43, 46, 51,52,53,54, 59, 65]. The majority of studies (n = 34, 68%) enrolled patients with Stage III/IV disease only [10, 19, 20, 22, 23, 26,27,28,29,30, 33, 34, 37, 39,40,41,42, 44,45,46,47,48,49,50,51, 53,54,55,56, 58, 59, 62, 64, 65]; 16 studies included patients with mixed Stages I–IV [18, 21, 24, 25, 31, 32, 35, 36, 38, 43, 52, 57, 60, 61, 63] and only 2 studies among these reported data for Stage I/II and Stage III/IV separately [25, 66]. Chemotherapy in the adjuvant setting was reported in 25 studies whilst 4 studies reported chemotherapy use in the neoadjuvant setting. Additionally, 18 studies reported using both neoadjuvant and adjuvant chemotherapy; usage of neoadjuvant and adjuvant chemotherapy was not reported in 3 studies. Due to the wide range of interventions used in the adjuvant and neoadjuvant setting, comparisons across treatments were not feasible.

Reporting of study measures: progression-free survival, overall survival, and residual disease status

The progression-free survival and overall survival definitions varied across studies [17]. Across all studies, residual disease status was defined as no residual disease (0 cm), optimal cytoreduction (residual disease measuring > 0–1 cm), and suboptimal cytoreduction (residual disease measuring > 1 cm). Optimal cytoreduction was defined using a variety of approaches across studies (residual disease 0.1–1 cm; residual disease 0.01–1 cm; residual disease 0–1 cm; residual disease > 0–1 cm; residual disease < 1 cm); these were all categorised as residual disease > 0–1 cm for the purposes of this meta-analysis. In 4 of these studies [24, 25, 35, 52] optimal cytoreduction also included patients with no residual disease. An additional category, residual disease > 2 cm, was also reported for overall survival in 3 studies [10, 37, 62].

Relationship between residual disease and survival

Median progression-free survival ranged from 9 months to 50.2 months and median overall survival ranged from 6 to 110 months across studies. When analysed by residual disease category, median progression-free survival and overall survival for ‘no residual disease’ (residual disease = 0 cm) was longer than for ‘any residual disease’ (residual disease >0 cm; Fig. 1A) and both median progression-free survival and median overall survival decreased across progressively higher residual disease categories. The median pooled progression-free survival (95% confidence interval [CI]) for the no residual disease category was 25.6 (23.1, 28.0) months, compared with significantly worse median pooled progression-free survival of 17.2 (15.3, 19.1) months for residual disease >0–1 cm, 12.2 (11.2, 13.1) months for residual disease >1 cm, and 14.0 (12.1, 15.9) months for any residual disease (p<0.05; Fig. 1A). Median pooled overall survival (95% CI) for the no residual disease category was 49.9 (42.1, 57.9) months, whereas all residual disease categories were significantly shorter; 31.6 (26.5, 36.8) months for residual disease >0–1 cm, 23.6 (19.1, 28.2) months for residual disease >1 cm, 6.8 (−1.7, 15.3) months for residual disease >2 cm, and 31.7 (25.5, 38.0) months for any residual disease (p<0.05; Fig. 1B).

Fig. 1
figure 1

Pooled median progression-free survival A and overall survival B by residual disease status across studies. N numbers represent number of data points used in analysis. Median progression-free survival per residual disease status was reported in 12 studies and median overall survival per residual disease status was reported in 27 studies. Residual disease > 1 cm category includes studies reporting residual disease 1–2 cm and residual disease > 1 cm. CI, confidence interval

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For studies that calculated the hazard ratio (HR) comparing progression-free survival and overall survival across residual disease categories, and adjusting for baseline characteristics on a study-by-study basis, HRs showed that lower residual disease categories were associated with improved progression-free survival and overall survival compared with higher residual disease categories (Fig. 2). The pooled HR for disease progression for any residual disease compared with no residual disease was 1.88 (95% CI 1.62, 2.18) and for reduced survival was 1.99 (95% CI 1.86, 2.12). The increased risk of earlier progression or death associated with residual disease compared with no residual disease became more pronounced with increasing residual disease: HRs versus no residual disease for disease progression were 1.75 (95% CI: 1.42, 2.16) for residual disease > 0–1 cm and 2.14 (95% CI 1.34, 3.39) for residual disease > 1 cm; for reduced survival, HRs versus no residual disease were 1.75 (95% CI 1.62, 1.90) for residual disease > 0–1 cm, 2.32 (95% CI 1.97, 2.72) for residual disease > 1 cm, and 2.37 (95% CI 2.08, 2.70) for residual disease > 2 cm. All comparisons were significant at p < 0.05.

Fig. 2
figure 2

Pooled HRs for progression-free survival A and overall survival B by residual disease status. *Random effects. †Fixed effects. Residual disease > 1 cm category includes studies reporting residual disease 1–2 cm and residual disease > 1 cm. All comparisons were considered significant (p < 0.05). CI, confidence interval; HR, hazard ratio

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Subgroup analyses

Subgroup analysis showed the same pattern of association between residual disease and median progression-free survival/overall survival, with pooled median progression-free survival and overall survival estimates decreased for higher residual disease categories compared with lower categories. A random effects model was considered appropriate, due to substantial heterogeneity (I2 ≥ 50) reported across the studies. Within type of surgery, disease stage, and type of adjuvant chemotherapy subgroups, progression-free survival was significantly worse with higher residual disease versus no residual disease categories, with no statistically significant differences between subgroups for type of surgery (Fig. 3A; p = 0.07), disease stage (Fig. 3B; p = 0.83), or adjuvant chemotherapy type (Fig. 3C; p = 0.09). Analyses of progression-free survival HRs by residual disease > 0 cm versus no residual disease are shown in Supplementary Fig. 1.

Fig. 3
figure 3

Progression-free survival by type of surgery A disease stage B and chemotherapy received C. Log HR for residual disease > 0 vs residual disease = 0. Thick dotted lines represent fixed effects and thin dotted lines represent random effects for the total effect size. CI, confidence interval; HR, hazard ratio; MRAW, raw or untransformed mean

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The corresponding subgroup analyses for overall survival per residual disease status are shown in Fig. 4. There was a statistically significant decrease in overall survival with residual disease > 0 cm versus no residual disease categories irrespective of subgroup, with no statistically significant differences between subgroups for type of surgery (Fig. 4A; p = 0.82), disease stage (Fig. 4B; p = 0.21), or adjuvant chemotherapy type (Fig. 4C; p = 0.17). Analyses of overall survival HRs by residual disease > 0 cm versus no residual disease are shown in Supplementary Fig. 2.

Fig. 4
figure 4

Overall survival by type of surgery A disease stage B and chemotherapy received C Log HR for residual disease > 0 vs residual disease = 0. Thick dotted lines represent fixed effects and thin dotted lines represent random effects for the total effect size. CI, confidence interval; HR, hazard ratio; MRAW, raw or untransformed mean

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Discussion

Summary of main results

This meta-analysis provides an update on the impact of residual disease status on survival outcomes following primary cytoreductive surgery or interval cytoreductive surgery as a first-line treatment for ovarian cancer. In our analysis, residual disease status was highly predictive of overall survival and progression-free survival, with higher levels of residual disease associated with increased disease progression and reduced survival compared with lower levels of residual disease, and particularly versus no residual disease. Subgroup analyses revealed that the relationship between residual disease and progression-free survival/overall survival was not affected by the type of surgery, disease stage, or type of chemotherapy.

Results in the context of published literature

Previous meta-analyses investigating the impact of residual disease in ovarian cancer have reported improved survival in patients with no/lower residual disease compared with patients who had higher residual disease [14,15,16]. In addition, a systematic review assessing survival outcomes in relation to residual disease status following interval cytoreductive surgery reported that the best survival outcomes were in patients with no macroscopic residual disease [67]. In this meta-analysis, we report on the impact of residual disease on survival outcomes in the setting of new therapies for ovarian cancer and showed that no residual disease confers the best progression-free survival and overall survival outcomes in patients with advanced ovarian cancer undergoing primary cytoreductive surgery or interval cytoreductive surgery. As such, a combination of tumour biology, disease distribution, and surgical approach are strong determinants of patient outcomes despite the introduction of new therapies.

Implications for practice and future research

The first period between initial diagnosis and recurrence is typically the longest treatment-free interval, with progression-free survival and overall survival becoming increasingly shorter after each line of treatment [68]. If residual disease can help predict that treatment-free interval, it could be used to determine which patients have the highest risk of earlier progression or death so that healthcare providers can tailor intensive monitoring and/or therapy accordingly. Following on, it would then be informative to investigate how a patient’s known residual disease status influences management decisions. In the primary cytoreductive surgery setting, the patient’s likely response to platinum-based chemotherapy is unknown at the time of surgery [69], and their subsequent residual disease status is likely affected by the disease biology and/or distribution. Conversely, with interval cytoreductive surgery, the patient’s residual disease status may be affected by their prior response to platinum-based chemotherapy [69]. Not only does this highlight the need for markers of chemoresistance [70], but future studies could evaluate residual disease status in response to chemotherapy as well as after primary cytoreductive surgery/interval cytoreductive surgery, to ascertain if such data could inform prognostic risk and management. Also, as residual disease status could potentially inform prognosis [69, 70], it could be used alongside other known risk factors to categorise patients as having low or high risk ovarian cancer. Moreover, cost–benefit analyses based on residual disease status may help to clarify if both high- and low-risk patients are eligible for maintenance therapy (if both high- and low-risk patients by residual disease status show similar benefit) or if a different strategy is needed for higher-risk patients. Ultimately, adopting a more personalised treatment approach is warranted, which takes residual disease-associated risk into account, alongside other prognostic factors including patient characteristics [71, 72], disease stage [5, 72], and tumour mutational burden [73]. The findings from this meta-analysis highlight the importance of residual disease in survival outcomes; a greater awareness of the potential of residual disease as a prognostic factor could aid disease management and thus contribute towards improving individual patient care.

Strengths and weaknesses

Although an adequate number of studies were included overall, limitations of our study include the predominance of data from observational studies. Comparison across treatments was not feasible due to the wide range of interventions used in adjuvant and neoadjuvant settings, and there were differences in how residual disease was defined across the studies. Availability of data on diagnosis, disease stage, and histology was relatively limited, restricting in-depth analysis of the impact of these factors on the overall results. Similarly, there were only limited data for factors affecting overall survival and progression-free survival with regard to residual disease status; any subtle differences in the effects of disease stage, type of cytoreductive surgery, and type of adjuvant chemotherapy on residual disease status could not be discerned, limiting any robust conclusions. Where available, data were stratified by known prognostic factors and these results were consistent with overall results; however, due to a limited number of studies for each subgroup analyses, multivariate analysis of factors was not possible. The considerable heterogeneity in data between studies – as shown by the high I2 values in Figs. 3 and 4 – was a likely consequence of variations in study types, design, and populations included in the meta-analysis. This was, however, partly mitigated by the use of random-effects models when I2 values were 50% or greater. Taken together, these limitations may reduce the generalisability of the study findings to clinical practice.

Another important factor to consider when interpreting these data is the ever-evolving ovarian cancer treatment landscape [74]. Introduction of maintenance therapies in the ovarian cancer treatment landscape has greatly improved patient outcomes [75,76,77,78]. Bevacizumab was first approved as a first-line maintenance therapy for patients with ovarian cancer, in Europe in November 2011 and in the United States in June 2018 [76, 77]. Poly-(ADP) ribose polymerase (PARP) inhibitors were then introduced as first-line maintenance therapies in the United States in December 2018 and in Europe in January 2019, and have significantly increased progression-free survival for patients with ovarian cancer [75, 78, 79]. Over half (n=29) of the studies included in this analysis were published between 2016 and 2020, coinciding with the introduction of maintenance therapies in the ovarian cancer treatment landscape. The remaining studies (n=23), however, pre-date the approval of PARP inhibitors, so the standard of care would have included cytoreductive surgery and platinum-based chemotherapy only [80]. It is possible that these maintenance therapies had considerable effects on PFS and OS, and could partially explain the high heterogeneity observed in this analysis as well as impacting the generalisability of the findings. Despite the introduction of maintenance therapies, residual disease status remained a strong predictor of patient outcomes. Future analysis is warranted to examine the effects of maintenance therapies on PFS and OS in relation to residual disease.

Conclusions

This meta-analysis demonstrated that higher residual disease categories, when compared with lower categories, were highly predictive of worse overall survival and progression-free survival in adults with ovarian cancer who have undergone primary cytoreductive surgery or interval cytoreductive surgery, despite changes in the treatment landscape of ovarian cancer over the last decade.

Methods

Systematic literature review data extraction

As previously described [17], a structured literature search of MEDLINE, Excerpta Medica Database (Embase) and Cochrane CENTRAL databases was conducted on July 7, 2020 (with date limits from January 1, 2011 to July 7, 2020), and was supplemented by searches of grey literature, bibliographic sources, and conference proceedings (American Society of Clinical Oncology, European Society for Medical Oncology, Society of Gynecologic Oncology 2019–2020) carried out between August 14 and August 20, 2020, identifying relevant publications over the previous 10 years (2011 to 2020). Full texts were obtained after assessing titles and abstracts for relevance. A comprehensive search strategy based on the population, intervention, comparator, outcome, and study type framework was used to evaluate search results. Key eligibility criteria for studies were clinical trials or observational studies involving > 200 adult women (typically ≥ 18 years) with ovarian cancer (including fallopian tube cancer and primary peritoneal cancer) where overall survival and progression-free survival were evaluated per residual disease status after primary cytoreductive surgery or interval cytoreductive surgery. Case studies and case reports were excluded.

Two independent reviewers assessed each citation for eligibility, with discrepancies resolved by a third reviewer. This same process was used for data extraction from eligible studies. Study quality was assessed by recommended instruments for randomised controlled trials [81] and observational studies [82] as previously described [17], with all included studies being fair quality or above.

Definitions for progression-free survival and overall survival were based on individual study definitions, and varied across studies [17]. Full systematic literature review details are reported per PRISMA guidelines in the prior systematic review publication [17].

Statistical analysis

Analyses were conducted in R (The R Foundation, Vienna, Austria). Pooled HRs and 95% CI were calculated from individual study HRs using a linear regression model, to determine any association between residual disease and progression-free survival or overall survival. Heterogeneity was assessed by the I2 statistic. Random effects were used when the I2 was 50% or greater; otherwise, fixed effects were used to compare progression-free survival and overall survival by residual disease levels across all studies. Residual disease levels were categorised as follows: > 0 cm versus 0 cm; > 0–1 cm versus 0 cm; > 1 cm versus 0 cm, and (for overall survival only) > 2 cm versus 0 cm. Pooled analyses that included more than two studies with residual disease categories were reported.

Subgroup analyses were performed to examine progression-free survival and overall survival by the following clinical characteristics: type of surgery (primary cytoreductive surgery; either interval cytoreductive surgery or primary cytoreductive surgery; cytoreductive surgery; and interval cytoreductive surgery), disease stage (mixed [I, II]; mixed [II, III, IV]; stage III only; mixed [III, IV]), and type of chemotherapy (adjuvant; neoadjuvant followed by adjuvant; or studies that reported both). All comparisons were considered significant at p < 0.05.

Availability of data and materials

GSK makes available anonymised individual participant data and associated documents from interventional clinical studies that evaluate medicines, upon approval of proposals submitted to https://www.gsk-studyregister.com/en/.

References

  1. Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.

    Article  PubMed  Google Scholar 

  2. Lheureux S, Braunstein M, Oza AM. Epithelial ovarian cancer: evolution of management in the era of precision medicine. CA Cancer J Clin. 2019;69(4):280–304.

    Article  PubMed  Google Scholar 

  3. American Cancer Society. Survival rates for ovarian cancer. Available from: https://www.cancer.org/cancer/types/ovarian-cancer/detection-diagnosis-staging/survival-rates.html. Cited 2023 29th September.

  4. Nag S, et al. Maintenance therapy for newly diagnosed epithelial ovarian cancer– a review. J Ovarian Res. 2022;15(88):1–18.

    Google Scholar 

  5. Wang D, et al. Choosing the right timing for interval debulking surgery and perioperative chemotherapy may improve the prognosis of advanced epithelial ovarian cancer: a retrospective study. J Ovarian Res. 2021;14(1):49.

    Article  MathSciNet  PubMed  PubMed Central  Google Scholar 

  6. Narod S. Can advanced-stage ovarian cancer be cured? Nat Rev Clin Oncol. 2016;13(4):255–61.

    Article  CAS  PubMed  Google Scholar 

  7. Greer A, et al. Impact of residual disease at interval debulking surgery on platinum resistance and patterns of recurrence for advanced-stage ovarian cancer. Int J Gynecol Cancer. 2021;31(10):1341–7.

    Article  PubMed  Google Scholar 

  8. van Zyl B, Tang D, Bowden NA. Biomarkers of platinum resistance in ovarian cancer: what can we use to improve treatment. Endocr Relat Cancer. 2018;25(5):R303–18.

    Article  PubMed  Google Scholar 

  9. Dabi Y, et al. Patients with stage IV epithelial ovarian cancer: understanding the determinants of survival. J Transl Med. 2020;18(1):134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sørensen SM, Schnack TH, Høgdall C. Impact of residual disease on overall survival in women with Federation of Gynecology and Obstetrics stage IIIB-IIIC vs stage IV epithelial ovarian cancer after primary surgery. Acta Obstet Gynecol Scand. 2019;98(1):34–43.

    Article  PubMed  Google Scholar 

  11. Manning-Geist BL, et al. A novel classification of residual disease after interval debulking surgery for advanced-stage ovarian cancer to better distinguish oncologic outcome. Am J Obstet Gynecol. 2019;221(4):326.e1-326.e7.

    Article  PubMed  Google Scholar 

  12. Chang SJ, Bristow RE. Evolution of surgical treatment paradigms for advanced-stage ovarian cancer: redefining “optimal” residual disease. Gynecol Oncol. 2012;125(2):483–92.

    Article  PubMed  Google Scholar 

  13. Wang J, et al. Is There a Survival benefit for patients with advanced ovarian clear cell carcinoma who complete more than 6 cycles of postoperative chemotherapy? Cancer Manag Res. 2020;12:11631–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chang S-J, et al. Survival impact of complete cytoreduction to no gross residual disease for advanced-stage ovarian cancer: a meta-analysis. Gynecol Oncol. 2013;130(3):493–8.

    Article  PubMed  Google Scholar 

  15. Allen DG, Heintz AP, Touw FW. A meta-analysis of residual disease and survival in stage III and IV carcinoma of the ovary. Eur J Gynaecol Oncol. 1995;16(5):349–56.

    CAS  PubMed  Google Scholar 

  16. Elattar A, et al. Optimal primary surgical treatment for advanced epithelial ovarian cancer. Cochrane Database Syst Rev. 2011;2011(8):Cd007565.

    PubMed  PubMed Central  Google Scholar 

  17. Chase DM, et al. Correlation between progression-free survival and overall survival in patients with ovarian cancer after cytoreductive surgery: a systematic literature review. Int J Gynecol Cancer. 2023;33(10):1602–11.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ataseven B, et al. Prognostic value of lymph node ratio in patients with advanced epithelial ovarian cancer. Gynecol Oncol. 2014;135(3):435–40.

    Article  PubMed  Google Scholar 

  19. Ataseven B, et al. Prognostic impact of debulking surgery and residual tumor in patients with epithelial ovarian cancer FIGO stage IV. Gynecol Oncol. 2016;140(2):215–20.

    Article  PubMed  Google Scholar 

  20. Ataseven B, et al. Skeletal Muscle Attenuation (Sarcopenia) predicts reduced overall survival in patients with advanced epithelial ovarian cancer undergoing primary debulking surgery. Ann Surg Oncol. 2018;25(11):3372–9.

    Article  PubMed  Google Scholar 

  21. Braicu E-IS. J; Richter, R; Pietzner, K; Denkert, C; Fotopoulou, C; Role of histological type on surgical outcome and survival following radical primary tumour debulking of epithelial ovarian, fallopian tube and peritoneal cancers. Br J Cancer. 2011;105(12):1818–24.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Bristow RE, et al. Analysis of racial disparities in stage IIIC epithelial ovarian cancer care and outcomes in a tertiary gynecologic oncology referral center. Gynecol Oncol. 2011;122(2):319–23.

    Article  PubMed  Google Scholar 

  23. Chang SJ, Bristow RE, Ryu HS. Impact of complete cytoreduction leaving no gross residual disease associated with radical cytoreductive surgical procedures on survival in advanced ovarian cancer. Ann Surg Oncol. 2012;19(13):4059–67.

    Article  PubMed  Google Scholar 

  24. Chen M, et al. A survival analysis comparing women with ovarian low-grade serous carcinoma to those with high-grade histology. Onco Targets Ther. 2014;7:1891–9.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Cheng XZ, Zhou Z, Yang MY, Cai YL, Deng F, Chen XX. Prognostic factors for types I and II epithelial ovarian cancer in the elderly. Eur J Gynaecol Oncol. 2020;41(1):7–15.

    Article  Google Scholar 

  26. Davidson BA, et al. Surgical complexity score and role of laparoscopy in women with advanced ovarian cancer treated with neoadjuvant chemotherapy. Gynecol Oncol. 2019;152(3):554–9.

    Article  PubMed  Google Scholar 

  27. Delga B, et al. 30 years of experience in the management of stage iii and iv epithelial ovarian cancer: impact of surgical strategies on survival. Cancers (Basel). 2020;12(3):768.

    Article  CAS  PubMed  Google Scholar 

  28. Di Giorgio A, et al. Cytoreduction (Peritonectomy Procedures) Combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in advanced ovarian cancer: retrospective italian multicenter observational study of 511 cases. Ann Surg Oncol. 2017;24(4):914–22.

    Article  PubMed  Google Scholar 

  29. Nickles Fader A, Java J, Ueda S, Bristow RE, Armstrong DK, Bookman MA, Gershenson DM. Gynecologic Oncology Group (GOG); , Survival in women with grade 1 serous ovarian carcinoma. Obstet Gynecol. 2013;122(2 Pt 1):225–32.

    Article  PubMed  Google Scholar 

  30. Fago-Olsen CL, et al. Does neoadjuvant chemotherapy impair long-term survival for ovarian cancer patients? a nationwide Danish study. Gynecol Oncol. 2014;132(2):292–8.

    Article  PubMed  Google Scholar 

  31. Feng Z, et al. Prognostic impact of the time interval from primary surgery to intravenous chemotherapy in high grade serous ovarian cancer. Gynecol Oncol. 2016;141(3):466–70.

    Article  PubMed  Google Scholar 

  32. Fleming ND, et al. Laparoscopic surgical algorithm to triage the timing of tumor reductive surgery in advanced ovarian cancer. Obstet Gynecol. 2018;132(3):545–54.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Gadducci A, et al. Patterns of recurrence and clinical outcome of patients with stage IIIC to stage IV epithelial ovarian cancer in complete response after primary debulking surgery plus chemotherapy or neoadjuvant chemotherapy followed by interval debulking surgery: an Italian multicenter retrospective study. Int J Gynecol Cancer. 2017;27(1):28–36.

    Article  PubMed  Google Scholar 

  34. Gao Y, et al. Evaluating the benefits of neoadjuvant chemotherapy for advanced epithelial ovarian cancer: a retrospective study. J Ovarian Res. 2019;12(1):85.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Deng F, et al. Age is associated with prognosis in serous ovarian carcinoma. J Ovarian Res. 2017;10(1):36.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Gonzalez-Martin A, et al. Exploratory outcome analyses according to stage and/or residual disease in the ICON7 trial of carboplatin and paclitaxel with or without bevacizumab for newly diagnosed ovarian cancer. Gynecol Oncol. 2019;152(1):53–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hosono S, et al. Comparison between serous and non-serous ovarian cancer as a prognostic factor in advanced epithelial ovarian carcinoma after primary debulking surgery. Int J Clin Oncol. 2011;16(5):524–32.

    Article  PubMed  Google Scholar 

  38. Kalapotharakos G, et al. High preoperative blood levels of HE4 predicts poor prognosis in patients with ovarian cancer. J Ovarian Res. 2012;5(1):20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kumar A, et al. Muscle composition measured by CT scan is a measurable predictor of overall survival in advanced ovarian cancer. Gynecol Oncol. 2016;142(2):311–6.

    Article  MathSciNet  PubMed  Google Scholar 

  40. Landrum LM, et al. Prognostic factors for stage III epithelial ovarian cancer treated with intraperitoneal chemotherapy: a Gynecologic Oncology Group study. Gynecol Oncol. 2013;130(1):12–8.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Langstraat C, Aletti GD, Cliby WA. Morbidity, mortality and overall survival in elderly women undergoing primary surgical debulking for ovarian cancer: a delicate balance requiring individualization. Gynecol Oncol. 2011;123(2):187–91.

    Article  CAS  PubMed  Google Scholar 

  42. Luyckx M, et al. Maximal cytoreduction in patients with FIGO stage IIIC to stage IV ovarian, fallopian, and peritoneal cancer in day-to-day practice: a retrospective french multicentric study. Int J Gynecol Cancer. 2012;22(8):1337–43.

    Article  PubMed  Google Scholar 

  43. Mahner S, et al. Prognostic impact of the time interval between surgery and chemotherapy in advanced ovarian cancer: analysis of prospective randomised phase III trials. Eur J Cancer. 2013;49(1):142–9.

    Article  CAS  PubMed  ADS  Google Scholar 

  44. Manning-Geist BL, et al. Moving beyond “complete surgical resection” and “optimal”: Is low-volume residual disease another option for primary debulking surgery? Gynecol Oncol. 2018;150(2):233–8.

    Article  PubMed  Google Scholar 

  45. Markauskas A, et al. Primary surgery or interval debulking for advanced epithelial ovarian cancer: does it matter? Int J Gynecol Cancer. 2014;24(8):1420–8.

    Article  PubMed  Google Scholar 

  46. Melamed A, et al. Associations between residual disease and survival in epithelial ovarian cancer by histologic type. Gynecol Oncol. 2017;147(2):250–6.

    Article  PubMed  Google Scholar 

  47. Mizuno M, et al. Prognostic value of histological type in stage IV ovarian carcinoma: a retrospective analysis of 223 patients. Br J Cancer. 2015;112(8):1376–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Munoz-Casares FC, et al. Peritonectomy procedures and HIPEC in the treatment of peritoneal carcinomatosis from ovarian cancer: Long-term outcomes and perspectives from a high-volume center. Eur J Surg Oncol. 2016;42(2):224–33.

    Article  CAS  PubMed  Google Scholar 

  49. Phelps DL, et al. Methylation of MYLK3 gene promoter region: a biomarker to stratify surgical care in ovarian cancer in a multicentre study. Br J Cancer. 2017;116(10):1287–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Phillips A, et al. Complete cytoreduction after five or more cycles of neo-adjuvant chemotherapy confers a survival benefit in advanced ovarian cancer. Eur J Surg Oncol. 2018;44(6):760–5.

    Article  PubMed  Google Scholar 

  51. Ren Y, et al. Radical surgery versus standard surgery for primary cytoreduction of bulky stage IIIC and IV ovarian cancer: an observational study. BMC Cancer. 2015;15:583.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Ren T, et al. Endometriosis is the independent prognostic factor for survival in Chinese patients with epithelial ovarian carcinoma. J Ovarian Res. 2017;10(1):67.

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  53. Rodriguez N, et al. Upper abdominal procedures in advanced stage ovarian or primary peritoneal carcinoma patients with minimal or no gross residual disease: an analysis of Gynecologic Oncology Group (GOG) 182. Gynecol Oncol. 2013;130(3):487–92.

    Article  PubMed  Google Scholar 

  54. Rosendahl M, et al. Specific regions, rather than the entire peritoneal carcinosis index, are predictive of complete resection and survival in advanced epithelial ovarian cancer. Int J Gynecol Cancer. 2018;28(2):316–22.

    Article  PubMed  Google Scholar 

  55. Rungruang BJ, et al. What is the role of retroperitoneal exploration in optimally debulked stage IIIC epithelial ovarian cancer? an NRG Oncology/Gynecologic Oncology Group ancillary data study. Cancer. 2017;123(6):985–93.

    Article  PubMed  Google Scholar 

  56. Rutten MJ, et al. Prognostic value of residual disease after interval debulking surgery for FIGO Stage IIIC and IV epithelial ovarian cancer. Obstet Gynecol Int. 2015;2015:464123.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Rutten IJ, et al. The influence of sarcopenia on survival and surgical complications in ovarian cancer patients undergoing primary debulking surgery. Eur J Surg Oncol. 2017;43(4):717–24.

    Article  CAS  PubMed  Google Scholar 

  58. Searle G, et al. Prolonged interruption of chemotherapy in patients undergoing delayed debulking surgery for advanced high grade serous ovarian cancer is associated with a worse prognosis. Gynecol Oncol. 2020;158(1):54–8.

    Article  CAS  PubMed  Google Scholar 

  59. Tewari KS, et al. Early initiation of chemotherapy following complete resection of advanced ovarian cancer associated with improved survival: NRG Oncology/Gynecologic Oncology Group study. Ann Oncol. 2016;27(1):114–21.

    Article  CAS  PubMed  Google Scholar 

  60. Timmermans M, et al. Interval between debulking surgery and adjuvant chemotherapy is associated with overall survival in patients with advanced ovarian cancer. Gynecol Oncol. 2018;150(3):446–50.

    Article  CAS  PubMed  Google Scholar 

  61. Trillsch F, et al. Treatment reality in elderly patients with advanced ovarian cancer: a prospective analysis of the OVCAD consortium. J Ovarian Res. 2013;6(1):42.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Trope CG, et al. Neoadjuvant chemotherapy, interval debulking surgery or primary surgery in ovarian carcinoma FIGO stage IV? Eur J Cancer. 2012;48(14):2146–54.

    Article  PubMed  Google Scholar 

  63. van Altena AM, et al. Efficacy of a regional network for ovarian cancer care. Obstet Gynecol. 2013;122(3):668–75.

    Article  PubMed  Google Scholar 

  64. Vincent L, et al. Prognostic factors of overall survival for patients with FIGO stage IIIc or IVa ovarian cancer treated with neo-adjuvant chemotherapy followed by interval debulking surgery: a multicenter cohort analysis from the FRANCOGYN study group. Eur J Surg Oncol. 2020;46(9):1689–96.

    Article  CAS  PubMed  Google Scholar 

  65. Zhou J, et al. The effect of lymphadenectomy in advanced ovarian cancer according to residual tumor status: a population-based study. Int J Surg. 2018;52:11–5.

    Article  PubMed  Google Scholar 

  66. Braicu E-I, et al. Role of histological type on surgical outcome and survival following radical primary tumour debulking of epithelial ovarian, fallopian tube and peritoneal cancers. Br J Cancer. 2011;105(12):1818–24.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Timmermans M, et al. The prognostic value of residual disease after neoadjuvant chemotherapy in advanced ovarian cancer a systematic review. Gynecol Oncol. 2019;153(2):445–51.

    Article  CAS  PubMed  Google Scholar 

  68. Hanker LC, et al. The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy. Ann Oncol. 2012;23(10):2605–12.

    Article  CAS  PubMed  Google Scholar 

  69. Vergote I, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363(10):943–53.

    Article  CAS  PubMed  Google Scholar 

  70. Fagotti A, et al. Randomized trial of primary debulking surgery versus neoadjuvant chemotherapy for advanced epithelial ovarian cancer (SCORPION-NCT01461850). Int J Gynecol Cancer. 2020;30(11):1657–64.

    Article  PubMed  Google Scholar 

  71. Inci MG, et al. ECOG and BMI as preoperative risk factors for severe postoperative complications in ovarian cancer patients: results of a prospective study (RISC-GYN—trial). Arch Gynecol Obstet. 2021;304(5):1323–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Winter WE III, et al. Prognostic factors for stage iii epithelial ovarian cancer: a gynecologic oncology group study. J Clin Oncol. 2007;25(24):3621–7.

    Article  PubMed  Google Scholar 

  73. Algethami M, et al. Towards personalized management of ovarian cancer. Cancer Manag Res. 2022;14:3469–83.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Konstantinopoulos PA, Lheureux S, Moore KN. PARP inhibitors for ovarian cancer: current indications, future combinations, and novel assets in development to target DNA damage repair. Am Soc Clin Oncol Educ Book. 2020;40:1–16.

    PubMed  Google Scholar 

  75. Arora S, et al. FDA approval summary: olaparib monotherapy or in combination with bevacizumab for the maintenance treatment of patients with advanced ovarian cancer. Oncologist. 2021;26(1):e164–72.

    Article  CAS  PubMed  Google Scholar 

  76. European Medicines Agency. AVASTIN (Bevacizumab) Summary of Product Characteristics. 2011. Available from: https://www.ema.europa.eu/en/documents/variation-report/avastin-h-c-582-ii-0041-epar-assessment-report-variation_en.pdf. Cited 2023 29th September.

  77. Food and Drug Administration. AVASTIN (Bevacizumab) Prescribing Information. 2018. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125085s0169lbl.pdf. Cited 2022 16th September.

  78. Wang Y, et al. PARP Inhibitors in patients with newly diagnosed advanced ovarian cancer: a meta-analysis of randomized clinical trials. Front Oncol. 2020;10:1204.

    Article  PubMed  PubMed Central  Google Scholar 

  79. European Medicines Agency. LYNPARZA (Olaparib) Summary of Product Characteristics. 2019; Available from: https://www.ema.europa.eu/en/documents/product-information/lynparza-epar-product-information_en.pdf. Cited 2023 29th September.

  80. Garrido MP, et al. Current treatments and new possible complementary therapies for epithelial ovarian cancer. Biomedicines. 2021;10(1):77.

    Article  PubMed  PubMed Central  Google Scholar 

  81. National Institute for Health and Care Excellence (NICE). National Institute for Health and Care Excellence (NICE): The guidelines manual: appendix C: methodology checklist: randomised controlled trials. 2012. Available from: https://www.nice.org.uk/process/pmg6/resources/the-guidelines-manual-appendices-bi-2549703709/chapter/appendix-c-methodology-checklist-randomised-controlled-trials. Cited 2022 20th April.

  82. Wells GA, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Cited 2022 20th April.

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Acknowledgements

The authors would like to acknowledge Hasan H. Jamal, MSc at GSK for their review and coordination of the manuscript. The authors would also like to acknowledge Tatia Woodward, MS, GSK, Philadelphia, PA, USA, for her contributions to the study design. Medical writing support was provided by Eithne Maguire, PhD, and Claire Kelly, PhD, Fishawack Indicia Ltd., UK, part of Avalere Health, and was funded by GSK.

Funding

This study was funded by GSK (OneCDP 214515).

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Authors and Affiliations

  1. David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    Dana M. Chase

  2. Bridge Medical, London, UK

    Anadi Mahajan, David Alexander Scott & Neil Hawkins

  3. GSK, Durham, NC, USA

    Linda Kalilani

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  1. Dana M. Chase
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  2. Anadi Mahajan
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Contributions

Dana Chase: Conceptualisation; Roles/Writing—original draft; Writing—review & editing; Anadi Mahajan: Data curation, Formal analysis; Validation; Roles/Writing—original draft; Writing—review & editing; David Scott: Data curation, Formal analysis; Validation; Data Curation; Roles/Writing—original draft; Writing—review & editing; Neil Hawkins: Data curation, Formal analysis; Validation; Roles/Writing—original draft; Writing—review & editing; Linda Kalilani: Conceptualization; Data curation; Formal analysis; Validation; Data Curation; Roles/Writing—original draft; Writing—review & editing.

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Correspondence to Dana M. Chase.

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Competing interests

DC reports speakers’ bureau fees and/or advisory roles from GSK, AstraZeneca, Takeda, Clovis, Roche, and Merck. AM, DAS, and NH have no conflict of interest to disclose. LK is an employee of GSK.

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Chase, D.M., Mahajan, A., Scott, D.A. et al. The impact of varying levels of residual disease following cytoreductive surgery on survival outcomes in patients with ovarian cancer: a meta-analysis. BMC Women's Health 24, 179 (2024). https://doi.org/10.1186/s12905-024-02977-5

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BMC Women's Health

ISSN: 1472-6874

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