Article Text

Cytoreductive surgery followed by chemotherapy and olaparib maintenance in BRCA 1/2 mutated recurrent ovarian cancer: a retrospective MITO group study
  1. Sabrina Chiara Cecere1,
  2. Lucia Musacchio2,3,
  3. Michele Bartoletti4,5,
  4. Vanda Salutari2,
  5. Laura Arenare6,
  6. Domenica Lorusso2,7,8,
  7. Graziana Ronzino9,
  8. Rossella Lauria10,
  9. Gennaro Cormio11,
  10. Emanuele Naglieri12,
  11. Paolo Scollo13,
  12. Claudia Marchetti2,
  13. Francesco Raspagliesi8,
  14. Stefano Greggi14,
  15. Saverio Cinieri15,
  16. Alice Bergamini16,17,
  17. Michele Orditura18,
  18. Giorgio Valabrega19,20,
  19. Giovanni Scambia2,7,
  20. Fabio Martinelli8,
  21. Elisabetta De Matteis9,
  22. Cinzia Cardalesi10,
  23. Vera Loizzi11,
  24. Giorgia Perniola3,
  25. Claudia Carella21,
  26. Giuseppa Scandurra13,
  27. Gaia Giannone19,20 and
  28. Sandro Pignata1
  1. 1 Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy
  2. 2 Department of Women and Child Health, Division of Gynecologic Oncology, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
  3. 3 Department of Maternal and Child Health and Urological Sciences, Policlinico Umberto I, Sapienza, University of Rome, Rome, Italy
  4. 4 Unit of Medical Oncology and Cancer Prevention, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano, CRO, Aviano, Italy
  5. 5 Department of Medicine, University of Udine, Udine, Italy
  6. 6 Clinical Trial Unit, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Campania, Italy
  7. 7 Department of Life Science and Public Health, Catholic University of Sacred Heart, Largo Agostino Gemelli, Rome, Italy
  8. 8 Gynecologic Oncology Unit, Fondazione Istituto Nazionale Tumori IRCCS, Milan, Italy
  9. 9 Medical Oncology Unit, Vito Fazzi Hospital, Lecce, Italy
  10. 10 Division of Medical Oncology, Azienda Ospedaliera Universitaria Federico II, Napoli, Campania, Italy
  11. 11 Gynecologic Oncology Unit, Department of Biomedical Sciences and Human Oncology, University of Bari, Bari, Italy
  12. 12 Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
  13. 13 Medical Oncology Unit, Cannizzaro Hospital, Catania, Italy
  14. 14 Gynecologic Oncology, National Cancer Institute, Institute for Hospitalization and Care Scientific Foundation Pascale, Napoli, Campania, Italy
  15. 15 Division of Medical Oncology, Ospedale “Senatore Antonio Perrino”, Brindisi, Brindisi, Italy
  16. 16 Department of Obstetrics and Gynecology, IRCCS, San Raffaele Hospital, Milan, Italy
  17. 17 Università Vita Salute San Raffaele, Milan, Italy
  18. 18 Università degli Studi della Campania Luigi Vanvitelli, Napoli, Campania, Italy
  19. 19 Candiolo Cancer Institute, FPO- IRCCS, Candiolo (TO), Italy
  20. 20 Department of Oncology, University of Turin, Torino, Piemonte, Italy
  21. 21 Interventional Oncology Unit with Integrated Section of Translational Medical Oncology, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy
  1. Correspondence to Professor Sandro Pignata, Gynecological Oncology, National Cancer Institute, Naples, Italy; s.pignata{at}


Introduction The role of cytoreductive surgery in the poly-ADP ribose polymerase inhibitors era is not fully investigated. We evaluated the impact of surgery performed prior to platinum-based chemotherapy followed by olaparib maintenance in platinum-sensitive BRCA-mutated recurrent ovarian cancer.

Methods This retrospective study included platinum-sensitive recurrent ovarian cancer BRCA-mutated patients from 13 Multicenter Italian Trials in Ovarian cancer and gynecological malignancies centers treated between September 2015 and May 2019. The primary outcomes were progression-free survival and overall survival. Data on post-progression treatment was also assessed.

Results Among 209 patients, 72 patients (34.5%) underwent cytoreductive surgery followed by platinum-based chemotherapy and olaparib maintenance, while 137 patients (65.5%) underwent chemotherapy treatment alone. After a median follow-up of 37.3 months (95% CI: 33.4 to 40.8), median progression-free survival in the surgery group was not reached, compared with 11 months in patients receiving chemotherapy alone (P<0.001). Median overall survival was nearly double in patients undergoing surgery before chemotherapy (55 vs 28 months, P<0.001). Post-progression therapy was assessed in 127 patients: response rate to chemotherapy was 29.2%, 8.8%, and 9.0% in patients with platinum-free interval >12 months, between 6 and 12 months, and <6 months, respectively.

Conclusion Cytoreductive surgery performed before platinum therapy and olaparib maintenance was associated with longer progression-free survival and overall survival in BRCA-mutated platinum-sensitive relapsed ovarian cancer patients. In accordance with our preliminary results, the response rate to chemotherapy given after progression during olaparib was associated with platinum-free interval.

  • ovarian cancer
  • cytoreduction surgical procedures

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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  • BRCA-mutated patients undergoing secondary cytoreductive surgery have improved outcomes.

  • Patients who underwent secondary surgery had longer progression-free survival and overall survival.

  • Response to subsequent chemotherapy given after olaparib progression is lower than expected.


Epithelial ovarian cancer remains the leading cause of death among gynecological malignancies, with an estimated 21 750 new cases and 13 940 deaths in 2020.1 Cytoreductive surgery, with the goal of no residual disease, and a platinum-based chemotherapy are still the cornerstones of treatment for advanced disease. Nevertheless, approximately 75% of patients experience relapse within 2 years from diagnosis, and the majority progressively develop resistance to chemotherapy.1 Increasing knowledge concerning the molecular and genetic characteristics underlying epithelial ovarian cancer, in particular the lack of a functional homologous recombination repair system, has led to the development of a new class of drugs called poly-ADP-ribose polymerase (PARP) inhibitors.

The improvements in progression-free survival documented in three randomized phase III clinical trials led to the approval of olaparib, niraparib, and rucaparib, respectively, as maintenance therapy in platinum-sensitive relapsed disease, reshaping the ovarian cancer treatment landscape.2–4 Moreover, results from recent phase III clinical trials have demonstrated significant activity of PARP inhibitors in the first-line maintenance setting in patients with or without BRCA mutation.5–7

Patients harboring a BRCA1/2 mutation seem to benefit the most from PARP inhibitors' maintenance and olaparib has demonstrated a clinically meaningful gain in survival in BRCA-mutated patients when compared with placebo in the recurrent setting.8 Notwithstanding the long benefit that some patients can derive from a maintenance therapy with PARP inhibitors, recurrent epithelial ovarian cancer remains a lethal disease, mainly due to the development of resistance to therapies.

Published data suggested that cytoreduction might increase olaparib efficacy in the recurrent setting9 while data from a post-hoc analysis of the SOLO1 study have shown an increasing benefit of olaparib in patients with no residual tumor at primary surgery, compared with those with residual tumor.10 The role of surgery in the management of recurrent ovarian cancer remains a topic of controversy and, recently, the DESKTOP III trial showed a significant overall survival benefit for selected patients who undergo optimal debulking at recurrence.11 The role of surgery at recurrence in the era of PARP inhibitors has been poorly investigated. We conducted this multicenter, retrospective study to evaluate the impact of cytoreductive surgery performed before platinum-based chemotherapy and olaparib maintenance in recurrent BRCA-mutated epithelial ovarian cancer.


This is an observational, multicenter, retrospective analysis conducted in 13 Multicenter Italian Trials in Ovarian cancer and gynecological malignancies (MITO) centers, coordinated by the National Cancer Institute of Naples from June 2015 to May 2019. Preliminary results from a dataset of 234 patients with recurrent platinum-sensitive ovarian cancer, harboring a BRCA1/2 germline and/or somatic mutation patients were previously reported.12

In the current analysis, only the 209 patients with information on cytoreductive surgery at the time of recurrence were included with an updated follow-up.

Cytoreductive surgery was defined as a surgical intervention following recurrence that included maximal cytoreduction effort, excluding procedures done for diagnosis of recurrence or palliative purpose. The overall study follow-up was updated and the patients were censored on May 31, 2020. Baseline characteristics of the overall population were reported using continuous variables as median and interquantile range, while categorical variables were expressed as absolute number and percentage. The comparison between categorical variables were tested by Pearson chi square test and the student T-test was applied for continuous variables. All statistical tests were considered significant using P<0.05. The main objective of this analysis was to evaluate the prognostic effect of cytoreductive surgery performed at disease relapse before beginning platinum therapy and olaparib maintenance on progression-free survival and overall survival. Progression-free survival was defined as the time between treatment with platinum-therapy start and progression or death for any cause. Overall survival was defined as the time between treatment with platinum therapy start and death for any cause. Patients who did not experience disease progression were censored on May 31, 2020. Progression-free survival and overall survival curves were described according to the Kaplan–Meier product limit method and compared with the Log Rank test.13 Median follow-up was calculated according to the inverted Kaplan–Meier technique. In order to assess the prognostic effect of cytoreductive surgery on both progression-free survival and overall survival, a multivariate Cox model was performed including age (continuous), Eastern Cooperative Oncology Group (ECOG) Performance Status (0 vs 1–2), number of chemotherapy lines received before surgery (>1 vs 1), residual disease at the first cytoreductive surgery (present vs absent), bevacizumab treatment in the previous lines (yes vs no), BRCA mutation (1 vs 2), using center as stratify variable. The assumption of hazard proportionality was checked using Schoenfeld’s residuals.14 To take into account the imbalances of patient characteristics between the two groups, a two-step sensitivity analysis for progression-free survival was also performed, excluding patients who had received more than one previous line of therapy (first step, n=93 patients) then excluding centers where secondary surgery was not performed or it was performed in all patients enrolled (second step, n=71 patients). The response to post-progression treatment was described and the association with platinum-free interval was tested using Fisher's exact test. In accordance with journal guidelines, we will provide our data for the reproducibility of this study in other centers if such is requested.


Overall, 234 patients were identified, of which 25 patients were excluded because data on surgery at disease recurrence was not collected (Online supplemental figure 1). In this study, 209 patients were evaluated, 72 patients (34.5%) underwent cytoreductive surgery before platinum-based chemotherapy and olaparib maintenance while 137 patients (65.5%) received chemotherapy alone.

Supplemental material

At initial diagnosis, 89% of patients had advanced epithelial ovarian cancer (78.0% FIGO stage III and 11.0% stage IV). No differences were found in terms of median age, FIGO stage, and bevacizumab maintenance between the two study groups at baseline. Regarding BRCA gene status, 68.4% of patients had a BRCA1 mutation while 31.1% had a BRCA2 mutation: only one patient had both BRCA genes mutated (Table 1). Patient characteristics at recurrence are reported in Table 1. Median age at relapse was 57.7 years (interquantile range: 51.1–63.0) in the overall population. Statistically significant differences were observed in terms of ECOG Performance Status (P=0.012), and number of previous chemotherapy lines (P=0.007) in favor of patients undergoing surgery before platinum-based chemotherapy and olaparib maintenance compared with those receiving chemotherapy only. Moreover, a statistically significant difference was found according to the center (P<0.001), suggesting that the indications to secondary surgery vary among the different physicians. No difference in the pattern of disease presentation was found between patients undergoing surgery and those who did not, in terms of peritoneal involvement, lymph node metastasis, and parenchymal recurrence (P=0.33). In the surgery group, the majority of patients (83.3%) were optimally debulked (no residual tumor), while 2.8% achieved a microscopic residual tumor (<1 cm) and 13.9% had macroscopic residual (≥1 cm). The majority of the patients (70.9%) received a platinum-based doublet before olaparib maintenance compared with platinum monotherapy.

Table 1

Patients' characteristics at recurrence disease before olaparib maintenance

The survival analysis was performed on 208 patients due to one missing case. At a median follow-up of 37.3 months (95% CI: 33.4 to 40.8), median progression-free survival in the surgery group was not reached, while in the group who received chemotherapy alone it was 11.1 months (log rank <0.001) (Figure 1a). Median overall survival was 55.1 months in the surgery group and 28.1 months for patients in the no surgery group (log rank <0.001) (Figure 1b). Moreover, in terms of progression-free survival, BRCA2-mutated patients had a better prognosis when compared with BRCA1 carriers (log rank=0.0498) (Online supplemental figure 2).

Figure 1

(A) progression-free survival in 72 patients undergoing surgery vs 136 not operated patients. (B) overall survival in 71 patients undergoing surgery vs 137 not operated patients.

In the multivariate Cox model (Table 2), surgery performed at disease relapse before chemotherapy and olaparib maintenance was confirmed as an independent prognostic factor for both progression-free survival (HR 0.19; 95% CI: 0.10 to 0.33, P<0.001) and overall survival (HR 0.17; 95% CI: 0.08 to 0.36, P<0.001), along with ECOG performance status (HR 2.29; 95% CI: 1.3 to 3.9, P=0.003) for progression-free survival and (HR 3.06; 95% CI: 1.6 to 5.8 P=0.001) for overall survival. Surgery was confirmed as the only independent prognostic factor for progression-free survival even at the sensitivity analysis performed to adjust for imbalances in patient characteristics between the groups (online supplemental tables 2 and 3).

Table 2

Multivariate analysis of progression-free survival and overall survival

Response to post-progression treatments was evaluated in 127 patients (Table 3). Among these patients receiving further treatment, 110 patients were evaluable for response. The overall response rate was 29.2% in patients with platinum-free interval more than 12 months, while overall response rates of 8.8% and 9.0% were achieved in patients with a platinum-free interval between 6 and 12 months, and less than 6 months, respectively.

Table 3

Response to chemotherapy in Patients treated after progression to olaparib

Platinum-based chemotherapy was the most frequent treatment administered (59 patients, 46.5%), followed by weekly paclitaxel (19 patients, 15.0%) and trabectedin (18 patients, 14.2%). Of 59 patients receiving platinum-based therapy after olaparib progression, the overall response rate was 0% in patients with platinum-free interval less than 6 months, 10.5% and 38% in patients with platinum-free interval between 6 and 12 months, and more than 12 months, respectively. Moreover, we found a statistically significant difference in terms of response to chemotherapy at the time of progression from olaparib between the two groups. Specifically, we found that patients undergoing cytoreductive surgery achieved a higher response, including partial and complete response, to subsequent chemotherapy, compared with those in the no surgery group (34.8% vs 12.6%, P=0.009).


Summary of Main Results

Our data showed that patients undergoing surgery at the time of epithelial ovarian cancer recurrence before starting platinum therapy and olaparib maintenance had longer overall survival (HR=0.17; 95% CI: 0.08 to 0.36) and progression-free survival (HR=0.19; 95% CI: 0.10 to 0.33) compared with those receiving only medical therapies. Although the retrospective nature of the data does not allow for definitive conclusions, we hypothesize that the removal of chemo/PARP inhibitors-resistant cells by surgery may determine better outcomes from maintenance therapy.

Results in the Context of Published Literature

The role of cytoreductive surgery at the time of ovarian cancer recurrence has been debated and explored in different retrospective and prospective analyses, with conflicting results.15–20 In GOG-213, involving patients with platinum-sensitive recurrent ovarian cancer, secondary surgical cytoreduction followed by chemotherapy did not result in longer overall survival than chemotherapy alone.16 On the other hand, SOC1 trial demonstrated that secondary cytoreductive surgery in selected patients resulted in a significant extension of progression-free survival (17.4 months in the surgery arm and 11.9 months in the no surgery arm, respectively, with HR=0.58, 95% CI 0.45 to 0.74, P<0.001).18 Recently, results from the prospective, randomized trial DESKTOP III showed that radical surgery in patients with a positive Arbeitsgemeinschaft Gynäkologische Onkologie score resulted in a median progression-free survival benefit of 4.4 months (18.4 months in the surgery arm vs 14 months in the no-surgery arm, P<0.001) and in a median overall survival benefit of 7.7 months (53.7 months in the surgery arm vs 46 months in the no surgery arm). This benefit seems to be achieved only in patients obtaining an optimal resection without residual tumor.11 However, the role of BRCA mutational status in the outcomes of these patients has not been investigated in the DESKTOP trial.

Only one retrospective study has been published regarding the impact of secondary cytoreduction surgery at epithelial ovarian cancer recurrence before olaparib maintenance. This case-control study with small sample size suggested that surgery increases time to first subsequent therapy compared with medical treatment alone (42 months vs 16 months; P=0.05).9 Results from the SOLO1 and PAOLA1 trials in the first-line setting, showed that patients undergoing optimal debulking surgery were those who benefited the most, compared with patients with residual disease after primary surgery (median progression-free survival not reached vs 15.3 months).10 21

Strengths and Weaknesses

The strength of our study lies in the fact that we evaluated the impact of secondary cytoreduction in the setting of BRCA-mutated patients who underwent chemotherapy followed by maintenance therapy with PARP inhibitors. This data should be interpreted with caution due to the retrospective nature of the study and because of the differences in patients' characteristics found between patients who did and did not have surgery, with more favorable characteristics for patients undergoing surgery (number of previous lines of chemotherapy and ECOG Performance Status). Clinical differences between the two groups reported above, may justify at least in part, the improved progression-free survival and overall survival of patients who underwent surgery. Given the results in favor of patients receiving surgery, it is possible to hypothesize that such results could be not only related to surgery but also to a higher efficacy of olaparib after primary resistant cells are removed. In accordance with our finding, we consider that the tumor burden removal increases effectiveness to chemotherapy and olaparib, decreasing the risk of resistance.

Implications for Practice and Future Research

It is known that patients with recurrent disease may develop resistance to platinum-based chemotherapy. Recent observations suggest that reactivation of the function homologous recombination pathway in initially homologous recombination deficiency, occurring by multiple different mechanisms, is strongly associated with the acquired platinum resistance mechanism and that resistance to platinum chemotherapy is predictive of resistance to PARP inhibitors.22 It is not yet clear whether mechanisms of acquired resistance to platinum agents and PARP inhibitors develop in parallel. Interestingly, an emerging area to explore is post-progression treatment and response after olaparib progression. In the preliminary report of this study, we found a lower than expected response rate to subsequent chemotherapy compared with what is expected according to the platinum-free interval.12

This updated analysis confirmed this observation, showing an overall response rate of only 29.2% in patients with a platinum-free interval of more than 12 months, 8.8% and 9.0% in women with a platinum-free interval between 6 and 12 months and less than 6 months, respectively. These findings are in accordance with the recent results of the SOLO2 trial showing that patients in the placebo arm benefit the most from a rechallenge with platinum compared with those who received olaparib with median times to a second progression of approximately 14 months vs 7 months, respectively.23


With the intrinsic limit of its retrospective nature, the present data are hypothesis-generating for the planning of a prospective trial investigating the role of surgery before a platinum-based therapy with PARP inhibitors' maintenance. A randomized controlled trial by the MITO Group is planned in patients progressing during or after first-line PARP inhibitors' maintenance.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

Ethics statements


The authors thank Margherita Tambaro, Gelsomina Iovane, Angela Maria Trujillo, and Patrizia Piccirillo for data management.


Supplementary materials

  • Supplementary Data

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  • SCC and LM are joint first authors.

  • Twitter @lucia_musacchio, @Barto_Med, @DrFMartinelli, @PignataSandro

  • SCC and LM contributed equally.

  • Correction notice Since Online First publication, the author's affiliations have been updated: affiliation 12 has been amended and affiliation 21 has been added.

  • Contributors Conceptualization SP, SCC; data curation LM, SCC, MB; formal analysis LA, LM; investigation SCC, LM, SP; methodology SCC, LM, SP; project administration SP; supervision SP; writing original draft SCC, LM, SP. All authors acquired data, and revised and approved the final version of the manuscript.

  • Funding SP is recipient of grants from Associazione Italiana per la Ricerca sul Cancro (AIRC). Grants numbers IG-5776, IG-13114, IG-18921.

  • Competing interests VS has been part of advisory boards of GSK, PharmaMar, Roche, MSD, EISAI, Clovis, AstraZeneca. DL reports personal financial interests (advisory roles) with AstraZeneca, Biocad, Clovis Oncology, Genmab, Merck, MSD, Roche, Tesaro-GSK, Amgen, Immunogen, Pharmamar, and institutional financial interests (Study Grants) with AstraZeneca, Clovis Oncology, MSD, Tesaro-GSK, Pharmamar, Roche. Others Global Clinical Lead ENGOT-CX11 Pembrolizumab; Board of Directors, GCIG (Gynecologic Cancer Inter Group). CM reports an advisory role for GSK, Arquer Diagnostic, Pharmamar, Clovis Oncology, and travel grant from Roche. FR reports honoraria from GSK, Pharmamar, Clovis, MSD as sponsors for meetings. GV is an advisor for AstraZeneca, GSK, Amgen, and received speaking honoraria from AstraZeneca, GSK, Roche, Pharmamar. GS reports honoraria from AstraZeneca, MSD, Roche, Clovis, GSK, Pharmamar, Roche (advisory role), and received institutional financial interest (study grants) from AstraZeneca, MSD, GSK, Pharmamar, and he is a member of the board of the National Health Institute. SP reports honoraria from AstraZeneca, MSD, Roche Clovis, GSK Pfizer Pharmamar.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.