Redondo et al. Journal of Ovarian Research (2021) 14:72 https://doi.org/10.1186/s13048-021-00816-x RESEARCH Open Access Management of advanced ovarian cancer in Spain: an expert Delphi consensus Andres Redondo1* , Ana Oaknin2, Maria Jesus Rubio3, Maria-Pilar Barretina-Ginesta4, Ana de Juan5, Luis Manso6, Ignacio Romero7, Cristina Martin-Lorente8, Andres Poveda9 and Antonio Gonzalez-Martin10 Abstract Background: To determine the state of current practice and to reach a consensus on recommendations for the management of advanced ovarian cancer using a Delphi survey with a group of Spanish gynecologists and medical oncologists specially dedicated to gynecological tumors. Methods: The questionnaire was developed by the byline authors. All questions but one were answered using a 9- item Likert-like scale with three types of answers: frequency, relevance and agreement. We performed two rounds between December 2018 and July 2019. A consensus was considered reached when at least 75% of the answers were located within three consecutive points of the Likert scale. Results: In the first round, 32 oncologists and gynecologists were invited to participate, and 31 (96.9%) completed the online questionnaire. In the second round, 27 (87.1%) completed the online questionnaire. The results for the questions on first-line management of advanced disease, treatment of patients with recurrent disease for whom platinum might be the best option, and treatment of patients with recurrent disease for whom platinum might not be the best option are presented. Conclusions: This survey shows a snapshot of current recommendations by this selected group of physicians. Although the majority of the agreements and recommendations are aligned with the recently published ESMO- ESGO consensus, there are some discrepancies that can be explained by differences in the interpretation of certain clinical trials, reimbursement or accessibility issues. Keywords: Ovarian cancer, Advanced disease, Recurrent disease, Management, Consensus Background treatment options for primary and recurrent ovarian Worldwide, ovarian cancer comprised 3.4% of all new cancer have improved outcomes for patients, they have cases of cancer in women in 2018 [1]. Despite the im- also increased the complexity of the management of this provement of survival in recent decades among patients condition, and several areas of controversy exist. with advanced disease [2], ovarian cancer remains the Although one of the objectives of clinical practice guide- leading cause of death among gynecological cancers in lines for ovarian cancer is to improve and harmonize the developed countries [3]. management of the disease and the availability of several As in other oncology settings, the treatment of ovarian clinical practice guidelines [4–6], considerable variation cancer is continuously evolving. Thus, although new exists among countries in both the recommendations and clinical practice regarding the management of this neo- * Correspondence: andres.redondos@uam.es plasm [7, 8]. Additionally, adherence to the clinical prac- 1 Medical Oncology Department, Hospital Universitario La Paz-IdiPAZ, Universidad Autónoma de Madrid, Paseo de la Castellana, 261, 28046 Madrid, tice guidelines is not always optimal [9, 10], and this Spain might have an impact on patient outcomes, including Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Redondo et al. Journal of Ovarian Research (2021) 14:72 Page 2 of 12 survival, as well as the efficiency of the healthcare system Regarding the addition of bevacizumab to paclitaxel [7, 11, 12]. and carboplatin, the respondents agreed to recommend The objective of this study was to determine the state this approach in patients who underwent primary sur- of current practice and to reach a consensus on recom- gery if they have stage IV (median 9) or stage III cancer mendations for the management of advanced ovarian with macroscopic residual disease > 1 cm (median 9). cancer using a Delphi survey with a group of Spanish Similarly, there was agreement in recommending adding medical oncologists specially dedicated to gynecological bevacizumab after IDS for patients who require NACT tumors. when there is macroscopic residual disease or for stage IV patients (median 9). Results Response rate Treatment of patients with recurrent disease for whom In the first round, 32 oncologists and gynecologists were platinum might be the best option invited to participate, and 31 (96.9%) completed the on- The specific responses to the 13 questions of this section line questionnaire. In the second round, the 31 first- and measures of consensus are presented in Table 2. round respondents were invited to participate, and 27 For selecting the treatment for patients with a (87.1%) completed the online questionnaire. treatment-free interval of platinum (TFIp) exceeding 6 months, there was consensus among respondents that First-line management of advanced disease the following 9 factors, ordered by degree of relevance, Detailed responses to all questions in this section, in- should be taken into account: BRCA status, histological cluding the location, proportion, and strength (i.e., me- subtype, performance status (median 9 for these 3 fac- dian) of consensus, are presented in Table 1. tors), location and extent of the disease, drugs already The initial assessment for resectability always includes received and number of prior lines, residual toxicity, computed tomography (CT) of the thorax, abdomen and symptoms, comorbidities and patient preferences (me- pelvis according to the vast majority of the respondents. Posi- dian 8 for these 6 factors). The magnitude of the TFIp tron emission tomography (PET)-CT and laparoscopy are (6–12 vs > 12 months) was not considered a very rele- sometimes used (median 5 and 6, respectively), while vant factor (median 7). diffusion-weighted whole-body magnetic resonance imaging A consensus was reached (median 9) to recommend (MRI) is rarely performed (median 1). There was consensus somatic BRCA testing at the time of relapse for patients for recommending a postsurgical CT scan for all patients with germline nonmutated BRCA if somatic testing had both for those undergoing primary surgery and those under- not been performed at diagnosis. going interval surgery (median 8 in both cases). The participants agreed that for patients with recurrent There was consensus in using primary debulking sur- disease and a TFIp exceeding 6 months, a secondary cytore- gery (PDS) instead of neoadjuvant chemotherapy ductive surgery should be considered if the patient meets the (NACT) followed by interval debulking surgery (IDS) for so-called AGO (Arbeitsgemeinschaft Gynäkologische Onko- patients with stage III disease considered suitable for pri- logie- German Working Group on Gynecological Oncology) mary debulking (median 9), but consensus was not score used in the DESKTOP III trial (ECOG 0, complete re- reached for selecting this strategy as the primary strategy section at primary surgery and the absence of large volume when minimal residual disease is expected to be left after [> 500 mL] ascites) and after assessment of the extension surgery (median 6). Regarding patients with stage IV dis- using PET-CT to rule out unresectable disease (median 8 in ease, if they are considered suitable for debulking sur- both cases). In patients with subsequent relapse after second- gery, two-thirds of the respondents preferred to start ary cytoreductive surgery and a TFIp > 6 months, there was with PDS instead of NACT in the subgroup of patients no agreement in considering tertiary cytoreductive surgery with inguinal adenopathy or patients with positive for selected patients (median 7). pleural effusion (Fig. 1). A consensus with a high degree In the BRCA-mutated recurrent OC population, of agreement (100% responding 8–9, median 9) was platinum-based chemotherapy followed by a PARP in- reached in recommending IDS after NACT unless there hibitor (PARPi) was considered the treatment of choice is tumor progression or the tumor is considered if the patients have not previously been treated with unresectable. PARPi, regardless of previous treatment with bevacizu- There was no agreement for recommending intraperi- mab (median 9). Consistently, for these patients, the toneal chemotherapy for either of the two proposed clin- combination of a doublet containing carboplatin with ical scenarios. However, an important proportion of bevacizumab is infrequently used (median 3). participants (59%) fairly to fully agreed (median 7) to In the BRCA nonmutated population who has not re- recommend it for patients with optimal cytoreduction if ceived a prior PARPi, regardless of previous treatment their physical condition allows it. with bevacizumab, there was no consensus for Redondo et al. Journal of Ovarian Research (2021) 14:72 Page 3 of 12 Table 1 First-line management of advanced-stage ovarian cancer % C proportion of consensus, CT Computed tomography, M Median, MRI Magnetic resonance imaging, PET-CT Positron emission tomography–computed tomography Black shadowed areas represent the presence of consensus (i.e., ≥75% of the responses are located within those three consecutive points of the Likert scale) Gray shadowed areas represent the triplet with a greater proportion of responses but without reaching consensus threshold Redondo et al. Journal of Ovarian Research (2021) 14:72 Page 4 of 12 Fig. 1 Preference of primary debulking surgery over neoadjuvant chemotherapy in different stage IV scenarios recommending platinum-based chemotherapy followed Factors considered more relevant (median degree of by a PARPi or platinum-based chemotherapy with beva- relevance 8–9) for determining the therapeutic option cizumab. The latter option is infrequently used for pa- for patients who are ineligible for platinum were per- tients who have received first-line treatment with formance status, the patient’s desire, residual toxicity bevacizumab. and the presence of symptoms. The most frequent thera- The respondents agreed that the following factors are peutic option used for these patients is treatment within relevant for deciding the addition of bevacizumab to a clinical trial whenever possible (median 9), followed by platinum-based chemotherapy: BRCA mutation status single agent chemotherapy in combination with bevaci- (median 9), history of intestinal subocclusion (median 9), zumab (median 7). When using bevacizumab, most of presence of ascites or large pleural effusion (median 7), the respondents agreed that the preferred chemotherapy and presence of symptoms (median 7). is weekly paclitaxel (median 8). The combination of pegylated liposomal doxorubicin The most relevant factors to be taken into consider- with trabectedin was only recommended as a valid strat- ation for not using bevacizumab in this population are a egy for patients with a history of platinum hypersensitivity recent (< 6 months) history of subocclusion and poor regardless of the TFIp (6–12 vs > 12 months) and BRCA performance status (median 7 in both cases); although status (median 7 for BRCA mutated and nonmutated). the cutoff for consensus was not reached, a recent his- tory of grade 3 deep vein thrombosis or pulmonary thromboembolism, history of poorly controlled hyper- Treatment of patients with recurrent disease for whom tension and, to a relatively lower extent, previous lines platinum might not be the best option of treatment were also considered relevant factors for The results of the 7 questions for this section are pre- not selecting bevacizumab (median 7 in all cases). sented in Table 3. If the patient is not eligible for platinum because of a There was consensus that patients could be considered history of hypersensitivity to carboplatin, the preferred ap- ineligible for platinum in the following clinical situa- proach is platinum rechallenge following a desensitization tions: patients who have had tumor progression during protocol (median 7). Platinum rechallenge is also the pre- platinum treatment (median 9), patients who have ferred option for a patient who was initially defined as in- shown hypersensitivity to platinum and are not candi- eligible for platinum due to a TFIp < 6 months and has dates for a desensitization protocol (median 9), and pa- been treated with several lines of nonplatinum regimens, tients with a TFIp < 6 months without a BRCA mutation showing a clinical benefit and maintaining a good per- (median 7). One-third of the participants showed a high formance status (median 7). degree of agreement that a TFIp < 6 months by itself de- fines ineligibility for platinum regardless of the BRCA Discussion mutation status, while another third of the respondents This expert consensus survey aimed to provide a snapshot disagreed with this statement (median 5). of the current practice and expert recommendations for Redondo et al. Journal of Ovarian Research (2021) 14:72 Page 5 of 12 Table 2 Recurrent ovarian cancer: treatment of patients eligible for platinum Redondo et al. Journal of Ovarian Research (2021) 14:72 Page 6 of 12 Table 2 Recurrent ovarian cancer: treatment of patients eligible for platinum (Continued) AGO Arbeitsgemeinschaft Gynäkologische Onkologie (German Working Group on Gynecological Oncology), % C proportion of consensus, ECOG Eastern Cooperative Oncology Group, M Median, PARP Poly(ADP-ribose) polymerase, PET-CT Positron emission tomography–computed tomography, TFIp Treatment-free interval of platinum Black shadowed areas represent the presence of consensus (i.e., ≥75% of the responses are located within those three consecutive points of the Likert scale) Gray shadowed areas represent the triplet with greater proportion of responses but without reaching the consensus threshold Redondo et al. Journal of Ovarian Research (2021) 14:72 Page 7 of 12 Table 3 Recurrent ovarian cancer: treatment of patients non-eligible for platinum % C proportion of consensus, ECOG Eastern Cooperative Oncology Group, M Median, TFIp Treatment-free interval of platinum Black shadowed areas represent the presence of consensus (i.e., ≥75% of the responses are located within those three consecutive points of the Likert scale) Gray shadowed areas represent the triplet with greater proportion of responses but without reaching the consensus threshold Redondo et al. Journal of Ovarian Research (2021) 14:72 Page 8 of 12 some key—and sometimes controversial—issues in the The results of this survey reflect the debate around this management of advanced ovarian cancer in Spain using a approach among the oncology community. Delphi survey. Overall, we accounted for a large participa- In our survey, there was agreement for using bevacizu- tion of the selected experts. mab for all patients with stage IV disease, both for those Initial extension assessment of the disease is a matter undergoing PDS and for those who require NACT and of discussion, and the latest ESMO-ESGO consensus IDS. However, in patients with stage III disease, bevacizu- recommends the necessity of standardization. CT, PET- mab is only widely recommended if there is macroscopic CT and diffusion-weighted whole-body MRI are among residual disease > 1 cm. The benefit of bevacizumab in the imaging techniques that can be used in the initial stage III patients without residual disease has yet to be workup [3]. According to the experts surveyed, the CT demonstrated, despite the results of an exploratory sub- scan is the most common test to evaluate the disease group analysis of the ICON7 trial showing that the stage at diagnosis. PET-CT is used less frequently, and addition of bevacizumab to front-line chemotherapy im- diffusion-weighted whole-body MRI is rarely used, prob- proves PFS regardless of the stage or presence of residual ably due to the more limited access to this technique. disease [20]. The results of two randomized phase II trials Although laparoscopy might provide a definite histo- did not show clear advantage for adding bevacizumab to pathological diagnosis and information on disease bur- neoadjuvant chemotherapy [21, 22]. However, the admin- den [3], according to our survey, it is not implemented istration of bevacizumab after IDS might provide a benefit as a first approach in all hospitals. regardless of whether complete cytoreduction is achieved, The goal of cytoreductive surgery must be complete as these patients are at higher risk of relapse due to greater cytoreduction, that is, the absence of macroscopic re- tumor burden at diagnosis precluding PDS). Nevertheless, sidual disease, since this is the most important prog- this hypothesis has not been proven, and therefore, most nostic factor in patients with advanced disease [13]. of the responders recommended restricting the use of bev- Several randomized clinical trials have shown no sig- acizumab after PDS for those patients with macroscopic nificant difference in progression free survival (PFS) residual disease. and overall survival (OS) between PDS and IDS [14, Of note, the evaluation of the first-line treatment of 15]. However, most clinical practice guidelines recom- this consensus was carried out without considering the mend PDS when the patient has an adequate per- recent results shown in the maintenance setting with formance status and complete cytoreduction is PARPi, as at the time of modeling the first survey no considered feasible [3], since in these cases, the OS of PARPi had been approved in the front line [23–26]. patients with PDS could be longer than with IDS as The use of the 6-month cutoff of TFIp for defining reported in a retrospective study [16]. The results of platinum sensitivity or resistance has been abandoned in this survey are consistent with this latter recommen- the ESMO-ESGO consensus, and a therapeutic-oriented dation, and the respondents prefer PDS when the definition is proposed classifying patients into two tumor is considered suitable for debulking, independ- groups: those for whom platinum might not be the best ent of FIGO stage III or IV. If IDS is an option, there option (defined by early symptomatic relapse, progres- was a strong agreement for recommending it after 3 sion on prior platinum-based chemotherapy, or platinum cycles (and no more than 4 cycles) of NACT. intolerability) and those for whom platinum might be The combination of carboplatin and paclitaxel has the best option or rechallenge appears justified (defined been the first-line standard chemotherapy for over 20 by a response to prior platinum-based chemotherapy years; other options include the administration of intra- and the absence of contraindications for platinum) [3]. peritoneal therapy, which has been a matter of great de- Consistent with clinical guidelines, in our study the fac- bate, and the addition of bevacizumab as part of the tors considered more relevant for selecting the treatment first-line treatment [17]. There was no consensus for in patients with a TFIp exceeding 6 months were BRCA recommending intraperitoneal chemotherapy as first- mutation status, histological subtype and performance line therapy, neither for patients with optimal debulking status; the location and extent of the disease, drugs and surgery nor for those with residual disease ≤1 cm. How- number of lines received, residual toxicity, presence of ever, more than 50% of respondents agreed that patients symptoms, comorbidities and patient preferences were with optimal cytoreduction may receive intraperitoneal also considered relevant. chemotherapy if they have adequate performance status. Aligned with the ESMO-ESGO consensus, the respon- Although the GOG 172 study showed a benefit in terms dents agreed that secondary debulking surgery should be of OS with the use of intraperitoneal chemotherapy, the offered to motivated patients with recurrent disease and a recent results of the GOG 252 trial have cast doubt on TFIp that exceeds 6 months if they meet the AGO score the superiority of intraperitoneal administration, at least of the DESKTOP III study based on the benefit on PFS when bevacizumab is added to chemotherapy [18, 19]. and OS recently communicated [27, 28]. Additionally, it Redondo et al. Journal of Ovarian Research (2021) 14:72 Page 9 of 12 would be advisable to perform PET-CT to have a better Patients with recurrent ovarian cancer for whom plat- evaluation of the disease extension and therefore increase inum might not be the best option have a poor prognosis the likelihood of successful complete surgery, as agreed and obtain very limited benefits from currently available upon in this consensus. Although there are some case treatments. Therefore, for these patients, a clinical trial with series that show a possible benefit with subsequent cytore- new therapies might be one of the best options, and this ductive surgeries (tertiary or quaternary cytoreduction) was the opinion of most of the participants in our survey. [29, 30], the limited evidence available has not allowed When there is no option for clinical trial, the preferred consensus to be reached on this point. therapeutic alternative according to the respondents is In patients for whom platinum might be the best option, single-agent chemotherapy, with weekly paclitaxel being there was consensus on treating patients with BRCA mu- the agent of choice, in combination with bevacizumab tations with a platinum-based combination followed by when indicated [38]. Factors considered relevant in our sur- maintenance with PARPi (olaparib, niraparib or ruca- vey for avoiding bevacizumab in these patients are a history parib), given the relevant benefit in terms of PFS shown in of intestinal subocclusion, poor performance status, history the SOLO2 [31], NOVA [32] and ARIEL3 trials [33]. of deep vein thrombosis or pulmonary thromboembolism, Moreover, an improvement in OS was shown recently in history of uncontrolled hypertension, and, to a lesser extent, the SOLO-2 trial [34]. There was also an agreement to several prior lines of treatment. These factors are fairly con- analyze the status of somatic BRCA in all patients who sistent with the exclusion criteria of the AURELIA trial that have a relapse when platinum might be the best option, led to the approval of bevacizumab in this setting [39]. and germline BRCA was non mutated at diagnosis. The results of the survey presented in this manuscript However, there was no consensus for recommending reflect therapeutic preferences on different topics of platinum-based therapy followed by PARPi in patients ovarian cancer treatment, expressed by a group of without BRCA mutations. The ESMO-ESGO consensus Spanish experts and systematized by the Delphi method. states that in these cases, patients could be offered a It is not possible to draw a global conclusion about the platinum-based rechallenge either with bevacizumab or therapeutic recommendations for advanced ovarian can- with PARPi maintenance in cases of response [3]. cer in our country due to the obvious limitation associ- Platinum-based rechallenge plus bevacizumab is usually ated with the bias inherent to the selection of a limited recommended for symptomatic patients for whom a number of participants who are considered national ex- rapid response is required, based on the higher response perts in the field. However, this survey shows a snapshot shown in the OCEANS [35] and GOG0213 [36] trials of current recommendations by this selected group of when bevacizumab is added to platinum-based chemo- physicians. Although the majority of the agreements and therapy. Consistently in our survey, there was also con- recommendations are aligned with the recently pub- sensus that the presence of large ascites or pleural lished ESMO-ESGO consensus, there are some discrep- effusion were relevant factors for considering the option ancies that can be explained by differences in the of adding bevacizumab to a platinum-based regimen in interpretation of certain clinical trials, reimbursement or the first relapse after a TFIp > 6 months. In the accessibility issues, making this type of survey a way to remaining patients, it would be advisable to opt for approach real clinical practices in specific countries. treatment with a platinum-based regimen followed by PARPi maintenance, based on the benefit in all sub- Methods groups showed by niraparib and rucaparib in NOVA Expert panel and development of the questionnaire [32] and ARIEL-3 [33] trials, respectively. The scientific committee comprised three experts The role of trabectedin in the management of recurrent (AR, AO and AGM) who selected a group of medical ovarian cancer is gradually being limited, and consistent oncologists and gynecologists throughout Spain with with this, there is only consensus for recommending tra- high expertise in the management of ovarian cancer bectedin in combination with pegylated liposomal doxo- to participate in this survey. The scientific committee, rubicin (PLD) as a valid strategy for patients with a history after revising the current literature and the clinical of platinum hypersensitivity, regardless of the pTFI and practice guidelines available at the time of the project BRCA mutation status. Furthermore, with the availability initiation, developed a first version of the question- of PARPis and their new indications, it is likely that the naire. That version was revised by a group of 7 ex- use of trabectedin plus PLD will be limited to patients perts—the review committee—who provided feedback who have received PARPi after prior platinum-based lines on the questionnaire to the scientific committee, who but still have a TFIp > 6 months, especially for those pa- then agreed on the final questionnaire (November tients with BRCA mutated tumors for whom a subanalysis 2018). of the trial OVC-3006 has shown a benefit in OS com- The questionnaire was divided into three areas con- pared to PLD [37]. cerning the treatment of advanced ovarian cancer: first- Redondo et al. Journal of Ovarian Research (2021) 14:72 Page 10 of 12 line treatment (10 questions), treatment of recurrent corresponding Likert scale. Using a cutoff point de- ovarian cancer in patients for whom platinum might be scribed elsewhere [41], a consensus was considered the best option (13 questions), and treatment of recur- reached when at least 75% of the answers were located rent ovarian cancer in patients for whom platinum within three consecutive points of the Likert scale. In might not be the best option (7 questions). All questions addition to the proportion of consensus and its location but one were answered using a 9-item Likert-like scale on the 9-point Likert scale, the median was also calcu- with three types of answers: frequency (1 = never, 9 = al- lated to determine the strength of the consensus [10]. ways), relevance (1 = scarcely relevant, 9 = very relevant) Abbreviations and agreement (1 = fully disagree, 9 = fully agree). AGO: Arbeitsgemeinschaft Gynäkologische Onkologie- German Working The project was scientifically endorsed by GEICO (the Group on Gynecological Oncology; CT: Computed tomography; Spanish Ovarian Cancer Research Group). GEICO: Spanish Ovarian Cancer Research Group; HRD: Homologous recombination deficiency; IDS: Interval debulking surgery; MRI: Magnetic resonance imaging; NACT: Neoadjuvant chemotherapy; OS: Overall survival; The Delphi method PARPi: PARP inhibitor; PDS: Primary debulking surgery; PET: Positron emission The Delphi method is a frequently used system for gath- tomography; PFS: Progression free survival; PLD: Pegylated liposomal doxorubicin; TFIp: Treatment-free interval of platinum ering opinions in a structured way from a group of ex- perts [40]. The key characteristics of the method are the Acknowledgements anonymous nature of the survey and that the partici- The authors wish to thank the following participants in this consensus (in alphabetical order): Jesús Alarcón (Palma, Spain), Mª José Bermejo (Málaga, pants receive feedback on their answers and may adjust Spain), Antonio Casado (Madrid, Spain), Luis Chiva (Pamplona, Spain), Cristina their initial answers to that feedback using an iterative Churruca (Donostia-San Sebastián, Spain), Juan Cueva (Santiago de process [40]. Compostela, Spain), Carmen Esteban (Toledo, Spain), Isaura Fernandez Perez (Vigo, Spain), José Fuentes (Sevilla, Spain), Elena García (Murcia, Spain), We performed two rounds of administering the ques- Santiago González-Santiago (Cáceres, Spain), Mª Mar Gordón (Jerez de la tionnaire via the internet on a website specifically designed Frontera, Spain), Eva Guerra (Madrid, Spain), Ana Herrero (Zaragoza, Spain), for the study. The participants had to register on the web- Sergi Martínez (Badalona, Barcelona, Spain), Juana Oramas (Santa Cruz de Tenerife, Spain), Isabel Palacio (Oviedo, Spain), Beatriz Pardo (Barcelona, site using a valid e-mail address and obtain a password in Spain), Alejandro Pérez Fidalgo (Valencia, Spain), Maria Quindós (A Coruña, advance to fill out the questionnaire; however, the e-mail Spain), Ana Santaballa (Valencia, Spain). The authors also wish to thank addresses were only known by the data manager in charge Alejandro Pedromingo (Bio-Estadística, Madrid, Spain) for the statistical analysis, Fernando Rico-Villademoros (COCIENTE S.L., Madrid, Spain) for his of the website. The website provided general instructions editorial assistance, and Sara Alonso (GSK, Madrid, Spain) for her assistance for completing the questionnaire and feedback on the with administrative support and for the coordination of the project. number of questions remaining to be answered. The first round took place between December 2018 and Authors’ contributions AR, AO and AG-M were members of the scientific committee and have January 2019, and 32 experts were invited to participate. participated in the conception, design, data analysis, interpretation of the The answers from the first round were analyzed (see results, and drafting of the manuscript; MJR, PB, AJ, LM, IR, CM and AP below) and were presented to the participants in an aggre- critically revised the survey questionnaire and the manuscript; all authors approved the final version of the manuscript. gate manner in a meeting that was held on May 24th, 2019. During the meeting, the scientific committee pre- Funding sented the results of the first round and promoted an open This study was sponsored by TESARO without restriction, nowadays a GlaxoSmithkline company. discussion on those questions, where a consensus (see def- inition below) was not reached. To facilitate the discussion Availability of data and materials among the attendees, they presented updated information Data is available upon request to the corresponding author. (e.g., recommendations from clinical practice guidelines, Declarations results of clinical trials) on those questions. The second round was carried out between June and Ethics approval and consent to participate This survey was conducted among physicians and no data on patients are July 2019, and using the same approach as in the first presented. round, the participants only answered questions from the first round for which a consensus could not be reached. Consent for publication Not applicable. Questions that required a frequency answer were not in- cluded in this round since they were considered to reflect Competing interests a situation/pattern instead of an opinion. To this end, each A. Redondo reports honoraria and advisory/consultancy (MSD, AstraZeneca, participant could look up the answer provided in the first Roche, GSK, Clovis, PharmaMar, Lilly, Amgen), research grant/funding to his institution (Eisai, PharmaMar, Roche), travel/accommodation/expenses round and modify his/her answer as appropriate. (AstraZeneca, Tesaro, PharmaMar, Roche), and speakers bureau (MSD, AstraZeneca, Roche, GSK, Clovis, PharmaMar), outside the submitted work. Statistical analysis A. Oaknin has served on advisory boards for Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro, Inmunogen and Genmab and received support for Descriptive statistical analysis was performed using the travel or accommodation from Roche, AstraZeneca, and PharmaMar; she also absolute and relative frequencies of each answer in the reports payments to the institution from Abbvie Deutschland, Abililty Redondo et al. Journal of Ovarian Research (2021) 14:72 Page 11 of 12 Pharmaceuticals, Advaxis Inc., Aeterna Zentaris, AMGEM, SA, Aprea 2. Wright JD, Chen L, Tergas AI, Patankar S, Burke WM, Hou JY, et al. Trends in Therapeutics AB, Clovis Oncology Inc., EISAI limited LTD, F. Hoffmann – La relative survival for ovarian cancer from 1975 to 2011. Obstet Gynecol. 2015; Roche LTD, Regeneron Pharmaceuticals, Immunogen Inc., Merck, Sharp & 125(6):1345–52. https://doi.org/10.1097/AOG.0000000000000854. Dohme de España SA, Millennium Pharmaceuticals Inc., Pharma Mar SA, 3. Colombo N, Sessa C, du Bois A, Ledermann J, McCluggage WG, McNeish I, Tesaro Inc., BMS, Bristrol Meyers Squibb. et al. ESMO-ESGO consensus conference recommendations on ovarian M.J. Rubio has served on advisory boards for MSD, AstraZeneca, Roche, GSK, cancer: pathology and molecular biology, early and advanced stages, Clovis, PharmaMar and received support for travel or accommodation from borderline tumours and recurrent diseasedagger. Ann Oncol. 2019;30(5): Roche, AstraZeneca, and PharmaMar. 672–705. https://doi.org/10.1093/annonc/mdz062. M-P. Barretina-Ginesta has served on Advisory boards for Roche, AstraZeneca, 4. Francis J, Coakley N, Elit L, Mackay H. The gynecologic Cancer disease site PharmaMar, Clovis Oncology, GSK, Merck Sharp & Dohme; has received group. Systemic therapy for recurrent epithelial ovarian cancer: a clinical speaker bureau honoraria from AstraZeneca, Roche, PharmaMar, GSK, Clovis practice guideline. Curr Oncol. 2017;24(6):e540–6. https://doi.org/10.3747/ Oncology and received support for travel or accommodation from Roche, co.24.3824. AstraZeneca, GSK and PharmaMar. 5. Armstrong DK, Alvarez RD, Bakkum-Gamez JN, Barroilhet L, Behbakht K, A. de Juan reports personal fees and other from Roche, AstraZeneca, Pharma Berchuck A, et al. NCCN guidelines insights: ovarian cancer, version 1.2019. J Mar, Clovis Oncology, Tesaro, Eisai Ltd., Pierre-Fabre and Pfizer, outside the Natl Compr Cancer Netw. 2019;17(8):896–909. https://doi.org/10.6004/ submitted work. jnccn.2019.0039. L. Manso has received advisory/consultancy honorarium from AstraZeneca, 6. Santaballa A, Barretina P, Casado A, García Y, González-Martín A, Guerra E, Clovis Oncology, Genmab, GSK, Merck Sharp & Dohme, Novartis, Pfizer/ et al. SEOM clinical guideline in ovarian cancer (2016). Clin Transl Oncol. Merck, PharmaMar, Roche; has received speaker bureau/expert testimony 2016;18(12):1206–12. https://doi.org/10.1007/s12094-016-1588-8. honorarium from AstraZeneca, PharmaMar, Roche, GSK, Roche; has received 7. White KM, Seale H, Harrison R. Enhancing ovarian cancer care: a systematic research grant/funding from TESARO: A GSK Company; and has received review of guideline adherence and clinical variation. BMC Public Health. travel/accommodation/expenses from AstraZeneca, Novartis, Roche, TESARO: 2019;19(1):296. https://doi.org/10.1186/s12889-019-6633-4. A GSK Company. 8. Funston G, Van Melle M, Baun MLL, Jensen H, Helsper C, Emery J, et al. I. Romero has received speaker’s bureau honorarium from AstraZeneca, Variation in the initial assessment and investigation for ovarian cancer in Pharmamar, GSK, Clovis, Roche; has received advisory board honorarium symptomatic women: a systematic review of international guidelines. BMC from AstraZeneca, GSK, Clovis, Roche; has received travel/expenses from Cancer. 2019;19:1028. AstraZeneca, Pharmamar, GSK, Roche; and has received research grant/ 9. Galvan-Turner VB, Chang J, Ziogas A, Bristow RE. Observed-to-expected ratio funding from Roche, GSK. for adherence to treatment guidelines as a quality of care indicator for C. Martin-Lorente reports honoraria and advisory/consultancy (AstraZeneca, ovarian cancer. Gynecol Oncol. 2015;139(3):495–9. https://doi.org/10.1016/j. Clovis Oncology, GSK, MSD, PharmaMar, Roche); travel/accommodation/ex- ygyno.2015.09.015. penses (AstraZeneca, Clovis Oncology, GSK, MSD, PharmaMar, Roche); and 10. Warren JL, Harlan LC, Trimble EL, Stevens J, Grimes M, Cronin KA. Trends in speakers bureau (AstraZeneca, Clovis Oncology, GSK, MSD, PharmaMar, the receipt of guideline care and survival for women with ovarian cancer: a Roche). population-based study. Gynecol Oncol. 2017;145(3):486–92. https://doi. A. Poveda has had a consulting or advisory role for AstraZeneca, PharmaMar, org/10.1016/j.ygyno.2017.03.016. Roche, Clovis Oncology, and Tesaro; and has received travel/ 11. Lee JY, Kim TH, Suh DH, Kim JW, Kim HS, Chung HH, et al. Impact of guideline accommodations/expenses from PharmaMar. adherence on patient outcomes in early-stage epithelial ovarian cancer. Eur J A. Gonzalez-Martín has received advisory/consultancy honorarium from Surg Oncol. 2015;41(4):585–91. https://doi.org/10.1016/j.ejso.2015.01.006. Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, Merck 12. Boac BM, Xiong Y, Apte SM, Wenham RM, Shahzad MM, Munroe DG, Sharp & Dohme, Novartis, Oncoinvent, Pfizer/Merck, PharmaMar, Roche, Sotio; et al. Adherence to practice guidelines is associated with reduced has received speaker bureau/expert testimony honorarium from AstraZeneca, referral times for patients with ovarian cancer. Am J Obstet Gynecol. PharmaMar, Roche, GSK; has received research grant/funding from Roche, 2018;218:436.e1–7. TESARO: A GSK Company; and has received travel/accommodation/expenses 13. du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. from AstraZeneca, Pharmamar, Roche, TESARO: A GSK Company. 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