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Abstract
Objective Laparoscopy is one of the diagnostic tools available for the complex clinical decision-making process in advanced ovarian, fallopian tube, and peritoneal carcinoma. This article presents the results of a survey conducted within the European Network of Gynaecological Oncology Trial (ENGOT) group aimed at reviewing the current patterns of practice at gynecologic oncology centers with regard to the evaluation of resection in advanced ovarian, fallopian tube, and peritoneal carcinoma.
Methods A 24-item questionnaire was sent to the chair of the 20 cooperative groups that are currently part of the ENGOT group, and forwarded to the members within each group.
Results A total of 142 questionnaires were returned. Only 39 respondents (27.5%) reported using some form of clinical (not operative) score for the evaluation of resection. The frequency of use of diagnostic laparoscopy to assess disease status and feasibility of resection was as follows: never, 21 centers (15%); only in select cases, 83 centers (58.5%); and routinely, 36 centers (25.4%). When laparoscopy was performed, 64% of users declared they made the decision to proceed with maximal effort cytoreductive surgery based on their personal/staff opinion, and 36% based on a laparoscopic score. To the question of whether laparoscopy should be considered the gold standard in the evaluation of resection, 71 respondents (50%) answered no, 66 respondents (46.5%) answered yes, whereas 5 respondents (3.5%) did not provide an answer.
Conclusions This study found that laparoscopy was routinely performed to assess feasibility of cytoreduction in only 25.4% of centers in Europe. However, it was commonly used to select patients and in a minority of centers it was never used . When laparoscopy was adopted, the treatment strategy was based on laparoscopic scores only in a minority of centers.
- ovarian neoplasms
- laparoscopes
- surgical procedures, operative
- peritoneal neoplasms
- fallopian tube neoplasms
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- ovarian neoplasms
- laparoscopes
- surgical procedures, operative
- peritoneal neoplasms
- fallopian tube neoplasms
HIGHLIGHTS
Diagnostic laparoscopy was used routinely to assess the extent of disease and feasibility of cytoreduction in 25.4% of centers.
In 37.8% of centers that performed routine/selective laparoscopy, laparotomy for complete cytoreduction was performed during the same surgical session as the diagnostic laparoscopy.
When laparoscopy was performed, 64% of respondents made a decision about proceeding with cytoreduction based on the laparoscopic score only 36% of the time.
Introduction
Complete cytoreduction is the strongest determinant of survival in patients with advanced ovarian, fallopian tube, and primary peritoneal carcinoma.1 Clinical staging, including imaging techniques such as computed tomography (CT) (with or without positron-emission tomography scan) and magnetic resonance imaging (MRI) (with or without diffusion weighted imaging) are limited in their ability to show disease localizations to achieve optimal surgical cytoreduction. The International Federation of Gynecology and Obstetrics (FIGO) staging system is unable to define the surgical operability of clinical stage IIIC–IV. Therefore, there is a need for tools to more accurately evaluate the feasibility of optimal surgical cytoreduction in patients with advanced ovarian, fallopian tube, or primary peritoneal carcinomas. Numerous scoring systems have been proposed to predict complete surgical cytoreduction.2–10 In particular, the proposal of laparoscopy-based scores has been interfaced by the concept of neoadjuvant chemotherapy.11
The current study presents the results of a survey conducted within the European Network of Gynaecological Oncology Trial (ENGOT) group aimed at reviewing the current patterns of practice at gynecological oncology centers with regard to the evaluation of cytoreduction in advanced ovarian, fallopian tube, and primary peritoneal carcinoma. In particular, the study focuses on trying to explore the implications of laparoscopic assessment in the complex strategy for the management of patients with advanced ovarian, fallopian tube, and primary peritoneal carcinoma.
Methods
This survey project was proposed by the Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies (MITO) group and was approved by the ENGOT group assembly on April 21, 2018, and subsequently endorsed by the ENGOT group in June 2018. A 24-item questionnaire was sent to the chair of the 20 cooperative groups that are currently part of the ENGOT group, and forwarded to the centers qualified for gynecologic cancer surgery within each group. Each group was asked to return the questionnaires by November 30, 2018.
In accordance with the Declaration of Helsinki, the current analysis was exempt from formal institutional review board approval. The survey was designed to assess the current patterns of practice at gynecological oncology referral centers with regard to the evaluation of tumor dissemination and, consequently, feasibility of surgical cytoreduction in women with advanced ovarian, fallopian tube, and primary peritoneal carcinoma. In particular, data were collected on: respondent- (age, postgraduate specialization) and institution-related characteristics (type of center, advanced ovarian/fallopian tube/peritoneal carcinoma case volume); method for evaluating patient fitness for cytoreductive surgery (operability); pre-operative imaging/clinical score and diagnostic laparoscopy to assess he extent of disease dissemination and feasibility of cytoreduction; performance of frozen section analysis at the time of diagnostic surgery; possibility of a predefined ‘two-step’ approach, that is, laparoscopy (and definitive pathological evaluation) followed by a delayed primary treatment (upfront surgery with cytoreductive intent or neoadjuvant chemotherapy); annual proportion of advanced ovarian/fallopian tube/primary peritoneal cancer patients undergoing neoadjuvant chemotherapy. The questionnaire is provided in full in the online supplementary appendix.
Supplemental material
Statistical analysis was performed with Statistical Package for Social Science (SPSS) software version 21.0. Categorical and continuous variables were reported as frequency and percentage and as median and range, respectively. Replies were compared using the Fischer’s exact test and the χ2 test, if needed. All p values were two-sided, and statistical significance was set at p<0.05.
Results
A total of 16 of the 20 cooperative groups that are part of the ENGOT group agreed to participate in the survey. One hundred and forty-two questionnaires of the 215 delivered (66%) were returned within the deadline: 31 from the MITO group, 17 from the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO)-Germany/Nord-Ostdeutsche Gesellschaft für Gynäkologische Onkologie (NOGGO), 16 from the Grupo Español de Investigación en Cáncer de Ovario (GEICO), 11 from the Swiss Group for Clinical Cancer Research (SAKK), 10 from the Groupe des Investigateurs Nationaux pour l'Etude des Cancers de l'Ovaire, gynécologiques et du sein (GINECO), 9 each from the Central and Eastern European Gynecologic Oncology Group (CEEGOG)/Polish Gynecologic Oncology Group (PGOG) and the Israeli Society of Gynecologic Oncology (ISGO), 8 each from the Turkish Society of Gynecologic Oncology (TRSGO) and National Cancer Research Institute (NCRI), 7 from the Mario Negri Gynecologic Oncology (MaNGO) group, 4 from Arbeitsgemeinschaft Gynäkologische Onkologie (AGO)-Austria Group, 3 each from the Dutch Gynecological Oncology Group (DGOG) and Ηellenic Cooperative Oncology Group (HeCOG), and 1 from the Belgium and Luxembourg Gynecological Oncology Group (BGOG), with 5 respondents failing to report the membership cooperative group.
Eighty-three respondents (58.5%) were ≤ 50 years of age. The large majority (89.4%) were gynecologic oncologists, while the remaining 10.6% were medical/clinical oncologists. Most respondents worked in academic/cancer centers (111; 78%), and reported operating on >20 primary cases of advanced ovarian/fallopian tube/primary peritoneal carcinoma per (last) year (102; 71.8%). In order to determine feasibility of cytoreduction, 111 respondents (78.1%) stated using all of the following variables: age, performance status according to Eastern Cooperative Oncology Group (ECOG), and American Society of Anesthesiologists (ASA) score; 18 (12.7%) used performance status and ASA score, while the remaining six respondents (4.2%) used age and ASA score. Twenty-seven of the 111 physicians using all the three aforementioned variables reported to also evaluate: the Charlson Comorbidity Index (12), nutritional status (8), and the frailty index/geriatric vulnerability score (7).
Only 39 respondents (27.5%) reported using some clinical (not operative) score for evaluation of the feasibility of cytoreduction. Fifteen (38.4%) respondents reported using the radiological Peritoneal Cancer Index score: by CT scan alone (13) or CT scan plus MRI (2).
In patients who were deemed fit for cytoreductive surgery, a diagnostic laparoscopy was reported to assess dissemination of disease and feasibility of cytoreduction: never, 21 centers (15%); only in selected cases, 83 centers (58.5%); and routinely, 36 centers (25.4%) (Figure 1). Among the latter, however, 39% of the centers excluded patients with no ascites and/or gross omental disease or bulky areas of adhesion to the abdominal wall. When laparoscopy was selectively adopted, it was performed mostly in patients for whom <1 cm surgical cytoreduction was very unlikely, according to clinical-radiological evaluation. Overall, 22.6% (27/119) of respondents excluded >50% of cases from laparoscopic evaluation.
(A) Adoption of laparoscopy (answers to the question: “Do you expose patients who have been deemed fit for cytoreductive surgery to diagnostic laparoscopy to assess dissemination status and resectability?”). (B) Opinion on its use as the gold standard to assess resectability (answers to the question: “Do you think that laparoscopy should be now considered as the gold standard in the evaluation of surgical cytoreduction?”).
In 45 of 119 centers (37.8%) performing routine/selective laparoscopy, laparotomy for complete cytoreduction, if feasible, was performed during the same surgical session as the diagnostic laparoscopy. This strategy was pursued depending on the specific surgical session or not adopted in 33 (27.7%) and 41 (34.4%) centers, respectively. Figure 2 shows opinions on the possibility of a predefined ‘two-step’ approach (laparoscopy and definitive pathological evaluation followed by primary treatment–upfront surgery with cytoreductive intent or neoadjuvant chemotherapy), and shows that 47% of respondents believed such an algorithm was useful and compatible with most clinical scenarios.
Opinions on the possibility of a predefined ‘two-step’ approach, that is, laparoscopy (and definitive pathological evaluation) followed by primary treatment.
When laparoscopy was performed, 64% of respondents reported making the decision on whether to proceed with maximal effort cytoreductive surgery based on their personal/staff opinion, and 36% based on a laparoscopic score. Figure 3 shows which strategy was preferred in operable patients, if laparoscopy was not performed.
Strategy adopted in operable patients, if laparoscopy is not performed. USS/CT, ultrasound/computed tomography.
Forty-two percent of respondents (60/142) reported that they did not routinely perform frozen section analysis at diagnostic surgery (laparoscopy/mini-laparotomy), due to: the need for definitive pathology before any therapeutic decision (61.6%), frozen section low accuracy (30%), or frozen section analysis routinely unavailable (8.3%).
Overall, excluding patients who were not fit for cytoreductive surgery, 65.5% of respondents reported a lower than 30% proportion of patients undergoing neoadjuvant chemotherapy in the last 12 months, and only 14 physicians (9.8%) considered it appropriate to administer neoadjuvant chemotherapy exclusively on the basis of a ‘laparoscopic score’ indicating complete surgical cytoreduction unlikely. To the question of whether laparoscopy should be considered as the gold standard in the feasibility of cytoreduction in advanced ovarian/fallopian tube/primary peritoneal carcinoma, 71 respondents (50%) answered no, 66 (46.5%) answered yes, and 5 (3.5%) did not provide an answer. The respondent’s age did not significantly impact his/her opinion; however, the type and geographical area of centers did have a significant impact on opinion: 57.5% of respondents from university hospital/cancer institutes (vs 34.5% from other centers; p=0.03) and 66.7% of centers in Central/Northern Europe (vs 36.5% from Southern Europe; p<0.001) did not consider laparoscopy to be the gold standard (Figures 1 and 4). Moreover, comparative analysis revealed that the referred proportion of patients undergoing neoadjuvant chemotherapy was significantly different depending on the outcomes of diagnostic laparoscopy, with higher use of laparoscopy in centers reporting >30% use of neoadjuvant chemotherapy (p<0.001) (Figure 5). Lastly, the higher the use of laparoscopy, the greater the intention to adopt the ‘two-step’ approach (p=0.006).
Laparoscopy as the gold standard in the evaluation of resectability in advanced ovarian/tubal/peritoneal carcinoma, according to institution pattern. NCI, national cancer institutes.
Laparoscopy use by neoadjuvant chemotherapy use. LPS, laparoscopy; NACT, neoadjuvant chemotherapy.
Discussion
This ENGOT-endorsed survey was conducted on a representative sample of gynecologic oncology reference centers in Europe with the aim to assess the real-world clinical behavior for the feasibility of cytoreduction. Laparoscopy is used by approximately 80% of centers, although only in selected cases by the majority, and with the adoption of laparoscopic scores only by a minority. Overall, the results of the survey show that a roadmap for prediction of optimal cytoreductive surgery is still a topic of interest, with an inconsistent approach among centers, with approximately half considering laparoscopy as the gold standard to assess feasibility of cytoreduction.
One hundred and forty-two respondents belonging to 16 national cooperative gynecologic oncology groups, with over 70% from high volume cancer institutes, may be considered a reliable sample to assess clinical practice in qualified centers for advanced ovarian, fallopian tube, and primary peritoneal cancer in Europe. Moreover, the centers’ geographical distribution was well balanced between Central/Northern (46%) and Southern (54%) Europe.
First, it appears that a structured model to assess patient fitness for cytoreductive surgery (operability) was lacking, with only 19% of the centers applying a more complex score system (Charlson Comorbidity Index and/or nutritional status, frailty index/geriatric vulnerability score) in addition to age, performance status, and ASA score. This is a crucial point, often underestimated, when the surgical performance, including its morbidity, is considered.12 13 As expected, less than one-third (27.5%) of centers reported using some form of imaging score for the feasibility of cytoreduction, and only 10% considered a radiological Peritoneal Cancer Index score based on CT±MRI. Several attempts have been made to predict cytoreductive outcome with models combining CT variables, with or without clinical (performance status, age, body mass index, comorbidities, smoking) and/or biochemical (serum CA125, albumin, blood platelet count) parameters.14 15 To date, unfortunately, there are no models that show a good predictive performance for residual disease when extrapolated to other centers.16
In patients deemed fit for cytoreductive surgery, a diagnostic laparoscopy was performed (routinely or selectively) to assess disease dissemination status and feasibility of cytoreduction in the majority of centers (84%). In most cases, however, laparoscopy was performed in selected cases only. In particular, 39% of routine laparoscopy users excluded laparoscopy in cases of no ascites and/or gross omental disease or bulky areas of adhesion to the abdominal wall. Thus, it is estimated that, overall, laparoscopy was not performed in approximately one-quarter (23%) of patients. Based on the literature, it is not clear what is the proportion of patients for whom laparoscopy is excluded from a minimally invasive predictive model for optimal cytoreduction.10 17–24 In fact, only Petrillo et al reported a very low rate (4%) of unfeasibility in a series of 244 consecutive advanced ovarian/tubal/peritoneal cancer cases.25
Interestingly, only approximately one-third (36%) of respondents reported making a surgical decision based on a laparoscopic score,3 25 and only 10% believed it appropriate to administer neoadjuvant chemotherapy exclusively on the basis of a laparoscopic score.
Almost half of respondents (46%) considered laparoscopy as the gold standard in the feasibility of cytoreduction in patients with advanced ovarian, fallopian tube or primary peritoneal carcinoma. These findings suggest that laparoscopy is included by the majority of centers among the diagnostic means available in the clinical armamentarium, for use in selected cases as part of the clinical assessment.
A review has been recently published by the Cochrane Library on laparoscopy for feasibility of cytoreduction in women with advanced ovarian cancer, including 18 studies on 1563 participants.24 Only one study, however, was a randomized controlled trial,20 and, due to the large heterogeneity, pooling of data was not possible for meta-analysis.24 This review suggested that laparoscopic assessment was able to predict optimal debulking surgery (no macroscopic up to <1 cm residual disease) in 54–96% of women who had macroscopic complete cytoreduction, and in 69–100% of women who had optimal (<1 cm residual tumor) cytoreduction.24 The only randomized trial published by Rutten et al demonstrated a significant reduction of futile laparotomy following a laparoscopic assessment (from 39% to 10%), showing superimposable curves of overall and progression-free survival.20 In fact, the 10% risk of futile laparotomy reported by Rutten et al seems to be much lower than the 33% reported by Petrillo et al following a model updated to show a higher discriminating performance of laparoscopy.25 A potential bias of Rutten’s study is represented by the inclusion of approximately 20% of stage I–IIIB patients, while the main criticism remains the low rate (25%) of complete cytoreduction at primary surgery in stage IIIC–IV.20
In our study, a comparative analysis revealed that the proportion of patients undergoing neoadjuvant chemotherapy varied depending on the attitude toward diagnostic laparoscopy, with higher use of laparoscopy in centers reporting >30% use of neoadjuvant chemotherapy (p<0.001). The introduction of laparoscopic scores, the quality (rate of complete cytoreduction) at primary surgery, and the choice of neoadjuvant chemotherapy are likely to be interrelated factors. Following the publication of the European Organization for Research and Treatment of Cancer (EORTC) trial on neoadjuvant chemotherapy versus primary cytoreductive surgery,11 neoadjuvant chemotherapy use has significantly increased, with wide variation among institutions in its adoption.26 27 The impact on survival of neoadjuvant chemotherapy remains controversial, but among women with stage IIIC disease who achieved microscopic or ≤1 cm postoperative residual disease, neoadjuvant chemotherapy was associated with decreased overall survival.26 The Trial of Radical Upfront Surgical Therapy in advanced ovarian cancer (TRUST) study is expected to address at least some of these issues.28
One should note that our study revealed that the majority of university hospital/cancer institutes (57.5%) and Central/Northern Europe centers (66.7%) did not agree on the definition of laparoscopy as the gold standard in the feasibility of cytoreduction. Almost half of respondents believed that a ‘two-step’ algorithm could be useful and compatible with the clinics in most cases. The 42% of centers missing frozen section analysis provides additional evidence of the need for a more comprehensive/precision case framing which should include a definitive pathology, but could also include a biomolecular/genetic assessment.
In conclusion, our study confirms that laparoscopy is one of the diagnostic means available for the complex clinical decision process in advanced ovarian/fallopian tube/primary peritoneal carcinoma, and is selectively used by most referral centers in Europe. When laparoscopy is adopted, the treatment strategy is based on laparoscopic scores only in a very low proportion of centers, while the judgment of the gynecologic oncologist still remains the final and concrete determinant of management. Laparoscopy seems to be associated with an increased number of patients undergoing neoadjuvant chemotherapy, which might have a negative impact on the overall survival rate. Moreover, this argument should be considered with caution, since the decision of neoadjuvant chemotherapy is taken on the basis of laparoscopy (scores) by only 10% of laparoscopy users. Finally, a ‘two-step’ algorithm with a more precise pre-treatment case definition could include laparoscopy and allow for the most accurate therapeutic decision to be reached.
References
Footnotes
Contributors All authors have significantly contributed to paper and they are in agreement with the content of the manuscript; moreover, they declare no financial support or relationships that may pose conflict of interest.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement The authors confirm at all data relevant to the study are included in the article or uploaded as supplementary information.