Management of epithelial cancer of the ovary, fallopian tube, and primary peritoneum. Long text of the Joint French Clinical Practice Guidelines issued by FRANCOGYN, CNGOF, SFOG, and GINECO-ARCAGY, and endorsed by INCa. Part 1 Diagnostic exploration and staging, surgery, perioperative care, and pathology

Bolze PA 8 , Bonnet F [START_REF]Service d'anesthésie[END_REF] , Bourgin C 10 , Chabbert-Buffet N [START_REF] Alfonsi | Soins péri-opératoires dans 121 le cancer de l'ovaire. Recommandations Françaises communes dU FRANCOGYN, du CNGOF, 122 d'ARCAGY-GINECO et de la SFOG[END_REF] , Collinet P [START_REF]11. Pôle Femmes-Parents-Enfants -Centre Clinico-Biologique d'AMP[END_REF] , Courbiere B 11 , De la motte rouge T 12 , Devouassoux-Shisheboran M [START_REF]Service d'anatomo-pathologie, Hospices civiles de Lyon[END_REF] , Falandry C 14 , Ferron G [START_REF]Service d'oncologie chirurgicale[END_REF] , Fournier L [START_REF]Service de radiologie[END_REF] , Gladieff L [START_REF]Service d'oncologie médicale[END_REF] , Golfier F 8 , Gouy S 18 , Guyon F 19 , Lambaudie E 20 , Leary A [START_REF]Service d'oncologie médicale[END_REF] , Lecuru F [START_REF]Service de chirurgie gynécologique et oncologique[END_REF] , Lefrere-Belda MA [START_REF]Service d'anatomo-pathologie[END_REF] , Leblanc E 24 , Lemoine A 9 , Narducci F 24 , Ouldamer L [START_REF]Service de chirurgie gynécologique[END_REF] , Pautier P [START_REF]Service d'oncologie médicale[END_REF] , Planchamp F 26 , Pouget N 27 , Ray-Coquard I [START_REF]Service d'oncologie médicale[END_REF] , Rousset-Jablonski C [START_REF]Service d'oncologie médicale[END_REF] , Senechal-Davin C 19 , Touboul C [START_REF]Service de chirurgie gynécologique[END_REF] , Thomassin-Naggara I 30 , Uzan C [START_REF]Service de chirurgie et cancérologie gynécologique et mammaire[END_REF] , You B [START_REF]Auteur correspondant : Pr Vincent Lavoué, Service de chirurgie gynécologique[END_REF] , Daraï E [START_REF] Alfonsi | Soins péri-opératoires dans 121 le cancer de l'ovaire. Recommandations Françaises communes dU FRANCOGYN, du CNGOF, 122 d'ARCAGY-GINECO et de la SFOG[END_REF] . Affiliations :

1. Service de gynécologie, CHU de Rennes, Hôpital sud, 16 An MRI is recommended for an ovarian mass that is indeterminate on ultrasound. The ROMA score (combining CA125 and HE4) can also be calculated (Grade A). In presumed early-stage ovarian or tubal cancers, the following procedures should be performed: an omentectomy (at a minimum, infracolic), an appendectomy, multiple peritoneal biopsies, peritoneal cytology (grade C), and pelvic and para-aortic lymphadenectomies (Grade B) for all histologic types, except the expansile mucinous subtypes, for which lymphadenectomies can be omitted (grade C). Minimally invasive surgery is recommended for early-stage ovarian cancer, when there is no risk of tumor rupture (grade B). For FIGO stages III or IV ovarian, tubal, and primary peritoneal cancers, a contrast-enhanced computed tomography (CT) scan of the thorax/abdomen/pelvis is recommended (Grade B), as well as laparoscopic exploration to take multiple biopsies (grade A) and a carcinomatosis score (Fagotti score at a minimum) (grade C) to assess the possibility of complete surgery (i.e., leaving no macroscopic tumor residue).

Complete surgery by a midline laparotomy is recommended for advanced ovarian, tubal, or primary peritoneal cancer (grade B). For advanced cancers, para-aortic and pelvic lymphadenectomies are recommended when metastatic adenopathy is clinically or radiologically suspected (grade B). When adenopathy is not suspected and when complete peritoneal surgery is performed as the initial surgery for advanced cancer, the lymphadenectomies can be omitted because they do not modify either the medical treatment or overall survival (grade B). Primary surgery (before other treatment) is recommended whenever it appears possible to leave no tumor residue (grade B). Key words: ovarian cancer; tubal cancer, primary peritoneal cancer, surgery; chemotherapy; guidelines A c c e p t e d M a n u s c r i p t Introduction Initial management of epithelial ovarian cancers is relatively heterogeneous in France, with treatment sequences that differ substantially between centers for primary or interval surgery.

Similarly, the extent of surgery and the surgical staging procedures vary according to patient characteristics (young vs elderly women, for example). Perioperative management, whether it concerns early recovery or fertility preservation, has not been standardized, although it can cause physical or psychological morbidity. Finally, cancer centers vary widely in their use of chemotherapy (and how they administer it), as well as of targeted therapies; a national strategy remains to be defined, according to different clinical contexts; a national strategy remains to be defined, according to different clinical contexts. Work to develop clinical practice guidelines is therefore necessary to enable practices to be in accordance with the best evidence and to improve prognosis for all patients.

Accordingly, the French research group for oncologic gynecologic surgery (FRANCOGYN), the French national college of gynecologists and obstetricians (CNGOF), the French society of gynecologic oncology (SFOG), and the national investigators' group for studies in ovarian and breast cancer (GINECO-ARCAGY) jointly brought together a working group to develop such guidelines. This text is a synthesis of clinical practice guidelines for the initial management of epithelial ovarian, tubal, or primary peritoneal cancers (excluding recurrence of ovarian cancer and borderline tumors). [START_REF] Huchon | Tumeurs épithéliales de l'ovaire. Méthodes et 98 organisation. Recommandations françaises communes du CNGOF, FRANCOGYN[END_REF] The development of these clinical practice guidelines followed the standards set by the French national authority for health (HAS) and the national cancer institute (INCa), with reviews by experts both within and outside the working group. [START_REF] Huchon | Tumeurs épithéliales de l'ovaire. Méthodes et 98 organisation. Recommandations françaises communes du CNGOF, FRANCOGYN[END_REF][START_REF] Thomassin-Naggara | valeur diagnostique de 101 l'imagerie (échographie, doppler, scanner, IRM, et PET scan) pour le diagnostic ET LE BILAN 102 D'EXTENSION d'un cancer de l'ovaire. Recommandations communes dU FRANCOGYN, du 103 CNGOF[END_REF][START_REF] Bendifallah | Pertinence des marqueurs 106 tumoraux, scores (cliniques et biologiques) et algorithmes à visée diagnostique et 107 pronostique devant une masse ovarienne suspecte d'un cancer épithélial: Recommandations 108 de Pratique Clinique communes de FRANCOGYN, CNGOF, SFOG, ARCAGY-GINECO[END_REF] INCa has endorsed these clinical practice guidelines. This article deals with the role of diagnostic explorations, surgery, perioperative care, and pathology studies of women with ovarian, tubal, or primary peritoneal cancers. -The mass is classified as malignant if at least one M (malignant) rule applies and no B (benign) rule applies.

-The mass is classified as benign if at least one B rule applies and no M rule applies.

-It cannot be classified (or is indeterminate) if at least one M rule and one B rule both apply or if no rule applies. Software is available without charge at the IOTA site (www.iotagroup.org), and an application is available for both Android and iOS. During the initial study, the simple rules were able to be applied in 76% of cases and the adnexal masses were correctly classified as benign or malignant with a sensitivity of 93% and a specificity of 90%; their positive and negative predictive values were 80% and 97% respectively. Around 25% of adnexal masses remain indeterminate with the Simple Rules and require a second-line examination. B). Contrast-enhanced dynamic MRI has confirmed that the time-signal intensity contrast uptake curve for the solid tissue under study, compared with the myometrium as reference (type 1: progressively increasing curve with no plateau; type 2 timesignal intensity curve, with a plateau and moderate wall enhancement, and not earlier than the myometrium; type 3 time-signal intensity curve within solid tissue: a curve steeper than that of the adjacent myometrium) makes it possible not only to differentiate benign tumors from malignant neoplasms with a sensitivity of 94%, a specificity of 84%, and a diagnostic precision of 92%, but also to distinguish within the malignant neoplasms borderline tumors from invasive tumors with a sensitivity of 88%, a specificity of 80%, and a diagnostic precision of 84% (LE3). Scores, in particular the ADNEX MR score, have been generated to establish the risk of malignancy (LE3). It is recommended that an MRI report characterizing an adnexal mass include a malignancy risk score (such as the ADNEX MR). Moreover, the use of the apparent distribution coefficient (ADC) allows the differentiation of borderline from invasive tumors, in particular, of seromucinous borderline tumors from invasive cancers on endometriomas of endometrioid or clear cells. A pathological hypothesis should be included in the MRI report of an adnexal mass (grade C).

When an adnexal mass is complex or indeterminate on ultrasound

Diagnostic value of serum markers for a suspicious adnexal mass 3

The diagnostic value of CA125 for an indeterminate ovarian mass to diagnose an epithelial ovarian cancer varies for sensitivity from 0.74 to 0.80, for specificity from 0.76 to 0.84, and for area under the ROC curve (AUC) from 0.85 to 0.88 (LE1). The diagnostic value of HE4 for an indeterminate ovarian mass to diagnose an epithelial ovarian cancer varies for sensitivity from 0.74 to 0.85, for specificity from 0.83 to 0.84, and for AUC from 0.82 to 0.89 Circulating tumoral DNA and tumor-associated auto-antibodies perform worse than or not better than CA125 or serum HE4 (LE4, LE1, LE2 respectively) and are not recommended for the assessment of a suspected ovarian cancer (grade C). Data about the CA19.9 and ACE serum markers for the positive diagnosis of ovarian cancer are sparse and do not justify any guidelines for their use to assess an ovarian mass that is indeterminate on imaging.

Diagnostic scores, both clinical and based on laboratory tests, have been developed for ovarian masses indeterminate on ultrasound. The diagnostic value of the ROMA score (Risk of Ovarian Malignancy Algorithm) for an indeterminate ovarian mass varies for sensitivity from 0.79 to 0.82, for specificity from 0.76 to 0.84, and for AUC from 0.91 to 0.93 (LE1).

The ROMA score is superior diagnostically to serum CA125 and serum HE4 assayed in isolation for an indeterminate adnexal mass (LE1).

The ROMA score (based on serum assays of HE4 and CA125) can be used for an adnexal mass that is indeterminate on ultrasound (grade A). The CNAM-TS (French national health insurance fund) does not reimburse the HE4 serum assay.

Other diagnostic scores (Copenhagen index (CPH-I) (LE4), the R-OPS score (LE3), and OVA500 (LE3)) have been proposed, but none are superior to ROMA for the diagnosis of an ovarian mass that is indeterminate on ultrasound, and they are not recommended.

Role of an intraoperative pathology examination of a suspicious ovarian mass 4

Intraoperative analysis of an excised ovarian mass is effective for both benign and malignant tumors, with an agreement rate between the intraoperative and definitive examinations of 94% and 99%, respectively (LE2). It is, however, less effective for borderline ovarian tumors, very large tumors, and mucinous tumors: the agreement rate between intraoperative and definitive A c c e p t e d M a n u s c r i p t 10 examinations for borderline ovarian tumors is 73%, with 21% of tumors finally classified as malignant and 6% as benign (LE2). When an adnexal mass is suspected to be an ovarian cancer, an intraoperative pathology examination can be performed to enable optimal surgical staging during a single surgical procedure and thus avoid the need for reintervention (grade B).

Modalities of surgery for early-stage ovarian cancer 5 (Figure 1)

Presumed early-stage epithelial ovarian cancer (< FIGO stage IIA, therefore limited to the internal genitalia) involves from 20 to 33% of the women with ovarian cancer. The rate of occult omental metastases in presumed early-stage ovarian cancer ranges from 2 to 4% depending on the study and results in up-staging 3% to 11% of women to stage IIIA.

Performance of an omentectomy does not modify their survival (LE3). Reported rates of metastasis to the appendix in early-stage ovarian cancer range from 0 to 26.7% (LE3). In the mucinous subtype, this rate can reach 53% if the appendix is macroscopically abnormal (LE2). The rate of positive peritoneal cytology in FIGO stages I and II ovarian cancers varies in the literature from 20.9% to 27%. The performance of peritoneal cytology leads to upstaging in 4.3% to 52% of cases, and positive results are a poor prognostic factor (LE3). The rate of occult peritoneal metastases varies from 1.1% to 16%. Performance of these biopsies results in an up-staging of 4% to 7.1% (LE3). In early-stage ovarian cancer, the lymph node invasion rate ranges from 6.3% to 22% according to the literature. It is 4.5% to 18% for stage I and 17.5% to 31% in stage II. The literature does not report lymph node involvement in the histologic subtypes of expansile mucinous carcinoma (LE3). This rate ranges from 1.7% to 10.7% for low-grade serous carcinoma. From 8.5% to 13% of women with presumed earlystage ovarian cancer are reclassified as stage IIIA1 (FIGO2014) after the lymphadenectomy

Pretreatment assessment of extension of carcinomatosis presumed to be of ovarian, tubal, or primary peritoneal origin 2

A thorax/abdomen/pelvis CT scan makes it possible to assess the extent of carcinomatosis (LE2) and to specify the tumor sites that might compromise complete surgical resection (i.e., with no macroscopic tumor residue). The diagnostic performance of a PET-scan and MRI are inferior to that of CT for assessing peritoneal disease (LE2). The performance of a PET-scan is slightly better than those of CT and MRI for assessing lymph node involvement and diagnosing remote disease in ovarian, tubal, or primary peritoneal cancers (LE3).

The role of serum tumor markers in the initial management of advanced stage epithelial ovarian cancer 3

Serum markers such as CA125 or a combination of CA125 and HE4 have been proposed to predict complete surgery (i.e., with no tumor residue). A CA125 threshold greater than 500 IU/mL has a sensitivity of 0.52 to 0.80 and a specificity of 0.40 to 0.89 for predicting no tumor residue after surgery (LE1). These mediocre performance levels, the low level of evidence in the literature, and the absence of a uniform threshold specific for these markers Role of laparoscopy and scores to assess resectability in ovarian, tubal, and primary peritoneal carcinomatosis [START_REF] Bendifallah | Pertinence des marqueurs 106 tumoraux, scores (cliniques et biologiques) et algorithmes à visée diagnostique et 107 pronostique devant une masse ovarienne suspecte d'un cancer épithélial: Recommandations 108 de Pratique Clinique communes de FRANCOGYN, CNGOF, SFOG, ARCAGY-GINECO[END_REF] (Figures 2 and3) Laparoscopy to assess ovarian, tubal, or primary peritoneal carcinomatosis reduces by 30% the number of laparotomies leading to nonoptimal surgery (i.e., tumor residue exceeding 1 cm) (LE1). Laparoscopy is recommended to assess the feasibility of surgical resection that leaves no macroscopic tumor residue (i.e., complete surgery) in a woman with ovarian, tubal, or primary peritoneal carcinomatosis before laparotomic surgery (grade A).

Several scores for assessing the extension of peritoneal carcinomatosis have been developed. The Fagotti score is a laparoscopic score based on 7 indicators rated 0 or 2 (Table 3).

With a Fagotti score ≥8, the probability of complete primary surgery at the laparotomy (i.e., no tumor residue) was 8.3% and the rate of futile exploratory laparotomy was 28.3%. With a Fagotti score ≥10, the probability of complete primary surgery at the laparotomy was 0% and that of futile exploratory laparotomy 33.2% (NP4). The Fagotti score is also useful in a situation of interval surgery after neoadjuvant chemotherapy. A score ≥ 4 shows a zero probability of optimal interval surgery and enables a 17% reduction in the number of nonoptimal laparotomies (LE4). A modified Fagotti score, reduced to four criteria graded 0 or 2 for diaphragmatic carcinomatosis, mesenteric retraction, gastric infiltration, and hepatic metastases has also been proposed, with a threshold ≥ 4 for predicting nonresectability. Its performance does not appear to be inferior to that of the 7-criteria Fagotti score, but because it has been less widely evaluated, it cannot currently be recommended.

Several scores for laparotomic assessment of tumor/carcinomatosis extension have been described: The Sugarbaker score or the PCI (Peritoneal Cancer Index), which divides the abdomen into 13 regions with a score of 0 to 3 according to the size of the tumor implants (total score range: 0 to 39) and the Eisenkop score, which divides the abdomen into 5 regions scored 0 to 3 (total score range: 0 to 15). Finally, the Aletti score assesses surgical complexity, with a score of 1 to 3 for each surgical procedure as a function of its complexity (score range: 0 to 18), correlated with the risk of postoperative complications. An external validation found the PCI score best for predicting the optimal surgery for all FIGO stages combined. In women undergoing laparotomy for ovarian, tubal, or primary peritoneal carcinomatosis, use of the Peritoneal Cancer Index (PCI) is recommended to assess the tumor burden (grade C). Surgery for advanced ovarian, tubal, or primary peritoneal cancer (FIGO stages IIB to IV) [START_REF] Ferron | Chirurgie des cancers avancés de l'ovaire. 118 Recommandations de Pratique Clinique communes de FRANCOGYN[END_REF] (Figures 2 and3)

The tumor residue after primary or interval surgery is an essential prognostic factor, regardless of histologic type (serous or other, high or low grade) (LE2). A higher volume of surgery for ovarian cancer per surgeon (≥10/year) and per hospital (≥20/year) increases the complete surgery rate, reduces postoperative morbidity and mortality, and thus improves In women with FIGO stage IV ovarian, tubal, or primary peritoneal cancer, pleural or pulmonary metastases have been observed in 41% of cases, abdominal wall metastasis in 40%, metastases in lymph nodes other than the pelvic and para-aortic in 19%, and hepatic metastases in 14%. Complete abdominal and peritoneal cytoreduction surgery (i.e., with no macroscopic tumor residue) is superior to surgery called optimal (i.e., leaving a tumor residue < 1 cm), which itself is superior to surgery leaving residues greater than a centimeter, which in turn is not superior to no surgery; median recurrence-free survival was respectively 50, 25, 16, and 19 months (LE4). For cytoreduction surgery, resection penetrating the diaphragm is associated with significantly more postoperative morbidity than stripping the diaphragmatic dome (LE4). In FIGO stage IV ovarian, tubal, and primary peritoneal cancer, surgery is recommended when a complete peritoneal abdominal resection (i.e., with no macroscopic tumor residue) is possible (grade C).

Three published meta-analyses, including both published cohorts and 3 randomized trials, have assessed the systematic surgical dissection of pelvic and para-aortic lymph nodes in advanced cancer (LE2). They show a benefit from systematic dissection with an improvement in overall survival (HR=0.74; 95% CI 0.59-0.94, P=0.01) including for the operations considered optimal (i.e., with tumor residue 1 cm or less in maximum diameter). concerning advanced stages (and included in these meta-analyses) found no improvement in 5-year overall survival but only a prolongation of recurrence-free survival (LE2). These data are consistent with the published abstract of the LION trial presented at ASCO in 2017, which randomized women with ovarian carcinomatosis and no observed adenopathy (not visible on CT nor palpable at primary surgery after complete resection) to either systematic dissection or no dissection. This study found an identical overall survival rate among women who did and did not have dissections among the selected population, i.e., women with neither radiologic nor clinical adenopathy (LE2). On the other hand, benefits for both overall and recurrencefree survival were observed for systematic dissections when clinically or radiologically suspicious lymph nodes were present (LE2).

In advanced ovarian, tubal, or primary peritoneal cancer with no macroscopic tumor residue at the end of surgery, para-aortic and pelvic lymphadenectomies are recommended when metastatic adenopathy is suspected, either clinically or radiologically (Grade B). In the absence of such suspected adenopathy and when complete peritoneal surgery is performed as the initial surgery for advanced ovarian, tubal, or primary peritoneal cancers, the lymphadenectomies can be omitted because they do not modify either the medical treatment or overall survival (grade B). The other lymphadenectomies (suprarenal, mesenteric, laparoscopic hepatic, cardiophrenic angle) are not recommended in the absence of clinical invasion (grade C). Finally, it is not possible to make particular recommendations about the role of dissection according to histologic subtype or grade, due to the lack of data.

The treatment sequences of primary cytoreductive surgery and then adjuvant chemotherapy vs neoadjuvant chemotherapy and interval surgery after 3 or 4 treatments have not shown differences for overall or progression-free survival (LE1) (Table 4). In a meta- In advanced ovarian, tubal, or primary peritoneal carcinomatosis, primary surgery is recommended when it appears that complete surgery (i.e., no macroscopic tumor residue in the abdomen) is possible on condition that the surgery is acceptable in terms of morbidity, given both the complexity of the procedure and the patient's comorbidities (grade B). If complete cytoreduction (no tumor residue) does not appear possible, neoadjuvant chemotherapy should be offered, to be followed by interval surgery (Grade

B) after 3 or 4 courses of chemotherapy (grade C). Makar's five categories are useful for choosing between primary surgery and interval surgery after neoadjuvant chemotherapy as the treatment strategy (grade C).

The specific histologic subtype is important: chemotherapy response is significantly poorer in low-grade compared to high-grade serous carcinomas (23.1% vs 90.1%) (LE3). Indirect data also show that the mucinous and clear-cell histologic subtypes respond less well to chemotherapy by platinum compounds and taxanes. For advanced ovarian, tubal, and primary peritoneal cancers of particular histologic subtypes (mucinous, clear-cell, and low-grade serous), primary surgery should be preferred over neoadjuvant chemotherapy when complete resection is possible from the start (grade C).

No guidelines can be issued about the type of procedure to perform for palliative surgery, or after the intraoperative recognition of the impossibility of complete (no macroscopic tumor residue) surgery in a patient with FIGO stage III or IV cancer after neoadjuvant chemotherapy. Any surgical procedure performed must be the least morbid possible.

Feasibility studies for the minimally invasive approach, as either primary or interval surgery, can help to choose between the xiphopubic midline laparotomy or a minimally invasive A c c e p t e d M a n u s c r i p t 20 approach, robot-assisted or not; no oncologic safety data (effect on survival) are available, however. The minimally invasive approach for primary surgery for advanced cancer (carcinomatosis) appears risky, but the data are sparse; this approach does seems possible for interval surgery with a complete biochemical and radiologic response to chemotherapy, but no guideline is justified. The benefit expected from the minimally invasive approach is a shorter length of stay and a better quality of life. Surgery by xiphopubic laparotomy for advanced ovarian, tubal, or primary peritoneal cancer remains the standard, as primary or interval surgery.

The surgical report for cytoreduction of advanced ovarian, tubal, or primary peritoneal cancer

Preoperative management

An intervention for epithelial ovarian cancer is major visceral surgery. It is accordingly eligible for a program of enhanced recovery after surgery (ERAS). These programs include measures of pre-, intra-and postoperative supportive care aimed at facilitating the patient's return to autonomy and at reducing the postoperative complication rate.

Moderate or severe malnutrition is frequent in women with ovarian cancer, especially carcinomatosis. The existence of such malnutrition before surgery promotes the onset of postoperative complications and reduces overall survival (LE2). Nonetheless, no study has yet assessed the benefits of correction of nutritional deficiencies on perioperative morbidity.

There are no data about the benefits of immunonutrition in ovarian cancer. Similarly, anemia before surgery is frequent and appears to be a factor associated with a poorer survival prognosis (LE3), but no ovarian cancer-specific data about the benefits of its preoperative correction exist.

For women with ovarian, tubal, or primary peritoneal cancer, screening is recommended before surgery for nutritional deficiencies (Grade B) and anemia (grade C). No data justify recommendations about preoperative correction of nutritional deficiencies, immunonutritional deficiencies, or anemia in women with ovarian, tubal, or primary peritoneal cancers.

In the absence of data specific to surgery for ovarian cancer, it appears useful to refer to the guidelines issued by the French-speaking society of clinical nutrition and metabolism (SNFEP) and the French society for anesthesia-intensive care (SFAR).

Bowel preparation before the intervention is a recurrent question when a segment of the colon or rectum appears likely to be the object of total or partial resection in gastrointestinal or A c c e p t e d M a n u s c r i p t 22 gynecologic oncology. Its aim is to reduce both the risk of anastomotic complications and the indications for protection by a temporary stoma. This preparation may be a no/low residue diet for 7 days, or mechanical preparation (osmotic solution) and/or a rectal enema, and/or preoperative antibiotic therapy. These different types of bowel preparation have been studied particularly in gastrointestinal surgery through randomized trials and meta-analyses, which report that mechanical preparation appears futile for elective colon surgery, but is indicated for rectal surgery. Surgery for ovarian cancer differs from colorectal surgery because it most often involves peritoneal cytoreduction, which often requires en bloc rectosigmoid resection (Hudson's extraperitoneal posterior pelvic exenteration), associated with other abdominal procedures. There are currently no data in the specific context of ovarian cancer about the benefits of preoperative bowel preparation. Similarly, no specific data about these ovarian, tubal, or primary peritoneal cancers justify guidelines for preoperative bowel preparation.

Intraoperative management

A study has shown that monitoring total blood volume in women with advanced ovarian cancer shortens the postoperative length of stay necessary for discharge home (LE2). No benefit was found, however, for women undergoing surgery for early-stage ovarian cancer.

For women with advanced ovarian, tubal, or primary peritoneal cancers, individualized monitoring to ensure intraoperative goal-directed fluid management is recommended (Grade B).

A randomized study has shown that infusion of a single dose of tranexamic acid moderately reduces blood loss in women undergoing surgery for ovarian cancer. A positive impact on the need for transfusion has not been shown (NP2). Women with epidural analgesia have lower levels of postoperative pain, both at rest and on coughing, than those receiving intravenous opioid analgesia (LE2). On the other hand, no relation can be established between epidural use and prognosis or medium-term postoperative survival. In the absence of an epidural, analgesia can be provided by morphine with a patientcontrolled pump. This analgesia is optimal as a bolus without continuous flow.

Epidural analgesia, in addition to general anesthesia, is recommended for the management of women undergoing laparotomic cytoreduction surgery for ovarian, tubal, or primary peritoneal cancer (Grade B). In the absence of epidural analgesia, patient-controlled administration of morphine is recommended, but without a continuous flow (Grade B).

No data justify a recommendation about intravenous administration of lidocaine or ketamine during surgery or the perioperative prescription of gabapentine or pregabalin.

Postoperative management

Early oral feeding reduces the time until return of normal bowel function and the length of hospitalization. It also increases patient satisfaction. Early oral feeding does not increase the postoperative complication rate, including after intestinal resection (LE2). Early mobilization helps reduce the length of stay. If rapid oral feeding is impossible, the use of chewing gum can be proposed to accelerate the resumption of transit and to reduce the length of hospitalization, but there are no data specific to ovarian cancer (LE3). biomarkers) in the management of ovarian, tubal, and primary peritoneal carcinomas [START_REF] Devouassoux | Biopathologie des carcinomes ovariens 111 des stades précoces et avancés : Recommandations françaises communes du CNGOF[END_REF] 3

No studies of women with peritoneal carcinomatosis of presumably ovarian, tubal, or primary 4 peritoneal origin have assessed the number, site, and size of the laparoscopic samples 5 necessary for histologic diagnosis. The demonstration of tumor heterogeneity at the genomic 6 level in ovarian, tubal, or primary peritoneal carcinomatoses indicates the need to take 7 multiple laparoscopic samples at different tumor sites (LE4). Cytologic examination has good 8 sensitivity for the diagnosis of malignancy, but does not allow the histologic subtypes or 9 carcinoma grade to be established (LE3). The use of a paraffin-embedded pellet (cytoblock) 10 increases the sensitivity of cytology as a diagnostic test (LE4). The ratio of noncontributory 11 biopsies among radioguided biopsies of carcinomatosis lesions is higher with 18G needles 12 than with needles with a larger diameter (LE3). After a biopsy for suspected ovarian, tubal, or primary peritoneal carcinomatosis, the 31 tissue samples should be fixed in neutral buffered formalin (with 4% formaldehyde) as 32 rapidly as possible (<1 h after excision) (for optimal morphologic, immunohistochemical, and 33 nucleic acid preservation) (grade C). Vacuum packing and storage at +4°C can be an 34 alternative, but only for very large pieces of excised tissue, to prolong this delay to a 35 maximum of 48 h (grade C). Tissue samples (for biopsies) should be fixed for at least 6 h 36

(grade C). 37

There are no data about the optimal number of surgical specimens to collect for ovarian 38 carcinomatosis. Mucinous tumors are more heterogeneous than the other histologic types, 39 with a mixture of benign, borderline, and invasive carcinoma zones that require more 40 extensive sampling than serous carcinomas (LE3). Some high-grade serous carcinomas of the 41 ovary and peritoneum are in fact of tubal origin, with the presence of high-grade serous tubal 42 intraepithelial carcinoma (STIC) and thus require histologic study of the tubes (LE3). 43

Sampling an omentectomy specimen with no macroscopic lesion by a mean of 3 to 6 blocks 44

A c c e p t e d M a n u s c r i p t 1

 1 Management of epithelial cancer of the ovary, fallopian tube, and primary peritoneum. Long text of the Joint French Clinical Practice Guidelines issued by FRANCOGYN, CNGOF, SFOG, and GINECO-ARCAGY, and endorsed by INCa. (Part 1: diagnostic exploration and staging, surgery, perioperative care, and pathology) Lavoue V 1* , Huchon C 2 , Akladios C 3 , Alfonsi P 4 , Bakrin N 5 , Ballester M 6 , Bendifallah S 7 ,

3 .

 3 Service de Gynécologie, Hôpital Hautepierre, CHU Strasbourg, France 4. Service d'Anesthésie, Hôpital Saint Joseph, Paris, France. 5. Service de chirurgie digestive, CHU Lyon-Sud, Pierre-Bénite, Lyon, France. 6. Service de gynécologie, GH Diaconesses Croix Saint Simon, Paris, France.

A c c e p t e d M a n u s c r i p t 6 7 2 (Figure 1 )

 6721 Their aim is to aid professionals (gynecologic surgeons, medical gynecologists, gynecologistobstetricians, pathologists, medical oncologists, radiologists, anesthetist-critical-care specialists, nuclear physicians, general practitioners, midwives and paramedical personnel) in managing women with ovarian cancer or with suspected ovarian, tubal, or primary peritoneal cancers.A c c e p t e d M a n u s c r i p tRole of imaging in the exploration of an ovarian mass suspected to be ovarian cancerAn adnexal mass is a tumor of the ovary or fallopian tubes detected by either a clinical or an imaging examination. Transvaginal and transabdominal (suprapubic) ultrasound are recommended for the analysis of an isolated ovarian mass (grade A).[START_REF] Thomassin-Naggara | valeur diagnostique de 101 l'imagerie (échographie, doppler, scanner, IRM, et PET scan) pour le diagnostic ET LE BILAN 102 D'EXTENSION d'un cancer de l'ovaire. Recommandations communes dU FRANCOGYN, du 103 CNGOF[END_REF] It is recommended that non-expert operators performing ultrasound use the Simple Rules (grade A). These rules must be combined with subjective analysis to equal the performance of expert ultrasonographers (grade A). According to the Simple Ultrasound Rules (

  , a pelvic MRI is recommended (grade A). MRI has excellent specificity and makes it possible to classify as benign numerous complex masses indeterminate on ultrasound (LE1). MRI to characterize an adnexal mass should use T2, T1, T1 Fat Sat, dynamic contrast-enhanced, diffusionweighted, and gadolinium-enhanced sequences (grade B) to improve diagnostic A c c e p t e d M a n u s c r i p t 8 sensitivity (grade

A c c e p t e d M a n u s c r i p t 9 (

 9 LE1). These sensitivity, specificity, and AUC values for CA 125 and serum HE4 are similar for the diagnosis of an ovarian mass that is indeterminate on ultrasound (LE1).

  . The performance of a pelvic and para-aortic lymphadenectomy improves survival in these women with presumed early-stage ovarian cancer (LE2).In presumed early-stage ovarian cancer, the following procedures should be performed:an omentectomy (at a minimum, infracolic), an appendectomy, peritoneal biopsies, peritoneal cytology (grade C), and pelvic and para-aortic lymphadenectomies (Grade B) except for the expansile mucinous subtypes, for which the lymphadenectomies can be omitted.If the initial staging was not performed or was incomplete (defined by any of: no omentectomy, no exploration or resection of the appendix, no pelvic or para-aortic lymphadenectomy or peritoneal biopsies) for a presumed early-stage ovarian cancer, surgical restaging is recommended, including omentectomy (at least infracolic) (gradeC), appendectomy (grade C), pelvic and para-aortic lymphadenectomies (grade B) (except for expansile mucinous cancer), and peritoneal biopsies (grade C), especially in the absence of an indication for chemotherapy.No studies examining either laparotomic or minimally invasive approaches have shown any disadvantage to the laparoscopic pathway compared with laparotomy for feasibility, oncologic safety, or postoperative recovery (LE3) in the surgical staging of women with presumed early-stage ovarian cancer. The benefits of the laparoscopic approach in terms of reduced intraoperative complications and accelerated postoperative recovery must be interpreted in the light of the various authors' laparoscopic experience. For the initial surgical management of early-stage ovarian cancer, the choice of approach depends on local conditions (tumor size, in particular) and surgical expertise. The published data show a reduction in recurrence-free survival (hazard ratio = 2.28) and overall survival (hazard ratio = 3.79) associated with intraoperative tumor rupture in early-stage ovarian cancer (FIGO stage IC1 if rupture) compared with no rupture (FIGO stage IA or IB) (LE2). The literature data do not currently A c c e p t e d M a n u s c r i p t 12 allow us to identify factors predictive of intraoperative tumor rupture, besides the presence of adhesions (LE4). No specific study answers the question about the benefit of surgery in 1 or 2 procedures when intraoperative diagnosis is performed for presumed early-stage ovarian cancer. Nonetheless, the high sensitivity and specificity of intraoperative pathology examination in this situation allows us to envision surgical staging in a single procedure if the intraoperative examination is positive. In presumed early-stage ovarian cancer, a minimally invasive approach is recommended if complete surgery is possible without the risk of tumor rupture (grade B). Otherwise, a midline laparotomy is recommended (grade B). All precautions must be taken to avoid the intraoperative rupture of an ovarian tumor, including an intraoperative decision to convert to open surgery (grade B). For surgical restaging, a minimally invasive approach should be preferred when the ovarian mass has already been removed (grade B).

  A c c e p t e d M a n u s c r i p t 13 A contrast-enhanced CT scan of the thorax/abdomen/pelvis is recommended for the preoperative workup of the extension and resectability of ovarian, tubal, or primary peritoneal carcinomatosis (grade B). The CT report should specify the presence of substantial ascites, the overall extent of the carcinomatosis, as well as involvement of the mesentery, the extended gastrointestinal tract, the lesser omentum, the hepatic hilum, suprarenal para-aortic adenopathy, abdominal parenchymal (hepatic etc.) or extraabdominal metastases (umbilical or parietal, pulmonary, inguinal, or mediastinal lymph nodes). If iodinated contrast agents are contraindicated (severe kidney failure, GFR < 30 mL/min, allergies), an abdominal/pelvic MRI supplemented by a CT scan without contrast enhancement can replace the thorax/abdomen/pelvis CT scan (grade C). Data assessing the diagnostic performance of radiologic examinations to assess response to chemotherapy are sparse. No guideline can be issued about the best type of imaging after neoadjuvant chemotherapy to assess the resectability of ovarian, tubal, or primary peritoneal carcinomatosis.

  A c c e p t e d M a n u s c r i p t 14 for predicting no tumor residue after interval surgery (after neoadjuvant chemotherapy)together they prevent us from offering a recommendation about the use of these markers to influence treatment strategy in women with ovarian cancer.

  For women with ovarian, tubal, or primary peritoneal carcinomatosis, the use of a carcinomatosis score (at least the Fagotti score) during laparoscopy is recommended to assess the risk of nonresectability during primary or interval surgery (grade C). A Fagotti score ≥8 is correlated with a low rate of complete A c c e p t e d M a n u s c r i p t 15 primary surgery (LE4). A Fagotti score ≥4 is correlated with a low rate of complete interval surgery (LE4).

A

  c c e p t e d M a n u s c r i p t 16 patient prognosis (LE3). Adjuvant chemotherapy started more than 6 weeks after surgery negatively influences recurrence-free and overall survival (LE3). Complete surgery (i.e., with no macroscopic tumor residue) of advanced ovarian, tubal, or primary peritoneal cancer is recommended (Grade B). Surgery for ovarian cancer should be performed in a high-volume hospital (defined by performance of at least 20 procedures for advanced ovarian cancer each year) (Grade C). Adjuvant chemotherapy should begin within 6 weeks after surgery for ovarian, tubal, or primary peritoneal cancer (Grade C).

  only prospective randomized trial (Panici et al.) currently published

A

  c c e p t e d M a n u s c r i p t 18 analysis by Bristow, after three cycles of preoperative chemotherapy, each supplementary cycle was significantly associated with a 4.1-month reduction in women's median duration of survival (P=0.046). The interval surgery strategies have shown a significant diminution of morbidity and mortality and an improved quality of life, especially in the advanced stages with a high tumor burden (LE2). The 5-category classification by Makar et al. is useful for assessing the tumor burden in FIGO stage III carcinomatosis (LE2): -Category 1: The tumor is localized in the pelvis, with little or no ascites and no need for gastrointestinal resection. Primary cytoreductive surgery is recommended -Category 2: The tumor is localized in the pelvis, with little or no ascites. Gastrointestinal resection is necessary for complete cytoreduction. Primary cytoreductive surgery is recommended -Category 3: A large portion of the tumor is localized in the supramesocolic space, with little or no ascites. No gastrointestinal resection is needed. Primary cytoreductive surgery is recommended -Category 4: A large portion of the tumor is localized in the supramesocolic space, with little or no ascites. Gastrointestinal resection is necessary for complete cytoreduction. Primary cytoreductive surgery is recommended. In cases of impaired general condition, comorbidities, or advanced age, interval surgery can instead be envisioned after 3 cycles of neoadjuvant chemotherapy. -Category 5: A very large portion of the tumor is localized in the supramesocolic space, with abundant ascites or miliary patterns on the mesentery. Initial cytoreduction may require several gastrointestinal resections. Neoadjuvant chemotherapy is recommended. Primary surgery is not contraindicated for FIGO stage 4 disease.

  then interval surgery are recommended for multiple intrahepatic masses, or pulmonary metastases, or substantial ascites with miliary patterns (LE1).

  should assess the tumor burden (grade C) according to the PCI (Peritoneal Cancer Index) score and should indicate the reasons for tumor nonresectability if no cytoreduction surgery was performed, indicate if the surgery was complete, and state the size and site of any tumor residue. Use of a standardized surgical report is helpful.

A c c e p t e d M a n u s c r i p t 21 Perioperative

 21 prehabilitation for and recovery from ovarian cancer surgery[START_REF] Alfonsi | Soins péri-opératoires dans 121 le cancer de l'ovaire. Recommandations Françaises communes dU FRANCOGYN, du CNGOF, 122 d'ARCAGY-GINECO et de la SFOG[END_REF]

A c c e p t e d M a n u s c r i p t 23 Women

 23 undergoing surgery for ovarian, tubal, or primary peritoneal cancer may be offered an infusion of a single dose of tranexamic acid to reduce intraoperative blood loss (Grade C).

  is recommended, including after gastrointestinal resection for ovarian, tubal, or primary peritoneal cancer (Grade B).Implementation of an ERAS protocol for major gynecologic surgery, combining no bowel preparation, a shorter fasting period, the absence of a nasogastric tube, smaller incisions and reduced use of drainage, monitoring intraoperative fluid management, early oral feeding, and early mobilization, has been shown to reduce length of postoperative stay without significantly reducing morbidity (LE4). The establishment of protocols for enhanced recovery after surgery (ERAS), including early mobilization, is recommended to reduce the length of stay after surgery for ovarian, tubal, and primary peritoneal cancer (Grade C).

A c c e p t e d M a n u s c r i p t 25 1

 25 Role of biopathology (pathology, intraoperative pathology examination, and 2

  Most studies have considered 2 to 5 (mean 3) 13 biopsies per tumor (LE3). An immunohistochemical study of a preoperative biopsy increases 14 the rate of agreement between the diagnosis of the histologic type of ovarian carcinoma and 15 the final diagnosis (LE3). The postchemotherapy modifications impair the morphologic 16 appearance of tumor cells and thus prevent the correct establishment of the histologic subtype 17 of the carcinoma (LE4). Different immunohistochemical studies before and after 18 chemotherapy do not show post-treatment modifications of the tumor's immune profile (LE3). 19 Before any chemotherapy, it is recommended that ovarian carcinomas (histologic type 20 and grade) be diagnosed positively from biopsy samples and not from cytology (grade 21 C). A surgical biopsy with multiple samples from different tumor sites is recommended 22 before neoadjuvant chemotherapy for women with carcinomatosis of a presumed 23 ovarian, tubal, or primary peritoneal origin (Grade C). A needle larger than 16G is 24 recommended for image-guided microbiopsies, and at least three biopsy cores should be Page 26 of 38 A c c e p t e d M a n u s c r i p t 26 taken (Grade C). If no immunohistochemical study has been performed on the sample 26 before chemotherapy or in cases of major morphologic discordance, this examination 27 can be performed on residual tumor material after chemotherapy (Grade C). 28 Preanalytic factors such as cold ischemia time, type of fixative, and the duration of fixing 29 modify morphology as well as the preservation of proteins and nucleic acids. (LP4). 30

(PageQFigure 1 :

 1 depending on the size of the specimen) enables detection of most of the microscopic damage 45 of the omentum (LE2). Use of the WHO 2014 classification and immunohistochemistry Page 28 of 38 A c c e p t e d M a n u s c r i p t 28 Response Score (CRS) score presents the best interobserver diagnostic reproducibility for 74 response to chemotherapy (LE3), especially for the omentum (LE3). 75 The pathology report of excised tissue after chemotherapy for ovarian, tubal, and 76 primary peritoneal cancers should state the size and the site of the bulkiest residual 77 tumor nodule (Grade C). The pathology report should also state if there are no (or < 78 5%) residual tumor cells after chemotherapy (Grade C). 79 The pathology report for ovarian, tubal, or primary peritoneal carcinomatosis should mention 80 the items listed above. 81 Management of presumed early-stage ovarian cancer Page 32 of 38 A c c e p t e d M a n u s c r i p t

Figure 2 :

 2 Figure 2: Management of a FIGO stage III ovarian, tubal, or primary peritoneal cancer

Figure 3 :

 3 Figure 3: Management of a FIGO stage IV ovarian, tubal, or primary peritoneal cancer

A c c e p t e d M a n u s c r i p t

2 :

 2 nodules infiltrating the stomach and/or spleen and/or lesser omentum 0: all other cases Hepatic metastases 2: any tumor with an area >2 cm 0: all other cases Page 38 of 38 A c c e p t e d M a n u s c r i p t

  Bd de Bulgarie 35000 Rennes, France. INSERM 1242, Chemistry, Oncogenesis, Stress and Signaling, Centre Eugène Marquis, Rue Bataille Flandres-Dunkerques, Rennes, France. 2. Service de Gynécologie, CHI Poissy, France.

Table

Table 1 :

 1 The 10 simple ultrasound rules for an adnexal mass

Rules for predicting a benign tumor Rules for predicting a malignant tumor B1

		Unilocular	M1	Irregular solid mass
	B2	The largest diameter of the largest	M2	Ascites
		solid component < 7 mm
	B3	Acoustic shadow	M3	≥4 papillary structures
	B4	Smooth multilocular tumor with	M4	Irregular multilocular tumor with
		largest diameter < 100 mm		maximum diameter ≥ 100 mm
	B5	No blood flow	M5	Intense vascularization on Doppler
				Page 36 of 38

Table 2 : ADNEX MR score to characterize the risk of malignancy of adnexal masses on MRI Risk of malignancy Classification

 2

	No mass visible on MRI

Table 4 : Summary of survival according to tumor residue and primary or interval surgery in advanced ovarian, tubal, and primary peritoneal cancers.

 4

	STAGE III -	Primary	Interval	Primary	Interval
	IV	surgery	surgery	surgery	surgery
		Recurrence-free survival	Overall survival (months)
		(months)
	No residue	20.1-33	16.4	64.1-71.9	66.6
	Residue < 1	13-16.8	9.8	28.7-42.4	39.7
	cm
	Residue > 1	12.9-14.1	7.4	30.7-35	28.4
	cm

(including the anti-EMA, CK7, CK20, PAX8, WT1, p53, RE, RP, HNF1b and/or napsin A

antibodies) helps to improve intra-and inter-observer agreement (LE2) for the diagnosis of

histologic subtypes.

HNF1b, and/or napsin A) (Grade B). 64

Women with somatic mutations of the BRCA genes must be referred for an oncogenetic 65 consultation. A study by INCa published in 2017 describes the importance of looking for a 66 constitutional BRCA mutation and its utility in monitoring women and their family members 67 at risk. 68

The size of the most bulky residual site gives the best prognostic correlation for neoadjuvant 69 chemotherapy for ovarian, tubal, or primary peritoneal carcinomatosis (LE3). Most studies 70 show a positive correlation between a complete histologic response (from none to <5% of 71 remaining tumor cells) and survival (LE3). No data show a significant correlation between 72 extent of response and survival (but no studies have used the same score). The Chemotherapy The authors thank the following professional societies: CNGOF, FRANCOGYN, SFOG, 90 SFAR, GINECO-ARCAGY, SCGP, SFCO, and the RRC; the IMAGIN patient association, 91 and the expert reviewers for their attentive review of these clinical practice guidelines: (list: 92 https://www.e-cancer.fr/Professionnels-de-sante/Recommandations-et-outils-d-aide-a-la-93 pratique). 94


Management of epithelial cancer of the ovary, fallopian tube, primary peritoneum. Long text of the joint French clinical practice guidelines issued by FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY, endorsed by INCa. (Part 2 systemic, intraperitoneal treatment, elderly patients, fertility preservation, follow-up) V Lavoue, C Huchon, C Akladios, P Alfonsi, N Bakrin, M Ballester, S

Lavoue V 1* , Huchon C 2 , Akladios C 3 , Alfonsi P 4 , Bakrin N 5 , Ballester M [START_REF] Uzan | Tumeurs épithéliales de l'ovaire : préservation de la fertilité[END_REF] , Bendifallah S [START_REF] Falandry | Tumeurs épithéliales de l'ovaire : les personnes âgées[END_REF] , Bolze PA 8 , Bonnet F [START_REF]Service d'anesthésie[END_REF] , Bourgin C 10 , Chabbert-Buffet N [START_REF] Falandry | Tumeurs épithéliales de l'ovaire : les personnes âgées[END_REF] , Collinet P [START_REF]11. Pôle Femmes-Parents-Enfants -Centre Clinico-Biologique d'AMP[END_REF] , Courbiere B 11 , De la motte rouge T 12 , Devouassoux-Shisheboran M [START_REF]Service d'anatomo-pathologie, Hospices civiles de Lyon[END_REF] , Falandry C 14 , Ferron G [START_REF]Service d'oncologie chirurgicale[END_REF] , Fournier L [START_REF]Service de radiologie[END_REF] , Gladieff L [START_REF]Service d'oncologie médicale[END_REF] , Golfier F 8 , Gouy S 18 , Guyon F 19 , Lambaudie E 20 , Leary A [START_REF]Service d'oncologie médicale[END_REF] , Lecuru F [START_REF]Service de chirurgie gynécologique et oncologique[END_REF] , Lefrere-Belda MA [START_REF]Service d'anatomo-pathologie[END_REF] , Leblanc E 24 , Lemoine A 9 , Narducci F 24 , Ouldamer L [START_REF]Service de chirurgie gynécologique[END_REF] , Pautier P [START_REF]Service d'oncologie médicale[END_REF] , Planchamp F 26 , Pouget N 27 , Ray-Coquard I [START_REF]Service d'oncologie médicale[END_REF] , Rousset-Jablonski C 28 , Senechal-Davin C 19 , Touboul C [START_REF]Service de chirurgie gynécologique[END_REF] , Thomassin-Naggara I 30 , Uzan C 31 , You B [START_REF]Service d'oncologie médicale[END_REF] , Daraï E [START_REF] Falandry | Tumeurs épithéliales de l'ovaire : les personnes âgées[END_REF] . Affiliations : 1. Service de gynécologie, CHU de Rennes, Hôpital sud, 16 Bd de Bulgarie 35000 Rennes, France. INSERM 1242, Chemistry, Oncogenesis, Stress and Signaling, Centre Eugène Marquis, Rue Bataille Flandres-Dunkerques, Rennes, France. 2. Service de Gynécologie, CHI Poissy, France. [START_REF] Devouassoux | Biopathologie des carcinomes ovariens des stades précoces et avancés : Recommandations françaises communes du CNGOF, FRANCOGYN, SFOG, GINECO-ARCAGY et labellisées INCa. Gynécologie, Obstétrique, Fertilité[END_REF]. Service de Gynécologie, Hôpital Hautepierre, CHU Strasbourg, France 4. Service d'Anesthésie, Hôpital Saint Joseph, Paris, France. [START_REF] Bakrin | Tumeurs épithéliales malignes de l'ovaire : place de la chimiothérapie intra-péritonéale et de la chimiothérapie hyperthermique intra-péritonéale (CHIP)[END_REF]. Service de chirurgie digestive, CHU Lyon-Sud, Pierre-Bénite, Lyon, France. [START_REF] Uzan | Tumeurs épithéliales de l'ovaire : préservation de la fertilité[END_REF]. Service de gynécologie, GH Diaconesses Croix Saint Simon, Paris, France. Adjuvant chemotherapy by carboplatin and paclitaxel is recommended for all high-grade ovarian and tubal cancers (FIGO stages I-IIA) (grade A). After primary surgery is complete, 6 cycles of intravenous chemotherapy (grade A) are recommended, or a discussion with the patient about intraperitoneal chemotherapy, according to her risk-benefit ratio. After complete interval surgery for FIGO stage III, hyperthermic intraperitoneal chemotherapy (HIPEC) can be proposed, in accordance with the modalities of the OV-HIPEC trial (grade B). In cases of postoperative tumor residue or in FIGO stage IV tumors, chemotherapy associated with bevacizumab is recommended (grade A).

Key words: ovarian cancer; tubal cancer, primary peritoneal cancer, surgery; chemotherapy; treatment sequences that differ substantially between centers for primary or interval surgery.

Similarly, the extent of surgery and the surgical staging procedures vary according to patient characteristics (young vs elderly women, for example). Perioperative management, whether it concerns early recovery or fertility preservation, has not been standardized, although it can cause physical or psychological morbidity. Finally, cancer centers vary widely in their use of chemotherapy (and how they administer it), as well as of targeted therapies; a national strategy remains to be defined, according to different clinical contexts. Work to develop clinical practice guidelines is therefore necessary to enable practices to be in accordance with the best evidence and to improve prognosis for all patients.

Accordingly, the French research group for oncologic gynecologic surgery (FRANCOGYN), the French national college of gynecologists and obstetricians (CNGOF), the French society of gynecologic oncology (SFOG), and the national investigators' group for studies in ovarian and breast cancer (GINECO-ARCAGY) brought together a working group to develop such guidelines. This text is a synthesis of clinical practice guidelines for the initial management of epithelial ovarian, tubal, or primary peritoneal cancers (excluding recurrence of ovarian cancer and borderline tumors). [START_REF] Huchon | Tumeurs épithéliales de l'ovaire. Méthodes et organisation. Recommandations françaises communes du CNGOF, FRANCOGYN, SFOG, GINECO-ARCAGY et labellisées INCa. Gynécologie, Obstétrique, Fertilité[END_REF] The development of these clinical practice guidelines followed the standards set by the French national authority for health (HAS) and the national cancer institute (INCa), with reviews by experts both within and outside the working group.

INCa has endorsed these clinical practice guidelines.

This article deals with the role of systemic and intraperitoneal treatments, the treatment of elderly women, fertility preservation, and the follow-up of women with ovarian, tubal, or primary peritoneal cancers.

A C C E P T E D

M A N U S C R I P T
Their aim is to aid professionals (gynecologic surgeons, medical gynecologists, gynecologistobstetricians, pathologists, medical oncologists, radiologists, anesthetist-critical-care specialists, nuclear physicians, general practitioners, midwives, and paramedical personnel) in managing women with ovarian cancer or with suspected ovarian, tubal, or primary peritoneal cancer. [START_REF] De | Traitements médicaux des cancers de l'ovaire lors de la prise en charge initiale[END_REF] An analysis of the literature has shown that at early stages adjuvant chemotherapy based on a platinum compound alone (especially carboplatin) or with another compound improves both relapse-free survival and 10-year overall survival (LE1). The optimal number of cycles of chemotherapy ranges from 3 to 6 (LE1).

A C C E P T E D

M A N U S C R I P T

Role of intravenous systemic treatments of early-stage ovarian or tubal cancer (FIGO stages I-IIA)

Adjuvant chemotherapy is recommended for all high-grade ovarian and tubal cancers (FIGO stages I-IIA) (grade A). Adjuvant chemotherapy for early-stage ovarian or tubal cancer must include a platinum compound (grade A), preferably carboplatin (grade A).

For high-grade serous carcinomas, an additional drug is recommended rather than use No guidelines can be issued about chemotherapy indications for early-stage ovarian carcinomas of the following types: low-grade serous, low-grade endometrioid, or clear-cell mucinous. It may be useful to refer to the guidelines of the network of rare ovarian tumors.

Role of systemic intravenous treatments of advanced (FIGO stages IIB-IV) ovarian,

tubal, or primary peritoneal cancers) [START_REF] De | Traitements médicaux des cancers de l'ovaire lors de la prise en charge initiale[END_REF] (Figures 1 and2)

A C C E P T E D M A N U S C R I P T
In advanced ovarian, tubal, or primary peritoneal cancers, polychemotherapy based on a platinum compound and taxane is superior to other combinations of chemotherapy for both overall survival and progression-free survival (LE1). The reference combination used in most clinical trials is carboplatin (AUC 5 or 6) and paclitaxel (175 mg/m² for 3 hours), every 3 weeks. Carboplatin is not inferior to cisplatin for either overall or progression-free survival, combined with paclitaxel; the latter combination has the best tolerance profile (LE1). A trial in Japan found that weekly fractionation of paclitaxel with an increase of dose-intensity to 80 mg/m2 combined with carboplatin AUC 5 or 6 every 3 weeks was superior (LE1). This superiority was not observed in a trial of a white population (LE1), except among those who had not received bevacizumab both with chemotherapy and then as maintenance (LE2).

Weekly fractionation of carboplatin and paclitaxel without increased dose-intensity (carboplatin AUC 2 on D1, D8, and D15, and paclitaxel 60 mg/m2 on D1, D8, and D15 every 3 weeks) is not inferior to the standard regimen and has a somewhat favorable tolerance profile (for neuropathy and alopecia) (LE1). As an alternative to paclitaxel, carboplatin can be combined with docetaxel, gemcitabine, or pegylated liposomal doxorubicin, but none of these combinations is superior to the standard treatment by carboplatin-paclitaxel (LE1). Although the efficacy of cisplatin is equivalent to that of carboplatin, cisplatin has a higher risk of nonhematologic toxicity, especially renal, gastrointestinal, and infectious (LE1). Oxaliplatin was assessed in association with cyclophosphamide in one trial with efficacy similar to that of the combination of cisplatin and paclitaxel (NP2). No clinical trial has demonstrated the superiority of any combination of 3 chemotherapy substances over the standard two-therapy combination (LE1). The number of cycles of chemotherapy administered in randomized clinical trials has ranged from 6 to 9. Moreover, the trials assessing the utility of strategies of chemotherapy maintenance have not shown any advantages over the standard regimen (LE1).

The randomized clinical trials aimed at assessing the value of neoadjuvant chemotherapy

A C C E P T E D M A N U S C R I P T
generally tested the standard regimen of carboplatin (AUC 5 or 6) on D1 and paclitaxel (175 mg/m2) on D1 every 3 weeks. Neoadjuvant chemotherapy was given for 3 to 4 cycles before interval cytoreduction surgery, then resumed in the postoperative period for 3 adjuvant cycles, for a total of 6 to 9 cycles overall. Most clinical trials begin adjuvant chemotherapy less than 4 weeks after surgery; a retrospective study of 3 randomized clinical trials reported the prognostic value of chemotherapy started after 19 days (LE3). Bevacizumab at a dose of 7.5 and 15 mg/kg every 3 weeks, combined with chemotherapy and then as maintenance, improved median progression-free survival of advanced stage III and IV ovarian cancer by 4 months for all stages combined, with the most benefit for the subgroups of women with poorer prognosis (i.e., stage IV and the Stage III women with postsurgery tumor residue and those with no surgery) (LE1). We note that more than 20% of the women had grade-3 toxicity (especially those with hypertension). Bevacizumab with chemotherapy must be omitted in cycle 1 if the treatment begins less than 4 weeks after surgical resection (NP1). Bevacizumab can be used in combination with a chemotherapy protocol including intensified weekly administration of paclitaxel at 80 mg/m² (LE3). The administration of bevacizumab after interval surgery does not increase its toxicity (LE2), and its use in combination with neoadjuvant chemotherapy does not increase perioperative morbidity during interval surgery (LE2). Nor does the use of bevacizumab in combination with neoadjuvant chemotherapy significantly increase the number of patients undergoing surgery or the rate of complete interval surgery (LE2). The role of hormone therapy has not been assessed for the treatment of advanced high-grade ovarian cancer. Olaparib is currently used for maintenance after chemotherapy in women with platinum-sensitive relapsed ovarian cancer who have a BRCA1/2 tumor or germline mutation. Its demonstrably high efficacy in this situation led to its authorization in 2014. The results of the SOLO-1 phase III randomized double-blinded, placebo-controlled trial that assessed olaparib as maintenance therapy after standard first-line

A C C E P T E D M A N U S C R I P T
treatment were published in the New England Journal of Medicine. The principal objective of this trial was to demonstrate the superiority of olaparib as maintenance treatment for progression-free survival. Overall, 391 women with FIGO stages III-IV high-grade serous or endometrioid cancer with a BRCA1/2 mutation were included; they were randomized 2:1 between olaparib and placebo after the end of the initial treatment sequence including primary or interval surgery and carboplatin-based chemotherapy. The maintenance treatment continued until progression or for a maximum of 24 months in its absence. The median follow-up was 41 months. The principal objective of the study was largely achieved, with a median progression-free survival corresponding to around 3 years in the olaparib group vs 13.8 months in the placebo group; HR=0.30; 95% CI 0.23-0.41; P<0.0001. The analyses of second progression-free survival (PFS2) (time from randomization to second disease progression or death), first subsequent treatment or death, and second subsequent treatment or death were also positive and confirm the principal endpoint. The data for overall survival remain immature. The groups did not differ for quality of life. From the perspective of toxicity, no new signal was observed for patients treated at relapse. The role of immunotherapy (anti-PD1 and PD-L1 and anti-CTLA4) is under evaluation for the management of advanced high-grade ovarian cancer as a first-line treatment. Role of the intraperitoneal approach for administering chemotherapy (hyperthermic (HIPEC) or normothermic) in advanced ovarian, tubal, or primary peritoneal cancers) [START_REF] Bakrin | Tumeurs épithéliales malignes de l'ovaire : place de la chimiothérapie intra-péritonéale et de la chimiothérapie hyperthermique intra-péritonéale (CHIP)[END_REF] (Figure 1)

Chemotherapy is recommended for all advanced (FIGO stages IIB-IV) ovarian, tubal, and primary peritoneal cancers (Grade A). A platinum compound (Grade A), preferentially carboplatin (Grade A), together with another substance (Grade

Intraperitoneal (IP) chemotherapy without hyperthermia

The meta-analysis by Jaaback et al. published in 2016 (LE1) covered 2119 women and 9 randomized trials comparing the intravenous (IV) and intraperitoneal (IP) administration of adjuvant chemotherapy after so-called optimal surgery (i.e., tumor residue < 1 cm). It reported that IP chemotherapy produced a significant gain in overall survival (8 studies), with a HR of 0.81 (95% CI 0.72-0.90) (LE1). This result is nearly identical to that found in considering only the 6 high quality studies (HR: 0.80 (95% CI 0.72-0.90) (LE1). This improvement in overall survival is independent of both the number of medications used and the dose. It should be noted that 6 of the 9 studies included in this meta-analysis did not use paclitaxel, and only 2 used carboplatin, due to the age of the studies; the most recent dated back to 2006 and used a control arm that did not correspond to current standards of IV chemotherapy. IP

Intraperitoneal pathway with hyperthermia: HIPEC

As of today, one phase III randomized trial has assessed the role of HIPEC for ovarian cancer with interval surgery. It demonstrated that, with strict OVHIPEC protocol adherence, median relapse-free survival in the surgery-only arm was 10.7 months and in the surgery + HIPEC arm, 14.2 months (P=0.003), with median overall survival 33.9 and 45.7 months (P=0.02), respectively, with a median follow-up of 4.7 years. Toxicity rates were equivalent in both arms (25% and 27% P=0.74; the most frequent grade 3-4 toxicity reports concerned abdominal pain, infections, and ileus. Durations of hospitalization were similar (8 vs 10 days).

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M A N U S C R I P T
The time to resumption of chemotherapy was almost the same in both arms (30 vs 33 days); 90% of the women in the surgery-only arm and 94% in the surgery + HIPEC arm received the 3 planned cycles of postoperative chemotherapy (LE1). These results underline the potential role of HIPEC but require confirmation, at a minimum by prospective registries. Modalities and strategies for fertility preservation for young women with FIGO stage I ovarian cancer [START_REF] Uzan | Tumeurs épithéliales de l'ovaire : préservation de la fertilité[END_REF] The possibility of fertility preservation in a woman with ovarian cancer concerns a small number of women: approximately 52 women per year in France. It must not be neglected, however, because 12.1% of the women with ovarian cancer are younger than 44 years, and their 5-year survival rate for stages IA and IB is 91.2%. The risk of recurrence for the contralateral ovary ranges from 6% to 13% for women of child-bearing age receiving conservative treatment of stage IA cancer. Women who wish for fertility preservation must be informed that there is a risk of recurrence ranging between 6 and 13% in the contralateral ovary.

In initially nonresectable FIGO stage III ovarian, tubal, and primary peritoneal cancers, hyperthermic intraperitoneal chemotherapy (HIPEC) can be offered after interval surgery expected to be complete or optimal (tumor residue < 1 cm), performed after 3 cycles of intravenous (IV) chemotherapy (grade B). The protocol must include

Management of older women with ovarian, tubal, or primary peritoneal cancer 7

Characteristics of treatments for older women

Women aged 70 years or older account for a constantly increasing portion of the population, given its continuous aging. Those with ovarian cancer have a poorer prognosis than younger women: overall survival at 1 year for women aged ≥ 80 years is 36.9%, from 75-79 years 59.3%, from 70-74 years 68.4%, and from 65-69 years 73.5% (LE4). In the different cohorts published, age is correlated with a reduction in recurrence-free survival and in overall survival (LE4). The characteristics of ovarian cancer in woman ≥ 70 years are generally more unfavorable: tumors that are less differentiated, more frequent mixed tumors, and more frequent high-grade serous carcinomas (LE4). Advanced age currently leads to especially heterogeneous management of ovarian cancer. The lower rates of complete and optimal surgery and of complete chemotherapy indicate undertreatment of elderly women with ovarian cancer. The rate of radical surgery falls significantly with age, including in expert centers. In the SEER database, the rate of radical surgery considered optimal (residues less than 1 cm) was 73.7% for the women younger than 60 years, 29.5% between 60 and 79 years and 21.7% at and after 80 years (LE4). Nonetheless, in the case of complete surgery, the benefit for elderly women is the same as that for their younger counterparts. The rate of exclusively surgical management, with no chemotherapy, increases with age: in the SEER database it is 8.1% for the women aged 65 to 69 years, 10.3% for those aged 70 to 74, 15.1% for those 75 to 79, 21.6% for those 80-84, and 37.5% for those ≥ 85 (LE4). Similarly, age is

A C C E P T E D M A N U S C R I P T
significantly associated with a delay in chemotherapy after surgery and a reduction in its dose intensity (LE4). For the women ≥ 75 years in the SEER database, the rate of standard surgery was 37.6%, of standard chemotherapy 51.2%, and of a standard medical/surgical strategy, 18.9% (LE4).

Toxicity of treatments in older women with ovarian cancer

Postoperative mortality is higher in elderly, than in younger, women with ovarian cancer: 30day postoperative mortality in women ≥ 80 years is 5.4% versus 2.4% for the younger women (OR = 2.3, P=0.036) (LE4). This excess mortality may be linked to a higher rate of emergency surgery (25% vs 14%, P<0.0003) and a lower rate of surgery in expert centers (6.6% vs 18.6%, P=0.001); elderly women with ovarian cancer had surgery more often in general hospitals than in specialized cancer centers or university hospitals (LE4). The risk of postoperative morbidity is higher in women ≥ 75 years. Three variables play a role in the postoperative morbidity rate: age ≥ 75 years, an ASA score ≥ 3, and surgical complexity (LE4). Similarly, chemotherapy toxicity is higher in elderly women with ovarian cancer, which results in a reduction in dose intensity (LE4).

What adaptation of treatment can be offered to elderly women with ovarian cancer?

The centralization of surgery for ovarian cancer has been identified as a major factor in better management. A study by Bristow et al. shows that the only independent risk factor for postoperative mortality in multivariate analysis is the number of annual surgical procedures for ovarian cancer performed (more than 20 procedures by hospital per year, and more than 10 per surgeon per year) (LE4). Age ≥ 60 years was correlated only with prolonged hospitalization. Another German study estimated that a "surgeon effect" reduced perioperative mortality by 29% when the surgeon performed more than 12 ovarian cancer procedures annually (LE4). scores are all significantly correlated with postoperative mortality (LE4). Several studies identified some categories of women who do not appear to benefit from primary cytoreduction surgery because of their high mortality in the first 60 days after surgery: mortality in the SEER database is 12.7% for the women older than 74 years with a FIGO stage IV tumor or with one or more comorbidities and a FIGO stage III tumor (LE4). In another retrospective study, the 60-day postoperative mortality for women older than 80 years who had surgery for advanced ovarian cancer (74% optimal) was 20%; moreover, among these women, 13% did not receive adjuvant chemotherapy, 22% were treated with a single chemotherapy agent, and 37% had only three chemotherapy cycles (LE4). Geriatric vulnerability can be assessed by various scores. Some of these scores are correlated with the performance of complete chemotherapy. The Geriatric Vulnerability Score (GVS) score has been correlated with the performance of 6 cycles of carboplatin alone (LE2) and the IADL score was predictive of the performance of at least 4 chemotherapy cycles in 70-yearold women (LE2). Authors have proposed chemotherapy protocols adapted for these vulnerable women, such as:

carboplatin as a single agent carboplatin AUC2 and paclitaxel 60 mg/m² 3 weeks/4.

carboplatin AUC 4-5 and paclitaxel 135 mg/m² carboplatin AUC5 D1; paclitaxel 60 mg/m² D1, D8, D15; D1=D28.

Elderly but not especially frail women with ovarian, tubal, or primary peritoneal cancers should receive intravenous chemotherapy identical to that for younger women (i.e., two agents, platinum-based) (grade B).

Neoadjuvant chemotherapy was most cost-effective in elderly women at high risk of complications (i.e., age ≥ 75 years and FIGO stage IV or age ≥ 75 years and stage III and at least 1 comorbidity) in the SEER database (LE4); in the EORTC study, it was associated with a lower complication rate and a higher rate of optimal surgery for elderly women (LE4).

In advanced ovarian, tubal, and primary peritoneal cancers, neoadjuvant chemotherapy diminishes the complexity of the surgical procedure and the perioperative morbidity and mortality of the interval surgery (LE1). In these advanced stage, starting with chemotherapy is a good alternative for those 70 years or older with comorbidities or with extensive peritoneal carcinomatosis requiring complex initial surgery (LE4).

Follow-up of high-grade serous epithelial cancers

Data specific to the follow-up of women treated for high-grade non-serous ovarian, tubal, or primary peritoneal cancers are sparse. The following guidelines concern women treated for a high-grade serous ovarian, tubal, or primary peritoneal carcinoma. In women in complete remission after surgery and chemotherapy for an advanced cancer of this type, 75 to 80% have a recurrence in the 2 years after the end of treatment (LE3). These recurrences are most often abdominal. Nonetheless the route of chemotherapy administration as well as the type of therapy chosen change the sites of recurrence. They may increase the rate of extra-abdominal and lymph node sites (LE4). The sensitivity of clinical examination to screen for recurrence of an epithelial ovarian tumor after initial treatment ranges from 7% to 78% for the diagnosis of a recurrence of ovarian, tubal, or primary peritoneal cancer (LE4). Personalized follow-up with a telephone interview asking about symptoms of recurrence, delegated to trained healthcare workers, at 3, 6, 12, 18 and 24 months after the end of treatment is equivalent to clinical monitoring (LE2).

After the conclusion of treatment of epithelial ovarian, tubal, or primary peritoneal cancer, an assessment of symptoms is recommended at 3, 6, 12, 18, and 24 months, and then yearly (Grade B)

In ovarian, tubal, and primary peritoneal cancers, CA125 at more than twice the upper limit of normal precedes clinical signs by 4.8 months (LE1). After treatment of these cancers, women are most satisfied when they receive the CA125 results for the monitoring consultation (LE4). Peritoneal cytology is not only invasive but also has poor sensitivity for the detection of a recurrence of ovarian cancer (LE4). Unless ascites is present, routine peritoneal cytology is not recommended for the diagnosis of a recurrence of ovarian, tubal, or primary peritoneal cancer (grade C).

After treatment of these cancers, the strategy of monitoring by CT thorax/abdomen/pelvis scan for the first two years is less effective and three times more expensive per diagnosis of recurrence than the CA125 assay alone (LE4). After treatment of ovarian, tubal, or primary peritoneal cancer, routine monitoring by CT scan of the thorax/abdomen/pelvis is not recommended (Grade C).

If epithelial ovarian, tubal, or primary peritoneal cancer recurs in asymptomatic women, treatment based solely on an elevated serum CA125 level does not increase overall survival, and it impairs their quality of life (LE1).

Early diagnosis of recurrence of ovarian, tubal, or primary peritoneal cancer that is accessible to complete surgical treatment (i.e. no macroscopic tumor residue) improves survival (LE3). Surgical management of a recurrence of epithelial ovarian, tubal, and primary peritoneal cancer is beneficial for overall survival only if surgical resection is macroscopically complete

A C C E P T E D M A N U S C R I P T (CC0) (LE1).
In cases of platinum-sensitive recurrence (i.e., recurrence > 6 months after the last line of chemotherapy) of ovarian, tubal, or primary peritoneal cancer, the AGO (Arbeitsgemeinschaft Gynäkologische Onkologie) score (based on a primary complete surgery (CC0), good overall condition (ECOG 0), and a limited recurrence (ascites <500 cc)) allows the selection of women eligible for complete surgical resection (LE3). After treatment of ovarian cancer, regular monitoring by other examinations for early screening of a recurrence, that is, before the onset of symptoms, is beneficial only if the second cytoreduction surgery is complete (with no macroscopic residue: CC0). In all cases, the prescription of HRT and its dosage and administration must follow the same guidelines as those for the general population (see, HAS guidelines 2014).

  Management of epithelial cancer of the ovary, fallopian tube, and primary peritoneum. Long Text of the Joint French Clinical Practice Guidelines issued by FRANCOGYN, CNGOF, SFOG, and GINECO-ARCAGY, and endorsed by INCa. (Part 2: systemic and intraperitoneal treatment, elderly patients, fertility preservation, and follow-up)

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 7 Service de Gynécologie-Obstétrique et Médecine de la Reproduction, Hôpital Tenon, 4 rue de La Chine, APHP, Institut Universitaire de Cancérologie Sorbonne Université, UMRS-938.

Introduction

  Initial management of epithelial ovarian cancers is relatively heterogeneous in France, with

  of this single agent (grade B). The chemotherapy recommended for early-stage ovarian or tubal cancer is based on the combination of carboplatin (AUC 5-6) on D1 and paclitaxel (175 mg/m2) on D1 every 3 weeks (grade B). Chemotherapy for stage IA or IB ovarian or tubal cancer must include at least 3 cycles and a maximum of 6 (grade A). For stage I high-grade serous carcinoma of the ovary or fallopian tubes and for the other histologic types of FIGO stages ≥ IC tumors, 6 cycles of chemotherapy are recommended (grade C).

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  A), is recommended as the standard chemotherapy for these advanced cancers. The preferential use of the combination of carboplatin (AUC 5-6) on D1 and paclitaxel (175 mg/m2) on D1 every 3 weeks is recommended and considered the standard regimen for advanced ovarian, tubal, and primary peritoneal cancers (Grade A). The following alternatives to this standard regimen may be proposed: Weekly fractionation of chemotherapy with carboplatin (AUC 2) on D1, D8, and D15, and paclitaxel (60 mg/m2) on D1, D8, and D15 every 3 weeks to limit their adverse effects (reduction in both alopecia and neurological toxicity) (Grade B). -If paclitaxel is contraindicated, the combination of carboplatin (AUC 5) on D1 and pegylated liposomal doxorubicin (30 mg/m2) on D1 every 4 weeks can be proposed (Grade B), as can single-agent chemotherapy with carboplatin (AUC 5) every 3 weeks (Grade B).-If carboplatin is contraindicated, cisplatin (75 mg/m2) can be combined with paclitaxel (175 mg/m2) every 3 weeks (Grade A).A duration of at least 6 treatment cycles is recommended for chemotherapy for advanced ovarian, tubal, and primary peritoneal cancers (Grade A).A regimen of carboplatin (AUC 5 or 6) and paclitaxel (175 mg/m2) every 3 weeks is recommended for neoadjuvant treatment for these advanced cancers (Grade A).Interval surgery is recommended after 3 to 4 cycles of treatment for these cancers (Grade C). The number of cycles of adjuvant chemotherapy after interval cytoreduction surgery will be 2 to 4, for a minimum total of 6 cycles and a maximum of 9 (Grade C).Chemotherapy should begin less than 6 weeks after cytoreduction surgery in advanced ovarian, tubal, and primary peritoneal cancer (grade C).Bevacizumab can be proposed together with chemotherapy by carboplatin and paclitaxel for up to 6 cycles of treatment and then alone as maintenance for a maximum of 15 months or until toxicity becomes unacceptable for women with FIGO stages III and IV cancers (FIGO 2014), especially those with the worst prognosis (stage IV, postoperative tumor residue, or no surgery) (grade A). Bevacizumab with chemotherapy must be omitted in cycle 1 if the treatment begins less than 4 weeks after primary (gradeA C C E P T E D M A N U S C R I P T A) or interval (Grade B) cytoreduction surgery. In the absence of any demonstration of the clinical utility of bevacizumab together with neoadjuvant chemotherapy, no recommendation in this situation is currently justified. Interval surgery after bevacizumab is not contraindicated. Olaparib as maintenance treatment after primary or interval surgery and first-line chemotherapy is recommended at a dose of 300-mg tablets × 2/24 h orally for 24 months or until progression in women with FIGO stages III-IV high-grade serous or endometrioid ovarian, tubal, or primary peritoneal cancer and a BRCA1/2 mutation (Grade B). At the time these guidelines were drafted, olaparib is not yet authorized as first-line treatment. As of now, no data are available about the combination of bevacizumab and olaparib. Rapid testing for BRCA mutations is necessary at diagnosis of ovarian cancer to determine if olaparib is indicated (figure 3).

  administration leads to a significant increase in fever, fatigue, gastrointestinal effects, infections, metabolic effects, pain, and neurological toxicity, with a concomitant reduction in the quality of life during and for 6 weeks after the chemotherapy, compared with IV administration (LE2). The IP pathway has complications specific to the level of the intraperitoneal trocars, notably, occlusion in 7 to 25% of cases and infection in 5 to 19%.Tolerance is better experienced teams perform the IP chemotherapy (LE4). The data in the current literature do not enable a definitive conclusion about the efficacy of IP carboplatin or about the use of IP chemotherapy after interval surgery.Experienced teams can offer adjuvant IP chemotherapy after primarysurgery with tumor residue < 10 mm for ovarian, tubal, or primary peritoneal carcinomatosis. The recommended protocol is paclitaxel 135 mg/m² for 3 h or 24 h intravenous (IV) on D1, cisplatin 75 to 100 mg/m² IP on D8, every 3 weeks for 6 cycles. The risk-benefit ratio of the IP versus the IV pathway should be discussed with the woman in view of the higher complication rate with IP. If IP chemotherapy must be interrupted, treatment must be continued by the IV pathway (Grade B). No data exist to justify a recommendation about the use of bevacizumab after IP chemotherapy.

  cisplatin 100 mg/m 2 distributed at 50 mg/m 2 at the beginning of the procedure, 25 mg/m 2 at 30 min, and 25 mg/m 2 at 60 min, for a total duration of 90 min at 40-41° C, combined with hyperhydratation and nephroprotection by IV sodium thiosulfate, by a bolus of 9 g/m 2 at the start of HIPEC, then 12 g/m 2 for 6 hours (grade B). At the publication of these guidelines, sodium thiosulfate is available only on temporary authorizations for a named patient (nominative ATU). No data exist to justify a recommendation about the use of bevacizumab after HIPEC.

  Women of child-bearing age should be informed about the possibility of conservative management of their fertility in cases of stage IA epithelial ovarian cancer (Grade C).Conservative surgical management of the uterus and the contralateral adnexa after a unilateral adnexectomy for a low-grade serous, mucinous, or endometrioid stage IA ovarian cancer may be offered to a woman of child-bearing age, on condition that complete peritoneal and lymph node staging are negative, along with the findings of the uterine curettage for the endometrioid and mucinous histologic subtypes (Grade C).

  FIGO stage IA or low-grade stage IC1 or IC2, a bilateral adnexectomy may be

  Adequate evidence does not currently exist to justify a recommendation to freeze ovarian cortex tissue for future grafting for women with epithelial ovarian cancers, or to judge the oncologic safety (or lack thereof) of ovarian stimulation by pituitary gonadotropins after conservative surgery for a stage IA grade 1 epithelial ovarian tumor.

  Several studies have shown the effect of geriatric and nongeriatric covariables on postoperative morbidity and mortality: gait speed, dependence assessed by the IADL (Instrumental Activities of Daily Living) and the SPPB (Short Physical Performance Battery)

  Older women with ovarian, tubal, or primary peritoneal cancer should receive cytoreduction surgery in high-volume centers (performing more than 20 procedures for advanced ovarian cancer annually (grade C). This surgery is recommended in elderly women (Grade B) provided that comorbidities and the likelihood of complete surgery allow it. The risk-benefit ratio of surgery for ovarian, tubal, and primary peritoneal cancer should be assessed on a case-by-case for the populations at the highest risk of complications (LE4), defined by: o Age ≥ 80 years, especially with albuminemia ≤ 37 g/L o Age ≥ 75 years and FIGO stage IV o Age ≥ 75 years, FIGO stage III and ≥ 1 comorbidity. assessment is recommended before the decisions about management of elderly women with ovarian, tubal, or primary peritoneal cancer (grade C).

  follow-up of ovarian, tubal, and primary peritoneal cancers and the role of hormone therapy 8 (Figure4)

  Elevation of the HE4 serum assay is more sensitive and earlier than that of CA125 for screening for the recurrence of these cancers (LE3). If paraclinical monitoring is indicated for a woman after treatment of an epithelial ovarian, tubal, or primary peritoneal cancer, HE4 serum assays can be recommended (grade B). The CNAM-TS does not reimburse the HE4 serum assay. In the absence of possible HE4 monitoring, CA125 serum assays can also be proposed (grade B).After treatment of epithelial ovarian, tubal, or primary peritoneal cancer, any finding of elevated serum HE4 or CA125 levels should be followed by an imaging examination (grade B).

For

  the follow-up of ovarian, tubal, or primary peritoneal cancer, women with complete initial surgery (no macroscopic tumor residue, CC0) and in good overall condition (ECOG 0) should be monitored by serum assays (HE4 or CA125) starting 6 months after the end of chemotherapy, then every 6 months, if the serum markers were initially high (Grade C) ( 5).Role of hormone therapy after the treatment of ovarian, tubal, or primary peritoneal cancer.Women younger than 45 years whose mucinous ovarian adenocarcinoma has been treated benefit from HRT in terms of cardiovascular and overall survival (LE3). Women younger than 45 years of age who have undergone nonconservative treatment for high-grade serous ovarian, tubal, or primary peritoneal cancer should be offered hormone replacement treatment (HRT) for menopause (grade C) HRT does not increase the risks of recurrence or mortality in women older than 45 years (LE2). HRT can be offered for menopausal symptoms to women with a history of highgrade serous ovarian, tubal, or primary peritoneal cancer, after an individual evaluation of her risk-benefit ratio (Grade B).

  Women younger than 45 years whose mucinous ovarian adenocarcinoma has been treated benefit from HRT in terms of cardiovascular survival and overall survival (LE4). HRT should be offered to women younger than 45 years after non-conservative treatment of mucinous ovarian cancer (grade C). HRT can be offered to a woman older than 45 years with a history of mucinous ovarian cancer for menopause symptoms after an individual evaluation of her risk-benefit ratio.Low-grade serous or endometrioid adenocarcinomas are hormone-sensitive histologic types, for which HRT use is a potential risk (LE4). Nonetheless, no specific data for these histologic types justify a guideline about HRT use in women with a history of low-grade serous or endometrioid ovarian cancer.

  https://www.e-cancer.fr/Professionnels-de-sante/Recommandations-et-outils-d-aide-a-la-

Figure 1 :

 1 Figure 1: Management of a FIGO stage III ovarian, tubal, or primary peritoneal cancer

Figure 2 :

 2 Figure 2: Management of a FIGO stage IV ovarian, tubal, or primary peritoneal cancer

Figure 3 :

 3 Figure 3: Management strategy in the era of first-line Olaparib

Figure 4 :

 4 Figure 4: Post-treatment follow-up of women with ovarian, tubal, or primary peritoneal cancer

Acknowledgments:

The authors want to thank Mme Marianne Duperray and Mme Sophie Morois for their valuable logistic support in the development of these clinical practice guidelines.

The authors thank the following professional societies: CNGOF, FRANCOGYN, SFOG, SFAR, GINECO-ARCAGY, SCGP, SFCO, and the RRC; the IMAGIN patient association, and the expert reviewers for their attentive review of these clinical practice guidelines: (list:

Declaration of interests

The authors' potential relationships of interests are listed at: https://www.transparence.sante.gouv.fr.