Cancer of the ovary, fallopian tube, and peritoneum: 2025 update.

MR, MF, and JB reviewed and updated the chapter on cancer of the ovary, fallopian tube, and peritoneum published in the 2021 Cancer Report.

Between 2006 and 2012, TCGA collected data on 12 different types of cancers with the goal of comparing the complete cancer genomes with the normal human genome and identifying characteristic and common genetic abnormalities in human cancers. 215 , 216 TCGA showed that approximately half of the analyzed high‐grade ovarian cancers had defects in the double‐strand DNA homologous repair (HR) pathway. 217 TCGA described four subtypes, which, in contrast to the findings of the TCGA for endometrial cancer, have not been shown to be of prognostic or therapeutic value. Ongoing efforts are focused on characterizing tumor heterogeneity 218 and tumor microenvironment. 219 The new class of ADCs (see above) directed against specific surface molecules, such as FOLR1, Her2, and Trop2, are recent examples of the successful application of precision oncology in ovarian cancer. Biobanking of ovarian cancer tissue and patient blood samples has been established in several national and international institutions. 220 , 221 , 222 Multiple efforts to improve the experimental in vitro model systems are on the way, including ascites‐derived spheroids and 3D culturing in patient‐derived organoids. 223 , 224

In general, the prognosis of epithelial ovarian, fallopian, and peritoneal malignancies is independently affected by the following: 1 , 86 , 87 stage of cancer at diagnosis, histologic type and grade, and maximum diameter of residual disease after cytoreductive surgery. A thorough staging laparotomy is an important part of management. If the preoperative suspicion is malignancy, a laparotomy should be performed. Minimally invasive staging surgery, however, can be considered. Studies have shown no difference in surgical outcomes, recurrences, and survival between open and minimally invasive staging surgeries. 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 If there is no visible or palpable evidence of metastasis, the following should be performed for adequate staging: 1 , 13 , 14 Careful evaluation of all peritoneal surfaces Retrieval of any peritoneal fluid or ascites; if there is none, washings of the peritoneal cavity should be performed Infracolic omentectomy Selective lymphadenectomy of the pelvic and para‐aortic lymph nodes, at least ipsilateral if the malignancy is unilateral Biopsy or resection of any suspicious lesions, masses, or adhesions Random peritoneal biopsies of normal surfaces, including from the undersurface of the right hemidiaphragm, bladder reflection, cul‐de‐sac, right and left paracolic recesses, and both pelvic sidewalls Total abdominal hysterectomy and bilateral salpingo‐oophorectomy in most cases; fertility‐sparing surgeries are discussed below Appendectomy for mucinous tumors, if the appendix appears abnormal. Careful evaluation of all peritoneal surfaces Retrieval of any peritoneal fluid or ascites; if there is none, washings of the peritoneal cavity should be performed Infracolic omentectomy Selective lymphadenectomy of the pelvic and para‐aortic lymph nodes, at least ipsilateral if the malignancy is unilateral Biopsy or resection of any suspicious lesions, masses, or adhesions Random peritoneal biopsies of normal surfaces, including from the undersurface of the right hemidiaphragm, bladder reflection, cul‐de‐sac, right and left paracolic recesses, and both pelvic sidewalls Total abdominal hysterectomy and bilateral salpingo‐oophorectomy in most cases; fertility‐sparing surgeries are discussed below Appendectomy for mucinous tumors, if the appendix appears abnormal. Upon opening the abdominopelvic cavity, the peritoneal fluid should be sent for cytology. In the absence of ascites, irrigation should be performed and washings sent for cytology. The laparotomy should proceed with a detailed examination of the contents, including all the peritoneal surfaces. In addition to the suspicious sites, biopsies from the peritoneal reflection of the bladder, the posterior cul‐de‐sac, both paracolic gutters, subdiaphragmatic surfaces, and both pelvic sidewalls should be taken. The primary tumor, if limited to the ovary, should be examined to look for capsular rupture. All obvious sites of tumor must be removed wherever possible in addition to total hysterectomy and bilateral salpingo‐oophorectomy. The omentum, pelvic, and para‐aortic lymph nodes should be removed for histologic examination. In younger women, fertility‐preservation may be desired. In these patients, conservative surgery, with preservation of the uterus and contralateral ovary, should be considered after informed consent. 76 Recent guidelines support fertility‐sparing surgery for patients with Stage I epithelial ovarian cancer, clear cell cancers, mucinous cancers, LGSCs, low‐grade endometrioid cancers, borderline tumors, granulosa cell tumors, and all stages of germ cell tumors. Reproductive specialists should be involved early in the process, ideally before the beginning of any oncological treatments. 101 , 102 Interested readers are encouraged to read the guidelines for greater detail. 101 Ovaries and fallopian tubes should be evaluated as thoroughly as possible to establish the site of origin. If visible, the entire tube, particularly the distal portion, should be submitted for pathology and examined using the SEE‐FIM protocol. 49 At least two‐thirds of patients with ovarian cancer present with Stage III or IV disease. This may affect the performance status and fitness for surgery. However, the most important prognostic indicator in patients with advanced‐stage ovarian cancer is the volume of residual disease after surgical debulking. Patients whose disease is completely resected to no macroscopic (microscopic only) residual disease have the best overall survival (OS). 87 , 103 Therefore, patients whose medical condition permits should generally undergo a primary laparotomy with total abdominal hysterectomy, bilateral salpingo‐oophorectomy, omentectomy, and maximal attempt at optimal cytoreduction. 1 , 86 , 87 This may necessitate bowel resection, and occasionally, partial or complete resection of other organs. Based on the randomized Lymphadenectomy in Ovarian Neoplasm (LION) trial, the removal of clinically negative lymph nodes during cytoreductive surgery does not increase the progression‐free survival (PFS) or OS and should not be undertaken 104 (Level of Evidence: A). In selected patients with apparent Stage IIIC and IV disease who are not considered to be good surgical candidates, 3–4 cycles of NACT may be given initially after histological confirmation of the diagnosis with core biopsies, followed by IDS and additional chemotherapy as demonstrated in the EORTC and Chemotherapy or Upfront Surgery (CHORUS) Trials. 105 , 106 These two randomized prospective trials showed that in selected patients, IDS after NACT showed equivalent survival with less morbidity compared with primary cytoreductive surgery. NACT followed by IDS may be particularly useful in patients with a poor performance status, significant medical co‐morbidities, or who have disease unlikely to be optimally cytoreduced, i.e., visceral metastases large volume pleural effusions or evidence of extraperitoneal disease. 107 , 108 In selected patients whose primary cytoreduction is considered suboptimal, particularly if a gynecologic oncologist did not perform the initial surgery, IDS may be considered after 2–3 cycles of systemic chemotherapy. 1 , 105 , 106 , 109 A histopathologic scoring system for measuring the response to NACT has been developed and validated by Bohm et al., 110 who reported criteria for defining a chemotherapy response score (CRS) based on a three‐tier system. A CRS of 3 (complete or near‐complete pathological response) was associated with a better prognosis. These results have been validated in an independent West Australian cohort. 111 Based on a more recent review of the National Cancer Database of over 7800 patients between 2013 and 2018, IDS might be safely performed by minimally invasive surgery with similar OS compared to laparotomy if the patient showed a good treatment response to NACT. 112 The NCCN guidelines recommend that in select patients, minimally invasive procedures may be used for IDS provided optimal cytoreduction can be achieved.

Ovarian sarcomas are rare and occur primarily in postmenopausal patients. 248 , 280 Nevertheless, accurate diagnosis and differentiation from other types of primary ovarian cancer are important, as the prognosis is generally poor. There are two types of sarcomas. Ovarian carcinosarcomas or the older term “malignant mixed Müllerian tumors” (MMMTs), the more common of the two, are biphasic tumors composed of both carcinomatous and sarcomatous elements. 280 , 281 Most authors agree that most MMMTs are monoclonal in origin and should be thought of and managed as a high‐grade epithelial cancer. The sarcomatous component is derived from carcinoma or from a stem cell that undergoes divergent differentiation. Thus, ovarian carcinosarcomas are best regarded as metaplastic carcinomas. Pure sarcomas are very rare and should be treated according to the specific histologic subtype. These rare sarcomas include fibrosarcomas, leiomyosarcomas, neurofibrosarcomas, rhabdomyosarcomas, chondrosarcomas, angiosarcomas, and liposarcomas. Their management is not discussed here. Patients with early‐stage ovarian carcinosarcomas have a better outcome than those with advanced‐stage disease; however, the overall prognosis is poor. They should be managed similarly to high‐grade pelvic serous cancers. Their rarity prohibits any prospective randomized trials. The principles of surgical management for ovarian carcinosarcomas are similar to those for high‐grade pelvic serous cancers. After surgery, patients should receive platinum‐based chemotherapy. 248 The follow‐up schedule aligns with that recommended for epithelial malignancies (Level of Evidence: C).

Patients with epithelial ovarian cancers confined to the ovary or fallopian tube at initial diagnosis have a very good prognosis. 75 , 76 , 77 , 78 The symptoms are often very insidious, and their duration is not very different between patients with early‐stage or advanced‐stage disease. 19 , 20 This may reflect the different biological behaviors of the various histologic subtypes; for example, clear cell, mucinous, and endometrioid cancers are commonly early stage at presentation, whereas HGSCs are most often Stage III because of early dissemination. Approximately two‐thirds of all epithelial “ovarian” cancers are Stage III or IV at diagnosis. Presenting symptoms include vague abdominal pain or discomfort, menstrual irregularities, dyspepsia, and other mild digestive disturbances, which may have been present for only a few weeks. 19 , 20 , 79 As the disease progresses, abdominal distention and discomfort from ascites generally worsen and may be associated with respiratory symptoms from increased intra‐abdominal pressure or from the transudation of fluid into the pleural cavities. Abnormal vaginal bleeding is an uncommon symptom. Serous fallopian tube and peritoneal cancers present with the same symptoms as ovarian cancer. Past analyses have been biased because many fallopian tube cancers have been presumed to arise in the ovaries as discussed earlier. A detailed medical history must be taken to ascertain possible risk factors, history of other cancers, and history of cancer in the family. A complete physical examination, including general, breast, pelvic, and rectal examination, must then be performed. 1 A preoperative chest radiograph should be taken to screen for pleural effusion and a CT scan of the abdomen and pelvis should be performed to delineate the extent of intra‐abdominal disease. However, in the absence of extra‐abdominopelvic disease, radiological scanning does not replace surgical staging. Tumor markers, including CA125, CA 19–9, and carcinoembryonic antigen (CEA), should be considered. 1 With a high CA125 level, the most common diagnosis would be epithelial ovarian, fallopian tube, or peritoneal cancer. Tumor markers, such as human gonadotropin (hCG) and alpha‐fetoprotein (AFP), are mandatory to exclude germ cell tumors in younger patients with a pelvic mass or suspicious enlargement of an ovary. Specific biomarkers and algorithms can aid in distinguishing malignant from benign pelvic masses. Ultrasound, CA125, and menopausal status have been combined to create a Risk of Malignancy Index (RMI) that achieved a sensitivity in the range of 71%–88% and specificity of 74%–97% for predicting the presence of ovarian cancers in women with pelvic masses. 80 OVA includes CA125, apolipoprotein A1, transthyretin, transferrin, and B2‐microglobulin combined with imaging and menopausal status; it demonstrates a sensitivity of 92% at a specificity of 42% in postmenopausal women, and a sensitivity of 85% at a specificity of 45% for premenopausal women. 81 A similar sensitivity and higher specificity have been attained with a Risk of Ovarian Malignancy Algorithm (ROMA) calculated from CA125 and HE4 values combined with menopausal status alone, without imaging. 82 The ROMA has been shown to be superior to the RMI. 83 A second‐generation OVERA panel test includes CA125, apolipoprotein A1, transferrin, follicle‐stimulating hormone, and HE4 producing a sensitivity of 91%, specificity of 69%, and negative predictive value of 97%. 84 Both the OVERA and ROMA panels have been approved for use by the U.S. Food and Drug Administration (FDA). Utilization of these panels could assure that women with suspicious adnexal masses are referred to gynecologic oncologists. A gastric or colonic primary with metastases to the ovaries may mimic ovarian cancer, and if CEA or CA 19–9 are elevated, this should be considered. A ratio of more than 25:1 (CA125 and CEA) favors an ovarian primary, though it does not completely rule out a primary in the gastrointestinal tract. 85 A current mammogram should be considered as patients are often in the age group where breast cancer is prevalent. A colonoscopy is indicated when symptoms suggest possible colorectal cancer. 1 The following factors point to the presence of a malignancy and are useful in the clinical assessment of masses: age of the patient (young for germ cell, older for epithelial malignancies), bilaterality, tumor fixation clinically, ascites, ultrasonographically complex—especially if solid areas, CT finding of metastatic nodules, and elevated tumor markers.

To date, there are no effective screening methods that have been shown to reduce the mortality of ovarian, fallopian tube, or peritoneal cancers. Studies using CA125 and/or ultrasonography of the pelvis do not have an acceptable level of sensitivity and specificity based on trials carried out in the general population 65 , 66 as well as the high‐risk population. 67 , 68 The U.S. Preventive Services Task Force (USPSTF) recommends against screening asymptomatic women for ovarian cancer with pelvic ultrasound or serum tumor marker measurements, which is in keeping with many other organizations. 69 The USPSTF noted that there was “fair evidence that earlier detection would likely have a small effect, at best, on mortality from ovarian cancer, but because of the low prevalence of ovarian cancer there is fair evidence that screening could likely lead to important harms which outweigh the potential benefits” . 70 A recent study on multimodal screening for high‐risk women, using CA125 levels assessed with the risk of ovarian cancer algorithm (ROCA) every 4 months and annual transvaginal sonography (TVS) (or earlier if indicated by the ROCA), found that screening was associated with a higher proportion of Stage 1 or 2 diagnoses and significantly increased rates of no residual disease after surgery. 71 The authors concluded that risk‐reducing salpingectomy‐oophorectomy remains the treatment of choice for women at high risk of ovarian/fallopian tube cancer. 71 The recently reported UK Collaborative Trial of Ovarian Cancer Screening trial, which recruited over 200 000 women, found that those in the multimodal screening group had a lower incidence of advanced‐stage disease at diagnosis (75% vs. 86%; P  = 0.0003), a higher likelihood of undergoing primary surgery (61% vs. 42%; P  < 0.0001), and a greater chance of having no residual disease after debulking surgery (46% vs. 30%; P  < 0.0001) compared to the no‐screening group. There was a borderline statistically significant increase in survival in the multimodal screening group at 18 years (21% vs. 14%). 66 , 72 The Normal Risk Ovarian Screening Study tested a two‐stage screening strategy in postmenopausal women where significantly rising CA125 levels prompted TVS and surgery if abnormal. They reported a positive predictive value of 50% and high proportion with Stage I or II cancers, but it should be noted that there were only two Stage I HGSCs. This study needs to be validated and needs to determine whether there is a survival benefit, and we recommend adhering to screening guidelines at present. 73 Women at increased genetic risk should be encouraged to consider risk‐reducing bilateral salpingo‐oophorectomy as this is the most effective way to reduce mortality in this population of women. 39 , 40 A bulletin from the American College of Obstetricians and Gynecologists has recommended that opportunistic (at the time of a clinically indicated hysterectomy) bilateral salpingectomy be considered in women not at genetic risk who wish to retain their ovaries as a way to reduce their risk of later developing HGSCs. 74

A second‐look laparotomy (or laparoscopy) was previously performed in patients who have no clinical evidence of disease after completion of first‐line chemotherapy to determine response to treatment. Although of prognostic value, it has not been shown to influence survival and is no longer recommended as part of the standard of care 170 (Level of Evidence: C). Secondary cytoreduction is defined as an attempt at cytoreductive surgery at some stage after completion of first‐line chemotherapy. Retrospective studies suggest that patients benefit if all macroscopic disease can be removed, which usually means patients with a solitary recurrence. Patients with a disease‐free interval longer than 12–24 months and those with only 1–2 sites of disease appear to derive most benefit. 171 , 172 The role of secondary cytoreductive surgery is being evaluated in randomized clinical trials. The role of secondary debulking surgery has been addressed in the DESKTOP III trial. 173 That study included patients with a PFS longer than 6 months after first‐line chemotherapy and who were considered to be good candidates for surgery based on a positive AGO Study Group score, defined as an ECOG performance status score of zero, ascites of 500 mL or less, and complete resection at initial surgery. Harter et al. 173 reported that the median PFS in 206 women who met these criteria and who were randomized to undergo surgery followed by chemotherapy was 18.4 months, compared with 14 months in 201 women who were randomized to receive only second‐line chemotherapy. Median PFS overall was 18.4 versus 14 months, and 21.1 (with complete cytoreduction) versus 13.7 months (with residual disease) versus 14 months (with chemotherapy only). Median OS showed an OS benefit of more than 12 months for patients undergoing complete secondary cytoreduction (61.9 vs. 46 months). OS for patients who underwent surgery and were only incompletely cytoreduced was only 28 months, stressing the importance of complete cytoreduction. Results of the GOG 213 trial, however, showed no statistically significant difference in PFS, with 18.9 versus 16.2 months and OS with 50.6 versus 64.7 months (with vs. without secondary cytoreduction). 174 In view of these two trials, secondary cytoreduction can be considered a safe option for carefully selected patients. In contrast, the GOG 213 trial did not demonstrate a survival advantage with secondary debulking surgery. The trial randomized 240 patients to secondary cytoreduction before chemotherapy and 245 to platinum‐based chemotherapy and bevacizumab. The HR for disease progression or death (surgery vs. no surgery) was 0.82 (95% CI 0.66–1.01; median PFS 18.9 and 16.2 months, respectively). The phase III SOC‐1 trial, 175 which randomized 357 patients with recurrent platinum‐sensitive disease to chemotherapy versus secondary debulking followed by chemotherapy, reported an improvement in PFS (17.4 vs. 11.9 months), but no significant advantage in OS (58.1 vs. 52.1 months; HR 0.8, 95% CI 0.61–1.05). 176 There is likely a role for secondary cytoreductive surgery, although patient selection is critical as outcomes are likely to be better in patients with a long treatment‐free interval, with a limited number of sites of disease and in whom complete resection is possible with macroscopic residual disease. Surgery is unlikely to be of benefit if there is evidence of ascites and carcinomatosis and in patients with poor performance status (Level of Evidence: B).

This group of ovarian tumors consists of a variety of histologically different subtypes that are all derived from the primitive germ cells of the embryonic gonad. Malignant ovarian germ cell tumors (MOGCTs) represent a relatively small proportion of all ovarian tumors. Before advances in chemotherapy, the prognosis for these aggressive tumors was poor. The use of platinum‐based chemotherapeutic regimes has made germ cell malignancies among the most highly curable cancers. 248 These are the most common ovarian tumors in the second and third decades of life. They are frequently diagnosed by finding a palpable abdominal mass in a young woman who complains of abdominal pain. The following are the symptoms of germ cell tumors in order of frequency: 248 acute abdominal pain, chronic abdominal pain, asymptomatic abdominal mass, abnormal vaginal bleeding, and abdominal distention. The classification of ovarian germ cell tumors is important to determine prognosis and for treatment with chemotherapy. Germ cell tumors are classified below. 2 , 248 Histological diagnosis may be difficult and immunohistochemical markers can be valuable and have been added here in parenthesis: dysgerminoma (OCT3/4, PLAP, D2‐40, NANOG, CD117), embryonal carcinoma (OCT3/4, CD30, NANOG, SOX10), teratoma (immature, mature, mature with carcinoma [squamous cell, carcinoid, neuroectodermal, malignant struma, etc.]) (SALL4 commonly positive in all MOGCTs including immature teratomas). Extra‐embryonal differentiation is as follows: non‐gestational choriocarcinoma (b‐hCG, inhibin), and endodermal sinus tumor (or yolk sac tumor) (AFP, glypican‐2 typically; PLAP can be positive). Ovarian germ cell tumors are staged similarly to epithelial carcinomas, although the staging system used for male germ cell tumors is probably more useful. The approach to treatment is based on the principles of management of metastatic germ cell tumors of the testis (i.e., low, intermediate, and poor risk). Dysgerminoma is the equivalent of seminoma in testicular cancer. 263 It is exquisitely sensitive to platinum‐based chemotherapy and is radiosensitive. The cure rate is high, irrespective of the stage. The other histological subtypes are equivalent to non‐seminomatous testicular cancers. The aggressiveness of the disease is dependent on the type, with the most aggressive being endodermal sinus and choriocarcinoma; however, with combination chemotherapy, they are highly curable. 264 , 265 , 266 , 267 , 268 As chemotherapy can cure the majority of patients, even with advanced disease, conservative surgery is standard in all stages of all germ cell tumors. Conservative surgery means laparotomy with careful examination and biopsy of all suspicious areas, with limited cytoreduction, thereby avoiding major morbidity. Fertility‐sparing surgery is considered the standard of care for young patients with early‐stage disease and should also be considered in advanced disease given the high chemosensitivity of the MOGCTs. 269 , 270 The choice of approach should be tailored to avoid rupture. Cystectomies should be avoided. The uterus and the contralateral ovary should be left intact. Wedge biopsy of a normal ovary is not recommended as it defeats the purpose of conservative therapy by potentially causing infertility. Even if both ovaries are involved, a partial oophorectomy on one side should be considered. Patients with advanced disease may benefit from 3 to 4 cycles of NACT using the BEP (platinum) regimen with preservation of fertility. 271 Patients who receive conservative surgery with the preservation of one ovary retain acceptable fertility rates despite adjuvant treatment with chemotherapy. There has been no report of higher adverse obstetric outcome or long‐term unfavorable sequelae in the offspring. Secondary surgery is of no proven benefit except in patients whose primary tumor contained teratomatous elements. Surgical resection of residual masses may be beneficial in such cases, although complete resection is not necessary if the procedure would be too invasive. Mature teratomatous nodules can continue to grow (growing teratoma syndrome) and, more rarely, may undergo malignant transformation over time into an incurable malignancy, such as squamous cell carcinoma. 272 Patients with Stage IA disease may be observed postoperatively. A small proportion may recur, but can be treated successfully at the time of recurrence, with a high cure rate. Patients with disease beyond the ovary should receive adjuvant chemotherapy. Although radiation therapy is effective, it is no longer used because of late effects, and chemotherapy is highly effective. A follow‐up surveillance regime for patients with Stage 1A dysgerminoma is outlined in Table  4 . This schedule is based on the experience of managing seminomas in men and the reports by Dark et al. 273 and Patterson et al. 274 This pragmatic follow‐up schedule has not been tested in randomized trials. Follow‐up regime for Stage I germ cell malignancies. a Abbreviations: AFP, alpha‐fetoprotein; CT, computed tomography; hCG, human chorionic gonadotropin; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging. Adapted from Patterson et al. 274 Dysgerminoma is extremely sensitive to chemotherapy, and treatment with chemotherapy cures the majority of patients, even with advanced disease. 248 , 275 The recommended chemotherapy regimen is as follows: etoposide (E) 100 mg/m 2 IV per day for 5 days every 3 weeks for three cycles, cisplatin (P) 20 mg/m 2 IV per day for 5 days every 3 weeks for three cycles, and bleomycin (B) 30 IU IV/IM on days 1, 8, and 15 for 12 weeks (optional) (note that bleomycin is dosed in International Units). If bleomycin is omitted, then four cycles of EP are commonly used (note that various schedules of bleomycin have been used and the role of bleomycin in dysgerminomas is controversial). In adolescent patients, other options include cisplatin, etoposide, and ifosfamide (PEI or VIP), as used in pediatric protocols. There is increased interest in the de‐escalation of chemotherapy in dysgerminomas as they are so chemosensitive and it may be possible to omit bleomycin and substitute carboplatin for cisplatin due to the acute adverse effects and potential long‐term adverse effects associated with BEP, including secondary malignancies, cardiovascular disease, hypertension, Raynaud's phenomenon, pulmonary toxicity, nephrotoxicity, neurotoxicity, deafness, decreased fertility, and psychosocial problems among others. GOG‐116 is an old trial that investigated carboplatin 400 mg/m 2 and etoposide 120 mg/m 2 on days 1–3 every 4 weeks in 39 patients with Stage IB–III dysgerminoma. 276 No patients relapsed despite the very modest dose of carboplatin and 3 days of etoposide every 4 weeks for three cycles only; however, the trial closed early after the results of two trials in male patients with non‐seminomatous testicular cancer reported inferior outcomes with carboplatin compared to cisplatin. Shah et al. 277 reported the results of pooled data from six trials (three pediatric and three adult) on behalf of the Malignant Germ Cell Tumor International Consortium (MaGIC), which included 126 patients with advanced‐stage (Stage IC–IV) dysgerminomas who were treated with either carboplatin‐ or cisplatin‐based chemotherapy. Survival outcomes were equivalent, with a 5‐year survival of 96% in both groups, with no differences seen according to age (25 years). Seven patients relapsed, including two who had received carboplatin‐based chemotherapy and five treated with BEP; all were salvaged. 277 When bulky residual disease is present, 3–4 courses of BEP or EP chemotherapy are commonly administered 278 (Level of Evidence: B). The optimal follow‐up schedule has not been clinically investigated in ovarian germ cancers, and the frequency of visits and investigations is controversial. Patients who have Stage I tumors and are offered surveillance need to be seen regularly. One option is to utilize the follow‐up regimen presented above. 273 Patients who have had chemotherapy have a lower risk of recurrence and the frequency of CT scans can be reduced, which is similar to the approach for testicular germ cell tumors. 274 Each follow‐up visit should involve taking a medical history, physical examination, and tumor marker determination. Although tumor markers are important, radiological imaging is also pertinent, especially for patients whose tumor markers were not raised at diagnosis. CT or MRI scans should be performed as clinically indicated. 273 Patients who have not received chemotherapy should be followed closely, as 90% of relapses occur within the first 2 years. In most cases, relapse can be successfully treated (see below) 273 (Level of Evidence: D). Non‐dysgerminoma germ cell malignancies are highly curable with chemotherapy, even with advanced disease. Patients with Stage IA grade 1–2 immature teratoma have a very good prognosis and should be only observed after primary conservative surgery. Adjuvant chemotherapy does not appear to add any survival benefit to this subgroup of patients. Although adjuvant chemotherapy has been routinely recommended to all other patients with Stage I non‐dysgerminomatous ovarian germ cell tumors, this approach has been challenged and there may be a role for close surveillance and chemotherapy reserved for the subset (such as Stage IA yolk‐sac tumors) as this is the standard of care in male patients with apparent Stage I testicular cancers. All other patients with non‐dysgerminomas, and higher‐stage and higher‐grade immature teratomas, should receive postoperative adjuvant chemotherapy. 248 The recommended chemotherapy regimen is etoposide 100 mg/m 2 per day for 5 days, combined with cisplatin 20 mg/m 2 per day for 5 days and bleomycin 30 IU IM/IV on days 1, 8, and 15, administered over a total of 12 weeks. For patients with good prognosis disease, three cycles of BEP are advised, while those with intermediate or poor risk disease should receive four cycles. 248 After chemotherapy, patients with metastatic immature teratomas may have residual masses composed entirely of mature elements. These masses can increase in size (growing teratoma syndrome) and should be surgically resected after the completion of chemotherapy 279 (Level of Evidence: B). All patients should have AFP and beta hCG to monitor their response to treatment. All patients treated with chemotherapy should be followed up with a medical history, physical examination, and appropriate tumor markers in the same way as dysgerminomas. CT or MRI scans should be performed as clinically indicated. 246 Relapses in patients usually occur within the first 2 years after diagnosis. 248 , 266 Patients who relapse after BEP may still attain a durable remission and cure with second‐line chemotherapy regimens such as paclitaxel–ifosfamide–cisplatin (TIP). 266 High‐dose chemotherapy and autologous marrow rescue may be considered in selected patients who should be managed in specialized units. There is no standard treatment for relapsed disease (Level of Evidence: D).

There is no evidence to show that intensive clinical monitoring during follow‐up after completion of primary surgery and chemotherapy with early initiation of chemotherapy in asymptomatic women with recurrent disease improves OS or quality of life. In asymptomatic patients with CA125 progression and small volume disease or no radiological evidence of recurrence, it is appropriate to delay starting chemotherapy. However, there may be a subset of patients who are suitable for secondary debulking surgery at the time of recurrence. The objectives of follow‐up include the following: early recognition and prompt management of treatment‐related complications, including provision of psychological support; early detection of symptoms or signs of recurrent disease; collection of data regarding the efficacy of any treatment and the complications associated with those treatments in patients treated in clinical trials; promotion of healthy behavior, including screening for breast cancer in patients with early‐stage disease, and screening for cervical cancer in patients undergoing conservative surgery. There are no evidence‐based guidelines regarding the appropriate follow‐up schedule. During the first year after treatment, patients are seen every 3 months with a gradual increase in intervals to every 4–6 months after 2 years and then annually after the fifth year. At each follow‐up, the patient should have her history retaken, including any change in family history of cancer and attention to any symptoms that could suggest recurrence; a physical and pelvic examination should also be performed. This is an opportunity to refer appropriate patients for genetic testing if it was not done at diagnosis or during treatment. CA125 has traditionally been checked at regular intervals, but there has been debate regarding the clinical benefit of using CA125 progression alone as a trigger for initiating second‐line chemotherapy. A large MRC OV05‐EORTC 55955 study showed that treating asymptomatic patients with recurrent ovarian cancer with chemotherapy on the basis of CA125 progression alone did not improve survival. It also showed that early treatment in asymptomatic patients had a negative impact on quality of life. 177 That study has generated considerable debate regarding the use of CA125 for follow‐up, but most agree that it is reasonable not to immediately initiate treatment unless there is a clear clinical indication to do so. However, it is worth reflecting on the fact that this trial was conducted in an era where there were limited treatment options for patients with recurrent ovarian cancer beyond re‐introduction of platinum‐based chemotherapy, which is very different today. Furthermore, this study was carried out well before PARP inhibitors were available and there are many more options available at recurrence, including multiple clinical trials. It seems timely to question the timing of treatment at recurrence. The timing of treatment should be based on symptoms, clinical and radiological findings, and the platinum‐free interval and with input from patients. Guidelines suggest that imaging tests, such as ultrasonography of the pelvis, CT, MRI, and/or PET scans, should be performed only when the clinical findings or the tumor markers suggest possible recurrence. This has been challenged recently by findings in patients with platinum‐sensitive recurrent ovarian cancer receiving maintenance therapy with a PARP inhibitor, where almost half of those with RECIST‐defined progressive disease did not exhibit CA125 progression. This raises important questions about the adequacy of relying solely on CA125 for surveillance and suggests the imaging should be incorporated, particularly for patients on maintenance therapy. 178

The majority of patients who present with advanced epithelial cancers of the ovary, fallopian tube, and peritoneum will relapse with a median time to recurrence of 16 months. Patients with recurrent ovarian cancer constitute a heterogeneous group with a variable prognosis and a variable response to further treatment. The most widely used clinical surrogate for predicting response to subsequent chemotherapy and prognosis has been the progression‐free interval or the “platinum‐free interval,” which is defined as the time from cessation of primary platinum‐based chemotherapy to disease recurrence or progression. 179 , 180 This has been useful to define specific patient populations; however, it has several limitations and depends on how patients are followed. In particular, it depends on how recurrence is detected and defined. Patients with a treatment‐free interval of less than 6 months are classified as platinum resistant and generally treated with non‐platinum–based chemotherapy, while those with a treatment‐free interval of more than 6 months are considered to be platinum sensitive and are commonly treated with platinum‐based chemotherapy. Patients who progress while on treatment or within 4 weeks of stopping chemotherapy are classified as platinum refractory. 179 , 180 There have been modifications to these definitions, and time to progression or recurrence rather than treatment‐free interval or platinum‐free interval has been used to define specific patient populations. There has been significant change in practice over the last 20 years and patients have been routinely followed with regular CA125 testing after completion of chemotherapy. For example, the “platinum‐resistant” subgroup may include asymptomatic patients with CA125 progression alone at 3 months after chemotherapy or radiological evidence of recurrence as well as those who are symptomatic with clinical recurrence. The Fourth Ovarian Cancer Consensus Conference reached agreement that distinct patient populations should be based on the interval from last platinum therapy and the time to progression. The progression‐free interval is defined from the last date of platinum dose until progressive disease is documented. 179 , 180 More recently, ESMO‐ESGO guidelines have moved away from the terms “platinum resistant” or “platinum sensitive” and now categorize patients as having platinum‐non‐eligible ovarian cancer, which includes those who progress on or immediately after their last platinum‐based chemotherapy or have contraindications to platinum. Platinum‐eligible ovarian cancer includes all other cases of relapse. Despite these guidelines, most clinicians and clinical trials still use the terms “platinum sensitive” and “platinum resistant,” and it will be hard to change this as it is so ingrained. 181 For patients whose disease is considered platinum‐sensitive, the ICON4 study showed an advantage in terms of OS and PFS for a combination of carboplatin and paclitaxel versus single‐agent carboplatin 182 (Level of Evidence: A). For patients with persistent neuropathy after first‐line treatment with paclitaxel, gemcitabine 183 or pegylated liposomal doxorubicin 184 may be substituted for paclitaxel. A large GCIG study (CALYPSO) compared carboplatin (AUC 5) and pegylated liposomal doxorubicin (30 mg/m 2 ) every 4 weeks (CD) with carboplatin and paclitaxel (CP) in 976 patients. 185 The CD arm had statistically superior PFS compared with the CP arm, with a median PFS of 11.3 versus 9.4 months, respectively. There was no significant difference in the OS between the treatment groups. The median OS was 33 versus 30.7 months for the CP and CD arms, respectively. The CD arm was better tolerated, with less severe toxicities, and this combination is now widely used (Level of Evidence: A). There is evidence that the addition of bevacizumab to the regimen of carboplatin and gemcitabine improves PFS compared with carboplatin and gemcitabine in platinum‐sensitive disease. In the OCEANS study, 186 484 patients with platinum‐sensitive disease were randomly assigned to carboplatin (AUC 4 on day 1) and gemcitabine 1000 mg/m 2 on days 1 and 8 with or without bevacizumab (15 mg/kg on day 1) every 21‐day cycles. Bevacizumab could be given concurrently with chemotherapy for a maximum of 10 cycles followed by bevacizumab alone until progression of the disease or toxicity. The addition of bevacizumab to carboplatin and gemcitabine resulted in an improvement in PFS (12 vs. 8 months; HR 0.48, 95% CI 0.39–0.61); however, there was no difference in OS between the two arms. Treatment with bevacizumab was associated with higher rates of serious hypertension (17% vs. <1%), proteinuria grade 3 or higher (9% vs. 1%), and non‐central nervous system bleeding (6% vs. 1%). 186 The OV21 trial randomized 682 patients with platinum‐sensitive recurrent ovarian cancer to six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (AUC 4, day 1) plus gemcitabine (1000 mg/m 2 , days 1 and 8) every 3 weeks (standard group) or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m 2 , day 1) every 4 weeks (experimental group), both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. The median PFS was 13.3 months (95% CI 11.7–14.2) in the experimental group versus 11.6 months (95% CI 11.0–12.7) in the standard group (HR 0.81, 95% CI 0.68–0.96; P  = 0.012). 187 The results of this trial support the experimental regimen in clinical practice. Furthermore, there is evidence that the addition of bevacizumab to carboplatin and pegylated liposomal doxorubicin shows an improved PFS compared to carboplatin plus gemcitabine and bevacizumab in platinum‐sensitive disease. 187 The median PFS in this phase trial of 682 patients with a first recurrence was noted to be 13.3 versus 11.6 months. The phase III trial MITO16B‐MaNGO OV2B‐ENGOT OV17 provided evidence in platinum‐sensitive disease that the re‐challenge with bevacizumab in combination with platinum‐doublets is associated with a prolonged PFS (8.8 vs. 11.8 months without and with bevacizumab). 188 There is a role for angiogenesis inhibitors in platinum‐resistant ovarian cancer. In the AURELIA trial, women with recurrent platinum‐resistant ovarian cancer were randomized to standard of care, i.e., weekly topotecan, weekly paclitaxel, or monthly liposomal doxorubicin versus these agents combined with bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks). 189 Patients in the experimental arm had a longer PFS of 6.7 versus 3.4 months and a higher overall response rate of 30.9% versus 12.6%. An exploratory subgroup analysis noted an increase in OS for weekly paclitaxel plus bevacizumab from 13.4 to 22.4 months (with and without bevacizumab). 190 The findings in the AURELIA trial changed the standard of care, although there are now other options with antibody‐drug conjugates (ADCs), which are discussed below. There has been a lot of interest in exploring the role of ICIs in patients with recurrent ovarian cancer, including those with platinum resistance. However, the general results of these studies have been disappointing, with low response rates reported. For example, KEYNOTE‐100 evaluated pembrolizumab, an anti‐PD‐1 antibody, in patients with recurrent ovarian cancer after multiple prior lines. 191 The overall response rate was 8%, with a combined positive score (quantifying the number of PD‐L1 positive cells) over 10 and the objective response rate (ORR) was in the range of 11%–18%. Similarly, the response rate with avelumab, an anti‐PD‐L1 antibody, was 10% in recurrent ovarian cancer. 192 However, there may be a role for combination regimens, which are being explored. For example, the phase I/II TOPACIO trial using niraparib and pembrolizumab in recurrent platinum‐resistant ovarian cancer showed a response rate of 18%. 193 The combination of the CTLA‐4 antibody ipilimumab with nivolumab, an anti‐PD‐1 antibody induction followed by nivolumab maintenance had an ORR of 31.4% compared to 12.2% with nivolumab alone in a recently reported randomized phase 2 trial. 194 Although the median PFS was longer with combination, it was only 3.9 versus 2 months and the benefit questionable given the increased toxicity. In the BrUOG phase II on ovarian and extrarenal clear cell cancers, the combination of 240 mg nivolumab every 2 weeks and 1 mg/kg ipilimumab every 6 weeks, an ORR of 33%, PFS of 5.6 months, and an OS of 24.6 months for the combination treatment were reported. 195 The multicohort Leap‐005 trial recently reported preliminary data on another combination treatment using pembrolizumab and the multi‐tyrosine kinase inhibitor lenvatinib. In 31 patients with recurrent ovarian cancer, the response rate was 32% and the disease control rate 74%. 196 Another phase II trial reported on the combination of pembrolizumab, bevazicumab, and oral metronomic cyclophosphamide (50 mg daily) in 30 patients with platinum‐resistant and 10 patients with platinum‐sensitive disease. A response rate of 47.5% and stable disease in 47.5% were noted. 197 There are still more trials in progress and these are likely to read out over the next few years. It will take time to define the role of ICIs in patients with recurrent ovarian cancer, but it seems likely that only a small subset benefits and the challenge is to identify who these patients are. ADCs are a class of anticancer drugs that employs the specificity of an antibody in combination with the cytotoxicity of a small molecule anticancer drug. The antibody provides selectivity. The cells take up the ADC by endocytosis. The cytotoxic drug, the payload, is released in intracellular compartments such as endosomes or lysosomes. The linker can be cleavable, e.g. by cathepsins that are located in lysosomes and activated by the low pH in lysosomes, or it can be non‐cleavable. In the latter case, the antibody will be degraded intracellularly and only the cytotoxic agents remain and thereby become active. In the former case, the cytotoxic agent may evade the cell and kill tumor cells nearby as well, the so‐called “bystander killing”. 198 , 199 Mirvetuximab soravtansine (IMGN853) is an ADC combining a monoclonal antibody against folate receptor α (FRα) with the maytansinoid DM4. 200 Maytansine inhibits microtubule assembly, induces mitotic arrest and is thereby cytotoxic. After a promising dose‐escalation study on single‐agent mirvetuximab, 201 a phase Ib trial of mirvetuximab soravtansine (MIRV, 6 mg/kg adjusted ideal body weight every 3 weeks) combined with bevacizumab in platinum‐resistant ovarian cancer showed that this combination was well tolerated and effective. The ORR was 39% (including 5 complete and 21 partial responses) and the median PFS was 6.9 months. 202 In the Forward I phase III trial, 366 patients with platinum‐resistant disease, 1–3 prior lines, and tumors positive for FRα were randomized 2:1 to 6 mg/kg MIRV versus standard chemotherapy. Overall, no difference in PFS was noted (4.1 vs. 4.4 months). The treatment was well tolerated with grade 3 adverse events in 25.1% versus 44%. In the high FRα subgroup, an improved ORR of 24% versus 10%, a CA125 of 53% versus 25%, and an improved PFS of 4.8 versus 3.3 months was noted. 203 In the single‐arm Soraya trial, 106 patients with FRα‐high platinum‐resistant ovarian cancer and prior bevacizumab use received MIRV. Using the Ventana FOLR1 assay, at least 75% of viable tumor cells should exhibit at least 2+ level membrane staining by immunohistochemistry (IHC). Furthermore, an exploratory analysis of patient samples from the Forward I trial showed that using this PS2+ scoring was more reliable than the 10x scoring used in the Forward I trial. An ORR of 32.4%, including 5 complete and 29 partial responses, was seen. 204 In the phase III Mirasol trial, 453 patients with FRα‐high (≥75% of cells with +2 staining) platinum‐resistant ovarian cancer were randomized to MIRV or investigator's choice chemotherapy. The ORR was 42.3% versus 15.9%, the median PFS was 5.6 versus 3.98 months ( P  < 0.001), and, most notably, the OS was significantly longer with MIRV (16.46 vs. 12.75 months, HR for death 0.67, 95% CI 0.5–0.89). In addition, fewer grade 3 or higher adverse events were noted (41.7% vs. 54.1%). 205 In April 2024, the FDA granted accelerated approval for trastuzumab deruxtecan in Her2‐positive (IHC 3+) solid tumors with no treatment alternatives, which included ovarian cancer. Trastuzumab deruxtecan targets Her2 expression cells and carries the topoisomerase inhibitor I as payload. The FDA approval is based on the phase II cohort study Pan‐Destiny02, which included a cohort of 40 patients with ovarian cancer. This trial showed an ORR of 45%, a median PFS of 11.1 months, and a median OS of 13.2 months in the ovarian cancer cohort. 206 Data on another ADC, datopotamab deruxtecan, was recently presented at ESMO 2024. 207 This ADC targets the surface protein Trop2 (trophoblast cell surface antigen 2), which has been associated with accelerated tumor growth and poor prognosis in solid tumors, including breast, gastric, lung and gynecological cancers. In the 26 patients with platinum‐resistant ovarian cancers, an ORR of 34.6%, a disease control rate (DCR) of 80.8%, and a median duration of response (DoR) of 5.6 months were noted. The initial approval of the PARP inhibitors for late‐line treatment was based on the following studies: study 42 for olaparib, 208 the QUADRA study for niraparib, 209 and an integrated analysis of data from study 10 part 2A and Ariel 2 parts 1 and 2 for rucaparib. 210 At the final OS analysis of the Ariel 4 trial, a possible detriment in OS was seen for rucaparib (median OS 19.4 vs. 25.4 months in the intention‐to‐treat population, and 14.2 vs. 22.2 months in the platinum‐resistant group). 211 A post‐hoc analysis of SOLO3 found a potential detriment for olaparib in patients who had received three or more prior lines. 212 Neither Ariel 4 nor SOLO3 were powered to assess between‐group differences in OS. These trial results lead to “Dear Health Care Provider Letters” in June 2022, and for rucaparib and olaparib in August 2022. Based on the totality of data and the single‐arm nature of the QUADRA trial, which prevents assessment of OS data, a letter for niraparib followed in September 2022. Subsequently, these PARP inhibitors were voluntarily withdrawn by the pharmaceutical companies for the single‐agent PARP‐inhibitor late‐line treatment. 213 With few exceptions, recurrent disease is not curable and the aim of treatment is to maintain quality of life and palliate symptoms, particularly in patients with platinum‐resistant ovarian cancer. 214 There are many potential treatment options, including chemotherapy, angiogenesis inhibitors, radiation therapy, or surgery in selected patients and inclusion in clinical trials. There is a subset of patients who may benefit from secondary surgical debulking. The optimal management of a patient with platinum‐resistant or refractory disease is complex and requires a careful assessment of the patient's performance status, symptoms, and extent of disease. Attention to symptom control and good palliative care are essential components of management.

Malignant tumors of the ovaries occur at all ages, with variation in histologic subtype by age. For example, in women aged under 20 years, germ cell tumors predominate, while borderline tumors typically occur in women in their 30s and 40s—10 or more years younger than in women with invasive epithelial ovarian cancers, which mostly occur after the age of 50 years. Although incidence and mortality have been slowly and continuously decreasing since the 1990s, ovarian cancer continues to have the highest fatality‐to‐case ratio of all the gynecologic malignancies. In 2023, there were nearly 19 710 new cases annually in the USA and an estimated 13 270 women lost their lives to the disease. 37 Despite declining mortality rates, ovarian cancer still accounts for approximately 5% of cancer‐related deaths in women and remains the fifth leading cause of cancer mortality among women. 38 The lifetime risk of being diagnosed with ovarian cancer is 1.3%, while the risk of dying from it is almost 0.9%. 39 Although ovarian cancer accounts for approximately 23% of gynecologic cancers, it is responsible for 47% of all deaths from female genital tract malignancies. The overall incidence of epithelial tumors is in the range of 9–17 per 100 000, with the highest rates observed in high‐income countries, except for Japan. 40 This incidence increases with age, with the largest number of patients with epithelial ovarian cancer found in the 60–64‐year age group. In low‐income countries, the median age at diagnosis is approximately a decade earlier. 41 , 42 Established risk factors for epithelial ovarian tumors include reproductive risk factors. Women who have never had children are twice as likely to develop this disease. Early menarche and late menopause increase the risk of ovarian cancer. 43 First pregnancy at an early age and the use of oral contraceptives have been associated with lower risks of ovarian cancer. 44 The relationship of these variables to fallopian tube cancer is unclear but is likely similar given that it is now recognized that the majority of HGSCs arise in the fallopian tube but have been designated ovarian in origin in the past, which would impact on findings from epidemiological studies. Hereditary factors are implicated in approximately 20% of ovarian, fallopian tube, and peritoneal cancers: 45 , 46 , 47 , 48 , 49 Most hereditary ovarian cancers are due to pathogenic mutations in either the BRCA1 or BRCA2 genes. At least 15% of women with high‐grade non‐mucinous ovarian cancers have germline pathogenic mutations in BRCA1/2 and, importantly, 44% do not have a family history of breast/ovarian cancer. All women with high‐grade non‐mucinous invasive ovarian cancers should be offered genetic testing irrespective of their family history of breast/ovarian cancer or age. Inherited deleterious mutations in BRCA1 and BRCA2 are the major genetic risk factors. Women with germline pathogenic mutations in BRCA1 and BRCA2 have a substantially increased risk of ovarian, tubal, and peritoneal cancer—ranging from lifetime risks of 39%–44% and 10%–20% with BRCA1 and BRCA2 mutations, respectively. 46 , 47 , 48 , 49 Typically, these cancers occur at an earlier age than sporadic cancers, particularly in BRCA1 mutation carriers, with a median age of diagnosis in the mid‐40s. 50 There are several other low‐ to moderate‐penetrance genes that can also predispose to ovarian, fallopian tube, or peritoneal cancer. A study using next‐generation sequencing of constitutional DNA samples from 1915 women with ovarian cancer was carried out to identify germline mutations using a panel of 20 genes, including BRCA1 and BRCA2 , DNA mismatch repair genes, double‐stranded DNA break repair genes, such as CHEK2 and ATM , as well as the BRCA1 ‐associated complex or the BRCA2 /Fanconi Anemia pathway genes (including BRIP1 , BARD1 , PALB2 , RAD50 , RAD51C , and RAD51D , among others). Approximately 80% of mutations were in BRCA1 or BRCA2 , and approximately 3% of patients carried mutations in the Fanconi Anemia pathway genes, whereas only 0.4% had mutations in mismatch repair genes. 51 In an earlier similar study of 360 patients, 24% carried germline loss‐of‐function mutations including 18% in BRCA1 or BRCA2 and 6% in BARD1 , BRIP1 , CHEK2 , MRE11A , MSH6 , NBN , PALB2 , RAD50 , RAD51C , or TP53 . 52 , 53 Women carrying inherited mutations in the mismatch repair genes associated with Lynch syndrome type II have an increased risk of several cancers, including colon, endometrial, and ovarian cancer. Typically, the ovarian cancers that occur are endometrioid or clear cell and are usually Stage I. 53 Most hereditary ovarian cancers are due to pathogenic mutations in either the BRCA1 or BRCA2 genes. At least 15% of women with high‐grade non‐mucinous ovarian cancers have germline pathogenic mutations in BRCA1/2 and, importantly, 44% do not have a family history of breast/ovarian cancer. All women with high‐grade non‐mucinous invasive ovarian cancers should be offered genetic testing irrespective of their family history of breast/ovarian cancer or age. Inherited deleterious mutations in BRCA1 and BRCA2 are the major genetic risk factors. Women with germline pathogenic mutations in BRCA1 and BRCA2 have a substantially increased risk of ovarian, tubal, and peritoneal cancer—ranging from lifetime risks of 39%–44% and 10%–20% with BRCA1 and BRCA2 mutations, respectively. 46 , 47 , 48 , 49 Typically, these cancers occur at an earlier age than sporadic cancers, particularly in BRCA1 mutation carriers, with a median age of diagnosis in the mid‐40s. 50 There are several other low‐ to moderate‐penetrance genes that can also predispose to ovarian, fallopian tube, or peritoneal cancer. A study using next‐generation sequencing of constitutional DNA samples from 1915 women with ovarian cancer was carried out to identify germline mutations using a panel of 20 genes, including BRCA1 and BRCA2 , DNA mismatch repair genes, double‐stranded DNA break repair genes, such as CHEK2 and ATM , as well as the BRCA1 ‐associated complex or the BRCA2 /Fanconi Anemia pathway genes (including BRIP1 , BARD1 , PALB2 , RAD50 , RAD51C , and RAD51D , among others). Approximately 80% of mutations were in BRCA1 or BRCA2 , and approximately 3% of patients carried mutations in the Fanconi Anemia pathway genes, whereas only 0.4% had mutations in mismatch repair genes. 51 In an earlier similar study of 360 patients, 24% carried germline loss‐of‐function mutations including 18% in BRCA1 or BRCA2 and 6% in BARD1 , BRIP1 , CHEK2 , MRE11A , MSH6 , NBN , PALB2 , RAD50 , RAD51C , or TP53 . 52 , 53 Women carrying inherited mutations in the mismatch repair genes associated with Lynch syndrome type II have an increased risk of several cancers, including colon, endometrial, and ovarian cancer. Typically, the ovarian cancers that occur are endometrioid or clear cell and are usually Stage I. 53 The Society of Gynecologic Oncology (SGO) and National Comprehensive Cancer Network (NCCN) guidelines as well as all international guidelines recommend that all women diagnosed with ovarian, fallopian tube, or peritoneal carcinoma, regardless of age or family history, should receive genetic counseling and be offered germline genetic testing. 54 Women whose family history suggests Lynch syndrome type II should undergo appropriate genetic counseling and testing. Women with a documented germline BRCA mutation, are advised to have a risk‐reducing bilateral salpingo‐oophorectomy (RR‐BSO) after appropriate counseling and at the completion of childbearing. Guidelines suggest that women with a pathogenic BRCA1 mutation have a RR‐BSO between the ages of 35 and 40 years and women with a BRCA2 pathogenic mutation between the ages of 40 and 45 years. 55 Surgical removal of both ovaries and fallopian tubes reduces this risk substantially and is associated with a reduction in ovarian cancer–specific mortality. 56 There is a small risk of subsequent diagnosis of peritoneal cancer after RR‐BSO, which is higher if STIC lesions are present. The risk of STIC lesions is increased in women who have RR‐BSO at ages older than recommended in the guidelines. 57 Global disparities in outcome have been described within any stage of ovarian cancer, suggesting that issues regarding access to care are likely critical factors. 58 , 59 Societal factors, economic barriers to treatment, inadequate resources at the hospital, the need for early detection programs, and lack of organization of the gynecologic oncology subspecialty 60 , 61 were identified as central in a recent analysis 62 of a global survey. 63 Furthermore, in low‐ and middle‐income countries, the mean age of diagnosis has been found to be approximately 10 years earlier, the reason for which is uncertain. 64

In 2014, the International Federation of Gynecology and Obstetrics (FIGO)'s Committee for Gynecologic Oncology revised its staging to incorporate ovarian, fallopian tube, and peritoneal cancer in the same system after extensive international consultation. Where possible, the primary site (i.e., ovary, fallopian tube, or peritoneum) is designated; however, if it is not possible to clearly identify the primary site, these should be listed as “undesignated”. 1 , 2 It has been presumed that fallopian tube malignancies were rare. 2 However, histologic, molecular, and genetic evidence shows that the vast majority of tumors that were previously classified as high‐grade serous carcinomas (HGSCs) of the ovary or peritoneum originate in the fimbrial end of the fallopian tube. 3 , 4 , 5 , 6 , 7 , 8 Therefore, the incidence of fallopian tube cancers has been substantially underestimated. Contemporary data support the view that high‐grade serous ovarian, fallopian tube, and peritoneal cancers should be considered collectively, and that the convention of designating these malignancies as having an ovarian origin should no longer be used, unless that is clearly the primary site. It has been suggested that extrauterine tumors of serous histology arising in the ovary, fallopian tube, or peritoneum should be described collectively as “Müllerian carcinomas” 1 , 2 or “pelvic serous carcinomas”. 9 The latter tumor designation is controversial because some peritoneal tumors might arise in extrapelvic peritoneum. Therefore, the simple term “serous carcinoma” is preferred, with most of these being HGSCs. 10 Although there has been no formal staging for peritoneal cancers, the FIGO staging system is used with the understanding that it is not possible to have a Stage I peritoneal cancer. Ovarian epithelial tumors may arise within endometriosis or cortical inclusions of Müllerian epithelium, likely a form of endosalpingiosis. These include low‐grade endometrioid carcinomas, clear cell carcinomas, borderline and low‐grade serous carcinomas (LGSCs), and mucinous carcinomas. These tumors are thought to evolve slowly from lower‐grade precursor conditions (such as endometriotic cysts and cystadenomas). 5 Fallopian tube carcinomas arise in the distal fallopian tube from premalignant serous proliferations with TP53 mutations (p53 signature) or from serous tubal intraepithelial carcinomas (STICs). The majority of these are HGSCs 11 but can also include carcinosarcomas. All of these high‐grade carcinomas are almost always associated with mutations in the TP53 gene. 5 , 12 The lymphatic drainage of the ovaries and fallopian tubes is via the utero‐ovarian, infundibulopelvic, and round ligament pathways and an external iliac accessory route into the following regional lymph nodes: external iliac, common iliac, hypogastric, lateral sacral, para‐aortic lymph nodes, and, occasionally, the inguinal nodes. 1 , 13 , 14 , 15 The peritoneal surfaces can drain through the diaphragmatic lymphatics and hence to the major venous vessels above the diaphragm. The peritoneum, including the omentum and pelvic and abdominal viscera, is the most common site for dissemination of ovarian and fallopian tube cancers. This includes diaphragmatic and liver surfaces. Pleural involvement is also seen. Other extraperitoneal or extrapleural sites are relatively uncommon but can occur. 1 , 13 , 14 , 15 After systematic, careful pathological review has excluded a tubal or ovarian site of origin, malignancies that appear to arise primarily on the peritoneum are designated as peritoneal cancer and have a similar pattern of spread. They may also frequently involve the ovaries and fallopian tubes secondarily. These “peritoneal” tumors may arise in endosalpingiosis or possibly from migrated p53 mutated tubal epithelia cells. 11 , 16 Although computed tomography (CT) scans can delineate the intra‐abdominal spread of disease, the specificity and sensitivity for predicting optimal surgical cytoreduction is relatively low. In addition, ovarian, fallopian tube, and peritoneal cancers should be staged surgically. 17 Fludeoxyglucose‐positron emission tomography (FDG‐PET)/magnetic resonance imaging (MRI) appear to have a higher diagnostic performance than CT scans but are costly and their role in routine practice is uncertain at present. 18 Operative findings determine the precise histologic diagnosis, stage, and therefore the prognosis of the patient. 1 , 9 , 13 , 15 , 19 , 20 In selected patients with advanced‐stage disease, it is appropriate to initiate chemotherapy before planned surgery after three cycles of treatment. In these cases, histological confirmation of the diagnosis is considered essential before starting neoadjuvant chemotherapy (NACT), not only to be certain of the diagnosis but also to ensure there is sufficient tissue for testing for homologous recombination deficiency (HRD) as well as somatic BRCA testing (see “Interval debulking surgery (IDS)” below). Chest radiographs may serve as a screen for pleural effusions. As distant metastases are infrequent, there is no requirement for other radiological evaluation unless symptomatic. Serum CA125 levels are useful in determining response to chemotherapy, but they do not contribute to staging. Fallopian tube involvement can be divided into three categories. In the first, an obvious intraluminal and grossly apparent fallopian tube mass is seen with tubal intraepithelial carcinoma (carcinoma in situ) that is presumed to have arisen in the fallopian tube. These cases should be staged surgically with a histological confirmation of disease. Tumor extension into the submucosa or muscularis and to and beyond the serosa can therefore be defined. These features, together with the laterality and the presence or absence of ascites, should all be taken into consideration. 1 , 3 , 6 , 7 In the second scenario, a widespread serous carcinoma associated with a tubal intraepithelial carcinoma is observed. A visible mass in the endosalpinx may not be seen but the histologic findings should be noted in the pathology report since they may indicate a fallopian tube primary. Tumors obliterating both fallopian tube and ovary may belong to this group; however, whether a presumptive assignment of a tubal origin can be made in such cases is controversial given that tubal intraepithelial carcinoma may not be confirmed. In the third scenario—risk‐reducing salpingo‐oophorectomy—tubal intraepithelial carcinoma may be the only finding. It should be reported as originating in the fallopian tube. The majority of early HGSCs are found in the fimbria of the fallopian tube, irrespective of genetic risk. 21 , 22 The updated, revised FIGO staging system combines the classification for ovarian, fallopian tube, and peritoneum cancers. It is based on findings made mainly through surgical exploration (as outlined above). Table  1 presents the 2014 FIGO staging classification for cancer of the ovary, fallopian tube, and peritoneum. The equivalents within the Union for International Cancer Control (UICC) TNM classification are presented in Table  2 . FIGO staging classification for cancer of the ovary, fallopian tube, and peritoneum. Cancer of the ovary, fallopian tube and peritoneum: FIGO staging (2014) compared with TNM classification. a Source : Prat J. 283 The primary site—that is, ovary, fallopian tube, or peritoneum—should be designated where possible. In some cases, it may not be possible to clearly delineate the primary site, and these should be listed as “undesignated.” The histological type should be recorded. The staging includes a revision of the Stage III patients and allotment to Stage IIIA1 is based on spread to the retroperitoneal lymph nodes without intraperitoneal dissemination, because an analysis of these patients indicates that their survival is significantly better than those who have intraperitoneal dissemination. Involvement of retroperitoneal lymph nodes must be proven cytologically or histologically. Extension of the tumor from the omentum to the spleen or liver (Stage IIIC) should be differentiated from isolated parenchymal splenic or liver metastases (Stage IVB). In addition to these changes, several other modifications of the former staging system have been made to better prospectively capture the data. Stage IC is now divided into three categories: IC1 (surgical spill), IC2 (capsule ruptured before surgery or tumor on ovarian or fallopian tube surface), and IC3 (malignant cells in the ascites or peritoneal washings). Stage IIC has been eliminated. The updated staging includes a revision of Stage IIIC based on spread to the retroperitoneal lymph nodes alone without intraperitoneal dissemination, because an analysis of these patients indicates that their survival is significantly better than those who have intraperitoneal dissemination. 23 This category is now subdivided into IIIA1(i) (metastasis ≤10 mm in the greatest dimension) and IIIA1(ii) (metastasis >10 mm in the greatest dimension). Stage IIIA2 is now “microscopic extrapelvic peritoneal involvement with or without positive retroperitoneal lymph node” metastasis. The wording of Stage IIIB has been modified to reflect the lymph node status. Stage IVB now includes metastases to the inguinal lymph nodes. The classifications for regional lymph nodes are as follows: NX = regional lymph nodes cannot be assessed, N0 = no regional lymph node metastasis, and N1 = regional lymph node metastasis. The classifications for distant metastasis are as follows: MX = distant metastasis cannot be assessed, M0 = no distant metastasis, and M1 = distant metastasis (excluding peritoneal metastasis). The majority of cases of ovarian cancer are of epithelial origin. FIGO endorses the WHO histologic typing of epithelial ovarian tumors. It is recommended that all ovarian epithelial tumors be subdivided according to the classification given below. 24 The histologic classification of ovarian, fallopian tube, and peritoneal neoplasia is as follows: serous tumors; mucinous tumors; endometrioid tumors; clear cell tumors; Brenner tumors; undifferentiated carcinomas (this group of malignant tumors is of epithelial structure, but they are too poorly differentiated to be placed in any other group); mixed epithelial tumors (these tumors are composed of two or more of the five major cell types of common epithelial tumors. The types are usually specified); and cases with HGSC in which the ovaries and fallopian tubes appear to be incidentally involved and not the primary origin can be labeled as peritoneal carcinoma or serous carcinoma of undesignated site, at the discretion of the pathologist. Epithelial tumors of the ovary and fallopian tube are further subclassified by histologic grading, which can be correlated with prognosis. This grading system does not apply to non‐epithelial tumors. 25 Two grading systems are applied. For non‐serous carcinomas (most endometrioid and mucinous), grading is identical to that used in the uterus, based on architecture with a one‐step upgrade if there is prominent nuclear atypia, as follows: GX = grade cannot be assessed, G1 = well differentiated, G2 = moderately differentiated, and G3 = poorly differentiated. In the 2014 WHO classification, grading for mucinous carcinomas was removed as it has no prognostic significance. 26 WHO recommended that mucinous ovarian cancers are classified as either expansile (confluent, non‐destructive) or infiltrative (stromal invasion) based on the classification suggested by Lee and Scully. 27 Such classification appears to be prognostic, particularly in FIGO Stage I mucinous ovarian cancers. In contrast, the International Collaboration on Cancer Reporting suggests that if grading is undertaken, the FIGO grading for endometrioid cancers should be used. 28 Similar to endometrial endometrioid cancers, endometrioid ovarian cancers can be associated with inactivating mutations of PTEN and activation of PI3 kinase signaling as well as to mutations in CTNNB1 (beta‐catenin), PIK3CA , and ARID1A . TP53 mutated endometrioid cancers are more aggressive with a poor prognosis. 29 The Cancer Genome Atlas (TCGA) molecular classification of endometrial cancer 30 can also be used for endometrioid ovarian cancers. 31 Serous carcinomas are the most common cell types in both the ovary and fallopian tube. More than 90% of fallopian tube carcinomas are HGSCs. Other cell types have been reported but are rare. 1 , 2 , 32 Serous carcinomas are graded in a two‐grade system befitting their biology. HGSCs, including both classic appearing and those with solid, endometrioid‐like, and transitional (SET) features, have a high frequency of mutations in TP53 . 33 , 34 , 35 The “moderately differentiated” serous carcinoma is no longer used as the vast majority have mutations in TP53 and are considered high‐grade tumors. 25 , 34 , 35 , 36 LGSCs are often associated with borderline or atypical proliferative serous tumors and associated with mutations in the mitogen‐activated protein (MAP) kinase gene pathway in approximately 50% of cases, including BRAF and KRAS mutations, and are wild‐type TP53 . Non‐epithelial cancers, although uncommon, are extremely important. These include granulosa cell tumors, germ cell tumors, sarcomas, and lymphomas. They are discussed below as separate entities. Metastatic neoplasms to the ovary, such as tumors arising in the breast, lower reproductive tract sites (cervix or uterine carcinomas), and gastrointestinal tract (signet ring cell [Krukenberg] carcinomas, low‐grade appendiceal or pancreaticobiliary mucinous tumors, and other neoplasms) are graded and staged in accordance with their respective sites of origin. 1 , 2

MR has nothing to disclose. MF receives honoraria for advisory boards from Astra Zeneca, GSK, MSD, Lilly, Novartis, and Takeda; speakers fees from Astra Zeneca; and institutional research funding from Astra Zeneca, Novartis, and Beigene. JB receives institutional research funding from Eisai, Immunogen, Tesaro; honoraria for DSMB from Merck.