Cancer of the ovary, fallopian tube, and peritoneum: 2021 update

Abstract In 2014, FIGO’s Committee for Gynecologic Oncology revised the staging of ovarian cancer, incorporating ovarian, fallopian tube, and peritoneal cancer into the same system. Most of these malignancies are high‐grade serous carcinomas (HGSC). 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). The updated staging includes a revision of Stage IIIC based on spread to the retroperitoneal lymph nodes alone without intraperitoneal dissemination. This category is now subdivided into IIIA1(i) (metastasis ≤10 mm in greatest dimension), and IIIA1(ii) (metastasis >10 mm in greatest dimension). Stage IIIA2 is now “microscopic extrapelvic peritoneal involvement with or without positive retroperitoneal lymph node” metastasis. This review summarizes the genetics, surgical management, chemotherapy, and targeted therapies for epithelial cancers, and the treatment of ovarian germ cell and stromal malignancies.


| Primary sites: ovarian, fallopian tube, and peritoneal cancer
In 2014, FIGO's Committee for Gynecologic Oncology revised the staging to incorporate ovarian, fallopian tube, and peritoneal cancer in the same system. Changing the staging system required extensive international consultation. The primary site (i.e. ovary, fallopian tube, or peritoneum) is designated, where possible. When it is not possible to clearly delineate 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 as many as 80% of tumors that were classified as high-grade serous carcinomas of the ovary or peritoneum may have originated in the fimbrial end of the fallopian tube. [3][4][5][6][7][8] Therefore, the incidence of fallopian tube cancers may have been substantially underestimated.
These new data support the view that high-grade serous ovarian, fallopian tube, and peritoneal cancers should be considered collectively, and that the convention of designating malignancies as having an ovarian origin should no longer be used, unless that is clearly the origination site. It has been suggested that extrauterine tumors of serous histology arising in the ovary, fallopian tube, or peritoneum might 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 DOI: 10.1002/ijgo.13878

F I G O C A N C E R R E P O R T 2 0 2 1
Cancer of the ovary, fallopian tube, and peritoneum: 2021 update peritoneum. Therefore, the simple term "serous carcinoma" is preferred, and most of these are high-grade serous carcinomas (HGSC).
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.

| Primary site
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, and mucinous carcinomas. These tumors are thought to evolve slowly from lowergrade precursor conditions (endometriotic cysts, cystadenomas, etc) and are classified as type I tumors. 5 Fallopian tube carcinomas arise in the distal fallopian tube and the majority of these are high-grade serous carcinomas. These are thought to evolve rapidly from more obscure precursors and are designated as type II tumors. 5,6 This latter group encompasses high-grade endometrioid carcinomas and carcinosarcomas. All of these high-grade carcinomas are nearly always associated with mutations in the TP53 gene. 5

| Lymphatic and lymph node drainage
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, paraaortic lymph nodes and, occasionally, to the inguinal nodes. 1,[10][11][12] The peritoneal surfaces can drain through the diaphragmatic lymphatics and hence to the major venous vessels above the diaphragm.

| Other metastatic sites
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 the diaphragmatic and liver surfaces. Pleural involvement is also seen. Other extraperitoneal or extrapleural sites are relatively uncommon, but can occur. 1,10-12 After systematic pathologic analysis has excluded a tubal or ovarian site of origin, malignancies that appear to arise primarily on the peritoneum have an identical spread pattern, and frequently may involve the ovaries and fallopian tubes secondarily. These "peritoneal" tumors are thought to arise in endosalpingiosis.

| Classification rules
Although CT scans can delineate the intra-abdominal spread of disease to a certain extent, ovarian, fallopian tube, and peritoneal cancers should be staged surgically. Operative findings determine the precise histologic diagnosis, stage, and therefore the prognosis, of the patient. 1,9,10,[12][13][14] In selected patients with advanced stage disease, it may be appropriate to initiate chemotherapy prior to surgical intervention, and in these cases there should be histologic or cytologic confirmation of the diagnosis prior to starting neoadjuvant chemotherapy (see 5.2.2. below).
Chest radiograms 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 may be useful in determining response to chemotherapy, but they do not contribute to staging.

| Fallopian tube involvement
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 histologic 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 is associated with a tubal intraepithelial carcinoma. 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 but whether a presumptive assignment of a tubal origin can be made in such cases is controversial given that tubal intraepithelial carcinoma cannot be confirmed.
In the third scenario-risk-reducing salpingo-oophorectomytubal intraepithelial carcinoma may be the only finding. It should be reported as originating in the fallopian tube and managed accordingly. The majority of early serous cancers detected are found in the fallopian tube, irrespective of genetic risk. 15

| FIGO staging
The updated, revised FIGO staging system combines the classification for ovarian, fallopian tube, and peritoneum cancer. It is based on findings made mainly through surgical exploration (as outlined above). Table 1 Table 2.
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 the 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. 18 This category is now subdivided into IIIA1(i) (metastasis ≤10 mm in greatest dimension), and IIIA1(ii) (metastasis >10 mm in 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.

Regional lymph nodes (N)
• NX: Regional lymph nodes cannot be assessed.

Distant metastasis (M)
• MX: Distant metastasis cannot be assessed.

| Histopathologic classification
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. 19 The histologic classification of ovarian, fallopian tube, and peritoneal neoplasia is as follows: • Serous 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).
• Cases with high-grade serous carcinoma in which the ovaries and fallopian tubes appear to be incidentally involved and not the primary origin can be labeled as peritoneal carcinoma or TA B L E 1 FIGO staging classification for cancer of the ovary, fallopian tube, and peritoneum The overall incidence of epithelial tumors varies from 9-17 per 100 000 and is highest in high-income countries, with the exception of Japan. 27  Notes: 1. The primary site-that is, ovary, fallopian tube, or peritoneumshould 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".
2. The histologic type should be recorded.
3. 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.
4. Involvement of retroperitoneal lymph nodes must be proven cytologically or histologically.
5. Extension of tumor from omentum to spleen or liver (Stage IIIC) should be differentiated from isolated parenchymal splenic or liver metastases (Stage IVB). a Source: Prat J. 17 associated with lower risks of ovarian cancer. 28 The relationship of these variables to fallopian tube cancer is unclear.
As noted above, it has been previously presumed that fallopian tube malignancies were rare; however, this has been challenged by evidence to show that many tumors that were classified as serous carcinomas of the ovary or peritoneal cancers appear to have their origin in the fallopian tube. [3][4][5][6][7] When the origin is uncertain, the convention of designating all serous cancers as originating in the ovary should no longer be used and the term "undesignated origin" may be applied at the discretion of the pathologist. 19

| SCREENING
To date, there are no documented effective screening methods that reduce the mortality of ovarian, fallopian tube, or peritoneal cancers. Studies using CA125, ultrasonography of the pelvis, and pelvic examination do not have an acceptable level of sensitivity and specificity, based on trials carried out in women in the general population 39,40 and those in the high-risk population. 41,42 The US Preventive Services Task Force recommends against screening asymptomatic women for ovarian cancer with pelvic examination, pelvic ultrasound, or serum tumor marker measurements. 43 The low prevalence of disease and lack of high-quality screening methods make it more likely to obtain false-positive results leading to unnecessary interventions. A recent study of multimodal screening using CA125 based on a risk of ovarian cancer algorithm (ROCA) every 4 months and transvaginal ultrasound annually or earlier where indicated by the ROCA in women at high risk of ovarian cancer reported that screening was associated with a low rate of high-volume disease at primary surgery and very high rates of no residual disease after surgery. 44 Given that the majority of women with advanced stage ovarian cancer, even with complete resection, will relapse after chemotherapy, this does not seem to be a good alternative to riskreducing surgery. The authors of the screening study concluded that risk-reducing salpingectomy-oophorectomy remains the treatment choice for women at high risk of ovarian/fallopian tube cancer. 44 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. 40 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).
• CT finding of metastatic nodules.

| PRIMARY SURG ERY
In general, the prognosis of epithelial ovarian, fallopian, and peritoneal malignancies is independently affected by the following 1,52,53 : • Stage of the cancer at diagnosis.
• Histologic type and grade.
• Maximum diameter of residual disease after cytoreductive surgery.

| Staging laparotomy
A thorough staging laparotomy is an important part of early management. If the preoperative suspicion is malignancy, a laparotomy should be performed. If there is no visible or palpable evidence of metastasis, the following should be performed for adequate staging 1,10,11 : • 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.
• 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, culde-sac, right and left paracolic recesses, and both pelvic sidewalls.
• Total abdominal hysterectomy and bilateral salpingo-oophorectomy in most cases.
• 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 of 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. 47 Clinical judgment is important in the approach to a pelvic mass in the young, reproductive-aged woman. If the suspicion is strong for malignancy, open laparotomy is generally indicated.
Laparoscopy may be more appropriate if the suspicion is more for benign disease, where tumor markers (including hCG and AFP) are normal. A biopsy of any suspicious lesion can be performed and frozen section obtained in order to proceed expeditiously with definitive surgery.
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. 33 Ovaries should be scrutinized for coexisting endometriotic cysts, adenofibromas, or other benign conditions that could serve as a nidus of tumor development.

| Primary debulking
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. 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. 1,52,53 This may necessitate bowel resection, and occasionally, partial or complete resection of other organs. Based on recent data from the randomized Lymphadenectomy in Ovarian Neoplasm (LION) trial, the removal of clinically negative lymph nodes during cytoreductive surgery does not increase the progression-free or overall survival and should not be undertaken. 54 Level of Evidence A.

| Interval debulking
In selected patients with cytologically proven Stage IIIC and IV disease who may not be good surgical candidates, 3-4 cycles of neoadjuvant chemotherapy (NACT) may be given initially, followed by interval debulking surgery and additional chemotherapy as demonstrated in the EROTC and CHORUS Trials. 55 of cycles in patients with Stage I disease has not been definitively established, but typically between 3 and 6 cycles are administered.
The Gynecologic Oncology Group (GOG) 157 study suggested that 3 cycles of carboplatin and paclitaxel was equivalent to 6 cycles, 49 but in subgroup analysis, 6 cycles appeared superior in patients with high-grade serous cancers. 63 There is no evidence to support adjuvant therapy for carcinoma in situ of the fallopian tube and it is not recommended. 1,2,64 Level of Evidence A.

| Chemotherapy for advanced stage ovarian cancer
Patients who have had primary cytoreduction should receive chemotherapy following surgery 1,65 ( Table 3). The accepted standard is 6 cycles of platinum-based combination chemotherapy, with a platinum (carboplatin or cisplatin) and a taxane (paclitaxel or docetaxel). [66][67][68][69][70] Docetaxel is an option in patients who have had a significant allergic reaction to paclitaxel or who develop early sensory neuropathy as it has less neurotoxicity, but it is more myelosuppressive than pacli-  to the JGOG trial and it seems that the likely explanation is due to pharmacogenomic differences between these two ethnic groups. 85 The recommended doses and schedule for intraperitoneal chemotherapy are paclitaxel 135 mg/m 2 intravenously on day one, followed by cisplatin 100 mg/m 2 intraperitoneally on day two, followed by paclitaxel 60 mg/m 2 intraperitoneally on day eight, every 3 weeks for 6 cycles, as tolerated. 77  The Chemotherapy or Upfront Surgery (CHORUS) trial randomized patients to NACT followed by interval debulking and then three additional cycles or PDS followed by six cycles of platinum-based chemotherapy. 56 The optimal debulking rate was only 16% in the PDS group compared with 40% following NACT, which are lower than would be expected. The median duration of surgery was only 120 min in both groups, which was criticized as it did not seem to be long enough for aggressive debulking surgery and optimal cytoreduction. There was a 5.6% postoperative mortality rate in the PDS group, which is high. The median progression-free survival was 12 months in both groups, and the median overall survival was simi-

| Maintenance chemotherapy
Almost 80% of women with advanced stage disease who respond to first-line chemotherapy relapse. There have been several trials conducted to determine if there is a benefit of maintenance chemotherapy in these patients immediately following their primary treatment in an effort to decrease the relapse rate. 95 These were all negative and there is no evidence to support maintenance chemotherapy after completion of first-line therapy.

| Maintenance therapy with PARP inhibitors
There is increasing evidence to support the role of maintenance therapy with PARP inhibitors following response to treatment in the first-line therapy setting as well as in patients with platinumsensitive recurrent ovarian cancer. In the SOLO1 trial, patients with Stage III and IV high-grade serous/high-grade endometrioid ovarian cancer, a germline or somatic BRCA1 or 2 mutation, and at least partial response to adjuvant platinum-based chemotherapy were randomized to olaparib maintenance or placebo. 96  There is also good evidence to support the role of PARP inhibitors as maintenance therapy following response to chemotherapy in patients with recurrent platinum-sensitive ovarian cancer, as well as monotherapy in selected patients with recurrent ovarian cancer. [100][101][102][103][104] Patients with BRCA mutations (both germline and somatic) have the greatest benefit, but a subset of patients with tumors with homologous recombination deficiency (HRD) also derive benefit from treatment with PARP inhibitors; the ongoing challenge is how best to identify these patients. The results of these trials are summarized in Table 4. Readers are directed to the article on targeted therapy by Basu et al. 105 for further discussion of PARP inhibitors.

| Immune checkpoint inhibitors
There may be a potential role for immune checkpoint inhibitors in the first-line therapy setting in combination with chemotherapy as well as in maintenance, either alone or in combination with a PARP inhibitor or angiogenesis inhibitor. A number of trials are addressing these important questions and the results are awaited.
Unfortunately JAVELIN100, the first trial to be reported, was a negative trial. 106

| Second-look laparotomy
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. 107 Level of Evidence C.

| FOLLOW-UP FOR MALIG NANT EPITHELIAL TUMOR S
There is no evidence to show that intensive clinical monitoring dur-  with those who were given tamoxifen. 114 The median progression-free

| CHEMOTHER APY FOR RECURRENT EPITHELIAL C AN CER OF THE OVARY, FALLOPIAN TUB E , AND PERITONEUM
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. 116,117 This has been useful to define specific patient populations, but it has a number of limitations and depends on how patients are followed. In particular, it depends on how recurrence is detected and defined. Patients with a treatmentfree interval of less than 6 months are classified as platinum resistant and generally treated with nonplatinum-based chemotherapy, while those with a treatment-free interval of more than 6 months are considered to be platinum sensitive and commonly treated with platinum-based chemotherapy. Patients who progress while on treatment or within 4 weeks of stopping chemotherapy are classified as platinum refractory. 116,117 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 post 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. 116,117 For patients whose disease is considered platinum sensitive, the ICON4 study showed advantage in terms of overall survival and progression-free survival for a combination of carboplatin and paclitaxel versus single-agent carboplatin. 118 Level of Evidence A.
For patients with neurotoxicity, gemcitabine 119  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). 134 Patients in the experimental arm had a longer progression-free survival of 6.7 months versus 3.4 months and a higher overall response rate of 30.9% versus 12.6%. An exploratory subgroup analysis noted an increase in overall survival for weekly paclitaxel plus bevacizumab from 13.4 months to 22.4 months (with and without bevacizumab). 135 The findings in the AURELIA trial changed the standard of care.

| Immune checkpoint inhibitors in recurrent ovarian cancer
There has been much interest in exploring the role of immune checkpoint inhibitors in patients with recurrent ovarian cancer including those with platinum resistance. However, in general the 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. 136 The overall response rate was 8%, with a combined positive score (CPS, quantifying the number of PD-L1 positive cells) over 10 the objective response rate was 11%-18%. Similarly, the response rate with avelumab, an anti-PD-L1 antibody, was 10% in recurrent ovarian cancer. 137 However, there may be a role for combination regimens, which are being explored. For example, the phase 1/2 TOPACIO trial using niraparib and pembrolizumab in recurrent platinum-resistant ovarian cancer showed a response rate of 18%. 138 The combination of the CTLA-4 antibody ipilimumab with nivolumab, an anti-PD-1 antibody induction, followed by nivolumab maintenance had an objective response rate of 31.4% compared with 12.2% with nivolumab alone in a recently reported randomized phase 2 trial. 139 Although the median progression-free survival was longer with combination, it was only 3.9 months versus 2 months, and the benefit questionable given the increased toxicity. The multicohort Leap-005 trial recently reported preliminary data on another combination treatment using pembrolizumab and the multityrosine kinase inhibitor lenvatinib. In 31 patients with recurrent ovarian cancer the response rate was 29%. 140 There are still more trials in progress that are likely to provide results over the next few years. It will take time to define the role of immune checkpoint inhibitors in patients with recurrent ovarian cancer, but it seems likely that only a small subset of patients benefits and the challenge is to identify who these patients are.
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 is an essential component of management.
With very 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. 141 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. patients with ovarian cancer treated with 600 mg rucaparib orally twice daily. 143 Investigator-assessed objective response rate was 54% and the median duration of response was 9.2 months. 143  chemotherapy. In addition, the median progression-free survival increased from 7.2 months with chemotherapy to 13 months with trametinib and overall survival was also increased, although this was not statistically significant. 155 This remains an area of active investigation.

| MANAG EMENT OF LOW-G R ADE SEROUS C ANCERS
Follow-up of patients with no evidence of disease is the same as for those with malignant epithelial carcinomas, but at less frequent intervals. Level of Evidence C.

| Management of low malignant potential (borderline) tumors
Compared with invasive epithelial cancers, borderline tumors tend to affect a younger population and constitute 15% of all epithelial tumors of the ovary. 156 Nearly 75% of these are Stage I at the time of diagnosis. The following can be said for these tumors 157 : • The diagnosis must be based on the pathology of the primary tumor.
• Extensive sectioning of the tumor is necessary to rule out invasive cancer.
• The prognosis of these tumors is extremely good, with a 10-year survival of about 95%.
• Invasive cancers that arise in borderline tumors are often indolent and generally have a low response to platinum-based chemotherapy.
• Spontaneous regression of peritoneal implants has been observed.
• Early stage, serous histology, and younger age at diagnosis are associated with a more favorable prognosis.
• Although gross residual disease after primary laparotomy is associated with poorer prognosis, mortality from the disease remains low.
• There is no evidence-based preference for inhibin B or antimüllerian hormone as a tumor marker. 173  • Acute abdominal pain.

| Histologic classification
The classification of germ cell tumors of the ovary is important to determine prognosis and for treatment with chemotherapy. Germ cell tumors are classified as follows 2,161 : • Dysgerminoma.  180 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 those patients whose tumor was not completely resected at the initial operation and who had teratomatous elements in their primary tumor.
Surgical resection of residual masses may be beneficial in such patients, as there may be mature teratomatous nodules that can continue to increase in size (growing teratoma syndrome), and more rarely can undergo malignant transformation over time to an incurable malignancy (e.g. squamous cell carcinoma). 181

| Postoperative management and follow-up of dysgerminoma
Patients with Stage IA disease may be observed after surgery. A small proportion of patients may recur, but they can be treated successfully at the time of recurrence with a high rate of cure. Patients with disease beyond the ovary should receive adjuvant chemotherapy. Although radiation therapy is effective, it is no longer used in view of late effects and chemotherapy is highly effective.
A follow-up surveillance regime for patients with Stage IA dysgerminoma is outlined in Table 5. This schedule is based on the experience managing seminomas in males and the reports by Dark et al. 182 and Patterson et al. 183 This pragmatic follow-up schedule and has not been tested in randomized trials.

| Chemotherapy for dysgerminoma
Dysgerminoma is extremely sensitive to chemotherapy and treatment with chemotherapy cures the majority of patients, even with advanced disease. 161,184 The recommended chemotherapy regimen is as follows: • Etoposide (E) 100 mg/m 2 IV per day for 5 days every 3 weeks for 3 cycles.
• Cisplatin (P) 20 mg/m 2 IV per day for 5 days every 3 weeks for 3 cycles.
• When there is bulky residual disease it is common to give 3-4 courses of BEP or EP chemotherapy. 187 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 and one option is to utilize the follow-up regimen presented above. 182 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. 183 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. 182 Patients who have not received chemotherapy should be followed closely. Ninety percent of relapses in these patients occur within the first 2 years. At relapse, with few exceptions, these patients can be successfully treated. 182 Level of Evidence D. Patients who relapse after BEP may still attain a durable remission and cure with second-line chemotherapy regimens such as paclitaxel-ifosfamide-cisplatin (TIP). 177 High-dose chemotherapy and autologous marrow rescue may be considered in selected patients. These patients should be managed in specialized units.

|
After chemotherapy, patients with metastatic immature teratomas can sometimes have residual masses, which are composed entirely of mature elements. These masses can grow (growing teratoma syndrome), and should be resected after the completion of chemotherapy. 188 Level of Evidence B.
All patients should have alpha-fetoprotein (AFP) and human gonadotropin (beta hCG) to monitor response to treatment. All patients treated with chemotherapy should be followed up with medical history, physical examination, and appropriate tumor markers in the same way as dysgerminomas. CT or MRI scans should be performed as clinically indicated. 159 Relapses in patients usually occur within the first 2 years after diagnosis 161,177 Level of Evidence D.

| SARCOMA OF THE OVARY
Ovarian sarcomas are rare and occur primarily in postmenopausal patients. 161,189 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 sarcoma. Malignant mixed Müllerian tumors (MMMTs) or ovarian carcinosarcomas, the more common of the two, are biphasic tumors composed of both carcinomatous and sarcomatous elements. 189,190 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 the 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 MMMTs/ovarian carcinosarcomas have a better outcome than those with advanced stage disease, but the overall prognosis is poor. They should be managed similarly to highgrade pelvic serous cancers. Their rarity prohibits any prospective

This chapter updates the information published in the FIGO Cancer
Report 2018, 191 with approval granted by the original authors.