Cancer of the ovary, fallopian tube, and peritoneum

The Gynecologic Oncology Committee of FIGO in 2014 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 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 lower-grade 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, para-aortic 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 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.
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. 17 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)
1. NX: Regional lymph nodes cannot be assessed.
2. N0: No regional lymph node metastasis. 3. N1: Regional lymph node metastasis. T A B L E 1 FIGO staging classification for cancer of the ovary, fallopian tube, and peritoneum.

| 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. 18 The histologic classification of ovarian, fallopian tube, and peritoneal neoplasia is as follows: IV Any T Any N M1 Regional nodes (N)

Nx
Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis The overall incidence of epithelial tumors varies from 9 to 17 per 100 000 and is highest in high-income countries, with the exception of Japan. 26 However, this incidence rate increases proportionately with age. The largest number of patients with epithelial ovarian cancer is found in the 60-64 years age group. The median age is about a decade earlier in low-income countries.
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. First pregnancy at an early age, early menopause, and the use of oral contraceptives have been associated with lower risks of ovarian cancer. 27 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. 18

| 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 and those in the high-risk population. The US Preventive Services Task Force recommends against screening asymptomatic women for ovarian cancer with pelvic examination, pelvic ultrasound, or serum tumor marker measurements. 38 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. 38 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 risk-reducing 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. 38 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 An ACOG bulletin 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 high-grade serous carcinomas. 41

| DIAGNOSIS
Patients with epithelial ovarian cancers confined to the ovary or fallopian tube at initial diagnosis have a very good prognosis. 42 13,14,46 As the disease progresses, abdominal distention and discomfort from ascites generally worsen, and may be associated with respiratory symptoms from increased intraabdominal 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 the same as ovarian cancer. Past analyses have been biased because many fallopian tube cancers have been presumed to arise in the ovaries.
A detailed medical history must be taken to ascertain possible risk factors, history of other cancers, and history of cancer in the family.
Then a complete physical examination, including general, breast, pelvic, and rectal examination, must be performed. 1 Prior to surgery a chest radiograph should be taken to screen for a 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 with laparotomy. Tumor markers including CA125, 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.
A gastric or colonic primary with metastases to the ovaries may mimic ovarian cancer, and if the CEA is elevated, this should be con- The following factors point to the presence of a malignancy, and are useful in the clinical assessment of masses: 1. Age of the patient (young for germ cell, older for epithelial malignancies).

| PRIMARY SURGERY
In general, the prognosis of epithelial ovarian, fallopian, and peritoneal malignancies is independently affected by the following 1,48,49 : 1. Stage of the cancer at diagnosis.

Histologic type and grade.
3. 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 1,10,11,13,14 : 1. Careful evaluation of all peritoneal surfaces.
2. Retrieval of any peritoneal fluid or ascites. If there is none, washings of the peritoneal cavity should be performed.
4. Selective lymphadenectomy of the pelvic and para-aortic lymph nodes, at least ipsilateral if the malignancy is unilateral.
5. Biopsy or resection of any suspicious lesions, masses, or adhesions.
6. 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.
7. Total abdominal hysterectomy and bilateral salpingo-oophorectomy in most cases.

Appendectomy for mucinous tumors.
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 may be an issue. In these patients, con-  (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). [60][61][62][63][64] 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 paclitaxel. 60    and it seems that the likely explanation is due to pharmacogenomic differences between these two ethnic groups. 74 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. 68,69 Many centers modify the dose of cisplatin to 75 mg/m 2 rather than 100 mg/m 2 that was used in GOG 172 to reduce toxicity, but this could be questioned based on GOG 262 results discussed above. 69 Others substitute carboplatin (AUC [5][6] for cisplatin in the regimen and the same caveats regarding lack of evidence apply. 69 The role of intraperitoneal carboplatin is being evaluated in JGOG and the results should be available in the near future.
Bevacizumab 7.5-15 mg/kg every 3 weeks may be added to these regimens. 77,78 Two studies have reported a modest, but statistically significant increase in progression-free survival in patients receiving maintenance bevacizumab following carboplatin, paclitaxel, and concurrent bevacizumab. 77,78 There is no evidence as yet to demonstrate an overall survival benefit, but a subgroup analysis of the International Unfortunately, the study did not have an arm with intraperitoneal cisplatin alone without HIPEC, therefore it is not possible to know whether the improved survival was due to the addition of intraperitoneal cisplatin alone or HIPEC.
In patients who may not tolerate combination chemotherapy because of medical comorbidities or advanced age, single-agent, intravenously administered carboplatin (AUC 5-6) can be given.

| 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 therapy in these patients immediately following their primary treatment in an effort to decrease the relapse rate. These were all negative and there is no evidence to support maintenance chemotherapy after completion of first-line therapy.

| PARP inhibitors
There is good evidence to support the role of PARP inhibitors as maintenance therapy following response to chemotherapy in patients with platinum-sensitive recurrent ovarian cancer, as well as monotherapy in selected patients with recurrent ovarian cancer. [81][82][83][84][85] 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. [83][84][85] Readers are directed to the chapter on targeted therapy in this Supplement by Basu et al. 86 for further discussion of PARP inhibitors.

| 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. 87 Level of Evidence C

| Secondary cytoreduction
Secondary cytoreduction may be defined as an attempt at cytoreduc-  with those who were given tamoxifen. 93 The median progression-free survival was 3.2 months in the thalidomide group versus 4.5 months in the tamoxifen group. This suggests that tamoxifen may have a role in selected patients with a rising CA125 level, and the relationship between estrogen receptor positivity and benefit of tamoxifen in this patient population is being evaluated in current studies.

| CHEMOTHERAPY FOR RECURRENT EPITHELIAL MALIGNANCIES
The majority of patients who present with advanced epithelial cancers of the ovary/fallopian tube/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 "platinumfree interval," which is defined as the time from cessation of primary platinum-based chemotherapy to disease recurrence or progression. 94,95 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 treatment-free interval of less than 6 months are classified as platinum resistant and generally treated with nonplatinum-based chemotherapy, while those with a treatmentfree 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. 94,95 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- The progression-free interval is defined from the last date of platinum dose until progressive disease is documented. 94,95 For patients whose disease is considered platinum-sensitive, the ICON 4 study showed advantage in terms of overall survival and progression-free survival for a combination of carboplatin and pacli-  99 The CD arm had statistically superior progression-free survival compared with the CP arm, with a median progression-free survival of 11.3 versus 9.4 months, respectively. There was no significant difference in the overall survival between the treatment groups. Median overall survival 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 progression-free survival compared with carboplatin and gemcitabine in platinum-sensitive disease.
In the OCEANS study, 100 484 patients with platinum-sensitive disease were randomly assigned to carboplatin (AUC 4 on day 1) and gemcitabine 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. 108 There are many potential treatment options, including chemotherapy, angiogenesis inhibitors, radiation therapy, or surgery in selected patients and inclusion in clinical trials. 89 There is a subset of patients who may benefit from secondary surgical debulking, but they constitute a minority. The role of secondary surgical debulking is being addressed in prospective randomized clinical trials. Level of Evidence C

| PARP inhibitors as monotherapy in patients with recurrent ovarian cancer
Olaparib is FDA approved for the treatment of patients with gBRCAmutated recurrent ovarian cancer who have received three or more prior lines of chemotherapy. 109,110 The FDA granted approval on the basis of the response rate in a single-arm study of olaparib in patients with BRCA mutations and with a wide range of different cancers. The response rate was 34% in heavily pretreated BRCA-positive patients with platinum-resistant recurrent ovarian cancer and the median progression-free survival was 7.9 months. 110 Rucaparib is also approved for treatment of BRCA-mutationassociated advanced ovarian cancer after completion of treatment with two or more chemotherapy regimens regardless of whether patients are platinum-sensitive or resistant. 111 Rucaparib's approval was based primarily on efficacy data from 106 patients with BRCA-associated recurrent ovarian cancer who had prior treatment with two or more chemotherapy regimens and safety data from 377 patients with ovarian cancer treated with rucaparib 600 mg orally twice daily on two openlabel, single-arm trials. 112 Investigator-assessed objective response rate was 54% and the median duration of response was 9.2 months. 112

| 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. 119 Nearly 75% of these are Stage I at the time of diagnosis. The following can be said for these tumors 120 : 1. The diagnosis must be based on the pathology of the primary tumor.
2. Extensive sectioning of the tumor is necessary to rule out invasive cancer.
3. 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.
5. Spontaneous regression of peritoneal implants has been observed.
6. Early stage, serous histology, and younger age at diagnosis are associated with a more favorable prognosis.
7. Although gross residual disease after primary laparotomy is associated with poorer prognosis, mortality from the disease remains low. The use of platinum-based chemotherapeutic regimes has made germ cell malignancies among the most highly curable cancers. 127

| Presentation
These

| 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 2,127 :

| 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, ovarian failure makes it undesirable for patients with an intact ovary.
A follow-up surveillance regime for patients with Stage 1A dysgerminoma is outlined in Table 5. This schedule is based on the experience managing seminomas in males and the reports by Patterson et al. 146 and Dark et al. 147 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. 127,148 The recommended chemotherapy regimen is as follows: When there is bulky residual disease, it is common to give 3-4 courses of BEP chemotherapy. 148 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. 147 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. 146 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. 147 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. 147  There are two types of sarcoma. Malignant mixed Müllerian tumors (MMMTs), the more common of the two, are biphasic tumors composed of both carcinomatous and sarcomatous elements. 150,151 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 have a better outcome than those with advanced stage disease, but 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 of ovarian MMMTS are the same as for high-grade pelvic serous cancers. 127 Following surgery, patients should receive platinum-based chemotherapy. 127,147,148 The follow-up schedule is as recommended for epithelial malignancies.