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    Ovarian Cancer

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    Nov.08.2024

    Ovarian Cancer

    Synopsis

    Key Points

    • Epithelial ovarian cancer is a common gynecologic malignancy with a variety of histologic subtypes, of which the most common form is high-grade serous carcinoma r1
    • Symptoms of ovarian cancer may include bloating or abdominal distention, early satiety or loss of appetite, and pelvic or abdominal pain r2
    • Occurs most commonly in postmenopausal females but can affect younger females, particularly those with BRCA1 or BRCA2 mutations or Lynch syndrome r3
    • Diagnosis may be suspected based on presenting symptoms or discovery of an adnexal mass on pelvic examination or imaging
    • Transvaginal and transabdominal ultrasonography are first line imaging modalities, and sonographic appearance can indicate whether adnexal mass is most likely to be benign or malignant; definitive diagnosis is established by histopathologic examination of surgically resected ovary in most cases r2r4
    • Recommended treatment varies according to disease stage; standard approach for most patients consists of total abdominal hysterectomy with bilateral salpingo-oophorectomy and comprehensive surgical staging, followed by postoperative chemotherapy and maintenance PARP therapy
    • Females who are carriers of BRCA1 and BRCA2 gene mutations are at high risk of developing ovarian cancer and should be offered risk-reducing salpingo-oophorectomy after completion of childbearing r1

    Pitfalls

    • Fine-needle aspiration biopsy of an ovarian mass is contraindicated if malignancy is suspected
    • Ovarian cancer is histologically and clinically similar to fallopian tube carcinoma, and differentiation may be difficult r5
    • There is no high-quality evidence to support physical examination (bimanual palpation of ovaries) or imaging as screening strategy for ovarian cancer in asymptomatic females who have an average risk of developing it r6r7

    Terminology

    Clinical Clarification

    • Epithelial ovarian cancer is a common gynecologic malignancy and a leading cause of cancer mortality among females. Epithelial cell tumors represent most cases, whereas malignant ovarian germ cell or stromal cell tumors are rare r1
    • Serous epithelial ovarian cancer (the most common subtype) is histologically and clinically similar to primary fallopian tube carcinoma and peritoneal carcinoma, and these are often considered a single clinical entity (eg, National Comprehensive Cancer Network issues 1 guideline for all 3 types) r2

    Classification

    • Histologic subtype r2
      • Main subtypes
        • High-grade serous carcinoma (70%) r8
        • Endometrioid carcinoma (10%) r8
      • Less common forms
        • Clear cell carcinoma (10%) r8
        • Low-grade serous carcinoma (5%) r8
        • Mucinous carcinoma (3%) r8
        • Transitional cell carcinoma (Brenner tumor)
        • Carcinosarcoma (malignant mixed müllerian tumor)
        • Seromucinous carcinoma
        • Undifferentiated carcinoma
        • Endometrioid stromal sarcoma
    • Molecular subtype (differing mode of carcinogenesis) r9
      • Type I
        • Tend to be diagnosed at earlier stage and have better prognosis
        • Consist of the following:
          • Endometriosis-related subtypes (ie, endometrioid, clear cell, seromucinous)
          • Low-grade serous carcinoma
          • Mucinous and transitional cell carcinoma (Brenner tumor)
      • Type 2
        • Typically advanced stage at diagnosis and have poor prognosis
        • Primarily high-grade serous carcinomas
    • TNM staging system r2
      • Tumor
        • Tx: cannot assess primary tumor
        • T0: no evidence of primary tumor
        • T1: tumor limited to 1 or both ovaries
          • T1a: tumor limited to 1 ovary; capsule intact; no tumor on ovarian surface; no malignant cells in ascites, and/or peritoneal washings
          • T1b: tumor limited to both ovaries; capsule intact; no tumor on ovarian surface; no malignant cells in ascites and/or peritoneal washings
          • T1c: tumor limited to 1 or both fallopian tubes with any of the following: capsule ruptured, tumor on ovarian surface, or with malignant cells in ascites and/or peritoneal washings
        • T2: tumor involves 1 or both ovaries with pelvic extension
          • T2a: extension or implants on uterus and/or fallopian tubes; no malignant cells in ascites and/or peritoneal washings
          • T2b: extension to other pelvic structures; no malignant cells in ascites and/or peritoneal washings
          • T2c: extension to uterus, fallopian tubes, or other pelvic structures; malignant cells in ascites and/or peritoneal washings
        • T3: tumor involves 1 or both ovaries with peritoneal metastasis outside the pelvis
          • T3a: microscopic peritoneal metastasis outside the pelvis (no macroscopic tumor)
          • T3b: macroscopic peritoneal metastasis outside the pelvis (2 cm or less at greatest dimension)
          • T3c: macroscopic peritoneal metastasis outside the pelvis (more than 2 cm at greatest dimension) and/or regional lymph node metastasis
      • Node
        • NX: regional lymph nodes cannot be assessed
        • N0: no metastasis to regional lymph nodes
        • N1: metastasis to regional lymph nodes
      • Metastasis
        • M0: no distant metastasis
        • M1: distant metastasis (exclusive of peritoneal metastasis)
      • Staging grouping r2
        • Stage I: T1 N0 M0
        • Stage IA: T1a N0 M0
        • Stage IB: T1b N0 M0
        • Stage IC: T1c N0 M0
        • Stage II: T2 N0 M0
        • Stage IIA: T2a N0 M0
        • Stage IIB: T2b N0 M0
        • Stage IIC: T2c N0 M0
        • Stage III: T3 N0 M0
        • Stage IIIA: T3a N0 M0
        • Stage IIIB: T3b N0 M0
        • Stage IIIC: T3c N0 M0 or any T, N1 M0
        • Stage IV: any T, any N, M1
    • FIGO staging system (International Federation of Gynecology and Obstetrics) r2r10
      • Stage I: tumor is limited to ovaries
        • Stage IA: an encapsulated tumor is located in only 1 ovary (capsule intact); no tumor on ovarian surface and no malignant cells in ascites and/or peritoneal washings
        • Stage IB: an encapsulated tumor is located in both ovaries; no tumor on ovarian surface and no malignant cells in ascites and/or peritoneal washings
        • Stage IC: tumor is in 1 or both ovaries with any of the following: surgical spill (IC1), ruptured capsule before surgery or tumor spread to the ovarian or fallopian tube surface (IC2), or malignant cells in ascites and/or peritoneal washings (IC3)
      • Stage II: tumor involves 1 or both ovaries, with pelvic extension or peritoneal cancer
        • Stage IIA: extension of tumor to uterus and/or fallopian tubes
        • Stage IIB: extension of tumor to other pelvic intraperitoneal tissues
      • Stage III: tumor involves 1 or both ovaries with spread into peritoneum outside the pelvis and/or metastasis to retroperitoneal lymph nodes
        • Stage IIIA: positive retroperitoneal lymph nodes only (IIIA1), metastasis up to 10 mm at greatest dimension (IIIAi), metastasis greater than 10 mm at greatest dimension (IIIAii), or microscopic extrapelvic peritoneal involvement with or without positive retroperitoneal lymph nodes (IIIA2)
        • Stage IIIB: macroscopic extrapelvic peritoneal metastasis up to 2 cm at greatest dimension, with or without positive retroperitoneal lymph nodes
        • Stage IIIC: macroscopic extrapelvic peritoneal metastasis greater than 2 cm at greatest dimension, with or without positive retroperitoneal lymph nodes (includes extension to capsule of liver or spleen)
      • Stage IV: distant metastasis (exclusive of peritoneal metastasis)
        • Stage IVA: pleural effusion with positive cytology results
        • Stage IVB: parenchymal metastasis and extra-abdominal metastasis

    Diagnosis

    Clinical Presentation

    History

    • Ovarian cancer can be asymptomatic until an advanced stage; symptoms, when present, are nonspecific c1
    • Symptoms may include: r2
      • Bloating or abdominal distention c2c3
      • Early satiety or loss of appetite c4c5
      • Urinary urgency or frequency c6c7
      • Pelvic or abdominal pain c8c9
    • Less common symptoms include: r11
      • Postmenopausal vaginal bleeding c10
      • Rectal bleeding c11
      • Weight loss c12
    • Advanced cases may present acutely with symptoms due to pleural effusion or bowel obstruction c13c14

    Physical examination

    • Abdominal or pelvic bimanual examination commonly identifies an adnexal mass; this may be an incidental finding c15
    • Ascites may be detected in a small proportion of patients c16
    • Rarely, inguinal lymph nodes may be palpable c17

    Causes and Risk Factors

    Causes

    • Causation and risk factors may vary by distinct histologic subtype of ovarian cancer; hormonal, reproductive, and genetic factors are probably implicated r12c18c19
    • It is now believed that there are 2 separate pathways by which ovarian carcinogenesis occurs and that many ovarian cancers originate from precursor lesions in the fallopian tube (serous tubal intraepithelial carcinoma) or endometrial tissue; hormonal and reproductive risk factors may have more effect on the development of some tumors than others r13r14

    Risk factors and/or associations

    Age
    • Occurs mostly in postmenopausal females, with peak incidence between ages 55 and 64 years, although it can occur in younger females, particularly those with hereditary cancer syndromes r3c20c21c22c23
    Genetics
    • Hereditary breast and ovarian cancer syndrome (OMIM #604370, #612555, and others)r15r16c24
      • Cancer predisposition condition caused by mutations in the BRCA1 and BRCA2 genes (DNA repair associated); various subtypes exist r1c25c26
      • Increased risks for various cancers: early-onset breast, multiple breast primaries, male breast, epithelial ovarian, fallopian tube, and primary peritoneal
      • Likelihood of identifying a BRCA1 or BRCA2 mutation in females with ovarian cancer at any age is around 13% to 18%
    • Lynch syndromer17 and related mismatch repair cancer syndrome (OMIM #120435r18 and #276300r19) c27
      • Condition of constitutional mismatch repair deficiency caused by biallelic mutations in MSH2, MLH1, PMS2, or MSH6c28c29c30c31
      • Increased risk of ovarian cancer in addition to colorectal and other cancers, such as small intestine, hepatobiliary tract, urinary tract, brain, and skin r20
    • Other inherited germline mutations associated with ovarian cancer include PALB2, BARD1, BRIP1, RAD51C, and RAD51Dr21c32c33c34c35c36
    Ethnicity/race
    • Incidence is higher in White females than in Black, Asian, or Hispanic females r22r23c37c38c39c40
    Other risk factors/associations r12r14
    • The following factors appear to be associated with an increased risk of ovarian cancer: r9
      • Family history of ovarian cancer in first-degree relative c41
      • Polycystic ovary syndrome c42
      • Endometriosis c43
      • Obesity c44
      • Increased height
      • Hormone replacement therapy c45
        • Transcutaneous hormone therapy may be associated with a lower risk of ovarian cancer than oral hormone therapy r9
      • Ovarian hyperstimulation due to infertility treatment (only when unsuccessful in achieving conception) c46c47
      • Intrauterine contraceptive use r12c48
      • Cigarette smoking r12c49
    • The following factors may be protective (by reducing ovulatory years): r9
      • Multiparity
      • Oral contraceptive use
      • Past breastfeeding
      • Tubal ligation
      • Salpingectomy and salpingo-oophorectomy
      • Depot medroxyprogesterone use

    Diagnostic Procedures

    Primary diagnostic tools

    • Diagnosis may be suspected based on presenting symptoms or discovery of an adnexal mass on pelvic examination or imaging r24c50
      • Transvaginal and transabdominal ultrasonography are first line imaging modalities r4r25
      • MRI may be performed if ultrasonographic results are suboptimal or if further imaging is required to determine whether surgical evaluation is indicated r26
    • Preoperative workup may include: r2
      • CT or MRI scan of the abdomen and pelvis with oral and IV contrast and rectal contrast if needed; fludeoxyglucose F 18 PET-CT from skull base to midthigh is an alternative r2r27
      • Baseline CBC, hepatic function panel, and biochemistry panel
      • Serum levels of CA 125 (cancer antigen 125) r28
      • Screening for other tumor markers (eg, carcinoembryonic antigen, inhibin, lactate dehydrogenase, alpha fetoprotein, CA 19-9, HE4 [human epididymis protein 4]) r2
      • β-hCG level to exclude pregnancy in patients of childbearing age c51
      • Chest radiograph or chest CT scan, if metastatic spread is suspected
      • Nutritional evaluation
    • Several prediction tools have been developed for preoperative assessment of the likelihood of malignancy among patients with an adnexal mass r2r29r30
      • OVA1 test uses combination of 5 serum biomarkers (transthyretin, apolipoprotein A1, transferrin, β2-microglobulin, and CA 125)
      • Assessment of Different NEoplasias in the adneXa model uses combination of age, serum CA 125, type of center, and ultrasonographic variables
      • Risk of Ovarian Malignancy Algorithm uses combination of menopausal status and 2 serum biomarkers (CA 125 and HE4)
      • Risk of Malignancy Index uses combination of menopausal status, ultrasonographic findings, and serum CA 125
      • International Ovarian Tumor Analysis Simple Rules risk model uses a combination of ultrasonographic findings
    • Diagnosis is confirmed by histopathologic examination of surgical specimen
      • Surgical removal of the complete ovary or ovaries, rather than tissue biopsy, is recommended to determine whether ovarian cancer is present c52
      • If malignancy is suspected, aspiration biopsy of an ovarian mass is contraindicated because of the risk of peritoneal contamination
    • Imaging alone may not demonstrate the full extent of either peritoneal carcinomatosis or serosal involvement of the mesentery and bowel; treatment planning is often based on laparoscopy or laparotomy findings r31
    • Genetic risk evaluation should be offered to all patients diagnosed with epithelial ovarian cancer r2
      • Perform germline and somatic genetic testing for BRCA1/2 and other ovarian cancer susceptibility genes r32r33r34
      • BRCA1/2 status guides selection of maintenance therapy r2
      • In the absence of BRCA1/2 variants, homologous recombination deficiency status can guide PARP (poly ADP-ribose polymerase) inhibitor therapy r32

    Laboratory

    • Serum CA 125 level (MUC16) c53
      • Sensitive marker of ovarian cancer but has poor specificity
        • More than 80% of ovarian malignancies express elevated levels of CA 125 r35
        • Elevated levels are more often detected in advanced or recurrent disease
      • The following are considered positive results:
        • Level greater than 50 units/mL in premenopausal females r36
        • Level greater than 40 units/mL in premenopausal females using oral contraceptives r36
        • Level greater than 30 units/mL in postmenopausal females r36
      • Can also be used to assess prognosis and monitor response to treatment
    • Serum HE4 level (WFDC2) c54
      • Tumor marker secreted and overexpressed by serous and endometrioid epithelial ovarian cancer
      • Serum HE4 level has a very high negative predictive value (approximately 99%), indicating that almost all patients with negative test results will have benign ovarian pathology r28
      • Combination of serum HE4 and CA 125 levels has higher sensitivity and specificity than either test used alone r28

    Imaging

    • Ultrasonography c55
      • Transvaginal ultrasonography of the pelvis with duplex Doppler is the preferred modality; transabdominal scan of pelvis may also be obtained r37
      • Sonographic appearance can indicate whether adnexal mass is most likely to be benign or malignant but cannot definitively determine diagnosis
      • Major ultrasonographic characteristics suggesting malignancy include: r38
        • Irregularly shaped solid tumor
        • Tumor with multiple (more than 4) papillary structures
        • Irregularly shaped solid, multiloculated tumor more than 10 cm at largest dimension
        • Tumor that demonstrates very strong flow on color Doppler
        • Ascites
    • MRI of abdomen and pelvis c56
      • Usually indicated to assess for local metastasis after initial ultrasonographic evaluation; may help if diagnosis is unclear based on ultrasonographic findings alone r2
        • More specific than ultrasonography for diagnosis of malignancy; may reduce false-positive findings r25
        • Superior to CT at detecting local metastasis to bladder, vagina, rectum, and pelvis
    • CT scan of abdomen and pelvis c57
      • Usually not useful for diagnosis but may be used to detect local metastases and assess tumor resectability after initial ultrasonography r2r37r39
      • CT scan can be helpful for assessing disease in lymph nodes and upper abdomen
    • Fludeoxyglucose F 18 PET-CT c58
      • May aid in diagnosis of indeterminate lesions; good at differentiating malignant from borderline or benign ovarian tumors; however, it cannot be used to reliably distinguish borderline and benign tumors r2r31
      • Useful in disease staging and surveillance for relapse r40

    Procedures

    Laparoscopy or laparotomy c59c60
    General explanation
    • Surgical resection of involved ovary is recommended for a histopathologic diagnosis; intraoperative confirmation by frozen section may assist in surgical management r2
      • Bilateral fallopian tubes, ovaries, and uterus are also frequently resected
      • In advanced disease, a tissue specimen may be obtained via core biopsy before neoadjuvant chemotherapy and surgery
    • Exploratory laparoscopy may have a role in evaluating patients with advanced ovarian cancer to assess resectability and help determine whether neoadjuvant chemotherapy is indicated before debulking surgery r41
    Indication
    • Suspected ovarian malignancy
    Interpretation of results
    • Histopathologic analysis of surgical specimen confirms diagnosis and assigns the histologic subtype and grade r2
    • Tumor molecular analysis should include next-generation sequencing for BRCA1/2 mutations, hormone receptor status, and tumor mutational burden r2r42
      • Additional testing includes:
        • Homologous recombination repair deficiency testing; identifies a subgroup of patients who may benefit from PARP inhibitor maintenance therapy r43r44r45
        • Mismatch repair testing; indicated for females with clear cell, endometrioid, or mucinous ovarian cancer r34
        • Microsatellite instability testing
        • Neurotrophic tyrosine receptor kinase testing r2

    Other diagnostic tools

    • Assessment of Different NEoplasias in the adneXa risk prediction model r46
      • Estimates the risk of 5 tumor types: benign, borderline, stage I primary invasive, stage II-IV primary invasive, and secondary metastatic based on clinical and ultrasonographic variables
        • Clinical variables
          • Age
          • Serum CA 125 level
          • Type of center (eg, oncology tertiary referral center, other)
        • Ultrasonography variables
          • Maximum diameter of lesion
          • Proportion of solid tissue
          • Number of papillary projections
          • Presence of more than 10 cyst locules
          • Presence of acoustic shadows
          • Presence of ascites

    Differential Diagnosis

    Most common

    • Benign ovarian cyst c61
      • Small ovarian cysts are common and may represent an ovarian follicle or corpus luteum; other benign cysts include dermoid cysts and endometriomas
      • As with ovarian cancer, adnexal masses may be palpated on bimanual examination
      • As with ovarian cancer, cysts are often clinically silent or can present with pelvic pain; unlike with ovarian cancer, acute severe pain can occur if a cyst undergoes torsion, rupture, or hemorrhage
      • Differentiated based on results of diagnostic imaging in most cases
        • Ultrasonographic characteristics indicating that a cyst is likely and is probably benign include round shape, thin walls, increased acoustic enhancement, anechoic fluid, and absence of septation or nodules
        • Specific diagnosis is confirmed by histopathologic findings at salpingo-oophorectomy if likelihood of malignancy is high or indeterminate on imaging
    • Primary fallopian tube carcinoma r5c62
      • Malignant neoplasm of fallopian tube; most commonly epithelial tumors
      • Like ovarian cancer, may be asymptomatic in early stages; in advanced disease, symptoms are nonspecific and may include bloating, abdominal or pelvic pain, early satiety, and frequent urination
      • Unlike with ovarian cancer, additional symptoms may include vaginal bleeding or spotting (including postmenopausal bleeding) and persistent vaginal discharge
      • Differentiated by results of diagnostic imaging and histopathologic findings at salpingo-oophorectomy
    • Benign fallopian tube cyst r47c63
      • Benign parovarian cysts are relatively common
      • Few or no symptoms; may be incidental finding (adnexal mass on bimanual examination)
      • Differentiated by diagnostic imaging or histopathologic findings on surgical exploration
    • Pelvic inflammatory disease r47c64c65d1
      • Infection of fallopian tube commonly caused by Neisseria gonorrhoeae or Chlamydia trachomatis that results in a spectrum of clinical disease r48
        • Salpingitis (acute edema in fallopian tubes with ascending infection and inflammation) c66c67
        • Pyosalpinx (acute infection with superimposed obstruction of fallopian tube and tube distention with pus) c68c69
        • Tubo-ovarian abscess (acute inflammatory mass surrounding fallopian tube and ovary) c70c71
        • Hydrosalpinx (fallopian tube chronically dilated by adhesions from past pelvic inflammatory disease) c72c73
      • Like ovarian cancer, may present with abdominal or pelvic pain and adnexal mass on bimanual examination
      • However, acute pelvic inflammatory disease is typically also accompanied by fever and chills, abnormal uterine bleeding, and abnormal vaginal discharge
      • May occur in postpartum setting or because of sexually transmitted infection
      • Differentiated by history, physical examination, inflammatory markers, diagnostic imaging findings, and microbiological testing
    • Ectopic pregnancy r49c74d2
      • Occurs when fertilized ovum implants outside uterine cavity
      • Like ovarian cancer, may present with pelvic or abdominal pain and adnexal mass on bimanual examination
      • Unlike ovarian cancer, may present with vaginal bleeding, syncope, or shock
      • Patient may have history of previous ectopic pregnancy, pelvic inflammatory disease, tubal sterilization, or tubal surgical procedures; may currently use an intrauterine device
      • Differentiated by history, physical examination, β-hCG level, and transvaginal ultrasonography

    Treatment

    Goals

    • Eradicate tumor
    • Prolong disease-free survival

    Disposition

    Admission criteria

    • Admit patients to hospital for surgery

    Recommendations for specialist referral r2

    • Refer to a gynecologic oncologist for clinically suspicious lesions and for comprehensive staging and surgical treatment
    • Refer to a gynecologic or medical oncologist for management of systemic chemotherapy
    • Refer to a reproductive endocrinologist for consultation regarding fertility preservation procedures
    • Refer to a genetic counselor for breast, ovarian, and colorectal cancer risk evaluation r50

    Treatment Options

    General overview

    • Stages IA to IV
      • Recommended treatment varies according to disease stage; however, standard approach for most patients consists of total abdominal hysterectomy with bilateral salpingo-oophorectomy and comprehensive surgical staging, followed by postoperative chemotherapy
      • Surgical treatment
        • Early-stage (stage I) disease
          • Patients with early-stage disease who wish to retain fertility may undergo unilateral salpingo-oophorectomy (stage IA) or bilateral salpingo-oophorectomy (stage IB) along with comprehensive surgical staging r2r51
          • Patients with early-stage disease who do not wish to retain fertility should undergo total abdominal hysterectomy with bilateral salpingo-oophorectomy with comprehensive surgical staging and cytoreductive surgery
          • Postoperative platinum-based chemotherapy may not be required by all patients r52
        • Advanced stage (stages II-IV)
          • Patients with advanced disease should undergo total abdominal hysterectomy with bilateral salpingo-oophorectomy with comprehensive surgical staging and cytoreductive surgery
            • Follow with platinum-based chemotherapy with or without the addition of bevacizumab or PARP inhibitors r9
          • Selected patients can be given neoadjuvant platinum-based chemotherapy followed by interval cytoreductive surgery with total abdominal hysterectomy with bilateral salpingo-oophorectomy
            • Patients with stages II to IV disease and significant disease-related symptoms (eg, severe pleural effusion, cachexia, hypoalbuminemia, poor nutritional status), low likelihood of optimal cytoreduction (eg, diffuse or deep involvement of stomach, bowel, mesentery), or poor prognostic factors may have neoadjuvant chemotherapy after histologic confirmation (via core biopsy) r2r53r54r55
            • There is a little difference in survival outcomes between primary cytoreductive surgery and neoadjuvant chemotherapy followed by interval cytoreductive surgery; however, neoadjuvant chemotherapy may reduce the risk of perioperative complications and the need for bowel resection r56r57
            • Accurate preoperative imaging allows selection of patients who may benefit most from either primary cytoreductive surgery or from neoadjuvant chemotherapy; CT, MRI, PET-CT, and diagnostic laparoscopy may be used r58r59
      • Comprehensive surgical staging and cytoreductive surgery consist of the following: r2
        • Aspiration of ascites or peritoneal washing, omentectomy, lymphadenectomy of lymph nodes with suspicious features, and bilateral pelvic and para-aortic lymph node dissection when extrapelvic tumor nodules smaller than 2 cm are present
        • Other debulking procedures for disease involving the pelvis and upper abdomen may include radical pelvic dissection, bowel resection, appendectomy, splenectomy, stripping of peritoneal surfaces, partial hepatectomy, partial gastrectomy, and partial cystectomy r2
        • Patients with residual disease after surgical debulking or cytoreduction for invasive or peritoneal disease may be candidates for intraperitoneal chemotherapy (normothermic or hyperthermic) r2r60
          • Studies have shown improved long-term survival with intraperitoneal chemotherapy, but its use is limited by a higher rate of toxicity and a reduced quality of life compared with IV chemotherapy r60r61r62r63
      • Systemic therapy
        • Platinum-based chemotherapy is indicated before or after cytoreductive surgery for most patients, except for some patients with stages IA and IB disease r2r52
        • Chemotherapy alone is an option for patients who cannot have surgery r52
        • Preferred chemotherapy regimens include paclitaxel-carboplatin or paclitaxel-carboplatin-bevacizumab plus maintenance bevacizumab
          • Capecitabine or fluorouracil-leucovorin plus oxaliplatin with or without bevacizumab is another option for mucinous carcinoma
          • Intraperitoneal or IV paclitaxel-cisplatin (for optimally debulked stages II-III disease)
        • Patients with stages II to IV high-grade serous or endometrioid ovarian cancer who have complete or partial response to first line platinum-based chemotherapy should be offered maintenance treatment with PARP inhibitors
          • Either olaparib or rucaparib for 2 years or niraparib for 3 years is recommended in patients with BRCA1 or BRCA2 mutations r43r64
            • Use a combination of olaparib and bevacizumab if bevacizumab was added to front line chemotherapy r43
            • Veliparib monotherapy is under investigation as option in patients with homologous recombination deficiency if this was added to front line chemotherapy r65
          • Either rucaparib for 2 years or niraparib for 3 years is recommended in patients with homologous recombination repair deficiency and may also be offered to patients without BRCA mutations or homologous recombination repair deficiency r64
          • Patients receiving bevacizumab with front line chemotherapy who are negative for homologous recombination deficiency do not benefit from the addition of olaparib to maintenance bevacizumab r43
    • Persistent or recurrent disease
      • Treatment may consist of secondary cytoreductive surgery, clinical trial, combination chemotherapy (platinum-based for platinum-sensitive disease), targeted therapy, immunotherapy, or supportive care r2r66
        • Platinum-sensitive disease
          • Common chemotherapy regimens include bevacizumab alone or added to carboplatin-gemcitabine, carboplatin–liposomal doxorubicin, and paclitaxel-carboplatin r1
          • After partial or complete response to platinum-based chemotherapy, patients with recurrent platinum-sensitive high-grade ovarian cancer should receive maintenance therapy with a PARP inhibitor (ie, olaparib, niraparib, rucaparib) r64r67
            • Progression-free survival is improved with these agents regardless of BRCA status; however, the effect may be more pronounced among patients with mutations in BRCA1 orBRCA2r51
            • There are concerns about a possible detrimental effect on overall survival, particularly for patients without germline BRCA mutations r29
            • In view of this, FDA approval for use of niraparib is limited to patients with deleterious or suspected deleterious germline BRCA mutation, and rucaparib and olaparib are limited to those with a deleterious or suspected deleterious germline or somatic BRCA mutation r2
            • In Europe, olaparib, niraparib, and rucaparib are approved for maintenance therapy in platinum-sensitive, high-grade tubo-ovarian carcinoma, irrespective of BRCA mutation status r29
        • Platinum-resistant disease
          • Chemotherapy options include docetaxel, oral etoposide, gemcitabine, paclitaxel with or without pazopanib, liposomal doxorubicin with or without bevacizumab, paclitaxel-bevacizumab, and topotecan with or without bevacizumab
          • PARP inhibitors (ie, olaparib, niraparib, rucaparib) are not recommended in this setting because of concerns regarding long-term outcomes and toxicities r52r64
          • Chemotherapy is the preferred approach for BRCA mutation carriers with platinum-resistant disease relapse
        • Additional systemic therapies for recurrent disease r1
          • Targeted therapies
            • Bevacizumab
            • Mirvetuximab soravtansine with or without bevacizumab (for FRα-expressing tumors) r68
            • Larotrectinib, entrectinib, or repotretinb (for tumors positive for NTRK gene fusion)
            • Trametinib or binimetinib (for low-grade serous carcinoma)
            • Dabrafenib-trametinib (for BRAF V600E–positive tumors)
            • Selpercatinib (for RET gene fusion–positive tumors)
            • Pazopanib
          • Immunotherapy
            • Pembrolizumab (for tumors with microsatellite instability high or DNA mismatch repair mutations or tumor mutational burden with 10 mutations/megabase or more)
            • Dostarlimab (for tumors with microsatellite instability or DNA mismatch repair mutations)
          • Hormone therapy
            • Aromatase inhibitors, leuprolide acetate, megestrol, fulvestrant (for low-grade serous carcinoma), and tamoxifen

    Rationale r2

    • Surgery is indicated to completely resect the primary tumor and debulk any extraovarian disease
    • Adjuvant chemotherapy is strongly recommended because the risk of metastasis and recurrence is high, even after optimum tumor debulking through surgery
    • Maintenance (postremission) treatment with PARP inhibitors reduces the risk of disease progression r43

    Outcomes

    • Patients with stage IA or IB disease (grade 1 or 2 tumor) have more than 90% survival with surgical treatment alone r2
      • Postoperative chemotherapy may prolong survival in patients with these early-stage tumors; however, the magnitude of benefit has not been established in patients with lower-risk or optimally staged disease r69
      • Current guidelines recommend observation after comprehensive surgical staging for these patients r2
    • Most other patients are treated with postoperative chemotherapy, which significantly improves recurrence-free survival and overall survival r52
    • Addition of bevacizumab to conventional postoperative cytotoxic therapy has been shown to further improve progression-free survival, but the effect on overall survival is unclear r53
    • Postremission maintenance treatment with PARP inhibitors improves progression-free survival in patients with stages III to IV, with partial or complete response to first line platinum-containing regimens after surgery r2r64r70
      • There are limited data on the use of maintenance PARP inhibitor therapy in patients with stage II disease r2r65
    • Combining IV and intraperitoneal chemotherapy may achieve greater improvements in recurrence-free survival and overall survival, but risks of serious toxicity are more than with IV chemotherapy alone r71
      • Intraperitoneal chemotherapy is not recommended as a first line treatment r53

    Drug therapy

    • Drug Therapy: Ovarian cancerFRα, folate receptor alpha; GnRH, gonadotropin-releasing hormone; G6PD, glucose-6-phosphatedehydrogenase; HUS, hemolytic uremic syndrome; ILD, interstitial lung disease; IP, intraperitoneal; PARP, poly-(ADP-ribose) polymerase; PD-1, programmed death receptor-1; PRES, posterior reversible encephalopathy syndrome; RPED, retinal pigment epithelial detachment; RVO, retinal vein occlusion; TMA, thrombotic microangiopathy; VEGF, vascular endothelial growth factor; VTE, venous thromboembolic events.Data from Cyclophosphamide for Injection. Package insert. Ingenus Pharmaceuticals LLC; September 2021. Carboplatin. Package insert. Bedford Laboratories; October 2009; Platinol (Cisplatin) for Injection. Package insert. WG Critical Care LLC; March 2022; Eloxatin (Oxaliplatin). Package insert. Sanofi-Aventis US LLC; April 2020; Xeloda (Capecitabine). Package insert. Genentech Inc; May 2021; Adrucil (Fluorouracil). Package insert. Teva Parenteral Medicines Inc; July 2007; Gemcitabine (Gemzar). Package insert. Eli Lilly and Company; May 2019; Arimidex (Anastrozole). Package insert. ANI Pharmaceuticals Inc; December 2022; Aromasin (Exemestane). Package insert. Amneal Pharmaceuticals LLC; November 2022; Femara (Letrozole). Package insert. Novartis Pharmaceuticals Corporation; May 2022; Soltamox (Tamoxifen Citrate). Package insert. Mayne Pharma; November 2021; Fulvestrant. Package insert. Fresenius Kabi USA LLC; November 2021. Elahere (Mirvetuximab Soravtansine). Package insert. ImmunoGen Inc; November 2022; Eligard (Leuprolide Acetate). Package insert. Tolmar Inc; February 2019; Mektovi (Binimetinib). Package insert. Array Biopharma Inc; January 2019; Tafinlar (Dabrafenib). Package insert. GlaxoSmithKline; November 2015. Rozlytrek (Entrectinib). Package insert. Genetech Inc; July 2022; Virakvi (Larotrectinib) Capsules and Oral Solution. Package insert. Loxo Oncology Inc; March 2021. Votrient (Pazopanib). Package insert. Novartis Pharmaceuticals Corporation; August 2022; Retevmo (Selpercatinib). Package insert. Eli Lilly and Company; September 2022; Mekinist (Trametinib). Package insert. Novartis Pharmaceuticals Corporation; June 2022; Taxotere (Docetaxel). Package insert. Sanofi-Aventis US LLC; May 2020; Paclitaxel. Package insert. Alembic Pharmaceuticals Inc; October 2022; Zejula (Niraparib). Package insert. GlaxoSmithKline Inc; June 2021; Lynparza (Olaparib). Package insert. AstraZeneca Pharmaceuticals LP; August 2022; Rubraca (Rucaparib). Package insert. Clovis Oncology Inc; June 2022; Jemperli (Dostarlimab-gxly). Package insert. Glaxo Smith Kline LLC; August 2021; Keytruda (Pembrolizumab). Package insert. Merck Sharp and Dohme Corp; May 2022; Megestrol Acetate. Package insert. Par Pharmaceutical Inc; May 2022; Hycamtin (Topotecan Hydrochloride) for Injection. Package insert. GlaxoSmithKline; September 2018; Doxil (Doxorubicin Hydrochloride Liposomal). Package insert. Baxter Healthcare Corporation; May 2022; Etoposide Injection. Package insert. Fresenius Kabi USA LLC; February 2016; and Avastin (Bevacizumab). Package insert. Genentech Inc; September 2022.
      MedicationCommon regimensLife-threatening or dose-limiting adverse reactionsNotable or nonemergent adverse reactionsSpecial considerations
      Alkylating agent: nitrogen mustard
      Cyclophosphamide• Cyclophosphamide (oral) + bevacizumab• Bone
      marrow suppression
      • Cardiotoxicity
      • Hyponatremia
      • Impaired wound healing
      • Nephrotoxicity
      • Pulmonary toxicity
      • Secondary malignancy
      • Urotoxicity
      • Veno-occlusive liver disease      		•
      Alopecia
      • Diarrhea
      • Febrile neutropenia
      • Fever
      • Nausea
      • Vomiting
      		•
      Effective contraception required during and for up to 1 year after therapy
      for females of reproductive potential
      Alkylating agent: platinum
      Carboplatin• Carboplatin + gemcitabine ± bevacizumab
      • Carboplatin + liposomal doxorubicin ± bevacizumab
      • Docetaxel + carboplatin
      • Docetaxel + carboplatin + bevacizumab + maintenance bevacizumab
      • Paclitaxel + carboplatin
      • Paclitaxel + carboplatin + bevacizumab + maintenance bevacizumab      		•
      Anaphylaxis
      • Bone marrow suppression
      • Nausea
      • Vomiting
      • Nephrotoxicity
      		•
      Electrolyte loss
      • Ototoxicity
      • Peripheral neuropathy
      • Secondary malignancy      		•
      Avoid coadministering nephrotoxic or ototoxic agents
      • Ensure adequate hydration
      Cisplatin•
      Cisplatin + gemcitabine
      • Paclitaxel IV + cisplatin IP + paclitaxel IP      		•
      Anaphylaxis
      • Bone marrow suppression
      • Nausea
      • Vomiting
      • Nephrotoxicity
      • Ocular toxicity
      		•
      Electrolyte loss
      • Ototoxicity
      • Peripheral neuropathy
      • Secondary malignancy      		•
      Avoid coadministering nephrotoxic or ototoxic agents
      • Ensure adequate hydration
      • Cisplatin has been associated with optic neuritis, papilledema, vision
      loss
      • Effective contraception required during and after therapy for 14 months
      for females of reproductive potential
      Oxaliplatin•
      Capecitabine + oxaliplatin ± bevacizumab
      • Fluorouracil + leucovorin + oxaliplatin ± bevacizumab      		•
      Anaphylaxis
      • Bleeding
      • Bone marrow suppression
      • Nausea
      • Vomiting
      • PRES
      • Pulmonary fibrosis
      • QT prolongation and ventricular arrhythmias
      • Rhabdomyolysis      		•
      Diarrhea
      • Fatigue
      • Increased hepatic enzymes
      • Peripheral sensory neuropathy
      • Stomatitis      		•
      Effective contraception required during and after therapy for 9 months for
      females of reproductive potential
      Capecitabine•
      Capecitabine + oxaliplatin ± bevacizumab      		• Bone
      marrow suppression
      • Cardiotoxicity
      • Dehydration
      • Dermatologic toxicity
      • Hyperbilirubinemia
      • Renal failure      		•
      Abdominal pain
      • Diarrhea
      • Fatigue/weakness
      • Nausea
      • Vomiting       		•
      Increased risk of serious or fatal adverse reactions in patients with low or
      absent dihydropyrimidine dehydrogenase activity
      • Effective contraception required during and after therapy for 6 months
      for females of reproductive potential
      Antimetabolite: nucleoside metabolic inhibitor
      Fluorouracil•
      Fluorouracil + leucovorin + oxaliplatin ± bevacizumab      		• Bone
      marrow suppression
      • Cardiotoxicity
      • Diarrhea
      • Hyperammonemic encephalopathy
      • Mucositis
      • Neurotoxicity
      • Palmar-plantar erythrodysesthesia (hand-foot syndrome)      		•
      Increased risk of serious or fatal adverse reactions in patients with low or
      absent dihydropyrimidine dehydrogenase activity
      • Effective contraception required during and after therapy for 3 months
      for females of reproductive potential
      Gemcitabine•
      Carboplatin + gemcitabine ± bevacizumab
      • Cisplatin + gemcitabine
      • Gemcitabine monotherapy      		• Bone
      marrow suppression
      • Capillary leak syndrome
      • HUS
      • Hepatotoxicity
      • PRES
      • Pulmonary toxicity      		•
      Dyspnea
      • Edema
      • Fever
      • Hematuria
      • Increased hepatic enzymes
      • Nausea
      • Vomiting
      • Proteinuria
      • Radiation sensitization
      • Rash
      		•
      Effective contraception required during and after therapy for at least 6
      months for females of reproductive potential
      Aromatase inhibitor
      Anastrozole•
      Anastrozole monotherapy      		• Bone
      loss/fractures
      • Ischemic cardiovascular events      		•
      Arthralgia
      • Arthritis
      • Asthenia
      • Back pain
      • Bone pain
      • Cough
      • Depression
      • Dyspnea
      • Headache
      • Hot flashes
      • Hypercholesterolemia
      • Hypertension
      • Insomnia
      • Lymphedema
      • Nausea
      • Vomiting
      • Pain
      • Peripheral edema
      • Pharyngitis
      • Rash
      		•
      Effective contraception required during and after therapy for at least 3
      weeks for females of reproductive potential
      Exemestane•
      Exemestane monotherapy      		• Bone
      loss/fractures
      • Ischemic cardiovascular events      		•
      Arthralgia
      • Fatigue
      • Headache
      • Hot flashes
      • Increased appetite
      • Insomnia
      • Nausea
      • Sweating      		• Drug
      interactions: may need to avoid or adjust dosage of certain drugs
      • Effective contraception required during and after therapy for 1 month for
      females of reproductive potential
      Letrozole•
      Letrozole monotherapy      		• Bone
      loss/fractures      		•
      Arthralgia
      • Asthenia
      • Bone pain
      • Dizziness
      • Edema
      • Flushing
      • Headache
      • Hot flashes
      • Hypercholesterolemia
      • Musculoskeletal pain
      • Sweating      		•
      Effective contraception required during and after therapy for at least 3
      weeks for females of reproductive potential
      Estrogen agonist/antagonist
      Tamoxifen•
      Tamoxifen monotherapy      		• Bone
      marrow suppression
      • Hepatotoxicity
      • Hypercalcemia
      • Ocular toxicity
      • Stroke
      • Uterine malignancy
      • VTE      		•
      Edema
      • Hot flashes
      • Mood disturbances
      • Nausea
      • Vaginal discharge
      • Vaginal bleeding      		•
      Effective nonhormonal contraception required during and after therapy for 2
      months for females of reproductive potential
      Estrogen receptor antagonist
      Fulvestrant•
      Fulvestrant monotherapy      		•
      Generally not applicable      		•
      Anorexia
      • Arthralgia
      • Asthenia
      • Back pain
      • Bone pain
      • Constipation
      • Cough
      • Dyspnea
      • Extremity pain
      • Fatigue
      • Headache
      • Hot flashes
      • Increased hepatic enzymes
      • Injection site reactions
      • Musculoskeletal pain
      • Nausea
      • Vomiting
      		•
      Fulvestrant can interfere with estradiol measurement by immunoassay,
      resulting in falsely elevated estradiol levels, due to structural
      similarity
      • Effective contraception required during and after therapy for 1 year for
      females of reproductive potential
      FRα-directed antibody and microtubule inhibitor conjugate
      Mirvetuximab soravtansine•
      Mirvetuximab soravtansine monotherapy
      • Mirvetuximab soravtansine + bevacizumab      		•
      Infusion-related
      reactions
      • Ocular toxicities
      • Peripheral neuropathy
      • Pneumonitis      		•
      Abdominal pain
      • Anemia
      • Constipation
      • Diarrhea
      • Fatigue
      • Hypoalbuminemia
      • Hypomagnesemia
      • Increased hepatic enzymes
      • Leukopenia
      • Lymphopenia
      • Nausea
      • Neutropenia      		•
      Effective contraception required during and after therapy for 7 months for
      females of reproductive potential
      GnRH agonist
      Leuprolide•
      Leuprolide monotherapy      		•
      Cerebrovascular and ischemic cardiovascular events
      • QT prolongation
      • Seizures
      • Spinal cord compression
      • Urinary tract obstruction      		•
      Fatigue
      • Hot flashes
      • Hyperglycemia
      • Malaise
      • Sweating
      Kinase inhibitor
      Binimetinib•
      Binimetinib monotherapy      		•
      Bleeding
      • Cardiomyopathy
      • Dermatologic toxicity
      • Hepatotoxicity
      • ILD
      • RVO
      • Rhabdomyolysis
      • Serous retinopathy
      • Uveitis
      • VTE      		•
      Abdominal pain
      • Diarrhea
      • Fatigue
      • Nausea
      • Vomiting
      		•
      Effective contraception required during and after therapy for at least 30
      days for females of reproductive potential
      Dabrafenib•
      Dabrafenib + trametinib      		•
      Bleeding
      • Cardiomyopathy
      • Dermatologic toxicity
      • Fever
      • New primary malignancy
      • Uveitis      		•
      Alopecia
      • Arthralgia
      • Headache
      • Hyperglycemia
      • Hyperkeratosis
      • Papilloma      		•
      Potential risk of hemolytic anemia in patients with G6PD deficiency
      • Effective nonhormonal contraception required during and after therapy
      for at least 2 weeks for females of reproductive potential
      Entrectinib•
      Entrectinib monotherapy      		• Bone
      marrow suppression
      • Heart failure
      • Hepatotoxicity
      • Hyperuricemia
      • Neurotoxicity
      • QT prolongation
      • Skeletal fractures
      • Vision disorders       		•
      Arthralgia
      • Cognitive impairment
      • Constipation
      • Cough
      • Diarrhea
      • Dizziness
      • Dysesthesia
      • Dysgeusia
      • Dyspnea
      • Edema
      • Fatigue
      • Fever
      • Increased hepatic enzymes
      • Myalgia
      • Nausea
      • Vomiting
      • Weight gain
      		•
      Effective contraception required during and after therapy for at least 5
      weeks for females of reproductive potential
      • Drug interactions: may need to avoid or adjust dosage of certain drugs
      Larotrectinib•
      Larotrectinib monotherapy      		•
      Hepatotoxicity
      • Neurotoxicity      		•
      Constipation
      • Cough
      • Diarrhea
      • Dizziness
      • Fatigue
      • Increased hepatic enzymes
      • Nausea
      • Vomiting
      		•
      Effective contraception required during and after therapy for at least 1 week
      for females of reproductive potential
      • Drug interactions: may need to avoid or adjust dosage of certain drugs
      Pazopanib•
      Pazopanib monotherapy      		•
      Bleeding
      • Cardiotoxicity
      • Gastrointestinal perforation or fistula
      • Hepatotoxicity
      • Hypertension
      • Hypothyroidism
      • Impaired wound healing
      • Infection
      • ILD/pneumonitis
      • PRES
      • Proteinuria
      • QT prolongation
      • Thromboembolic events
      • TMA
      • Tumor lysis syndrome      		•
      Anorexia
      • Diarrhea
      • Dysgeusia
      • Dyspnea
      • Fatigue
      • Hair depigmentation
      • Headache
      • Hypertension
      • Musculoskeletal pain
      • Nausea
      • Vomiting
      • Skin hypopigmentation
      • Tumor pain
      • Weight loss
      		• Drug
      interactions: may need to avoid or adjust dosage of certain drugs
      • Withhold therapy for at least 1 week before elective surgery and at
      least 2 weeks after major surgery and until adequate wound healing
      • Effective contraception required during and after therapy for at least 2
      weeks for females of reproductive potential
      Selpercatinib•
      Selpercatinib monotherapy      		•
      Bleeding
      • Hepatotoxicity
      • Hypersensitivity reactions
      • Hypertension
      • Hypothyroidism
      • Impaired wound healing
      • ILD/pneumonitis
      • QT prolongation
      • Tumor lysis syndrome      		•
      Abdominal pain
      • Constipation
      • Diarrhea
      • Dry mouth
      • Edema
      • Fatigue
      • Headache
      • Hypertension
      • Hypocalcemia
      • Hyponatremia
      • Increased hepatic enzymes
      • Lymphopenia
      • Nausea
      • Rash      		• Drug
      interactions: may need to avoid or adjust dosage of certain drugs
      • Withhold therapy for at least 1 week before elective surgery and at
      least 2 weeks after major surgery and until adequate wound healing
      • Effective contraception required during and after therapy for 1 week for
      females of reproductive potential
      Trametinib•
      Dabrafenib + trametinib
      • Trametinib monotherapy      		•
      Bleeding
      • Cardiomyopathy
      • Colitis and gastrointestinal perforation
      • Dermatologic toxicity
      • Fever
      • ILD/pneumonitis
      • New primary malignancy
      • RPED
      • RVO
      • VTE      		•
      Diarrhea
      • Hyperglycemia
      • Lymphedema
      • Rash      		•
      Effective contraception required during and after therapy for 4 months for
      females of reproductive potential
      Microtubule inhibitor
      Docetaxel•
      Docetaxel monotherapy
      • Docetaxel + carboplatin
      • Docetaxel + carboplatin + bevacizumab + maintenance bevacizumab      		•
      Asthenia
      • Bone marrow suppression
      • Cystoid macular edema
      • Dermatologic toxicity
      • Diarrhea
      • Edema
      • Enterocolitis and neutropenic colitis
      • Febrile neutropenia
      • Hepatotoxicity
      • Hypersensitivity reactions
      • Infections
      • Neurotoxicity
      • Stomatitis/mucositis
      • Toxic deaths      		•
      Alopecia
      • Anorexia
      • Constipation
      • Dysgeusia
      • Dyspnea
      • Myalgia
      • Nail disorders
      • Nausea
      • Vomiting
      • Pain
      • Secondary malignancy
      		• Drug
      interactions: may need to avoid or adjust dosage of certain drugs
      • Some docetaxel injection formulations contain alcohol and may affect the
      central nervous system and ability to drive or operate machinery
      • Effective contraception required during and after therapy for 6 months
      for females of reproductive potential
      Paclitaxel•
      Paclitaxel + carboplatin
      • Paclitaxel + carboplatin + bevacizumab + maintenance bevacizumab
      • Paclitaxel IV + cisplatin IP + paclitaxel IP      		•
      Anaphylaxis
      • Bone marrow suppression
      • Cardiotoxicity
      • Neurotoxicity      		•
      Alopecia
      • Arthralgia
      • Diarrhea
      • Increased hepatic enzymes
      • Injection site reactions
      • Mucositis
      • Myalgia
      • Nausea
      • Vomiting
      		• Some
      paclitaxel formulations contain alcohol and may affect the central nervous
      system and ability to drive or operate machinery
      PARP inhibitor
      Niraparib•Niraparib monotherapy• Bone
      marrow suppression
      • Hypertension
      • Myelodysplastic syndrome/acute myeloid leukemia
      • PRES      		•
      Abdominal pain
      • Anorexia
      • Constipation
      • Cough
      • Diarrhea
      • Dizziness
      • Dyspnea
      • Fatigue
      • Headache
      • Hypomagnesemia
      • Insomnia
      • Musculoskeletal pain
      • Nausea
      • Vomiting
      • Nephrotoxicity
      • Rash
      • Urinary tract infection
      		•
      Effective contraception required during and after therapy for 6 months for
      females of reproductive potential
      Olaparib•
      Olaparib monotherapy      		• Bone
      marrow suppression
      • Myelodysplastic syndrome/acute myeloid leukemia
      • Pneumonitis
      • VTE      		•
      Anorexia
      • Asthenia/fatigue
      • Cough
      • Diarrhea
      • Dizziness
      • Dysgeusia
      • Dyspepsia
      • Dyspnea
      • Headache
      • Nausea
      • Vomiting
      		• Drug
      interactions: may need to avoid or adjust dosage of certain drugs
      • Effective contraception required during and after therapy for 6 months
      for females of reproductive potential
      Rucaparib•
      Rucaparib monotherapy      		• Bone
      marrow suppression
      • Myelodysplastic syndrome/acute myeloid leukemia      		•
      Asthenia/fatigue
      • Abdominal pain/distention
      • Anorexia
      • Constipation
      • Diarrhea
      • Dysgeusia
      • Dyspnea
      • Increased hepatic enzymes
      • Nasopharyngitis/upper respiratory tract infection
      • Nausea
      • Vomiting
      • Rash
      • Stomatitis      		•
      Effective contraception required during and after therapy for 6 months for
      females of reproductive potential
      PD-1 blocking antibody
      Dostarlimab•
      Dostarlimab monotherapy      		•
      Adrenal insufficiency
      • Colitis
      • Diabetic ketoacidosis
      • Exfoliative dermatitis
      • Hepatitis
      • Hyperthyroidism
      • Hypophysitis
      • Hypothyroidism
      • Infusion-related reactions
      • Myocarditis
      • Nephritis
      • Pneumonitis
      • Thyroiditis      		•
      Anemia
      • Asthenia
      • Diarrhea
      • Fatigue
      • Nausea      		•
      Effective contraception required during and after therapy for 4 months for
      females of reproductive potential
      Pembrolizumab•
      Pembrolizumab monotherapy      		•
      Adrenal insufficiency
      • Anaphylaxis
      • Colitis
      • Diabetic ketoacidosis
      • Exfoliative dermatitis
      • Hepatitis
      • Hyperthyroidism
      • Hypophysitis
      • Hypothyroidism
      • Myocarditis
      • Nephritis
      • Pneumonitis
      • Thyroiditis      		•
      Abdominal pain
      • Anorexia
      • Constipation
      • Cough
      • Diarrhea
      • Dyspnea
      • Fatigue
      • Fever
      • Myalgia
      • Nausea
      • Pruritus
      • Rash      		•
      Effective contraception required during and after therapy for at least 4
      months for females of reproductive potential
      Synthetic progestin
      Megestrol•
      Megestrol monotherapy      		•
      Adrenal insufficiency
      • Cushing syndrome
      • Diabetes mellitus onset/exacerbation
      • Heart failure
      • VTE      		•
      Alopecia
      • Asthenia
      • Carpal tunnel syndrome
      • Dyspnea
      • Edema
      • Hot flashes
      • Hypertension
      • Lethargy
      • Malaise
      • Metrorrhagia
      • Mood changes
      • Nausea
      • Vomiting
      • Rash
      • Sweating
      • Tumor flare
      • Weight gain
      Topoisomerase I inhibitor
      Topotecan•
      Topotecan monotherapy
      • Topotecan + bevacizumab      		• Bone
      marrow suppression
      • Febrile neutropenia
      • ILD      		•
      Asthenia
      • Abdominal pain
      • Diarrhea
      • Dyspnea
      • Fatigue
      • Nausea
      • Vomiting
      • Pain
      • Pneumonia
      		•
      Effective contraception required during and after therapy for 6 months for
      females of reproductive potential
      Topoisomerase II inhibitor: anthracycline
      Liposomal doxorubicin•
      Carboplatin + liposomal doxorubicin ±
      bevacizumab
      • Liposomal doxorubicin monotherapy      		• Bone
      marrow suppression
      • Cardiomyopathy
      • Infusion-related reactions
      • Palmar-plantar erythrodysesthesia (hand-foot syndrome)
      • Secondary oral neoplasms
      • Stomatitis      		•
      Anorexia
      • Asthenia
      • Constipation
      • Diarrhea
      • Fatigue
      • Fever
      • Nausea
      • Vomiting
      • Rash
      		• Can
      cause reddish-orange discoloration of urine and other bodily fluids after
      administration
      • Effective contraception required during and after therapy for 6 months
      for females of reproductive potential
      Topoisomerase II inhibitor: epipodophyllotoxin
      Etoposide•
      Etoposide (oral) monotherapy      		• Anaphylaxis
      • Bone marrow suppression      		• Alopecia
      • Nausea
      • Vomiting
      • Secondary malignancy

      		• Effective contraception required during and after therapy for at least 6 months for females of reproductive potential
      VEGF inhibitor
      Bevacizumab•
      Bevacizumab monotherapy
      • Capecitabine + oxaliplatin ± bevacizumab
      • Carboplatin + gemcitabine ± bevacizumab
      • Carboplatin + liposomal
      doxorubicin ± bevacizumab
      • Cyclophosphamide (oral) + bevacizumab
      • Docetaxel + carboplatin + bevacizumab + maintenance bevacizumab
      • Fluorouracil + leucovorin + oxaliplatin ± bevacizumab
      • Liposomal doxorubicin + bevacizumab
      • Paclitaxel + carboplatin + bevacizumab + maintenance bevacizumab
      • Mirvetuximab soravtansine + bevacizumab
      • Niraparib + bevacizumab
      • Paclitaxel + bevacizumab      		•
      Bleeding
      • Gastrointestinal perforation or fistula
      • Heart failure
      • Hypertension
      • Impaired wound healing
      • Infusion-related reactions
      • Nephrotoxicity and proteinuria
      • Ovarian failure
      • PRES
      • Thromboembolic events      		•
      Abdominal pain
      • Anorexia
      • Constipation
      • Cough
      • Diarrhea
      • Dizziness
      • Dyspnea
      • Fatigue
      • Headache
      • Hypomagnesemia
      • Insomnia
      • Musculoskeletal pain
      • Nausea
      • Vomiting
      • Nephrotoxicity
      • Rash
      • Urinary tract infection
      		•
      Withhold therapy for at least 28 days before elective surgery and for 28
      days after major surgery and until adequate wound healing
      • Effective contraception required during and after therapy for 6 months
      for females of reproductive potential

    Nondrug and supportive care

    Tailor supportive care measures to meet each patient's needs according to age, performance status, disease status, and specific chemotherapeutic agents used; treatment may include: r2

    • Antiemetic support c75
    • IV fluids c76
    • Nutritional support (enteral or parenteral) c77c78c79
    • Bowel regimen to prevent constipation c80
    • Pain management c81
    • Prophylaxis against opportunistic infections c82
    • Management of toxicity or adverse effects associated with specific agents c83c84
    • Management of menopausal symptoms c85d3

    Palliative measures may include: r2

    • Paracentesis c86
    • Ureteral stent c87
    • Gastrostomy tube c88
    • Thoracentesis or pleurodesis c89c90
    Procedures
    Total abdominal hysterectomy with bilateral salpingo-oophorectomy r2c91
    General explanation
    • Surgical removal of uterus, cervix, both fallopian tubes, and both ovaries via an abdominal incision
    • Comprehensive surgical staging and debulking are done concurrently, including at a minimum r2
      • Evaluation of entire abdominopelvic cavity to determine extent of disease
      • Systematic pelvic and para-aortic lymphadenectomy
      • Infracolic omentectomy
      • Peritoneal washing
      • Biopsies of any suspicious areas, including abdominal and pelvic peritoneum
    Indication
    • Suspected ovarian cancer
    Contraindications
    • Untreated coagulopathy
    • Pregnancy
    Complications
    • Premature menopause
    • Ureteral injury
    • Urinary incontinence

    Special populations

    • Patients older than 70 years
      • Older patients may not tolerate combination chemotherapy regimens, as recommended by the National Comprehensive Cancer Network
      • Alternative regimens may be appropriate for older patients with stages I to IV epithelial ovarian cancer, specifically paclitaxel-carboplatin but at reduced doses or modified schedule r2
    • Recurrent disease
      • Inform patients of the availability of clinical trials and discuss risks and benefits of various treatments

    Monitoring

    • Follow-up with clinical assessment every 2 to 4 months for 2 years, then every 3 to 6 months for 3 years, then annually thereafter r2
      • Retake history and perform physical examination (including breast, pelvic, and rectal examination) at each visit to assess for clinical signs of recurrence c92c93c94c95
      • Measure serum levels of CA 125 or other tumor markers if levels were elevated preoperatively c96
      • Obtain laboratory test results and imaging (eg, chest radiograph, CT or MRI scan of chest, abdomen, and pelvis, fludeoxyglucose F 18 PET-CT) as clinically indicated r27c97c98c99c100c101c102c103

    Complications and Prognosis

    Complications

    • Local invasion
      • Metastasis to peritoneal cavity is common among patients with advanced disease c104
      • May result in intestinal or ureteric obstruction or ascites c105c106c107
    • Distant metastasis c108
    • Premature menopause secondary to oophorectomy c109d3
    • Complications associated with chemotherapy, including: c110
      • Myelosuppression c111
      • Peripheral neuropathy c112
      • Hepatic or renal dysfunction c113c114
      • Metabolic derangements c115
      • Infusion reactions c116
      • Opportunistic infections c117
    • Disease recurrence c118
      • Commonly recurs in extrapelvic locations, usually in association with intraperitoneal recurrence
      • Associated with poor prognosis

    Prognosis

    • Prognosis is influenced by disease stage, depth of neoplastic invasion, extent of residual disease after surgery, and possibly tumor grade r2
      • Volume of residual disease after debulking surgery has the greatest influence on progression-free survival and overall survival r61r72
      • 5-Year survival rates r3
        • 91.9% for localized ovarian cancer (approximately 19% of cases)
        • 71.5% for cancer that has spread to regional lymph nodes only
        • 31.4% for cancer with distant metastasis (this represents most cases)
      • The following factors are associated with a favorable prognosis: r52
        • Younger age
        • Good performance status
        • Early-stage disease
        • Well-differentiated tumor
        • Cell type other than mucinous or clear cell
        • Lower volume of disease before surgical debulking
        • Smaller residual tumor after primary cytoreductive surgery r63
        • Absence of ascites
        • BRCA1 or BRCA2 mutation carrier

    Screening and Prevention

    Screening

    At-risk populations

    • Females who are carriers of BRCA1 and BRCA2 gene mutations are at high risk of developing cancer of the ovaries and fallopian tubes and other malignancies r1

    Screening tests

    • Routine screening is not recommended for asymptomatic females with an average risk of developing ovarian cancer r6r7r51
      • Recommendation applies to all methods: bimanual palpation of ovaries, imaging, and biomarker levels
      • Available evidence suggests that screening for ovarian cancer in asymptomatic females not known to be at high risk for ovarian cancer does not reduce ovarian cancer mortality r73
    • Offer genetic testing for ovarian cancer susceptibility genes in the following: r1c119
      • Patients with a first- or second-degree relative diagnosed with epithelial ovarian cancer at any age r34
      • Patients who have probability of BRCA1 or BRCA2 pathogenic variant of greater than 5% based on probability models
    • Some experts recommend monitoring females at high risk of developing ovarian cancer with serum CA 125 level and transvaginal ultrasonography starting at age 30 to 35 years; however, this screening strategy is of uncertain benefit r1r74c120c121c122c123

    Prevention

    • Surgical risk reduction
      • Risk-reducing salpingo-oophorectomy
        • Offer patients with BRCA1 and BRCA2 pathogenic or likely pathogenic variants risk-reducing salpingo-oophorectomy after completion of childbearing r1c124c125
          • Usually recommended between ages 35 and 40 years for patients with BRCA1 mutations and between 40 and 45 years for patients with BRCA2 mutations
          • Onset of ovarian cancer is usually later in patients with BRCA2 variants than with BRCA1; however, take into consideration age at diagnosis in family members
        • Also consider risk-reducing salpingo-oophorectomy between ages 45 and 50 years in patients with BRIP1, RAD51C, RAD51D, and PALB2 mutations
      • Salpingectomy r1
        • Option for premenopausal patients with hereditary cancer risk who are not yet ready for oophorectomy
        • Opportunistic salpingectomy during benign gynecologic and obstetric surgery can be offered to females at risk for ovarian cancer and who have completed childbearing r75r76
        • Reduces the risk of ovarian cancer in the general population; however, one analysis suggested that salpingectomy reduces risk for ovarian cancer when performed before 50 years, but not when done at 50 years or older r9
        • Consider continuation of combination oral contraceptive pills or levonorgestrel intrauterine device for continued ovarian cancer risk reduction until completion oophorectomy is performed
    • Nonsurgical risk reduction r1
      • Consider combination estrogen and progestin oral contraceptive pills for ovulation suppression
        • Significant risk reduction benefits in patients with BRCA1 and BRCA2 pathogenic or likely pathogenic variants
      • Levonorgestrel intrauterine device is an alternative; has been shown to reduce the risk for ovarian cancer in the average risk population
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