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Ovarian Cancer

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Jan.31.2023

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 women but can affect younger women, particularly those with BRCA1/BRCA2 mutations or Lynch syndrome r3
  • Diagnosis may be suspected on the basis of 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
  • Women 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 strategies for ovarian cancer in asymptomatic women 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 women. 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
      • Consists of:
        • Endometriosis-related subtypes (ie, endometrioid, clear cell, seromucinous)
        • Low-grade serous
        • Mucinous and transitional cell (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/peritoneal washings
        • T1b: tumor limited to both ovaries; capsule intact; no tumor on ovarian surface; no malignant cells in ascites/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/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/peritoneal washings
        • T2b: extension to other pelvic structures; no malignant cells in ascites/peritoneal washings
        • T2c: extension to uterus, fallopian tubes, or other pelvic structures; malignant cells in ascites/peritoneal washings
      • T3: tumor involves 1 or both ovaries with peritoneal metastasis outside of pelvis
        • T3a: microscopic peritoneal metastasis outside pelvis (no macroscopic tumor)
        • T3b: macroscopic peritoneal metastasis outside pelvis (2 cm or less in greatest dimension)
        • T3c: macroscopic peritoneal metastasis outside pelvis (more than 2 cm in 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/peritoneal washings
      • Stage IB: an encapsulated tumor is located in both ovaries; no tumor on ovarian surface and no malignant cells in ascites/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/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 pelvis and/or metastasis to retroperitoneal lymph nodes
      • Stage IIIA: positive retroperitoneal lymph nodes only (IIIA1), metastasis up to 10 mm in greatest dimension (IIIAi), metastasis greater than 10 mm in 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 in greatest dimension, with or without positive retroperitoneal lymph nodes
      • Stage IIIC: macroscopic extrapelvic peritoneal metastasis greater than 2 cm in 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 impact on the development of some tumors than others r13r14

Risk factors and/or associations

Age
  • Occurs mostly in postmenopausal women, with peak incidence between ages 55 and 64 years, although it can occur in younger women, 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 a woman 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 women than in Black, Asian, or Hispanic women r22r23c37c38c39c40
Other risk factors/associations r12r13
  • 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
    • Hormone replacement therapy c45
      • Transcutaneous hormone therapy may be associated with a lower risk of ovarian cancer than oral hormone therapy r9
    • Unsuccessful infertility treatment (ovarian hyperstimulation) c46c47
    • Intrauterine contraceptive use r12c48
    • Cigarette smoking r12c49
  • The following factors may be protective: r9
    • Multiparity
    • Oral contraceptive use
    • Past breastfeeding
    • Tubal ligation and hysterectomy

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 of abdomen and pelvis with oral and IV contrast and rectal contrast if needed; fluorodeoxyglucose PET-CT from skull base to midthigh is an alternative r2r27
    • Baseline CBC, hepatic function panel, and biochemistry panel
    • Serum levels of CA 125 (MUC16; cancer antigen 125) r28
      • HE4 (WFDC2; human epididymis protein 4) has been proposed as an additional biomarker; however, this is not recommended routinely in clinical practice r29
    • Screening for other tumor markers (eg, carcinoembryonic antigen, inhibin, lactate dehydrogenase, alpha fetoprotein, CA 19-9) if clinically indicated to assess for uncommon histologic subtypes (germ cell or sex cord–stromal tumors)
    • β-hCG level to exclude pregnancy in women of childbearing age c51
    • Chest radiograph or chest CT, if metastatic spread is suspected
    • Nutritional evaluation
  • 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 r30
  • 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 r31r32

Laboratory

  • Serum CA 125 level (MUC16; cancer antigen 125) c53
    • Sensitive marker of ovarian cancer but has poor specificity
      • Over 80% of ovarian malignancies express elevated levels of CA 125 r33
      • Elevated levels are more often detected in advanced or recurrent disease
    • The following are considered positive results:
      • Level above 50 units/mL in premenopausal women r34
      • Level above 40 units/mL in premenopausal women using oral contraceptives r34
      • Level above 30 units/mL in postmenopausal women r34
    • Can also be used to assess prognosis and monitor response to treatment
  • Serum HE4 level (WFDC2; human epididymis protein 4) 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
    • Not routinely used in clinical practice r29

Imaging

  • Ultrasonography c55
    • Transvaginal ultrasonography with color Doppler is the preferred modality; some centers perform additional transabdominal scan r4
    • 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: r35
      • Irregularly shaped solid tumor
      • Tumor with multiple (more than 4) papillary structures
      • Irregularly shaped solid, multiloculated tumor more than 10 cm in largest dimension
      • Tumor that demonstrates very strong flow on color Doppler
      • Ascites
  • MRI of abdomen/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
    • Findings suggestive of malignancy include presence of vascular vegetations in cystic masses and ascites r4
  • CT of abdomen/pelvis c57
    • Usually not useful for diagnosis but may be used to detect local metastases and assess tumor resectability after initial ultrasonography r2r4r36
    • CT can be helpful for assessing disease in lymph nodes and upper abdomen
  • Fluorodeoxyglucose 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 r2r30
    • Useful in disease staging and surveillance for relapse r37

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 r38
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 r2r39
    • Additional testing includes
      • Homologous recombination repair deficiency testing; identifies a subgroup of patients who may benefit from PARP inhibitor maintenance therapy r40r41r42
      • Mismatch repair testing; indicated for women with clear cell, endometrioid, or mucinous ovarian cancer r31
      • Microsatellite instability testing
      • Neurotrophic tyrosine receptor kinase testing r2

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 r43c63
    • 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 r43c64c65d1
    • Infection of fallopian tube commonly caused by Neisseria gonorrhoeae or Chlamydia trachomatis that results in a spectrum of clinical disease r44
      • 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/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 as a result of sexually transmitted infection
    • Differentiated by history, physical examination, inflammatory markers, diagnostic imaging findings, and microbiological testing
  • Ectopic pregnancy r45c74d2
    • 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 surgeries; 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 gynecologic oncologist for clinically suspicious lesions and for comprehensive staging and surgical treatment
  • Refer to gynecologic or medical oncologist for management of systemic chemotherapy
  • Refer to reproductive endocrinologist for consultation regarding fertility preservation procedures
  • Refer to genetic counselor for breast, ovarian, and colorectal cancer risk evaluation r46

Treatment Options

General overview

  • Stage 1A 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
      • Patients with early stage disease who wish to retain fertility may undergo unilateral salpingo-oophorectomy (stage 1A) or bilateral salpingo-oophorectomy (stage 1B) along with comprehensive surgical staging r2
      • Patients with early stage disease who do not wish to retain fertility, and patients with more advanced (stages II to IV) disease, should undergo total abdominal hysterectomy with bilateral salpingo-oophorectomy with comprehensive surgical staging and cytoreductive surgery
      • 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) followed by interval cytoreductive surgery with total abdominal hysterectomy with bilateral salpingo-oophorectomy r2r29r47r48
        • There is 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 need for bowel resection r49r50
        • 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 utilized r51r52
    • Comprehensive surgical staging and cytoreductive surgery consists 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 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/cytoreduction for invasive or peritoneal disease may be candidates for intraperitoneal chemotherapy (normothermic or hyperthermic) r2r53
        • Studies have shown improved long-term survival with intraperitoneal chemotherapy, but use is limited by higher rate of toxicity and a reduced quality of life as compared with intravenous chemotherapy r53r54r55r56
    • Adjuvant platinum-based chemotherapy is indicated after cytoreductive surgery for most patients, with the exception of those with stage IA and IB disease r2
      • 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 (IP)/IV paclitaxel-cisplatin (for optimally debulked stage II–III disease)
    • Patients with stage III 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 r41r57
        • Use a combination of olaparib and bevacizumab if bevacizumab was added to front line chemotherapy r41
        • Veliparib monotherapy is under investigation as option in patients with homologous recombination deficiency if this was added to front line chemotherapy r58
      • Either rucaparib for 2 years or niraparib for 3 years is recommended in patients with homologous recombination repair deficiency and may also be offered patients without BRCA mutations or homologous recombination repair deficiency r57
      • 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 r41
  • 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 r2r59
      • 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 (olaparib, niraparib, rucaparib) regardless of BRCA1 and BRCA2 status r57r60
          • 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 orBRCA2
          • May also improve overall survival r61
        • Rucaparib monotherapy is recommended for patients with recurrent platinum-sensitive ovarian cancer and a BRCA mutation who are unable to receive platinum-based chemotherapy r60
      • 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 (olaparib, niraparib, and rucaparib) are not recommended in this setting because of concerns regarding long-term outcomes and toxicities r57r62
        • Chemotherapy is the preferred approach for BRCA mutation carriers with platinum-resistant disease relapse
      • Additional systemic therapies for recurrent disease r1
        • Targeted therapies
          • Bevacizumab and mirvetuximab soravtansine with or without bevacizumab (for FRα-expressing tumors)
          • Larotrectinib or entrectinib (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 ≥10 mutations/megabase)
          • Dostarlimab (for tumors with microsatellite instability/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 risk of disease progression r41

Outcomes

  • Patients with stage IA or IB disease (grade 1 or 2 tumors) 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 r63
    • 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 r62
  • Addition of bevacizumab to conventional postoperative cytotoxic therapy has been shown to further improve progression-free survival, but effect on overall survival is unclear r29
  • Postremission maintenance treatment with PARP inhibitors improves the progression-free survival in patients with stage III to IV with partial or complete response to first line platinum-containing regimens after surgery r2r57r64
    • There are limited data on the use of maintenance PARP inhibitor therapy in patients with stage II disease r2r58
  • Combining IV and intraperitoneal chemotherapy may achieve greater improvements in recurrence-free survival and overall survival, but risks of serious toxicity are greater than with IV chemotherapy alone r65
    • Intraperitoneal chemotherapy is not recommended as a first line treatment r29

Drug therapy

  • Drug Therapy: Ovarian CancerCyclophosphamide for injection package insert. Orlando, FL: Ingenus Pharmaceuticals, LLC; 2021 Sept. Carboplatin package insert. Bedford, OH: Bedford Laboratories; 2009 Oct. Platinol (cisplatin) for injection package insert. Paramus, NJ: WG Critical Care, LLC; 2022 March. Eloxatin (oxaliplatin) package insert. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2020 April. Xeloda (capecitabine) package insert. South San Francisco, CA: Genentech, Inc; 2021 May. Adrucil (fluorouracil) package insert. Irvine, CA: Teva Parenteral Medicines, Inc; 2007 July. Gemcitabine (Gemzar) package insert. Indianapolis, IN: Eli Lilly and Company; 2019 May. Arimidex (anastrozole) package insert. Baudette, MN: ANI Pharmaceuticals, Inc.; 2022 Dec. Aromasin (exemestane) package insert. Bridgewater, NJ: Amneal Pharmaceuticals LLC; 2022 Nov. Femara (letrozole) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2022 May. Soltamox (tamoxifen citrate) package insert. Greenville, NC: Mayne Pharma; 2021 Nov. Fulvestrant package insert. Lake Zurich, IL: Fresenius Kabi USA, LLC; 2021 Nov. Elahere (mirvetuximab soravtansine) package insert. Waltham, MA: ImmunoGen, Inc.; 2022 Nov. Eligard (leuprolide acetate) package insert. Fort Collins, CO: Tolmar, Inc.; 2019 Feb. Mektovi (binimetinib) package insert. Array Biopharma Inc.: Array Biopharma Inc.; 2019 Jan. Tafinlar (dabrafenib) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2015 Nov. Rozlytrek (entrectinib) package insert. South San Francisco, CA: Genetech Inc.; 2022 July. Virakvi (larotrectinib) capsules and oral solution package insert. Stamford, CT: Loxo Oncology, Inc.; 2021 March. Votrient (pazopanib) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2022 Aug. Retevmo (selpercatinib) package insert. Indianapolis, IN: Eli Lilly and Company; 2022 Sept. Mekinist (trametinib) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2022 June. Taxotere (docetaxel) package insert. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2020 May. Paclitaxel package insert. Bedminster, NJ: Alembic Pharmaceuticals Inc.; 2022 Oct. Zejula (niraparib) package insert. Research Triangle Park, NC: GlaxoSmithKline, Inc.; 2021 Jun. Lynparza (olaparib) package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2022 Aug. Rubraca (rucaparib) package insert. Boulder, CO: Clovis Oncology, Inc; 2022 June. Jemperli (dostarlimab-gxly) package insert. Research Triangle Park, NC: Glaxo Smith Kline LLC; 2021 Aug. Keytruda (pembrolizumab) package insert. Whitehouse Station, NJ: Merck Sharp and Dohme Corp.; 2022 May. Megestrol acetate package insert. Chestnut Ridge, NY: Par Pharmaceutical, Inc.; 2022 May. Hycamtin (topotecan hydrochloride) for injection package insert. Research Triangle Park, NC: GlaxoSmithKline; 2018 Sept. Doxil (doxorubicin hydrochloride liposomal) package insert. Deerfield, IL: Baxter Healthcare Corporation; 2022 May. Etoposide injection package insert. Lake Zurich, IL: Fresenius Kabi USA, LLC; 2016 Feb. Avastin (bevacizumab) package insert. South San Francisco, CA: Genentech, Inc.; 2022 Sept.
    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
    • Posterior reversible encephalopathy syndrome (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
    • Hemolytic uremic syndrome (HUS)
    • Hepatotoxicity
    • Posterior reversible encephalopathy syndrome (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
    • Venous thromboembolic events (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 concentrations, due to structural
    similarity
    • Effective contraception required during and after therapy for 1 year for
    females of reproductive potential
    Folate receptor alpha (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
    Gonadotropin-releasing hormone (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
    • Interstitial lung disease (ILD)
    • Retinal vein occlusion (RVO)
    • Rhabdomyolysis
    • Serous retinopathy
    • Uveitis
    • Venous thromboembolism (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 glucose-6-phosphate
    dehydrogenase (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
    • Interstitial lung disease (ILD)/pneumonitis
    • Posterior reversible encephalopathy syndrome (PRES)
    • Proteinuria
    • QT prolongation
    • Thromboembolic events
    • Thrombotic microangiopathy (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 prior to 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
    • Interstitial lung disease (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 prior to 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
    • Interstitial lung disease (ILD)/pneumonitis
    • New primary malignancy
    • Retinal pigment epithelial detachment (RPED)
    • Retinal vein occlusion (RVO)
    • Venous thromboembolism (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 impact 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 impact the central nervous
    system and ability to drive or operate machinery
    Poly-(ADP-ribose) polymerase (PARP) inhibitor
    Niraparib•Niraparib monotherapy• Bone
    marrow suppression
    • Hypertension
    • Myelodysplastic syndrome/acute myeloid leukemia
    • Posterior reversible encephalopathy syndrome (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
    • Venous thromboembolism (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 infection
    • Nausea/vomiting
    • Rash
    • Stomatitis

    Effective contraception required during and after therapy for 6 months for
    females of reproductive potential
    Programmed death receptor-1 (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
    • Venous thromboembolic events (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
    • Interstitial lung disease

    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
    Vascular endothelial growth factor (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
    • Posterior reversible encephalopathy syndrome (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 prior to 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/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 is 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 stage 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 of chest/abdomen/pelvis; fluorodeoxyglucose 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 r56r66
    • 5-year survival rates r3
      • 93.1% for localized ovarian cancer (approximately 15% of cases)
      • 74.2% for cancer that has spread to regional lymph nodes only
      • 30.8% for cancer with distant metastasis (this represents most cases)
    • The following factors are associated with a favorable prognosis: r62
      • 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 r54
      • Absence of ascites
      • BRCA1 or BRCA2 mutation carrier

Screening and Prevention

Screening

At-risk populations

  • Women 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 women with an average risk of developing ovarian cancer r6r7
    • Recommendation applies to all methods: bimanual palpation of ovaries, imaging, and biomarker levels
    • Available evidence suggests that screening for ovarian cancer in asymptomatic women not known to be at high risk for ovarian cancer does not reduce ovarian cancer mortality r67
  • 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 r31
    • Patients who have probability of BRCA1/BRCA2 pathogenic variant of greater than 5% based on probability models
  • Some experts recommend monitoring women 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 r1r68c120c121c122c123

Prevention

  • Offer patients with BRCA1 and BRCA2 gene mutations risk-reducing salpingo-oophorectomy after completion of childbearing (typically between ages 35 and 40 years for BRCA1 mutations and 40 to 45 years for BRCA2 mutations) r1c124c125
    • Also consider risk-reducing salpingo-oophorectomy between ages 45 and 50 years in patients with BRIP1, RAD51C, and RAD51D mutations, and after age 45 years in patients with PALB2 mutation
  • Prophylactic (opportunistic) salpingectomy during benign gynecologic and obstetric surgery can be offered to women at risk for ovarian cancer and who have completed childbearing r69r70
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