General Information About Ovarian Epithelial Cancer, Fallopian Tube Cancer (FTC), and Primary Peritoneal Cancer (PPC)

This PDQ summary addresses the staging and treatment of ovarian epithelial cancer, fallopian tube cancer (FTC), and primary peritoneal cancer (PPC).

Regardless of the site of origin, the hallmark of these cancers is their early peritoneal spread of metastases. The inclusion of FTC and PPC within the ovarian epithelial cancer designation is generally accepted because of much evidence that points to a common Müllerian epithelium derivation and similar management of these three neoplasms. The hypothesis that many high-grade serous ovarian cancers (the most common histologic subtype) may arise from precursor lesions that originate in the fimbriae of the fallopian tubes has been supported by findings from risk-reducing surgeries in healthy women with BRCA1 or BRCA2 mutations.[1 ] In addition, histologically similar cancers diagnosed as primary peritoneal carcinomas share molecular findings, such as loss or inactivation of the tumor-suppressor p53 and BRCA1 or BRCA2 proteins.[2 ] Therefore, high-grade serous adenocarcinomas arising from the fallopian tube and elsewhere in the peritoneal cavity, together with most ovarian epithelial cancers, represent extrauterine adenocarcinomas of Müllerian epithelial origin and are staged and treated similarly to ovarian cancer. Since 2000, FTC and PPC have usually been included in ovarian cancer clinical trials.[3 ]

Clear cell and endometrioid ovarian cancers that are linked to endometriosis have different gene-expression signatures, as do mucinous subtypes.[2 ]

Stromal and germ cell tumors are relatively uncommon and comprise fewer than 10% of cases. (Refer to the PDQ summaries on Ovarian Germ Cell Tumors Treatment and Ovarian Low Malignant Potential Tumors Treatment for more information.)

Incidence and Mortality

Epithelial carcinoma of the ovary is one of the most common gynecologic malignancies, with 50% of all cases occurring in women older than 65 years. It is the fifth most frequent cause of cancer death in women.[4 ]

Estimated new cases and deaths from ovarian cancer in the United States in 2020:[5 ]

• New cases: 21,750.
• Deaths: 13,940.

Anatomy

The fimbriated ends of the fallopian tubes are in close apposition to the ovaries and in the peritoneal space, as opposed to the corpus uteri (body of the uterus) that is located under a layer of peritoneum.

Normal female reproductive system anatomy.

Risk Factors

Increasing age is the most important risk factor for most cancers. Other risk factors for ovarian (epithelial) cancer include the following:

• Family history of ovarian cancer.[6 ,7 ,8 ]
  • A first-degree relative (e.g., mother, daughter, or sister) with the disease.
• Inherited risk.[9 ]
  • BRCA1 or BRCA2 gene mutations.[6 ,10 ]
• Other hereditary conditions such as hereditary nonpolyposis colorectal cancer (HNPCC; also called Lynch syndrome).[6 ,9 ]
• Endometriosis.[11 ,12 ,13 ]
• Hormone therapy.[14 ,15 ]
  • Postmenopausal hormone replacement therapy.
• Obesity.[16 ,17 ,18 ]
  • High body mass index.
• Tall Height.[16 ,17 ,18 ]

Family history and genetic alterations

The most important risk factor for ovarian cancer is a history of ovarian cancer in a first-degree relative (mother, daughter, or sister). Approximately 20% of ovarian cancers are familial, and although most of these are linked to mutations in either the BRCA1 or BRCA2 gene, several other genes have been implicated.[19 ,20 ] The risk is highest in women who have two or more first-degree relatives with ovarian cancer.[21 ] The risk is somewhat less for women who have one first-degree relative and one second-degree relative (grandmother or aunt) with ovarian cancer.

In most families affected with breast and ovarian cancer syndrome or site-specific ovarian cancer, genetic linkage to the BRCA1 locus on chromosome 17q21 has been identified.[22 ,23 ,24 ]BRCA2, also responsible for some instances of inherited ovarian and breast cancer, has been mapped by genetic linkage to chromosome 13q12.[25 ]

The lifetime risk for developing ovarian cancer in patients harboring germline mutations in BRCA1 is substantially increased over that of the general population.[26 ,27 ] Two retrospective studies of patients with germline mutations in BRCA1 suggest that the women in these studies have improved survival compared with BRCA1 mutation–negative women.[28 ,29 ][Level of evidence: 3iiiA] Most women with a BRCA1 mutation probably have family members with a history of ovarian and/or breast cancer; therefore, the women in these studies may have been more vigilant and inclined to participate in cancer screening programs that may have led to earlier detection.

For women at increased risk, prophylactic oophorectomy may be considered after age 35 years if childbearing is complete. In a family-based study among 551 women with BRCA1 or BRCA2 mutations, of the 259 women who had undergone bilateral prophylactic oophorectomy, 2 (0.8%) developed subsequent papillary serous peritoneal carcinoma, and 6 (2.8%) had stage I ovarian cancer at the time of surgery. Of the 292 matched controls, 20% who did not have prophylactic surgery developed ovarian cancer. Prophylactic surgery was associated with a reduction in the risk of ovarian cancer that exceeded 90% (relative risk, 0.04; 95% confidence interval, 0.01–0.16), with an average follow-up of 9 years;[30 ] however, family-based studies may be associated with biases resulting from case selection and other factors that influence the estimate of benefit.[31 ] After a prophylactic oophorectomy, a small percentage of women may develop a primary peritoneal carcinoma that is similar in appearance to ovarian cancer.[32 ] (Refer to the Description of the Evidence section in the PDQ summary on Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Prevention for more information.)

(Refer to the Clinical Management of BRCA Mutation Carriers section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.)

Clinical Presentation

Ovarian, fallopian tube, or peritoneal cancer may not cause early signs or symptoms. When signs or symptoms do appear, the cancer is often advanced. Signs and symptoms include the following:

• Pain, swelling, or a feeling of pressure in the abdomen or pelvis.
• Urinary urgency or frequency.
• Difficulty eating or feeling full.
• A lump in the pelvic area.
• Gastrointestinal problems such as gas, bloating, or constipation.

These symptoms often go unrecognized, leading to delays in diagnosis. Efforts have been made to enhance physician and patient awareness of the occurrence of these nonspecific symptoms.[33 ,34 ,35 ,36 ,37 ]

Screening procedures such as gynecologic assessment, vaginal ultrasound, and cancer antigen 125 (CA-125) assay have had low predictive value in detecting ovarian cancer in women without special risk factors.[38 ,39 ] As a result of these confounding factors, annual mortality in ovarian cancer is approximately 65% of the incidence rate.

Most patients with ovarian cancer have widespread disease at presentation. Early peritoneal spread of the most common subtype of high-grade serous cancers may relate to serous cancers starting in the fimbriae of the fallopian tubes or in the peritoneum, readily explaining why such cancers are detected at an advanced stage. Conversely, high-grade serous cancers are underrepresented among stage I cancers of the ovary. Other types of ovarian cancers are, in fact, overrepresented in cancers detected in stages I and II. This type of ovarian cancer usually spreads via local shedding into the peritoneal cavity followed by implantation on the peritoneum and via local invasion of bowel and bladder. The incidence of positive nodes at primary surgery has been reported to be as high as 24% in patients with stage I disease, 50% in patients with stage II disease, 74% in patients with stage III disease, and 73% in patients with stage IV disease. The pelvic nodes were involved as often as the para-aortic nodes.[40 ] Tumor cells may also block diaphragmatic lymphatics. The resulting impairment of lymphatic drainage of the peritoneum is thought to play a role in development of ascites in ovarian cancer. Transdiaphragmatic spread to the pleura is common.

Diagnostic and Staging Evaluation

The following tests and procedures may be used in the diagnosis and staging of ovarian epithelial, fallopian tube, or primary peritoneal cancer:

• Physical exam and history.
• Pelvic exam.
• CA-125 assay.
• Ultrasound exam (pelvic or transvaginal).
• Computed tomography (CT) scan.
• Positron emission tomography (PET) scan.
• Magnetic resonance imaging (MRI).
• Chest x-ray.
• Biopsy.

CA-125 levels can be elevated in other malignancies and benign gynecologic problems such as endometriosis. CA-125 levels and histology are used to diagnose epithelial ovarian cancer.[41 ,42 ]

Prognostic Factors

Prognosis for patients with ovarian cancer is influenced by multiple factors. Multivariate analyses suggest that the most important favorable prognostic factors include the following:[43 ,44 ,45 ,46 ,47 ]

• Younger age.
• Good performance status.
• Cell type other than mucinous or clear cell.
• Well-differentiated tumor.
• Early-stage disease.
• Absence of ascites.
• Lower disease volume before surgical debulking.
• Smaller residual tumor after primary cytoreductive surgery.
• BRCA1 or BRCA2 mutation carrier.

For patients with stage I disease, the most important prognostic factor associated with relapse is grade, followed by dense adherence and large-volume ascites.[48 ] Stage I tumors have a high proportion of low-grade serous cancers. These cancers have a derivation distinctly different from that of high-grade serous cancers, which usually present in stages III and IV. Many high-grade serous cancers originate in the fallopian tube and other areas of extrauterine Müllerian epithelial origin.

If the tumor is grade III, densely adherent, or stage IC, the chance of relapse and death from ovarian cancer is as much as 30%.[48 ,49 ,50 ,51 ]

The use of DNA flow cytometric analysis of tumors from stage I and stage IIA patients may identify a group of high-risk patients.[52 ] Patients with clear cell histology appear to have a worse prognosis.[53 ] Patients with a significant component of transitional cell carcinoma appear to have a better prognosis.[54 ]

Case-control studies suggest that BRCA1 and BRCA2 mutation carriers have improved responses to chemotherapy when compared with patients with sporadic epithelial ovarian cancer. This may be the result of a deficient homologous DNA repair mechanism in these tumors, which leads to increased sensitivity to chemotherapy agents.[55 ,56 ]

Follow-up

Because of the low specificity and sensitivity of the CA-125 assay, serial CA-125 monitoring of patients undergoing treatment for recurrence may be useful. However, whether that confers a net benefit has not yet been determined. There is little guidance about how patients should be followed up after initial induction therapy, and neither early detection by imaging or by CA-125 elevation has been shown to alter outcomes.[57 ] (Refer to the Recurrent or Persistent Ovarian Epithelial, FTC, and PPC Treatment section of this summary for more information.)

Related Summaries

Other PDQ summaries containing information related to ovarian epithelial, fallopian tube, and primary peritoneal cancer include the following:

• Genetics of Breast and Gynecologic Cancers
• Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Prevention
• Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Screening
• Childhood Ovarian Cancer Treatment

References:

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3. Dubeau L, Drapkin R: Coming into focus: the nonovarian origins of ovarian cancer. Ann Oncol 24 (Suppl 8): viii28-viii35, 2013.
4. Yancik R: Ovarian cancer. Age contrasts in incidence, histology, disease stage at diagnosis, and mortality. Cancer 71 (2 Suppl): 517-23, 1993.
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7. Weissman SM, Weiss SM, Newlin AC: Genetic testing by cancer site: ovary. Cancer J 18 (4): 320-7, 2012 Jul-Aug.
8. Hunn J, Rodriguez GC: Ovarian cancer: etiology, risk factors, and epidemiology. Clin Obstet Gynecol 55 (1): 3-23, 2012.
9. Pal T, Akbari MR, Sun P, et al.: Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer 107 (10): 1783-90, 2012.
10. Gayther SA, Pharoah PD: The inherited genetics of ovarian and endometrial cancer. Curr Opin Genet Dev 20 (3): 231-8, 2010.
11. Poole EM, Lin WT, Kvaskoff M, et al.: Endometriosis and risk of ovarian and endometrial cancers in a large prospective cohort of U.S. nurses. Cancer Causes Control 28 (5): 437-445, 2017.
12. Pearce CL, Templeman C, Rossing MA, et al.: Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. Lancet Oncol 13 (4): 385-94, 2012.
13. Mogensen JB, Kjær SK, Mellemkjær L, et al.: Endometriosis and risks for ovarian, endometrial and breast cancers: A nationwide cohort study. Gynecol Oncol 143 (1): 87-92, 2016.
14. Lacey JV, Brinton LA, Leitzmann MF, et al.: Menopausal hormone therapy and ovarian cancer risk in the National Institutes of Health-AARP Diet and Health Study Cohort. J Natl Cancer Inst 98 (19): 1397-405, 2006.
15. Trabert B, Wentzensen N, Yang HP, et al.: Ovarian cancer and menopausal hormone therapy in the NIH-AARP diet and health study. Br J Cancer 107 (7): 1181-7, 2012.
16. Engeland A, Tretli S, Bjørge T: Height, body mass index, and ovarian cancer: a follow-up of 1.1 million Norwegian women. J Natl Cancer Inst 95 (16): 1244-8, 2003.
17. Lahmann PH, Cust AE, Friedenreich CM, et al.: Anthropometric measures and epithelial ovarian cancer risk in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 126 (10): 2404-15, 2010.
18. Collaborative Group on Epidemiological Studies of Ovarian Cancer: Ovarian cancer and body size: individual participant meta-analysis including 25,157 women with ovarian cancer from 47 epidemiological studies. PLoS Med 9 (4): e1001200, 2012.
19. Lynch HT, Watson P, Lynch JF, et al.: Hereditary ovarian cancer. Heterogeneity in age at onset. Cancer 71 (2 Suppl): 573-81, 1993.
20. Pennington KP, Swisher EM: Hereditary ovarian cancer: beyond the usual suspects. Gynecol Oncol 124 (2): 347-53, 2012.
21. Piver MS, Goldberg JM, Tsukada Y, et al.: Characteristics of familial ovarian cancer: a report of the first 1,000 families in the Gilda Radner Familial Ovarian Cancer Registry. Eur J Gynaecol Oncol 17 (3): 169-76, 1996.
22. Miki Y, Swensen J, Shattuck-Eidens D, et al.: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266 (5182): 66-71, 1994.
23. Easton DF, Bishop DT, Ford D, et al.: Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet 52 (4): 678-701, 1993.
24. Steichen-Gersdorf E, Gallion HH, Ford D, et al.: Familial site-specific ovarian cancer is linked to BRCA1 on 17q12-21. Am J Hum Genet 55 (5): 870-5, 1994.
25. Wooster R, Neuhausen SL, Mangion J, et al.: Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265 (5181): 2088-90, 1994.
26. Easton DF, Ford D, Bishop DT: Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 56 (1): 265-71, 1995.
27. Struewing JP, Hartge P, Wacholder S, et al.: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336 (20): 1401-8, 1997.
28. Rubin SC, Benjamin I, Behbakht K, et al.: Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Engl J Med 335 (19): 1413-6, 1996.
29. Aida H, Takakuwa K, Nagata H, et al.: Clinical features of ovarian cancer in Japanese women with germ-line mutations of BRCA1. Clin Cancer Res 4 (1): 235-40, 1998.
30. Rebbeck TR, Lynch HT, Neuhausen SL, et al.: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346 (21): 1616-22, 2002.
31. Klaren HM, van't Veer LJ, van Leeuwen FE, et al.: Potential for bias in studies on efficacy of prophylactic surgery for BRCA1 and BRCA2 mutation. J Natl Cancer Inst 95 (13): 941-7, 2003.
32. Piver MS, Jishi MF, Tsukada Y, et al.: Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer. A report of the Gilda Radner Familial Ovarian Cancer Registry. Cancer 71 (9): 2751-5, 1993.
33. Goff BA, Mandel L, Muntz HG, et al.: Ovarian carcinoma diagnosis. Cancer 89 (10): 2068-75, 2000.
34. Friedman GD, Skilling JS, Udaltsova NV, et al.: Early symptoms of ovarian cancer: a case-control study without recall bias. Fam Pract 22 (5): 548-53, 2005.
35. Smith LH, Morris CR, Yasmeen S, et al.: Ovarian cancer: can we make the clinical diagnosis earlier? Cancer 104 (7): 1398-407, 2005.
36. Goff BA, Mandel LS, Melancon CH, et al.: Frequency of symptoms of ovarian cancer in women presenting to primary care clinics. JAMA 291 (22): 2705-12, 2004.
37. Goff BA, Mandel LS, Drescher CW, et al.: Development of an ovarian cancer symptom index: possibilities for earlier detection. Cancer 109 (2): 221-7, 2007.
38. Partridge E, Kreimer AR, Greenlee RT, et al.: Results from four rounds of ovarian cancer screening in a randomized trial. Obstet Gynecol 113 (4): 775-82, 2009.
39. van Nagell JR, Miller RW, DeSimone CP, et al.: Long-term survival of women with epithelial ovarian cancer detected by ultrasonographic screening. Obstet Gynecol 118 (6): 1212-21, 2011.
40. Burghardt E, Girardi F, Lahousen M, et al.: Patterns of pelvic and paraaortic lymph node involvement in ovarian cancer. Gynecol Oncol 40 (2): 103-6, 1991.
41. Berek JS, Knapp RC, Malkasian GD, et al.: CA 125 serum levels correlated with second-look operations among ovarian cancer patients. Obstet Gynecol 67 (5): 685-9, 1986.
42. Atack DB, Nisker JA, Allen HH, et al.: CA 125 surveillance and second-look laparotomy in ovarian carcinoma. Am J Obstet Gynecol 154 (2): 287-9, 1986.
43. Omura GA, Brady MF, Homesley HD, et al.: Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience. J Clin Oncol 9 (7): 1138-50, 1991.
44. van Houwelingen JC, ten Bokkel Huinink WW, van der Burg ME, et al.: Predictability of the survival of patients with advanced ovarian cancer. J Clin Oncol 7 (6): 769-73, 1989.
45. Neijt JP, ten Bokkel Huinink WW, van der Burg ME, et al.: Long-term survival in ovarian cancer. Mature data from The Netherlands Joint Study Group for Ovarian Cancer. Eur J Cancer 27 (11): 1367-72, 1991.
46. Hoskins WJ, Bundy BN, Thigpen JT, et al.: The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 47 (2): 159-66, 1992.
47. Thigpen T, Brady MF, Omura GA, et al.: Age as a prognostic factor in ovarian carcinoma. The Gynecologic Oncology Group experience. Cancer 71 (2 Suppl): 606-14, 1993.
48. Dembo AJ, Davy M, Stenwig AE, et al.: Prognostic factors in patients with stage I epithelial ovarian cancer. Obstet Gynecol 75 (2): 263-73, 1990.
49. Ahmed FY, Wiltshaw E, A'Hern RP, et al.: Natural history and prognosis of untreated stage I epithelial ovarian carcinoma. J Clin Oncol 14 (11): 2968-75, 1996.
50. Monga M, Carmichael JA, Shelley WE, et al.: Surgery without adjuvant chemotherapy for early epithelial ovarian carcinoma after comprehensive surgical staging. Gynecol Oncol 43 (3): 195-7, 1991.
51. Kolomainen DF, A'Hern R, Coxon FY, et al.: Can patients with relapsed, previously untreated, stage I epithelial ovarian cancer be successfully treated with salvage therapy? J Clin Oncol 21 (16): 3113-8, 2003.
52. Schueler JA, Cornelisse CJ, Hermans J, et al.: Prognostic factors in well-differentiated early-stage epithelial ovarian cancer. Cancer 71 (3): 787-95, 1993.
53. Young RC, Walton LA, Ellenberg SS, et al.: Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials. N Engl J Med 322 (15): 1021-7, 1990.
54. Gershenson DM, Silva EG, Mitchell MF, et al.: Transitional cell carcinoma of the ovary: a matched control study of advanced-stage patients treated with cisplatin-based chemotherapy. Am J Obstet Gynecol 168 (4): 1178-85; discussion 1185-7, 1993.
55. Vencken PM, Kriege M, Hoogwerf D, et al.: Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients. Ann Oncol 22 (6): 1346-52, 2011.
56. Safra T, Borgato L, Nicoletto MO, et al.: BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin. Mol Cancer Ther 10 (10): 2000-7, 2011.
57. Rustin GJ, van der Burg ME, Griffin CL, et al.: Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Lancet 376 (9747): 1155-63, 2010.

Cellular Classification of Ovarian Epithelial Cancer, FTC, and PPC

Table 1 describes the histologic classification of ovarian epithelial cancer, fallopian tube cancer (FTC), and primary peritoneal cancer (PPC).

Table 1. Ovarian Epithelial Cancer, FTC, and PPC Histologic Classification

Histologic Classification	Histologic Subtypes
FTC = fallopian tube cancer; PPC = primary peritoneal cancer.
Serous cystomas	Serous benign cystadenomas.
	Serous cystadenomas with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (refer to the PDQ summary on Ovarian Low Malignant Potential Tumors Treatmentfor more information).
	Serous cystadenocarcinomas.
Mucinous cystomas	Mucinous benign cystadenomas.
	Mucinous cystadenomas with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (low malignant potential or borderline malignancy).
	Mucinous cystadenocarcinomas.
Endometrioid tumors (similar to adenocarcinomas in the endometrium)	Endometrioid benign cysts.
	Endometrioid tumors with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (low malignant potential or borderline malignancy).
	Endometrioid adenocarcinomas.
Clear cell (mesonephroid) tumors	Benign clear cell tumors.
	Clear cell tumors with proliferating activity of the epithelial cells and nuclear abnormalities but with no infiltrative destructive growth (low malignant potential or borderline malignancy).
	Clear cell cystadenocarcinomas.
Unclassified tumors that cannot be allotted to one of the above groups
No histology (cytology-only diagnosis)
Other malignant tumors (malignant tumors other than those of the common epithelial types are not to be included with the categories listed above)

Stage Information for Ovarian Epithelial Cancer, FTC, and PPC

In the absence of extra-abdominal metastatic disease, definitive staging of ovarian cancer requires surgery. The role of surgery in patients with stage IV ovarian cancer and extra-abdominal disease is yet to be established. If disease appears to be limited to the ovaries or pelvis, it is essential at laparotomy to obtain peritoneal washings and to examine and biopsy or obtain cytologic brushings of the following:

• Diaphragm.
• Both paracolic gutters.
• Pelvic peritoneum.
• Para-aortic and pelvic nodes.
• Infracolic omentum.[1 ]

The Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) Staging

The FIGO and the American Joint Committee on Cancer (AJCC) have designated staging to define ovarian epithelial cancer. The FIGO-approved new staging system for ovarian epithelial cancer, fallopian tube cancer (FTC), and primary peritoneal cancer (PPC) is the one most commonly used.[2 ,3 ]

Table 2. Definitions of FIGO Stage I^a

Stage	Definition	Illustration
a Adapted from the Fédération Internationale de Gynécologie et d'Obstétrique.[2 ]
I	Tumor confined to ovaries or fallopian tube(s).
IA	Tumor limited to one ovary (capsule intact) or fallopian tube; no tumor on ovarian or fallopian tube surface; no malignant cells in the ascites or peritoneal washings.
IB	Tumor limited to both ovaries (capsules intact) or fallopian tubes; no tumor on ovarian or fallopian tube surface; no malignant cells in the ascites or peritoneal washings.
IC	Tumor limited to one or both ovaries or fallopian tubes, with any of the following:
	IC1: Surgical spill.
	IC2: Capsule ruptured before surgery or tumor on ovarian or fallopian tube surface.
	IC3: Malignant cells in the ascites or peritoneal washings.

Table 3. Definitions of FIGO Stage II^a

Stage	Definition	Illustration
a Adapted from the Fédération Internationale de Gynécologie et d'Obstétrique.[2 ]
II	Tumor involves one or both ovaries or fallopian tubes with pelvic extension (below pelvic brim) or primary peritoneal cancer.
IIA	Extension and/or implants on the uterus and/or fallopian tubes and/or ovaries.
IIB	Extension to other pelvic intraperitoneal tissues.

Table 4. Definitions of FIGO Stage III^a

Stage	Definition	Illustration
a Adapted from the Fédération Internationale de Gynécologie et d'Obstétrique.[2 ]
b Includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ.
III	Tumor involves one or both ovaries, or fallopian tubes, or primary peritoneal cancer, with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes.
IIIA1	Positive retroperitoneal lymph nodes only (cytologically or histologically proven):
	IIIA1(i): Metastasis up to 10 mm in greatest dimension.
	IIIA1(ii): Metastasis >10 mm in greatest dimension.
IIIA2	Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes.
IIIB	Macroscopic peritoneal metastases beyond the pelvis ≤2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes.
IIIC	Macroscopic peritoneal metastasis beyond the pelvis >2 cm in greatest dimension, with or without metastasis to the retroperitoneal nodes.b

Table 5. Definitions of FIGO Stage IV^a

Stage	Definition	Illustration
a Adapted from the Fédération Internationale de Gynécologie et d'Obstétrique.[2 ]
b Isolated parenchymal metastases are stage IVB.
IV	Distant metastasis excluding peritoneal metastases.
IVA	Pleural effusion with positive cytology.
IVB	Parenchymal metastases and metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity).b

References:

1. Hoskins WJ: Surgical staging and cytoreductive surgery of epithelial ovarian cancer. Cancer 71 (4 Suppl): 1534-40, 1993.
2. Prat J; FIGO Committee on Gynecologic Oncology: Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet 124 (1): 1-5, 2014.
3. Ovary, fallopian tube, and primary peritoneal carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 681-90.

Treatment Option Overview

Treatment options for patients with all stages of ovarian epithelial cancer, fallopian tube cancer (FTC), and primary peritoneal cancer (PPC) have consisted of surgery followed by platinum-based chemotherapy.

Early stage refers to stages I and II. However, because of high recurrence rates for stage II patients in early-stage disease trials, patients with stage II cancers have been included with patients who have more advanced-stage cancer in Gynecologic Oncology Group clinical trials since 2009. Going forward, stage I will remain a separate category for treatment considerations, but high-grade serous stage II cancers are likely to be included with more advanced stages.

Numerous clinical trials are in progress to refine existing therapies and test the value of different approaches to postoperative drug and radiation therapy. Patients with any stage of ovarian cancer are appropriate candidates for clinical trials.[1 ,2 ] Information about ongoing clinical trials is available from the NCI website.

The treatment options for ovarian epithelial cancer, FTC, and PPC are presented in Table 6.

Table 6. Treatment Options for Ovarian Epithelial Cancer, FTC, and PPC

Stage	Treatment Options
OS = overall survival; PARP = poly (ADP) ribose-polymerase.
Early stage	Surgery with or without chemotherapy
Advanced stage	Surgery followed by platinum-based chemotherapy
	Surgery before or after platinum-based chemotherapy and/or additional consolidation therapy
	Surgery before or after platinum-based chemotherapy and the addition of bevacizumab to induction therapy and/or consolidation therapy
	Surgery before or after platinum-based chemotherapy and the addition of PARP inhibitors to induction therapy and/or consolidation therapy
	Chemotherapy for patients who cannot have surgery (although the impact on OS has not been proven)
Recurrent	Platinum-containing chemotherapy regimens
	Bevacizumab, other targeted drugs, and PARP inhibitors with or without chemotherapy
	Chemotherapy
	Chemotherapy and/or bevacizumab

References:

1. Ozols RF, Young RC: Ovarian cancer. Curr Probl Cancer 11 (2): 57-122, 1987 Mar-Apr.
2. Cannistra SA: Cancer of the ovary. N Engl J Med 329 (21): 1550-9, 1993.

Early-Stage Ovarian Epithelial Cancer, FTC, and PPC Treatment

Early stage refers to stage I and stage II. However, because of high recurrence rates for stage II patients in early-stage disease trials, patients with stage II cancers have been included with patients who have more advanced-stage cancer in Gynecologic Oncology Group (GOG) clinical trials since 2009. Going forward, stage I will remain a separate category for treatment considerations, but high-grade serous stage II cancers are likely to be included with more advanced stages.

Standard Treatment Options for Early-Stage Ovarian Epithelial Cancer, FTC, and PPC

Standard treatment options for early-stage ovarian epithelial, fallopian tube cancer (FTC), and primary peritoneal cancer (PPC) include the following:

1. Surgery with or without chemotherapy.

Surgery with or without chemotherapy

If the tumor is well differentiated or moderately well differentiated, surgery alone may be adequate treatment for patients with stage IA or IB disease. Surgery includes hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. The undersurface of the diaphragm is visualized and biopsied. Biopsies of the pelvic and abdominal peritoneum and the pelvic and para-aortic lymph nodes are also performed. Peritoneal washings are routinely obtained.[1 ,2 ] In patients who desire childbearing and have grade I tumors, unilateral salpingo-oophorectomy may be associated with a low risk of recurrence.[3 ]

In the United States, except for the most favorable subset of patients (those with stage IA well-differentiated disease), evidence based on double-blinded, randomized, controlled trials with total mortality endpoints supports adjuvant treatment with cisplatin, carboplatin, and paclitaxel.

Evidence (surgery with or without chemotherapy):

1. In two large European trials, the European Organization for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm trial (EORTC-ACTION) and International Collaborative Ovarian Neoplasm trial (MRC-ICON1 [NCT00002477]), patients with stage IA (grade II) and stage IB (grade III), all stage IC and stage II ovarian epithelial, and all stage I and stage IIA clear cell carcinoma were randomly assigned to receive adjuvant chemotherapy or observation.[4 ,5 ,6 ]
   1. The EORTC-ACTION trial required at least four cycles of carboplatin or cisplatin-based chemotherapy as treatment. Although surgical staging criteria were monitored, inadequate staging was not an exclusion criterion.[4 ]
      • Recurrence-free survival (RFS) was improved in the adjuvant chemotherapy arm (hazard ratio [HR], 0.63; P = .02), but overall survival (OS) was not affected (HR, 0.69; 95% confidence interval [CI], 0.44–1.08; P = .10).
      • OS was improved by chemotherapy in the subset of patients with inadequate surgical staging.
   2. The MRC-ICON1 trial randomly assigned patients to six cycles of single-agent carboplatin or cisplatin or platinum-based chemotherapy (usually cyclophosphamide, doxorubicin, and cisplatin) versus observation and had entry criteria similar to the EORTC-ACTION trial; however, the MRC-ICON1 trial did not monitor whether adequate surgical staging was performed.[5 ] When the results of the trials were combined, the difference in OS achieved statistical significance.
      • Both RFS and OS were significantly improved; 5-year survival figures were 79% with adjuvant chemotherapy versus 70% without adjuvant chemotherapy.
   3. An analysis of pooled data from both studies demonstrated the following:[6 ][Level of evidence: 1iA]
      • There was significant improvement in RFS with chemotherapy (HR, 0.64; 95% CI, 0.50–0.82; P = .001) and OS (HR, 0.67; 95% CI, 0.50–0.90; P = .008). These data showed an OS at 5 years of 82% with chemotherapy and 74% with observation, with a 95% CI in the difference of 2% to 12%.[6 ][Level of evidence: 1iA]
      • An accompanying editorial emphasized that the focus of subsequent trials must be to identify patients who do not require additional therapy among the early ovarian cancer subset.[7 ] Optimal staging is one way to better identify these patients.
2. The GOG-0157 trial evaluated whether six cycles of chemotherapy were superior to three cycles for patients with early-stage, high-risk epithelial ovarian cancer after primary surgery. Eligible patients were those with stage IA grade 3 or clear cell histology, stage IB grade 3 or clear cell histology, all stage IC, and all stage II. Patients were randomly assigned to receive either three or six cycles of the combination of paclitaxel (175 mg/m² administered over 3 hours) and carboplatin dosed (area under the curve, 7.5) over 30 minutes and given every 21 days. The primary endpoint was RFS, and the study was powered to detect a 50% decrease in the recurrence rate at 5 years. A total of 427 patients were eligible.[8 ]
   • No significant difference in cumulative incidence of recurrence was found when three cycles (25.4%) were compared with six cycles (20.1%) (HR, 0.76; 95% CI, 0.5–1.13) or OS for three cycles (81%) versus six cycles (83%) (HR, 1.02; P = .94).[8 ][Level of evidence: 1iiDi]
   • As expected, the use of six cycles was associated with increased grade 3 or 4 neurologic toxic effects and increased grade 4 hematologic toxic effects.
   • Although surgical staging was required for study entry, an audit revealed that 29% of the patients had either incomplete documentation of their surgery or insufficient surgical effort.
   • In a post hoc analysis of the patients who underwent complete surgical staging, three additional cycles of chemotherapy decreased the risk of recurrence by only 3%. The cumulative incidence of recurrence within 5 years was 18% for women with stage I disease and 33% for women with stage II disease.

   Given the increased risk of recurrence in patients with stage II disease and in those classified as having high-grade serous cancer, the GOG after 2007 opted to include patients with stage II disease in advanced ovarian cancer trials (refer to the Advanced-Stage Ovarian Epithelial Cancer, FTC, and PPC Treatment section of this summary for more information). Although the routine use of six cycles of chemotherapy is promulgated by guidelines, on subset analyses it is a source of controversy. Platinum-based chemotherapy including paclitaxel for three or six cycles has been evaluated by the GOG in additional trials that included prolonged maintenance paclitaxel, before phasing out early-stage clinical trials.

3. Patients with stage II ovarian cancer were enrolled in a Japanese Gynecology Oncology Group study (JGOG-3016 [NCT00226915]) that tested a weekly dosing schedule versus the conventional every-3-week dosing schedule in first-line ovarian cancer.[9 ,10 ,11 ]

The following treatments have been largely displaced by the adoption of carboplatin plus paclitaxel for early stages of high-grade ovarian cancers:

• Intraperitoneal phosphorus P 32 or radiation therapy.[1 ,12 ,13 ]
• Platinum-based systemic chemotherapy alone or in combination with alkylating agents.[1 ,12 ,14 ,15 ,16 ]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Young RC, Decker DG, Wharton JT, et al.: Staging laparotomy in early ovarian cancer. JAMA 250 (22): 3072-6, 1983.
2. Fader AN, Java J, Ueda S, et al.: Survival in women with grade 1 serous ovarian carcinoma. Obstet Gynecol 122 (2 Pt 1): 225-32, 2013.
3. Zanetta G, Chiari S, Rota S, et al.: Conservative surgery for stage I ovarian carcinoma in women of childbearing age. Br J Obstet Gynaecol 104 (9): 1030-5, 1997.
4. Trimbos JB, Vergote I, Bolis G, et al.: Impact of adjuvant chemotherapy and surgical staging in early-stage ovarian carcinoma: European Organisation for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm trial. J Natl Cancer Inst 95 (2): 113-25, 2003.
5. Colombo N, Guthrie D, Chiari S, et al.: International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer. J Natl Cancer Inst 95 (2): 125-32, 2003.
6. Trimbos JB, Parmar M, Vergote I, et al.: International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst 95 (2): 105-12, 2003.
7. Young RC: Early-stage ovarian cancer: to treat or not to treat. J Natl Cancer Inst 95 (2): 94-5, 2003.
8. Bell J, Brady MF, Young RC, et al.: Randomized phase III trial of three versus six cycles of adjuvant carboplatin and paclitaxel in early stage epithelial ovarian carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 102 (3): 432-9, 2006.
9. Katsumata N, Yasuda M, Takahashi F, et al.: Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet 374 (9698): 1331-8, 2009.
10. Katsumata N, Yasuda M, Isonishi S, et al.: Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol 14 (10): 1020-6, 2013.
11. Scambia G, Salutari V, Amadio G: Controversy in treatment of advanced ovarian cancer. Lancet Oncol 14 (10): 920-1, 2013.
12. Vergote IB, Vergote-De Vos LN, Abeler VM, et al.: Randomized trial comparing cisplatin with radioactive phosphorus or whole-abdomen irradiation as adjuvant treatment of ovarian cancer. Cancer 69 (3): 741-9, 1992.
13. Piver MS, Lele SB, Bakshi S, et al.: Five and ten year estimated survival and disease-free rates after intraperitoneal chromic phosphate; stage I ovarian adenocarcinoma. Am J Clin Oncol 11 (5): 515-9, 1988.
14. Bolis G, Colombo N, Pecorelli S, et al.: Adjuvant treatment for early epithelial ovarian cancer: results of two randomised clinical trials comparing cisplatin to no further treatment or chromic phosphate (32P). G.I.C.O.G.: Gruppo Interregionale Collaborativo in Ginecologia Oncologica. Ann Oncol 6 (9): 887-93, 1995.
15. Piver MS, Malfetano J, Baker TR, et al.: Five-year survival for stage IC or stage I grade 3 epithelial ovarian cancer treated with cisplatin-based chemotherapy. Gynecol Oncol 46 (3): 357-60, 1992.
16. McGuire WP: Early ovarian cancer: treat now, later or never? Ann Oncol 6 (9): 865-6, 1995.

Advanced-Stage Ovarian Epithelial Cancer, FTC, and PPC Treatment

Treatment options for patients with all stages of ovarian epithelial cancer, fallopian tube cancer (FTC), and primary peritoneal cancer (PPC) have consisted of surgery followed by platinum-based chemotherapy. Because of high recurrence rates for stage II patients in early-stage disease trials, patients with stage II cancers have been included with patients who have more advanced-stage cancer in Gynecologic Oncology Group (GOG) clinical trials since 2009. Going forward, stage I will remain a separate category for treatment considerations, but high-grade serous stage II cancers are likely to be included with more advanced stages.

The most common approach to advanced ovarian cancer is surgery followed by adjuvant platinum-based chemotherapy. Published trials, most with primary endpoints of progression-free survival (PFS), are listed in Table 7. A PFS endpoint was endorsed by the Gynecologic Cancer InterGroup (GCIC), but subsequently it was questioned in a systematic review and meta-analysis conducted by the GCIC.[1 ] After a MEDLINE search of randomized clinical trials of newly-diagnosed patients with ovarian epithelial cancer, FTC, or PPC, all studies with a minimum sample of 60 patients published from 2001 through 2016 were used to extract PFS and overall survival (OS) at an individual level. The PFS was mostly based on measurement of CA-125 levels confirmed by radiological examination or by GCIC criteria. Of 17 trials that were individually assessed, five tested the addition of maintenance therapy, seven tested additional induction drugs, and five tested intensification therapy. No poly (ADP) ribose-polymerase (PARP) inhibitor trials were included in this meta-analysis. The analysis concluded that PFS is not an adequate surrogate for OS, but it was limited by the narrow range of treatment effects observed and by poststudy treatments.

Standard Treatment Options for Advanced-Stage Ovarian Epithelial Cancer, FTC, and PPC

Standard treatment options for advanced-stage ovarian epithelial cancer, FTC, and PPC include the following:

1. Surgery followed by platinum-based chemotherapy.
2. Surgery before or after platinum-based chemotherapy and/or additional consolidation therapy.
3. Surgery before or after platinum-based chemotherapy and the addition of bevacizumab to induction therapy and/or consolidation therapy.
4. Surgery before or after platinum-based chemotherapy and the addition of PARP inhibitors to induction therapy and/or consolidation therapy.
5. Chemotherapy for patients who cannot have surgery (although the impact on OS has not been proven).

Platinum-based chemotherapy is the initial treatment for all patients diagnosed with advanced disease who undergo surgical resection and are staged with cancer that has spread to the pelvic peritoneum (stage II) and beyond (stages III and IV). The role of surgery for patients with stage IV disease is unclear, but in most instances, the bulk of the disease is intra-abdominal, and surgical procedures similar to those used in the management of patients with stage II and III disease are applied.

Surgery has historically been done by open laparotomy performed by gynecologic oncology surgeons, and has included hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and debulking of peritoneal implants (often including resection of the bowel or adjacent organs as needed) to reduce tumor to microscopic, if it can safely be performed.

The volume of disease left at the completion of the primary surgical procedure in GOG studies has been related to patient survival.[2 ,3 ,4 ,5 ] A literature review showed that patients with optimal cytoreduction had a median survival of 39 months compared with survival of only 17 months in patients with suboptimal residual disease.[2 ][Level of evidence: 3iA]

However, in an analysis of 2,655 of the 4,312 patients enrolled in the largest GOG study (GOG-0182 [NCT00011986]) (refer to the Surgery followed by platinum-based chemotherapy section of this summary for more information), only cytoreduction to nonvisible disease that is R0 (i.e., complete surgical resection) had an independent effect on survival.[6 ] The GOG had conducted separate trials to establish a role for intraperitoneal (IP) therapy for women whose disease has been optimally cytoreduced (defined as ≤1 cm residuum) and for those who had suboptimal cytoreductions (>1 cm residuum) (refer to the Surgery before or after platinum-based chemotherapy and/or additional consolidation therapy section of this summary for a review of these trials).

Suboptimally debulked stage III and stage IV patients have inferior 5-year survival rates, but the gap has narrowed in trials that included taxanes and other drugs added to platinums.[7 ] By contrast, optimally debulked stage III patients treated with a combination of intravenous (IV) taxane and IP platinum plus taxane achieved a median survival of 66 months in a GOG trial.[8 ][Level of evidence: 1iiA]

Surgery followed by platinum-based chemotherapy

Platinum agents, such as cisplatin or its less-toxic second-generation analog, carboplatin, given either alone or in combination with other drugs, are the foundation of chemotherapy regimens used. Trials by various cooperative groups (conducted from 1999 to 2010) addressed issues of optimal dose-intensity [9 ,10 ,11 ] for both cisplatin and carboplatin,[12 ] schedule,[13 ] and the equivalent results obtained with either of these platinum drugs, usually in combination with cyclophosphamide.[14 ]

With the introduction of the taxane paclitaxel, two trials confirmed the superiority of cisplatin combined with paclitaxel when compared with the previous standard treatment of cisplatin plus cyclophosphamide.[15 ,16 ] However, two trials that compared single-agent paclitaxel with either cisplatin or carboplatin (ICON3 and GOG-132) failed to confirm such superiority in all outcome parameters (i.e., response, time-to-progression, and survival) (refer to Table 7 for a list of these studies).

Based on the evidence, the initial standard treatment for patients with ovarian cancer is the combination of cisplatin or carboplatin with paclitaxel (defined as induction chemotherapy).

Evidence (combination of cisplatin or carboplatin with paclitaxel)

1. GOG-132 was widely regarded as showing that sequential treatment with cisplatin and paclitaxel was equivalent to the combination of cisplatin-plus-paclitaxel; however, many patients crossed over before disease progression. Moreover, the cisplatin-only arm was more toxic than the combination of cisplatin (75 mg/m²) and paclitaxel because it utilized a 100 mg/m² cisplatin dose per cycle.[17 ]
2. The Medical Research Council study (MRC-ICON3) compared carboplatin monotherapy with the combination of carboplatin and paclitaxel. While MRC-ICON3 had fewer early crossovers than GOG-132, it yielded similar outcomes for carboplatin monotherapy, including OS (albeit with less toxicity) compared with the combination treatment.[18 ]

Since the adoption of the standard combination of platinum plus taxane nearly worldwide, clinical trials have demonstrated the following:

1. Noninferiority of carboplatin plus paclitaxel versus cisplatin plus paclitaxel.[15 ,16 ,19 ]
2. Noninferiority of carboplatin plus paclitaxel versus carboplatin plus docetaxel.[20 ]
3. No advantage but increased toxic effects of adding epirubicin to the carboplatin plus paclitaxel doublet.[21 ]
4. Noninferiority of carboplatin plus paclitaxel versus sequential carboplatin-containing doublets with either gemcitabine or topotecan; or, triplets with the addition of gemcitabine or pegylated liposomal doxorubicin to the reference doublet as shown below:[22 ,23 ]
   1. From February 2001 to September 2004, 4,312 women with stage III or stage IV ovarian epithelial cancer, FTC, or PPC participating in the GOG-0182 trial were randomly assigned to four different experimental arms or to a reference treatment consisting of carboplatin (area under the curve [AUC], 6) and paclitaxel (175 mg/m²) every 3 weeks for eight cycles.[22 ] Stratification factors were residual-disease status and the intention to perform interval debulking surgery.
      • None of the experimental regimens was inferior.
      • Lethal events attributable to treatment occurred in less than 1% of patients without clustering to any one regimen.
      • With a median follow-up of 3.7 years, the adjusted relative risk of death ranged from 0.952 to 1.114, with the control arm achieving a PFS of 16.0 months and a median OS of 44.1 months.

      Moreover, for the stage III patients who made up 84% to 87% of patients, PFS differences were only noted if surgery achieved R0 resections:[22 ]

      • PFS in patients with residuum larger than 1 cm was 13 months, and OS was 33 months.
      • With residuum 1 cm or smaller, PFS was 16 months, and OS was 40 months.
      • With R0 resection (e.g., no residuum or microscopic residuum only), PFS was 29 months, and OS was 68 months.

In gynecologic cancer, as opposed to breast cancer, weekly paclitaxel was not explored in phase III trials before 2004. The positive results from the Japanese Gynecologic Oncology Group (JGOG) 3016 study subsequently led to early adoption of divided-dose paclitaxel as the standard treatment, but with only partial confirmation of its superior results.

Evidence (dose-dense [weekly] treatment schedule):

1. A JGOG trial (JGOG-3016 [NCT00226915]) accrued 637 patients and randomly assigned them to six to nine cycles of weekly (dose-dense) paclitaxel (80 mg/m²) or to the standard every-21-day schedule of paclitaxel at 180 mg/m². Both regimens were given with carboplatin (AUC, 6) in every-3-week cycles. With a primary endpoint of PFS, an increase from 16 to 21 months in the PFS of the weekly paclitaxel-based regimen was sought.[24 ,25 ] Although more toxic, the weekly paclitaxel regimen did not adversely affect quality of life when compared with the intermittent schedule.[26 ][Level of evidence: 1iiDiii]

   Other than ethnicity, this trial population may have differed from GOG and other studies in that patients were younger (average age, 57 years). Twenty percent of patients had stage II disease and 33% of patients had histologies other than high-grade serous or endometrioid cancer. Also, 11% of patients were entered while receiving neoadjuvant treatment, which was an all-inclusive way of assessing treatments other than chemotherapy in first-line settings. The JGOG-3016 study results demonstrated the following:

   • At the 1.5-year follow-up after cessation of treatment, the weekly regimen had a median PFS of 28.0 months (95% confidence interval [CI], 22.3–35.4 months), and the intermittent regimen had a median PFS of 17.2 months (range, 15.7–21.1 months; hazard ratio [HR], 0.71), favoring the weekly regimen (P = .0015).
   • A 2013 update revealed an increase in median survival for the weekly regimen (median OS, 8.3 years vs. 5.1 years; P = .040); the intermittent regimen results are also noteworthy relative to other clinical trials of weekly dosing schedules.
2. In a phase III trial (MITO-7 [NCT00660842]), the outcomes of 406 patients assigned to weekly paclitaxel (60 mg/m²) administered with weekly carboplatin (AUC, 2) were compared with those of 404 patients receiving the conventional every-3-week regimen of paclitaxel and carboplatin.[27 ][Level of evidence: 1iiA]
   • The results failed to confirm the superiority of this weekly schedule (18.3 months PFS for the weekly arm vs. 17.3 months PFS for the standard arm [HR, 0.96; 95% CI, 0.80–1.16]).
   • The treatments did not differ in toxic effects. A decrease in quality of life (assessed by the Functional Assessment of Cancer Therapy Ovarian Trial Outcome Index questionnaire) was not seen in the weekly arm compared with the every-3-week arm.
3. GOG-0262 [NCT01167712] is a phase III study that compared weekly paclitaxel (80 mg/m²) to every-3-week dosing (175 mg/m²), both with the conventional every-3-week carboplatin (AUC, 6) regimen.[28 ][Level of evidence: 1iiDiii] An option to give bevacizumab every 3 weeks beginning with cycle two and continuing until cycle six and followed by bevacizumab alone for 1 year, as in GOG-0218, was included for both arms. This option was applied in about 84% of all patients.
   • Overall, the weekly paclitaxel regimen failed to prolong PFS compared with the every-3-week regimen (14.7 months vs. 14.0 months), with an HR for progression or death of 0.89 (95% CI, 0.74–1.06).
   • However, among patients not receiving bevacizumab, the weekly paclitaxel arm had significantly prolonged PFS (14.2 months vs. 10.3 months), with an HR of 0.62 (95% CI, 0.40–0.95; P = .03)
   • The weekly paclitaxel regimen had a higher rate of grade 3 or 4 anemia (36% vs. 16%) and grade 2 to 4 sensory neuropathy (26% vs. 18%).

Table 7. Selected Phase III Studies of Intravenous Adjuvant Therapy for Advanced Ovarian Cancer After Initial Surgery

Trial	Treatment Regimens	No. of Patients	Progression-free Survival (mo)	Overall Survival (mo)
AUC = area under the curve; EORTC = European Organization for Research and Treatment of Cancer; Est = estimated; GOG = Gynecologic Oncology Group; ICON = International Collaboration on Ovarian Neoplasms; JGOG = Japanese Gynecologic Oncology Group; MITO = Multicentre Italian Trials in Ovarian cancer; MRC = Medical Research Council; No. = number; NR = not reported.
a Control arms are bolded.
b Statistically inferior result (P < .001–< .05).
c Optimally debulked only.
d Every 3 weeks for six cycles unless specified.
e JGOG-3016 included stage II patients.
GOG-111 (1990–1992)a[29 ]	Paclitaxel (135 mg/m2, 24 h) and cisplatin (75 mg/m2)	184	18	38
	Cyclophosphamide (750 mg/m2) and cisplatin (75 mg/m2)	202	13b	24b
EORTC-55931	Paclitaxel (175 mg/m2, 3 h) and cisplatin (75 mg/m2)	162	15.5	35.6
	Cyclophosphamide (750 mg/m2) and cisplatin (75 mg/m2)	161	11.5b	25.8b
GOG-132 (1992–1994)	Paclitaxel (135 mg/m2, 24 h) and cisplatin (75 mg/m2)	201	14.2	26.6
	Cisplatin (100 mg/m2)	200	16.4	30.2
	Paclitaxel (200 mg/m2, 24 h)	213	11.2b	26
MRC-ICON3[18 ]	Paclitaxel (175 mg/m2, 3 h) and carboplatin (AUC, 6)	478	17.3	36.1
	Carboplatin (AUC, 6)	943	16.1	35.4
	Paclitaxel (175 mg/m2, 3 h) and carboplatin (AUC, 6)	232	17	40
	Cyclophosphamide (500 mg/m2) and doxorubicin (50 mg/m2) and cisplatin (50 mg/m2)	421	17	40
GOG-158 (1995–1998)c	Paclitaxel (135 mg/m2, 24 h) and cisplatin (75 mg/m2 )d	425	14.5	48
	Paclitaxel (175 mg/m2, 3 h) and carboplatin (AUC, 6)	415	15.5	52
JGOG-3016 (2002–2004)e	Paclitaxel (180 mg/m2) and carboplatin (AUC, 6)d	319	17.5	62.2
	Paclitaxel (80 mg/m2) and carboplatin (AUC, 6)	312	28.5	100.5
MITO-7[27 ,30 ]	Paclitaxel (175 mg/m2) and carboplatin (AUC, 6)d	404	17.3	NR
	Paclitaxel (60 mg/m2) and carboplatin (AUC, 6)	406	18.3	NR
GOG-0262[28 ]	Paclitaxel (80 mg/m2) and carboplatin (AUC, 6) plus optional bevacizumab cycles 2–6, and every 3 wk until progression	346	14.7	Est 42
	Paclitaxel (175 mg/m2) and carboplatin (AUC, 6) (× 6 cycles) plus optional bevacizumab cycles 2–6, and every 3 wk until progression	346	14.0	Est 42
GOG-218	Paclitaxel (175 mg/m2) and carboplatin (AUC, 6) (× 6 cycles) and placebo cycles 2–22	625	10.3	39.3
	Paclitaxel (175 mg/m2) and carboplatin (AUC, 6) (× 6 cycles) and bevacizumab cycles 2–6, and placebo cycles 7–22	625	11.2	38.7
	Paclitaxel (175 mg/m2) and carboplatin (AUC, 6) (× 6 cycles) and bevacizumab cycles 2–22	623	14.1	39.7
ICON7[31 ]	Paclitaxel (175 mg/m2) and carboplatin (AUC, 5 or 6) and bevacizumab (7.5 mg/kg) (× 6 cycles) and bevacizumab alone cycles 7–18	764	19.0	45.5
	Paclitaxel (175 mg/m2) and carboplatin (AUC, 5 or 6) (× 6 cycles)	764	17.3	44.6

Surgery before or after platinum-based chemotherapy and/or additional consolidation therapy

The pharmacologic basis for the delivery of anticancer drugs by the IP route was established in the late 1970s and early 1980s. When several drugs were studied, mostly in the setting of minimal residual disease at reassessment after patients had received their initial chemotherapy, cisplatin alone and in combination received the most attention. Favorable outcomes from IP cisplatin were most often seen when tumors had shown responsiveness to platinum therapy and with small-volume tumors (usually defined as tumors <1 cm).[32 ]

In the 1990s, randomized trials were conducted to evaluate whether the IP route would prove superior to the IV route. IP cisplatin was the common denominator of these randomized trials.

Evidence (surgery followed by IP chemotherapy):

1. The use of IP cisplatin as part of the initial approach in patients with stage III optimally debulked ovarian cancer is supported principally by the results of three randomized clinical trials (SWOG-8501, GOG-0114, and GOG-0172 [NCT00003322]).[8 ,33 ,34 ] These studies tested the role of IP drugs (IP cisplatin in all three studies and IP paclitaxel in the last study) against the standard IV regimen.
   • In the three studies, superior PFS and OS favoring the IP arm were documented.

   Specifically, the most recent study, GOG-0172, demonstrated the following:[8 ][Level of evidence:1iiA]

   • A median survival of 66 months for patients on the IP arm versus 50 months for patients who received IV administration of cisplatin and paclitaxel (P = .03).
   • Toxic effects were greater in the IP arm because of the cisplatin dose per cycle (100 mg/m²); sensory neuropathy resulted from the additional IP chemotherapy and from the systemic administration of paclitaxel.
   • The rate of completion of six cycles of treatment was also less frequent in the IP arm (42% vs. 83%) because of the toxic effects and catheter-related problems.

   An updated combined analysis of GOG-0114 and GOG-0172 included 876 patients with a median follow-up of 10.7 years and reported the following results.[35 ]

   • Median survival with IP therapy was 61.8 months (95% CI, 55.5–69.5) compared with 51.4 months (95% CI, 46.0–58.2) for IV therapy.
   • IP therapy was associated with a 23% decreased risk of death (adjusted hazard ratio [AHR], 0.77; 95% CI, 0.65–0.90; P = .002).
   • IP therapy improved the survival of patients with gross residual (≤1 cm) disease (AHR, 0.75; 95% CI, 0.62–0.92; P = .006).
   • Risk of death decreased by 12% for each cycle of IP chemotherapy completed (AHR, 0.88; 95% CI, 0.83–0.94; P < .001).
   • Factors associated with poorer survival included clear and mucinous versus serous histology (AHR, 2.79; 95% CI, 1.83–4.24; P < .001), gross residual versus no visible disease (AHR, 1.89; 95% CI, 1.48–2.43; P < .001), and fewer versus more cycles of IP chemotherapy (AHR, 0.88; 95% CI, 0.83–0.94; P < .001).
   • Younger patients were more likely to complete the IP regimen, with a 5% decrease in probability of completion with each year of age (odds ratio, 0.95; 95% CI, 0.93–0.96; P < .001).
2. A Cochrane-sponsored meta-analysis of all randomized IP-versus-IV trials showed an HR of 0.79 for disease-free survival and 0.79 for OS, favoring the IP arms.[36 ]
3. In another meta-analysis of seven randomized trials assessing IP versus systemic chemotherapy conducted by Cancer Care of Ontario, the relative ratio (RR) of disease progression at 5 years based on the three trials that reported this endpoint was 0.91 (95% CI, 0.85–0.98), and the RR of death at 5 years based on six trials was 0.88 (95% CI, 0.81–0.95) for the IP route.[37 ]
4. In the subsequent IP trial (GOG-252), modifications of the IP regimen used in GOG-0172 were made to improve its tolerability (e.g., to reduce by ≥25% the total 3-hour amount of cisplatin given; and, to shift from the less practical 24-hour IV administration of paclitaxel to a 3-hour IV administration).[38 ]

   In this study, 1,560 patients were randomly assigned to receive six cycles of IV paclitaxel (80 mg/m² once per week with IV carboplatin [AUC, 6] every 3 weeks) versus IV paclitaxel (80 mg/m² once per week with IP carboplatin [AUC, 6] [the IP carboplatin arm]) versus-once-every-3-weeks IV paclitaxel (135 mg/m² over 3 hours on day 1, IP cisplatin 75 mg/m² on day 2, and IP paclitaxel 60 mg/m² on day 8 [the IP cisplatin arm]). The last regimen was the modified IP superior arm of GOG-0172. All participants received bevacizumab (15 mg/kg IV every 3 weeks in cycles 2−22) and bevacizumab (15 mg/kg every 3 weeks) was added to all three arms.

   • The median PFS duration was 24.9 months in the IV carboplatin arm, 27.4 months in the IP carboplatin arm, and 26.2 months in the IP cisplatin arm.
   • For the subgroup of 1,380 patients with stage II/III and residual disease of 1 cm or less, the median PFS was 26.9 months in the IV carboplatin arm, 28.7 months in the IP carboplatin arm, and 27.8 months in the IP cisplatin arm.
   • The median PFS for patients with stage II/III disease and no residual tumor was 35.9, 38.8, and 35.5 months, respectively.
   • The median OS for all enrolled patients was 75.5, 78.9, and 72.9 months, respectively; the median OS for patients with stage II/III disease with no gross residual tumor was 98.8 months, 104.8 months, and not reached, respectively.
   • This study concluded that compared with the IV carboplatin reference arm, PFS was not significantly increased with either IP regimen when combined with bevacizumab.[38 ][Level of evidence: 1iiDiii]

Surgery before or after platinum-based chemotherapy and the addition of bevacizumab to induction and/or consolidation therapy

Two phase III studies compared the outcome of standard primary cytoreductive surgery with that of neoadjuvant chemotherapy followed by interval cytoreductive surgery; both studies (described below) demonstrated that PFS and OS were noninferior with the use of primary cytoreductive surgery.[39 ,40 ]

Evidence (chemotherapy followed by surgery):

1. Between 1998 and 2006, a study led by the European Organization for the Research and Treatment of Cancer (EORTC) Gynecological Cancer Group, together with the National Cancer Institute of Canada Clinical Trials Group (EORTC-55971 [NCT00003636]), included 670 women with stages IIIC and IV ovarian epithelial cancer, FTC, and PPC.[39 ][Level of evidence: 1iiA] The women were randomly assigned to undergo primary debulking surgery followed by at least six courses of platinum-based chemotherapy or to receive three courses of neoadjuvant platinum-based chemotherapy followed by interval debulking surgery, and at least three more courses of platinum-based chemotherapy.

   Methods included efforts to ensure accuracy of diagnosis (e.g., rule out peritoneal carcinomatosis of gastrointestinal origin) and stratification by largest preoperative tumor size (excluding ovaries) (<5 cm, >5 cm–10 cm, >10 cm–20 cm, or >20 cm). Other stratification factors included institution, method of biopsy (i.e., image-guided, laparoscopy, laparotomy, or fine-needle aspiration), and tumor stage (i.e., stage IIIC or IV). The primary endpoint of the study was OS, with primary debulking surgery considered the standard.[39 ][Level of evidence: 1iiA]

   • Median OS for primary debulking surgery was 29 months, compared with 30 months for patients assigned to neoadjuvant chemotherapy.
   • The HR_death in the group assigned to neoadjuvant chemotherapy followed by interval debulking, as compared with the group assigned to primary debulking surgery followed by chemotherapy, was 0.98 (90% CI, 0.84–1.13; P = .01 for noninferiority).[39 ][Level of evidence: 1iiA]
   • Perioperative and postoperative morbidity and mortality were higher in the primary debulking surgery group (7.4% severe hemorrhage and 2.5% deaths, compared with 4.1% severe hemorrhage and 0.7% deaths in the neoadjuvant group).
   • The strongest independent predictor of prolonged survival was the absence of residual tumor after surgery.
   • The subset of patients achieving optimal cytoreduction (≤1 cm residuum), whether after primary debulking surgery or after neoadjuvant chemotherapy followed by interval debulking surgery, had the best median OS.
2. Between 2004 and 2010, a group of 87 hospitals in the United Kingdom and New Zealand enrolled 550 women with stage III or IV ovarian epithelial cancer and randomly assigned them to undergo primary cytoreductive surgery followed by six cycles of chemotherapy or primary (neoadjuvant) chemotherapy for three cycles, followed by surgery and three additional cycles of chemotherapy. In contrast to the EORTC study, the chemotherapy consisted of conventional carboplatin (AUC, 5 or AUC, 6) and paclitaxel (175 mg/m², in 76% of patients), or carboplatin alone (23% of patients), or nonpaclitaxel chemotherapy (1% of patients).[40 ][Level of evidence: 1iiA]

   A minimization method was used to randomly assign patients in a 1:1 ratio.[41 ] Participants were stratified by randomizing center, largest radiologic tumor, and prespecified chemotherapy regimen. The primary endpoint was to establish noninferiority, with the upper bound of a one-sided 90% CI for the HR_death at less than 1.18.

   • As of May 2014, 451 deaths had occurred, and the HR_death favored neoadjuvant chemotherapy, with the upper bound of the one-sided 90% CI of 0.98 (95% CI, 0.72‒1.05).
   • The most common grade 3 or 4 postoperative adverse event was hemorrhage in both groups, with 8 women (3%) having this problem with primary cytoreductive surgery versus 14 (6%) in the neoadjuvant chemotherapy group. Grade 3 and 4 toxic events from chemotherapy occurred in 110 (49%) of 225 women randomly assigned to primary cytoreductive surgery and in 102 (40%) of the 253 women receiving neoadjuvant chemotherapy, with one fatal event of neutropenic sepsis occurring in the primary chemotherapy group.

These studies and additional observational and partially published phase III studies have led to the publication of a Clinical Practice Guideline on behalf of the Society of Gynecologic Oncology and the American Society of Clinical Oncology.[42 ]

Hyperthermic peritoneal chemotherapy (HIPEC) is another pharmacologically based modality to enhance the antitumor effects via direct drug delivery to peritoneal surfaces. It was initially tested against mucinous tumors of gastrointestinal origin.[43 ] Increasingly, HIPEC is being applied to ovarian cancers, with considerable variation in patient selection, drugs administered, and time at target temperatures (most often 30 minutes at 42°C). The role of HIPEC remains experimental in the treatment of patients with high-grade serous ovarian cancers.

Experience with HIPEC spans more than two decades after initial publications that have since been summarized.[44 ] Evidence for its use in ovarian cancer includes a randomized study.

1. The final results of a phase III, open-label Dutch study NCT00426257) have been published. The study was performed in eight hospitals and included 245 patients with newly diagnosed ovarian cancer who were at least stable after receiving three cycles of carboplatin (AUC, 5–6) and paclitaxel 175 mg/m², both of which were given by IV every 3 weeks.[45 ] Randomization took place at the time of surgery, and patients were assigned to undergo either cytoreductive surgery without HIPEC (n = 123) or with HIPEC (n = 122). All patients subsequently received three additional cycles of IV chemotherapy. The study was reported with a median follow-up of 4.7 years, after the surgical intervention. HIPEC consisted of perfusion of the abdominal cavity with cisplatin 100 mg/m² in heated saline at 40°C (104°F) that was maintained for 60 minutes. Sodium thiosulfate was given at the start of the perfusion as an IV bolus of 9 g/m² in 200 mL followed by continuous infusion IV (12 g/m² in 1L) for 6 hours.[46 ]
   • After a median follow-up of 4.7 years, 209 of the 245 patients had a recurring disease event or died. In an intention-to-treat analysis, 110 of 123 patients in the surgery group and 99 of 122 patients in the HIPEC group had such an event (HR, 0.66; 95% CI, 0.50–0.87; P = .003).
   • The median recurrence-free survival was 3.5 months longer in the HIPEC group (14.2 months vs. 10.7 months).
   • In the surgery group, 76 of 123 patients (62%) had died, but in the HIPEC group, 61 of 122 patients (50%) had died at the time of publication (HR, 0.67; 95% CI, 0.48–0.94; P = .02) with median OS of 33.9 months in the surgery group and 45.7 months in the HIPEC group.
   • In the two groups, patient characteristics were mostly balanced with regard to age (median age, 61 years in both groups), histologic cell type in patients with high-grade serous ovarian carcinoma (87% in the surgery group and 92% in the HIPEC group), residual disease after surgery, and the number of patients completing adjuvant chemotherapy after surgery (90% in the surgery group and 94% in the HIPEC group).

In the institutions that have experience performing HIPEC, adverse events were comparable in the two groups. Patients in the HIPEC group had higher incidences of ileus (3% vs. 8%), fever (8% vs. 12%), and thromboembolic events (2% vs. 6%), but in that group, there were smaller differences in electrolyte changes (5% vs. 6%) and neuropathy (27% vs. 31%) than in patients in the surgery group, and both groups of patients had added IV chemotherapy. The use of sodium thiosulfate most likely accounts for this favorable safety profile vis-à-vis cisplatin, which was given as part of HIPEC in a published phase I trial.[47 ] HIPEC should be considered an option for patients who receive neoadjuvant therapy if they have access to a surgical team who has experience performing HIPEC.

Two phase III trials (GOG-0218 [NCT00262847] and ICON7 [NCT00483782]) have evaluated the role of bevacizumab in first-line therapy for ovarian epithelial cancer, FTC, and PPC after surgical cytoreduction.[48 ,49 ] Both trials showed a modest improvement in PFS when bevacizumab was added to initial chemotherapy and continued every 3 weeks for 16 and 12 additional cycles, as a maintenance phase.

Evidence (surgery followed by chemotherapy and bevacizumab):

1. GOG-0218 was a double-blinded, randomized, controlled trial that included 1,873 women with stage III or IV disease, all of whom received chemotherapy—carboplatin (AUC, 6) and paclitaxel (175 mg/m² for six cycles). Forty percent of the women had suboptimally resected stage III disease, and 26% had stage IV disease. The primary endpoint of the study was PFS.[48 ][Level of evidence:1iDiii] Participants were randomly assigned to receive the following:
   • Chemotherapy plus placebo (cycles 2–22) (the control group).
   • Chemotherapy plus bevacizumab (15 mg/kg cycles 2–6), followed by placebo (cycles 7–22) (the bevacizumab-initiation group).
   • Chemotherapy plus bevacizumab (15 mg/kg cycles 2–22) (the bevacizumab-throughout group).

   Results from the trial demonstrated the following:

   • There was no difference in PFS between the control group and the bevacizumab-initiation group.
   • There was a statistically significant increase in PFS in the bevacizumab-throughout group when compared with the control group (14.1 months vs. 10.3 months), with an HR_{disease progression} or_death of 0.717 in the bevacizumab-throughout group (95% CI, 0.625–0.824; P < .001).
   • Median OS was 39.3 months for the control group, 38.7 months for the bevacizumab-initiation group, and 39.7 months for the bevacizumab-throughout group.
   • Quality of life was not different between the three groups. Hypertension grade 2 or higher was more common with bevacizumab than with placebo.
   • There were more treatment-related deaths in the bevacizumab-throughout arm (10 of 607, 2.3%) than in the control arm (6 of 601, 1.0%).
2. ICON7 randomly assigned 1,528 women after initial surgery to chemotherapy—carboplatin (AUC, 5 or 6) plus paclitaxel (175 mg/m² for six cycles)—or to chemotherapy plus bevacizumab (7.5 mg/kg for six cycles), followed by bevacizumab alone for an additional 12 cycles. Nine percent of patients had early-stage, high-grade tumors; 70% had stage IIIC or IV disease; and 26% had more than 1 cm of residual tumor before initiating chemotherapy. PFS was the main outcome measure.[49 ][Level of evidence: 1iiDiii]
   1. Median PFS was 17.3 months in the control group and 19 months in the bevacizumab group. HR_{disease progression} or_death in the bevacizumab group was 0.81 (95% CI, 0.70–0.94; P = .004).
   2. Grade 3 or higher adverse events were more common in the bevacizumab group, with an increase in bleeding, hypertension (grade 2 or higher), thromboembolic events (grade 3 or higher), and gastrointestinal perforations.
   3. Quality of life was not different between the two groups.
   4. In 2015, the ICON7 authors reported an updated survival analysis.[31 ]
      • There was no significant difference with 44.6 months (95% CI 43.2–45.9) in patients on standard chemotherapy versus 45.5 months (44.2–46.7) in patients receiving bevacizumab with the chemotherapy induction, and then completing 1 year of bevacizumab maintenance (log-rank P = 0.85).

These two studies supported U.S. Food and Drug Administration (FDA) approval of bevacizumab in the first-line setting, both during induction and as consolidation therapy, after bevacizumab first gained approval in the platinum-resistant setting (AURELIA [NCT00976911] trial).

Surgery before or after platinum-based chemotherapy and the addition of poly (ADP-ribose) polymerase (PARP) inhibitors to induction and/or consolidation therapy

PARP is a family of enzymes involved in base-excision repair of DNA single-strand breaks. In patients with homologous recombination deficiency, including patients with germline BRCA1 or BRCA2 (gBRCA) mutations or with nongermline homologous recombination deficiency–positive tumors, the inhibition of PARP results in the production of double-strand breaks of DNA. Human DNA repair mechanisms largely rely on one intact copy of the gene. Cells with a double-strand break are usually targeted for cell death. This susceptibility of BRCA-deficient or BRCA-mutant cells to PARP inhibition,[50 ,51 ] has spurred the clinical development of this class of agents. Initially, these agents were tested in women who had been pretreated with chemotherapy. (Refer to the Bevacizumab, other targeted drugs, and poly(ADP-ribose) polymerase (PARP) inhibitors with or without chemotherapy section of this summary for more information.)

Evidence (surgery before or after chemotherapy and PARP inhibitors):

1. A double-blind phase III trial (SOLO-1) (NCT01844986) compared maintenance olaparib (300 mg tablets bid) with a placebo in patients with newly diagnosed, high-grade serous or endometrioid advanced ovarian cancer with mutations of BRCA1, BRCA2, or both, who had a complete or partial clinical response after platinum-based chemotherapy.[52 ] The study of 391 randomly assigned patients ran from September 2013 to March 2015. Of those patients, 260 were assigned to receive olaparib, and 131 patients were assigned to receive a placebo. All but three patients had germline mutations in BRCA1 (n = 191) or BRCA2 (n = 66). The analysis of the primary endpoint was stopped after 2 years if there was no evidence of disease or was continued until investigator-assessed disease progression. Patients with partial responses at 2 years were permitted to receive the intervention in a blinded manner. Crossover was not specified, but after discontinuation, patients could receive treatments at the discretion of the investigator. The primary endpoint was PFS, which was defined as from the time of randomization to objective disease progression on imaging (q 12 weeks up to 3 years), or death from any cause.
   • After a median follow-up of 41 months, the risk of disease progression or death was 70% lower with olaparib than with a placebo (Kaplan-Meier estimates of PFS at 3 years, 60% vs. 27%; HR, 0.3; 95% CI, 0.23–0.41; P < .001).
   • Grades 3 and 4 adverse events were present in 39% of the patients who received olaparib versus 18% who received a placebo. The most common events with olaparib were fatigue, vomiting, and anemia. Drug discontinuation occurred in 12% of the patients who received olaparib versus 2% who received a placebo.
   • No significant changes in quality of life occurred in either group.[52 ][Level of evidence: 1iiDiii]

   The trial results support the use of maintenance olaparib as consolidation therapy in this preselected population. This is the first indication of a PARP inhibitor following first-line chemotherapy and achieving complete or partial responses in the presence of germline BRCA1 and BRCA2 mutations.

2. A double-blind phase III trial (PRIMA [NCT02655016]) compared maintenance niraparib (300 mg tablets once daily and later amended to 200 mg in women <77 kg and/or baseline platelet count <150,000/µL) versus placebo in patients with 95% high-grade serous ovarian cancer before the last cycle of platinum-based chemotherapy.[53 ] Homologous recombination deficiency as determined by myChoice (Myriad) was present in 50.9% of patients. In a 2:1 randomization (niraparib, n = 487; placebo, n = 246) from June 2016 to May 2018, patients were assigned for comparison of primary endpoints of PFS for homologous recombination deficiency (50.9%) and for the overall population.
   • At a median follow-up of 13.8 months, the risk of progression in the homologous recombination deficiency population had an HR of 0.43 (95% CI, 0.31−0.59; P < .001) corresponding to a median PFS of 21.9 months versus 10.4 months favoring the drug compared with the placebo. In the overall population selected for this trial, the HR was 0.62, which corresponded to a median PFS of 13.8 months versus 8.2 months (95% CI, 0.50−0.76; P < .001).
   • Grade 3 or higher adverse events, none fatal, consisted of anemia in 31% of patients, thrombocytopenia in 28.7% of patients, and neutropenia in 12.8% of patients; 58 of 307 discontinuations of niraparib were due to adverse events versus 5 of 175 discontinuations of the placebo.
3. VELIA/GOG-3005 (NCT02470585), a phase III placebo-controlled study, assessed the efficacy of oral veliparib added to first-line induction chemotherapy with carboplatin/paclitaxel and continued as maintenance chemotherapy.[54 ] The study randomly assigned 1,140 patients in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance, chemotherapy plus veliparib followed by placebo maintenance, and chemotherapy plus veliparib induction and maintenance (labeled as ‘veliparib throughout'). Doses of veliparib were 150 mg twice daily during induction, and patients who completed six cycles without progression received single-agent veliparib (or matching placebo) at 300 mg twice daily for 2 weeks (labeled as the transition period), and if no dose-limiting side effects were noted, escalated to 400 mg twice daily for an additional 30 cycles of 3 weeks of oral drug. The study accrued patients from July 2015 to July 2017, and the data was analyzed at a median 28 months duration of follow-up. As in the PRIMA study above, efficacy analyses were performed in three sequential inclusive populations: 1) the BRCA mutation cohort, 2) the homologous recombination deficiency cohort (that included the preceding cohort), and 3) the intention-to-treat population.
   • At a median follow-up of 28 months, the BRCA-mutation cohort experienced a PFS of 34.7 months with veliparib throughout versus 22.0 months in the chemotherapy-only arm (induction veliparib added without veliparib maintenance was not compared). This corresponded to an HR of 0.44 (95% CI, 0.28−0.68; P < .001).
   • For the homologous recombination deficiency population, PFS occurred at a median of 31.9 months for the veliparib throughout arm versus 20.5 months for the chemotherapy-alone arm, with an HR of 0.57 (95% CI, 0.43−0.76; P < .001).
   • In the overall population selected, the median PFS was 23.5 months for the veliparib throughout arm versus 17.3 months for the chemotherapy-alone arm, corresponding to an HR of 0.68 (95% CI, 0.56−0.83; P < .001).
   • Veliparib contributed to a higher rate of anemia and thrombocytopenia when combined with chemotherapy, and contributed overall to nausea and fatigue. Adverse events unrelated to progression during the maintenance phase lead to drug discontinuation in 82 patients. Forty of 377 patients going onto maintenance therapy in the veliparib throughout cohort withdrew consent for the trial drug, 22 patients in the chemotherapy-plus-placebo cohort of 371 patients withdrew consent for the trial drug, and 24 patients in the veliparib only as maintenance (not further analyzed in the comparisons) cohort of 383 patients withdrew consent for the trial drug.
4. PAOLA1 (NCT02477644), a placebo-controlled trial, compared first-line chemotherapy with carboplatin/paclitaxel followed by bevacizumab maintenance for 2 years, to the inclusion of olaparib versus placebo in the maintenance phase.[55 ] This study included 537 patients who were assessed for BRCA mutations (including somatic mutations) and a non-homologous recombination deficiency cohort.
   • PFS in the 29% of patients with BRCA mutations was 37.2 months for bevacizumab-plus-olaparib group versus 21.7 months for the bevacizumab-alone maintenance group, which corresponded to an HR of 0.31.
   • For the non-BRCA population, the HR was 0.71, which corresponded to a median PFS of 18.9 months versus 16.0 months.
   • For the overall population, the HR was 0.59, which corresponded to a PFS of 22.1 months for the bevacizumab-plus-olaparib group versus 16.6 months for the bevacizumab-alone maintenance group.

Other consolidation and/or maintenance therapy trials

Phase III trials of consolidation and/or maintenance therapy have been carried out with cytotoxic drugs, small molecules,[56 ] vaccines,[57 ] and radioimmunoconjugates [58 ] with negative results. Extending duration of paclitaxel has resulted in modest lengthening of PFS in randomized trials.[59 ,60 ]

Trials ongoing with anti-angiogenic drugs (other than bevacizumab) and PARP inhibitors are described in the Treatment Options under Clinical Evaluation section that follows.

Treatment Options Under Clinical Evaluation

Trials are ongoing with anti-angiogenic drugs (other than bevacizumab) and with PARP inhibitors. PARP is a family of enzymes involved in base-excision repair of DNA single-strand breaks. In patients with homologous recombination deficiency, including patients with germline BRCA1 or BRCA2 (gBRCA) mutations or with nongermline homologous recombination deficiency–positive tumors, inhibition of PARP results in production of double-strand breaks of DNA. Human DNA repair mechanisms largely rely on one intact copy of the gene; cells with a double-strand break are usually targeted for cell death. This susceptibility of BRCA-deficient or BRCA-mutant cells to PARP inhibition [50 ,51 ] has spurred the clinical development of this class of agents. Sensitivity to platinum compounds is a feature of homologous recombination deficiency, and a population of platinum-sensitive patients is expected to be homologous recombination deficiency enriched and most likely to benefit from PARP inhibition. Several of these drugs have been studied in ovarian cancer as monotherapy or drug combinations and have demonstrated activity in the recurrent setting, with olaparib, rucaparib, and niraparib achieving FDA approval with varying indications. (Refer to the Recurrent or Persistent Ovarian Epithelial Cancer, FTC, and PPC Treatment section of this summary for more information.) Phase III studies are ongoing with these three agents after first-line treatments, and also with a fourth drug, veliparib, which is not otherwise commercially available.

Information about ongoing clinical trials is available from the NCI website.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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48. Burger RA, Brady MF, Bookman MA, et al.: Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365 (26): 2473-83, 2011.
49. Perren TJ, Swart AM, Pfisterer J, et al.: A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365 (26): 2484-96, 2011.
50. Bryant HE, Schultz N, Thomas HD, et al.: Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434 (7035): 913-7, 2005.
51. Farmer H, McCabe N, Lord CJ, et al.: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434 (7035): 917-21, 2005.
52. Moore K, Colombo N, Scambia G, et al.: Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med 379 (26): 2495-2505, 2018.
53. González-Martín A, Pothuri B, Vergote I, et al.: Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med 381 (25): 2391-2402, 2019.
54. Coleman RL, Fleming GF, Brady MF, et al.: Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer. N Engl J Med 381 (25): 2403-2415, 2019.
55. Ray-Coquard I, Pautier P, Pignata S, et al.: Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N Engl J Med 381 (25): 2416-2428, 2019.
56. Vergote IB, Jimeno A, Joly F, et al.: Randomized phase III study of erlotinib versus observation in patients with no evidence of disease progression after first-line platin-based chemotherapy for ovarian carcinoma: a European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group, and Gynecologic Cancer Intergroup study. J Clin Oncol 32 (4): 320-6, 2014.
57. Berek JS, Taylor PT, Gordon A, et al.: Randomized, placebo-controlled study of oregovomab for consolidation of clinical remission in patients with advanced ovarian cancer. J Clin Oncol 22 (17): 3507-16, 2004.
58. Verheijen RH, Massuger LF, Benigno BB, et al.: Phase III trial of intraperitoneal therapy with yttrium-90-labeled HMFG1 murine monoclonal antibody in patients with epithelial ovarian cancer after a surgically defined complete remission. J Clin Oncol 24 (4): 571-8, 2006.
59. Markman M, Liu PY, Wilczynski S, et al.: Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 21 (13): 2460-5, 2003.
60. Pecorelli S, Favalli G, Gadducci A, et al.: Phase III trial of observation versus six courses of paclitaxel in patients with advanced epithelial ovarian cancer in complete response after six courses of paclitaxel/platinum-based chemotherapy: final results of the After-6 protocol 1. J Clin Oncol 27 (28): 4642-8, 2009.

Recurrent or Persistent Ovarian Epithelial Cancer, FTC, and PPC Treatment

Overall, approximately 80% of patients diagnosed with ovarian epithelial cancer, fallopian tube cancer (FTC), and primary peritoneal cancer (PPC) will relapse after first-line platinum-based and taxane-based chemotherapy and may benefit from subsequent therapies. Early detection of persistent disease by second-look laparotomies after completion of first-line treatment is no longer practiced. When the outcomes in institutions practicing such procedures (50% of institutions) were informally compared with the outcomes in institutions not using such procedures, lack of support for second-look laparotomies grew. This was confirmed in the Gynecologic Oncology Group (GOG) GOG-0158 trial.[1 ]

On the other hand, the practice of close follow-up of patients completing treatment by measuring cancer antigen 125 (CA-125) levels at intervals of 1 to 3 months was nearly universally adopted. In patients who are in clinical complete remission, increases in CA-125 from their initial treatment represent the most common method to detect disease that will eventually relapse clinically.

Treatment based on abnormal increases in CA-125 in the absence of symptoms or imaging evidence of disease has been addressed in a clinical trial.

Evidence (early vs. delayed initiation of treatment):

1. A trial by the Medical Research Council (MRC) (MRC-OV05) and the European Organisation for Research and Treatment of Cancer examined the consequences of early treatment for an elevated CA-125 level versus treatment delayed until clinical symptoms appeared.[2 ] Patients in clinical complete remission after platinum-based chemotherapy were registered and followed with CA-125 levels and clinical visits only. Upon detection of a twofold elevation over the normal range, patients were randomly assigned to disclosure of the result and early treatment for recurrence versus continued blinding and treatment upon development of signs and symptoms indicative of clinical relapse. The number of randomly assigned patients was to exceed 500 to yield a superior survival outcome at 2 years with early institution of therapy; this required 1,400 registrations, which were accrued between May 1996 and August 2005.
   • Among 1,442 patients, 29% continued to show no evidence of relapse; however, in 19% of patients, the CA-125 level was noninformative at clinical relapse, or a doubling occurred concurrently with clinical relapse.
   • Patients had stage III and stage IV disease in 67% of the cases; however, these stages represented 80% of the patients with a twofold or higher increase in CA-125 level who subsequently were randomly assigned.
   • The median survival of all patients registered was 70.8 months.
   • Median survival for patients randomly assigned to early treatment (n = 265) was 25.7 months compared with 27.1 months for patients in the delayed-treatment group (n = 264) (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.8–1.2).
   • The median delay in instituting second-line chemotherapy was 4.8 months, and the median delay in instituting third-line chemotherapy was 4.6 months. Second-line chemotherapy treatments were comparable among the two groups (mostly platinum- and taxane-based), whereas third-line treatments were less often applied to the delayed-treatment group.
   • The study concluded that there was no benefit in the detection of early presence of disease by CA-125. This finding is consistent with the failure of second-look surgeries to provide improved outcomes after early detection of persistent disease.

A quality-of-life assessment accompanying this study found a detrimental effect in the early treatment when it was compared with waiting for the development of signs and symptoms.[3 ]

The impact of these findings on CA-125 surveillance patterns over a decade in five U.S. Cancer Centers was disappointingly low.[4 ,5 ] Monitoring CA-125 levels in follow-up was used to separate platinum-sensitive from platinum-resistant recurrences and plays a role in identifying appropriate candidates for secondary cytoreduction, although this strategy awaits confirmation with a randomized trial.

Treatment Options for Patients with Recurrent or Persistent Ovarian Epithelial Cancer, FTC, and PPC

Treatment options for patients with recurrent disease are subdivided as follows:

1. Platinum-sensitive recurrence: For patients whose disease recurs more than 6 months after cessation of the induction, re-treatment with a platinum or platinum-containing combination, such as carboplatin, should be considered (refer to Table 8).
2. Platinum-refractory or platinum-resistant recurrence: For patients who progress before cessation of induction therapy (platinum refractory) or within 6 months after cessation of induction therapy (platinum resistant), platinum therapy is generally not useful as part of the treatment plan. Clinical trials should be considered.

Other agents that have shown activity in phase II trials are listed in Table 10 and may also be used alone or in combination with other drugs, but such treatments are best done in prospective trials.

Cytoreduction may be used;[4 ] this intervention is being studied in the setting of a randomized clinical trial (GOG-0213).

The role of radiation therapy in patients with recurrent ovarian cancer has not been defined.

Platinum-sensitive recurrence

Platinum-containing chemotherapy regimens

Table 8 shows the chemotherapy regimens used in first relapse for the treatment of platinum-sensitive recurrent ovarian cancer.

Table 8. Chemotherapy Regimens Used in Platinum-Sensitive First Relapse

Eligibility (mo since end of initial therapy)	Regimen	No. of Patients	Comparator	Comments on Outcome (mo)
No. = number; OS = overall survival; PFS = progression-free survival; PLD = pegylated liposomal doxorubicin.
a Trabectedin has been approved for use in treating recurrent ovarian cancer in Europe and Canada.
b OS data were not mature at the time the manuscript was published.[6 ]
c P< .0001.
d P = .012.
Most Commonly Used
Platinum sensitive (>6)	Cisplatin or carboplatin + paclitaxel	802	Single-agent nontaxane + platinum agents	PFS 11 vs. 9; OS 24 vs. 19[5 ]
Platinum sensitive (>6)	Carboplatin + gemcitabine	356	Carboplatin	PFS 8.6 vs. 5.8; OS 18 vs. 17[7 ]
Platinum sensitive (>6)	Carboplatin + PLD	976	Carboplatin + paclitaxel	PFS 11.3 vs. 9.4; OS 30.7 vs. 33.0[8 ]
Other Regimens
Platinum sensitive (>6)	Carboplatin + epirubicin	190	Carboplatin	Powered for response differences; OS 17 vs. 15[9 ]
Platinum sensitive (≥12)	Cisplatin + doxorubicin + cyclophosphamide	97	Paclitaxel	PFS 15.7 vs. 9; OS 34.7 vs. 25.8[10 ]
Platinum sensitive + resistant	PLD + trabectedina	672	PLD	PFS 7.3 vs. 5.8; OS 20.5 vs. 19.4b
Platinum sensitive	Paclitaxel + carboplatin	674	Paclitaxel + carboplatin + bevacizumab	PFS 10.4 vs. 13.8c; OS 37.4 vs. 42.2[11 ]
Platinum sensitive	Carboplatin + PLD + bevacizumab	682	Carboplatin + gemcitabine + bevacizumab	PFS 12.4 vs. 11.3d, OS 31.9 vs. 27.8[12 ]

On the basis of improved survival with etoposide or fluorouracil, carboplatin was approved in 1987 for the treatment of patients with ovarian cancer whose disease recurred after treatment with cisplatin.[13 ] In a randomized phase II trial of paclitaxel, a currently used second-line drug, the cisplatin-containing combination of cisplatin plus doxorubicin plus cyclophosphamide, yielded a superior survival outcome.[10 ] This study and subsequent studies (see Table 8) have reinforced the use of carboplatin as the treatment core for patients with platinum-sensitive recurrences. Cisplatin is occasionally used, particularly in combination with other drugs, because of its lesser myelosuppression, but this advantage over carboplatin is counterbalanced by greater patient intolerance.

Oxaliplatin, initially introduced with the hope that it would overcome platinum resistance, has activity mostly in platinum-sensitive patients [14 ] but has not been compared with carboplatin alone or in combinations.

With all platinum agents, outcome is generally better the longer the initial interval without recurrence from the initial platinum-containing regimens.[15 ] Therefore, on occasion, patients with platinum-sensitive recurrences relapsing within 1 year have been included in trials of nonplatinum drugs. In one such trial, comparing the pegylated liposomal doxorubicin to topotecan, the subset of patients who were platinum sensitive had better outcomes with either drug (and in particular with pegylated liposomal doxorubicin) relative to the platinum-resistant cohort.[16 ]

Several randomized trials have addressed whether the use of a platinum in combination with other chemotherapy agents is superior to single agents (see Table 8).

Evidence (platinum in combination with other chemotherapy agents):

1. In an analysis of data examining jointly the results of trials performed by the MRC/Arbeitsgemeinschaft Gynaekologische Onkologie (MRC/AGO) and the International Collaborative Ovarian Neoplasm (ICON) investigators (ICON4), the following results were observed:[5 ,9 ][Level of evidence: 1iiA]
   • A platinum-plus-paclitaxel combination yielded superior response rates, progression-free survival (PFS), and overall survival (OS), compared with carboplatin as a single agent or other platinum-containing combinations as controls.
   • Platinum plus paclitaxel was compared with several control regimens, although 71% used carboplatin as a single agent in the control, and 80% used carboplatin plus paclitaxel. Prolonged PFS (HR, 0.76; 95% CI, 0.66–0.89; P = .004) and OS (HR, 0.82; 95% CI, 0.69–0.97; P = .023) were improved in the platinum-plus-paclitaxel arm.[9 ]; [5 ][Level of evidence: 1iiA]
   • The AGO had previously compared the combination of epirubicin plus carboplatin with carboplatin alone and had not found significant differences in outcome.
   • A meta-analysis of five trials (three of which are in Table 8), with four reviewing independent patient data, supports the use of platinum agents in combination with other active agents rather than carboplatin alone for patients with platinum-sensitive recurrent ovarian cancer.[17 ]
2. Another trial by European and Canadian groups compared gemcitabine plus carboplatin with carboplatin.
   • The PFS of 8.6 months with the combination was significantly superior to 5.8 months for the carboplatin alone (HR, 0.72; 95% CI, 0.58–0.90; P = .003).[7 ][Level of evidence: 1iiDiii]
   • The study was not powered to detect significant differences in OS, and the median survival for both arms was 18 months (HR, 0.96; CI, 0.75–1.23; P = .73).
3. In a phase III trial, carboplatin plus pegylated liposomal doxorubicin was compared with carboplatin plus paclitaxel in patients with platinum-sensitive recurrence (>6 months). The primary endpoint was PFS.
   • The median PFS for the carboplatin-plus-pegylated-liposomal-doxorubicin arm was 11.3 months versus 9.4 months for the carboplatin-plus-paclitaxel arm (HR, 0.823; 95% CI, 0.72–0.94; P = .005).[18 ][Level of evidence: 1iiDiii]
   • Long-term follow-up revealed no difference in OS rates between the two arms (30.7 months for carboplatin plus pegylated liposomal doxorubicin vs. 33.0 months for carboplatin plus paclitaxel).[8 ]
   • The carboplatin-plus-paclitaxel arm was associated with increased severe neutropenia, alopecia, neuropathy, and allergic reaction. The carboplatin-plus-pegylated-liposomal-doxorubicin arm was associated with increased severe thrombocytopenia, nausea, and hand-foot syndrome.

   Given its toxicity profile and noninferiority to the standard regimen, carboplatin plus pegylated liposomal doxorubicin is an important option for patients with platinum-sensitive recurrence.

Carboplatin plus paclitaxel has been considered the standard regimen for platinum-sensitive recurrence in the absence of residual neurological toxic effects. The GOG-0213 trial is comparing this regimen with the experimental arm that adds bevacizumab to carboplatin plus paclitaxel.

Bevacizumab, other targeted drugs, and poly (ADP-ribose) polymerase (PARP) inhibitors with or without chemotherapy

Evidence (bevacizumab with gemcitabine-carboplatin chemotherapy):

1. The Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Diseases (OCEANS [NCT00434642]), assessed the role of bevacizumab in the treatment of platinum-sensitive recurrence (see Table 8 for other trials in this setting). In this double-blind, placebo-controlled, phase III trial of chemotherapy (gemcitabine + carboplatin) with or without bevacizumab for recurrent ovarian epithelial cancer, FTC, or PPC, 242 patients were randomly assigned to each arm. In contrast to the first-line studies, treatment was allowed to continue beyond six cycles to ten cycles in responding patients, but there was no maintenance therapy.[19 ]
   • A subsequent analysis will appear when additional survival data become mature; however, at the time of publication, differences in median OS were not apparent, and crossover from a placebo to bevacizumab had occurred in 31% of the patients.
   • Median PFS for patients receiving bevacizumab was 12.4 months versus 8.4 months for those receiving a placebo.
   • The HR for the effect of bevacizumab on disease progression in patients assigned to the bevacizumab arm compared with placebo was 0.484 (95% CI, 0.388–0.605; P < .0001).
   • Objective responses to chemotherapy were increased when combined with bevacizumab (78.5% vs. 57.4%; P < .0001).
   • Bevacizumab-associated toxicities such as hypertension and proteinuria were more prominent than in the first-line trials, but feared safety issues such as gastrointestinal perforations did not occur during the study.
   • Discontinuing treatment because of adverse events was more common with bevacizumab (n = 55 vs. n = 12 for placebo), but fewer patients discontinued treatment because of disease progression (n = 104 for bevacizumab vs. n = 160 for placebo).

Evidence (bevacizumab with paclitaxel-carboplatin chemotherapy):

1. NRG Oncology Group, or National Clinical Trials Network group, a combined research effort of the National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the GOG (GOG-0213 [NCT00565851]) assessed both the role of surgical debulking and the addition of bevacizumab induction and maintenance in women with platinum-sensitive recurrences of ovarian cancer.[11 ][Level of evidence: 1iiA] The nonsurgical portion of GOG-0213 had 81% power for a true HR of 0.75; it enrolled 674 women from December 2007 to August 2011, and the published analysis took place after a median follow-up exceeding 4 years.
   • OS was not significantly different: 37.3 months (95% CI, 32.6–39.7) versus 42.2 months (95% CI, 37.7–46.2).
   • The secondary endpoint of median PFS was significantly in favor of the addition of bevacizumab: 10.4 months (95% CI, 9.7–11) for chemotherapy alone versus 13.8 months (95% CI, 13.0–14.7).
   • Bevacizumab (15 mg/kg q 3 weeks) with chemotherapy and its use in maintenance led to an excess of grade 3 and 4 adverse events (8% for chemotherapy alone vs. 30%), any bleeding (12% vs. 42%), and any hypertension (3% vs. 41%).

Evidence (bevacizumab + pegylated liposomal doxorubicin/carboplatin vs. bevacizumab + gemcitabine/carboplatin):

Refer to Table 8 for results of clinical trials that used gemcitabine/carboplatin.[12 ,19 ] Adverse events differed among the two comparators but serious adverse events were 10% with pegylated liposomal doxorubicin/carboplatin and 9% with gemcitabine/carboplatin. Specifically, hypertensive crisis, presumably related to bevacizumab, occurred in five patients after receiving pegylated liposomal doxorubicin/carboplatin and in three patients after receiving gemcitabine/carboplatin.

Evidence (PARP inhibitors with or without anti-angiogenic agents):

PARP is a family of enzymes involved in base-excision repair of DNA single-strand breaks. In patients with homologous recombination deficiency, including patients with germline BRCA1 or BRCA2 (gBRCA) mutations or with nongermline homologous recombination deficiency–positive tumors, inhibition of PARP results in production of double-strand breaks of DNA. Human DNA repair mechanisms largely rely on one intact copy of the gene; cells with a double-strand break are usually targeted for cell death. This susceptibility of BRCA-deficient or BRCA-mutant cells to PARP inhibition [20 ,21 ] has spurred the clinical development of this class of agents. Sensitivity to platinum compounds is a feature of homologous recombination deficiency, and a population of platinum-sensitive patients is expected to be homologous recombination deficiency-enriched and most likely to benefit from PARP inhibition. Clinical studies with olaparib have been ongoing since 2005 when a phase I study enrolled women with ovarian cancer who were known BRCA mutation carriers. Because of objective responses in this initial trial, olaparib, and subsequently rucaparib and niraparib, have been studied after several lines of treatment for recurrence; these studies lead to an initial approval for olaparib, and then rucaparib and niraparib, as listed in Table 9.

Table 9. Indications for PARP Inhibitors in Ovarian Cancer

Drug	PARP−trapping Potency	FDA-approved Indications	Dose	Key Trials	Toxicities	Other Features
AML = acute myeloid leukemia; CR = complete response; bid = twice a day; FDA = U.S. Food and Drug Administration; FTC = fallopian tube cancer; gBRCA= germlineBRCA; HRD = homologous recombination deficiency; MDS = myelodysplastic syndrome; PARP = poly (ADP-ribose) polymerase; PO = by mouth; PPC = primary peritoneal cancer; PR = partial response; tBRCA= tumorBRCA.
Olaparib	Intermediate	Treatment of deleterious or suspected deleterious gBRCAmutated advanced ovarian cancer after >2 lines of chemotherapy; maintenance treatment of recurrent ovarian epithelial cancer, FTC, or PPC in patients with CR or PR to platinum-based chemotherapy, regardless ofBRCAstatus	300 mg tablet bid (replacing the 400 mg capsules)	Study 19, Study 42,SOLO2(NCT01874353),SOLO1(NCT01844986) (updated October 2018), others ongoing	Nausea, fatigue, myelosuppression (especially anemia), abdominal pain; rare cases of MDS/AML	Companion diagnostic evaluating for deleterious gBRCAmutations when olaparib is used in treatment (not maintenance)
Rucaparib	Low-intermediate	Treatment of deleterious gBRCAor tBRCAmutated ovarian epithelial cancer, FTC, or PPC in patients who have been treated with ≥2 previous lines of chemotherapy; maintenance treatment of recurrent ovarian epithelial cancer, FTC, or PPC in patients with CR or PR to platinum-based chemotherapy, regardless ofBRCAstatus	600 mg PO bid	Study 10,ARIEL2(NCT01891344),ARIEL3(NCT01968213),ARIEL4(NCT02855944) (ongoing), many others ongoing	Nausea, fatigue, elevated liver enzymes, myelosuppression (especially anemia), abdominal pain; rare cases of MDS/AML	Companion diagnostic evaluating for deleteriousBRCAmutations when rucaparib is used in treatment (not maintenance); HRD assays used, but are not yet approved for use
Niraparib	Intermediate-high	Maintenance treatment of recurrent ovarian epithelial cancer, FTC, or PPC in patients with CR or PR to platinum-based chemotherapy, regardless ofBRCAstatus	300 mg PO once daily	NOVA(NCT01847274),QUADRA(NCT02354586),TOPACIO(NCT02657889) (ongoing),PRIMA(NCT02655016) (ongoing), others ongoing	Nausea, fatigue, constipation, hypertension, myelosuppression (especially ↓ platelets); rare cases of MDS/AML	HRD assays were used in the key clinical trials, but are not yet approved for use
Veliparib	Low	None yet		Ongoing trials combining veliparib with chemotherapy
Talazoparib	High	None yet		Ongoing trials, some with immunotherapy

1. In a randomized, double blind, placebo-controlled phase II trial of olaparib maintenance therapy, eligible patients had platinum-sensitive, high-grade serous ovarian cancer. Patients were randomly assigned to receive olaparib (400 mg bid) or placebo. Having a gBRCA1 or gBRCA2 mutation was not required for eligibility; however, 23% of patients in the experimental group and 22% of patients in the placebo group had a known BRCA1 or BRCA2 mutation. The primary endpoint was PFS.[22 ][Level of evidence: 1iiDiii]
   • PFS was longer in the olaparib arm; median 8.4 months versus 4.8 months (HR, 0.35; 95% CI, 0.25–0.49; P < .001).
   • OS was not different between the two groups, as noted in an updated report.[23 ]
   • The more common adverse events in the olaparib group were nausea, fatigue, vomiting, and anemia.
2. Olaparib tablets (as opposed to the previous capsule formulation) underwent evaluation in SOLO2 (NCT01874353), a double-blind, randomized, placebo-controlled phase III trial in patients with high-grade serous or endometrioid cancer, PPC, or FTC. Patients had platinum-sensitive relapses and were preselected for BRCA1/2 mutations.[24 ][Level of evidence: 1iiDiii] Stratification for response (complete vs. partial) to previous platinum and platinum-free intervals (>6–12 vs. >12) and 2:1 random allocation to olaparib in two 150-mg twice-daily or matching placebo tablets took place. Of 295 eligible patients enrolled, 196 were assigned to olaparib, and 99 were assigned to a placebo.
   • The primary endpoint was PFS and significantly favored olaparib 19.1 months (95% CI, 16.3–25.7) more than placebo (5.5 months [range, 5.2–5.8 months]; HR, 0.30 [95% CI, 0.22–0.41]; P < .0001).
   • Serious adverse events were experienced by 18% of patients who received olaparib and by 8% who received placebo. The adverse events consisted mostly of anemia, abdominal pain, and intestinal obstruction.
   • In this trial, a comprehensive assessment of health-related quality-of-life measurements was carried out in patients who received olaparib compared with patients who received placebo.[25 ] The Trial Outcome Index score was used in a prespecified analysis of changes, showing that several measurements were met. In addition, time without significant symptoms of toxicity and quality-adjusted PFS were longer in patients who were treated with olaparib. These assessments supplement other measurements such as time to first treatment and time to subsequent therapy or death that have been sought to supplement PFS as a primary endpoint for drug approval.
3. The SOLO3 trial [NCT00628251], a phase III study that employed 2:1 randomization, compared olaparib tablets with physicians' choice of nonplatinum chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, gemcitabine, or topotecan) for the treatment of recurrent platinum-sensitive ovarian cancer and gBRCA1/BRCA2 mutations.[26 ] A previous randomized phase II study of dose levels of olaparib capsules at either 200 or 400 mg twice daily versus pegylated liposomal doxorubicin had failed to show an advantage over chemotherapy.[27 ] In SOLO3, 178 patients were allocated to receive olaparib and 88 patients received physicians' choice chemotherapy. The primary endpoint was overall response rate.
   • Of 151 patients assessed, 109 had objective responses to olaparib (14 complete responses), whereas of 72 patients assessed, 37 had objective responses to chemotherapy (2 complete responses).
   • Adverse events were consistent with established safety profiles of olaparib and the chemotherapy comparators, but in this pretreated population, four patients assigned to receive olaparib and three patients assigned to receive chemotherapy developed acute myeloid leukemia (AML)/myelodysplasia; new primary malignancies also occurred in three patients assigned to receive olaparib.[26 ][Level of evidence: 1iiDiii]
4. Rucaparib underwent phase II evaluation in ARIEL2 (NCT01891344), an open-label study enrolling 206 patients, 204 of whom were actually receiving the drug (192 were actually in classifiable subgroups) and had high-grade platinum-sensitive recurrences between October 2013 and November 2014.[28 ][Level of evidence: 3iiDiii] The following three predefined homologous recombination deficiency subgroups on the basis of tumor mutational analysis were studied:
   • BRCA mutant (deleterious genetic or somatic) (n = 40).
   • BRCA wild type and high loss of heterozygosity (LOH) quantified by next-generation sequencing analysis (LOH high) (n = 82).
   • BRCA wild type and low LOH (LOH low) (n = 70).
   The drug was given orally at 600 mg twice daily, and patients were treated until disease progression or other reasons for discontinuation. Median duration of treatment for the 204 patients was 5.7 months.
   • Median PFS after the start of rucaparib treatment for patients with deleterious BRCA mutations was 12.8 months (95% CI, 9.0–14.7); for those with LOH, high was 5.7 months (range, 5.3–7.6 months), and low was 5.2 months (range, 3.6–5.5 months).
   • The study also showed that mutation and methylation status of BRCA and other homologous recombination-related genes, such as RAD51C, can be associated with high genomic LOH in BRCA wild-type tumors, conferring higher rates of response to rucaparib than are seen in patients with low genomic LOH.
5. Rucaparib was later assessed as maintenance therapy after response to platinum therapy in a randomized double-blind, placebo-controlled phase III trial (ARIEL 3 [NCT01968213]).[29 ] To be eligible, patients had high-grade carcinomas that were previously treated with at least two platinum-containing regimens and had achieved complete or partial responses to the last platinum-containing regimen. In a 2:1 treatment allocation, from April 2014 to July 2016, 375 patients received rucaparib, and 189 patients received placebo. PFS, as determined by the investigator, was the primary endpoint using a step-down procedure for the following three determined, nested treatment cohorts:
   • Patients known to have deleterious germline or somatic BRCA mutations: PFS of 16.6 months in the rucaparib group (95% CI, 13.4–22.9) versus 5.4 months in the placebo group (95% CI, 3.4–6.7; HR, 0.23; 95% CI, 0.16–0.34; P < .0001).
   • Patients with homologous recombination deficiencies: PFS of 13.6 months in the rucaparib group (95% CI, 10.9–16.2) versus 5.4 months in the placebo group (95% CI, 5.1–5.6; HR, 0.32; 95% CI, 0.24–0.42; P < .00011).
   • The intention-to-treat population: PFS of 10.8 months in the rucaparib group (95% CI, 8.3–11.4) versus 5.4 months in the placebo group (95% CI, 5.3–5.5; HR, 0.24–0.42; P < .0001.
   Treatment-emergent adverse events of grade 3 or higher in the rucaparib group versus the placebo group consisted primarily of anemia (19% vs. 1%) and increased alanine or aspartate aminotransferases (10% vs. 0%). In an updated outcomes intention-to-treat and safety analysis for all cohorts, at a median follow-up of 28 months, rucaparib had significant, persistent advantages in PFS compared with placebo (14.3 months vs. 8.8 months [HR, 0.43; 95% CI, 0,35−0.53]).[30 ][Level of evidence: 1iiDiii] Time to first subsequent therapy, time to progression on subsequent therapy, and time to start a second subsequent treatment were also significantly in favor of rucaparib. Three occurrences of AML/myelodysplasia treatment-related events had been previously reported, and treatment-emergent serious adverse events were recorded in 22% of patients who received rucaparib versus 11% of patients who received placebo. Anemia was the most common toxicity attributed to rucaparib (in 22% of patients).
6. Niraparib activity as late-line treatment for patients with ovarian cancer was studied from 2015 to 2017 in a multicenter, open-label, single-arm phase II trial (QUADRA [NCT02354586]).[31 ] It enrolled 463 women who had received a median of four (range, 3−5) previous regimens (151 patients were platinum resistant and 161 patients were platinum refractory).
   • In the primary efficacy measurable population, 13 of 47 patients responded according to Response Evaluation Criteria in Solid Tumors (RECIST).[31 ][Level of evidence: 3iiiDiii]
   • Homologous recombination deficiency was a predictor of response.
7. Niraparib was evaluated further in a double-blind, placebo-controlled phase III trial of 533 patients with platinum-sensitive, predominantly high-grade serous ovarian cancer, who were randomly assigned in a 2:1 ratio to maintenance with oral niraparib or placebo and followed for the primary endpoint of PFS.[32 ] Patients were categorized according to the presence or absence of gBRCA or non-BRCA homologous recombination deficiency–positive ovarian cancer or non-BRCA homologous recombination deficiency–negative ovarian cancer, based on BRCAAnalysis testing (Myriad Genetics) from tumor and blood samples.
   1. Patients who received niraparib had significantly longer median PFS duration compared with a placebo.[32 ][Level of evidence: 1iiDiii] Comparisons across categories ranged from HR, 0.27 for gBRCA cancer (21.0 months vs. 5.5 months), HR, 0.38 for non-BRCA cancer, homologous recombination deficiency-positive cancer (12.9 months vs. 3.8 months), and HR, 0.45 for non-BRCA, homologous recombination deficiency-negative cancer (9.3 months vs. 3.9 months).
   2. Deaths during the study occurred in 16.1% of patients who received niraparib and 19.3% of patients on placebo.
   3. One-third to nearly one-half of the patients had received at least three previous lines of therapy that included the following:
      • Grade 3 or 4 adverse events that were managed with dose modifications while patients received niraparib included thrombocytopenia (in 33.8% of patients), anemia (in 25.3%), and neutropenia (in 19.6%).
      • Other excess severe toxicities in patients who received niraparib occurred at starting doses of 300 mg once daily and included fatigue (in 30 patients vs. 1 patient on the placebo), hypertension (in 30 patients vs. 4 on the placebo), nausea (in 11 patients vs. 2 on the placebo), and vomiting (in 7 patients vs. 1 on the placebo).
      • A subsequent analysis of the ENGOT-OV16/NOVA trial (NCT01847274) updates PFS after maintenance niraparib or placebo according to the best response (partial response [PR] or complete response [CR]) from the last platinum-based chemotherapy in patients with gBRCA mutations and in non-gBRCA mutation cohorts.[33 ]
        • The HR was significant for niraparib versus placebo, and was seen in both groups.
        • No meaningful differences in patient-reported outcomes were observed.
   4. A phase III, randomized, double-blind, placebo-controlled study of niraparib maintenance in patients with homologous recombination deficiency–positive advanced ovarian cancer following response to front-line platinum-based chemotherapy (NCT01847274) is closed to patient accrual and results are pending.
   5. Other PARP inhibitor trials have been exploring their role in platinum-resistant disease and their role in combination with other agents.
8. Olaparib was also evaluated as a single agent in a multicenter phase II trial for patients with documented germline BRCA1- or BRCA2 mutations.[34 ][Level of evidence: 3iiiDiv] This trial was open to patients with platinum-resistant ovarian cancer, breast cancer treated with three or more previous regimens, pancreatic cancer with previously administered gemcitabine, or prostate cancer previously treated with hormonal therapy and one systemic therapy. Olaparib was given at 400 mg twice a day. The primary endpoint was response rate. A total of 298 patients were included.
   • The overall response rate was 26.2%; the response rate was 31.1% in patients with ovarian cancer.[34 ][Level of evidence: 3iiiDiv]

   The data from this trial were used by the U.S. Food and Drug Administration (FDA) to approve olaparib for patients with ovarian cancer who have known BRCA1 or BRCA2 mutations and have failed three previous regimens.

9. Several other trials have combined olaparib with either cytotoxic chemotherapy or other biologic therapy.[35 ,36 ] .
   • Extension in PFS, but not in OS, has been noted.

Platinum-refractory or platinum-resistant recurrence

Chemotherapy

Clinical recurrences that take place within 6 months of completion of a platinum-containing regimen are considered platinum-refractory or platinum-resistant recurrences. Anthracyclines (particularly when formulated as pegylated liposomal doxorubicin), taxanes, topotecan, and gemcitabine are used as single agents for these recurrences on the basis of activity and their favorable therapeutic indices relative to agents listed in Table 10. The long list underscores the marginal benefit, if any, of these agents. Clinical trials should be considered for patients with platinum-resistant disease.

Drugs used to treat platinum-refractory or platinum-resistant recurrences include the following:

• Paclitaxel.

  Treatment with paclitaxel historically provided the first agent with consistent activity in patients with platinum-refractory or platinum-resistant recurrences.[37 ,38 ,39 ,40 ,41 ] Patients generally received paclitaxel in front-line induction regimens. Re-treatment with paclitaxel, particularly in weekly schedules, had activity comparable with that of other drugs. Residual neuropathy upon recurrence may shift the choice of treatment towards other agents.

• Topotecan.

  Randomized studies have indicated that the use of topotecan achieved results that were comparable with those achieved with paclitaxel.[42 ]

  Evidence (topotecan):

  1. Topotecan was compared with pegylated liposomal doxorubicin in a randomized trial of 474 patients and demonstrated similar response rates, PFS, and OS at the time of the initial report. Responses occurred primarily in the platinum-resistant subsets.[43 ]
  2. In phase II studies, topotecan administered intravenously on days 1 to 5 of a 21-day cycle yielded objective response rates ranging from 13% to 16.3% and other outcomes that were equivalent or superior to paclitaxel.[44 ,45 ,46 ]
     • Objective responses were reported in patients with platinum-refractory disease.
     • Substantial myelosuppression followed administration. Other toxic effects included nausea, vomiting, alopecia, and asthenia. Some schedules and oral formulations to reduce toxicity are under evaluation.
  3. In a phase III study, 235 patients who did not respond to initial treatment with a platinum-based regimen, but who had not previously received paclitaxel or topotecan, were randomly assigned to receive either topotecan as a 30-minute infusion daily for 5 days every 21 days or paclitaxel as a 3-hour infusion every 21 days.[42 ][Level of evidence: 1iiDiii]
     • The overall objective response rate was 20.5% for patients who were randomly assigned to treatment with topotecan and 13.2% for patients who were randomly assigned to treatment with paclitaxel (P = .138).
     • Both groups experienced myelosuppression and gastrointestinal (GI) toxic effects. Nausea and vomiting, fatigue, and infection were observed more commonly after treatment with topotecan, whereas alopecia, arthralgia, myalgia, and neuropathy were observed more commonly after treatment with paclitaxel.[42 ]
  4. The combination of weekly topotecan and biweekly bevacizumab was evaluated in a phase II study.
     • Results showed an objective response rate of 25% (all partial responses) in a platinum-resistant patient population.[47 ]
     • The most common grade 3 and grade 4 toxicities were hypertension, neutropenia, and GI toxicity, although no bowel perforations occurred.
• Pegylated liposomal doxorubicin

  Evidence (pegylated liposomal doxorubicin):

  1. In a phase II study encapsulated doxorubicin was given intravenously (IV) once every 21 to 28 days.[48 ]
     • Results demonstrated one complete response and eight partial responses in 35 patients with platinum-refractory or paclitaxel-refractory disease (response rate, 25.7%).
     • In general, liposomal doxorubicin has few acute side effects other than hypersensitivity. The most frequent toxic effects (stomatitis and hand-foot syndrome) were usually observed after the first cycle, and were more pronounced after dose rates exceeded 10 mg/m² per week. Neutropenia and nausea were minimal, and alopecia rarely occurred.
  2. Pegylated liposomal doxorubicin and topotecan have been compared in a randomized trial of 474 patients with recurrent ovarian cancer.[43 ][Level of evidence: 1iiA]
     • Response rates (19.7% vs. 17.0%; P = .390), PFS (16.1 weeks vs. 17.0 weeks; P = .095), and OS (60 weeks vs. 56.7 weeks; P = .341) did not differ significantly between the pegylated liposomal doxorubicin and topotecan arms.[43 ][Level of evidence: 1iiA]
     • Survival was longer for the patients with platinum-sensitive disease who received pegylated liposomal doxorubicin.[16 ]
• Docetaxel.

  This drug has shown activity in paclitaxel-pretreated patients and is a reasonable alternative to weekly paclitaxel in the recurrent setting.[49 ]

• Gemcitabine.

  Evidence (gemcitabine):

  1. Several phase II trials of gemcitabine as a single-agent–administered IV on days 1, 8, and 15 of a 28-day cycle have been reported.[50 ,51 ,52 ]
     • The response rate ranged from 13% to 19% in evaluable patients.
     • Responses have been observed in patients whose disease was platinum refractory and/or paclitaxel refractory as well as in patients with bulky disease.
     • Leukopenia, anemia, and thrombocytopenia were the most common toxic effects. Many patients reported transient flu-like symptoms and a rash after drug administration. Other toxic effects, including nausea, were usually mild.
  2. A randomized trial of gemcitabine versus pegylated liposomal doxorubicin showed noninferiority and no advantage in therapeutic index of one drug over the other.[53 ]

• Pemetrexed.

  Evidence (pemetrexed):

  1. A randomized, double-blinded phase II European trial with 102 patients evaluated pemetrexed at two doses: standard-dose (500 mg/m²) versus high-dose (900 mg/m²) IV every 3 weeks.[54 ]
     • The response rate was 9.3% for the standard dose and 10.4% for the high dose.
     • The toxicity profile favored the standard dose, with fatigue, nausea, and vomiting as the most common severe toxicities.
  2. A phase II study by the GOG utilized pemetrexed (900 mg/m²) IV every 3 weeks in 51 patients with platinum-resistant recurrent disease.[55 ]
     • The response rate was 21% in a heavily pretreated population in which 39% of the patients had received five or more regimens previously.
     • Myelosuppression and fatigue were the most common severe toxicities.

Chemotherapy and/or bevacizumab

• Chemotherapy with or without bevacizumab.

  The FDA has approved the use of bevacizumab in combination with pegylated liposomal doxorubicin, paclitaxel, or topotecan as a result of the OCEANS and AURELIA trials.

  OCEANS (NCT00434642) assessed the role of bevacizumab in the treatment of platinum-sensitive recurrences. (Refer to the Bevacizumab with chemotherapy in platinum-sensitive recurrence section of this summary for more information.)

  Evidence (bevacizumab with chemotherapy):

  1. The Avastin Use in Platinum-Resistant Epithelial Ovarian Cancer (AURELIA [NCT00976911]) trial was an open-label, randomized trial designed to evaluate the effect of adding bevacizumab to standard chemotherapy in patients with platinum-resistant recurrent ovarian cancer.[56 ] Eligible patients had platinum-resistant disease (progression within 6 months of finishing a regimen) and no more than two previous regimens. Patients with platinum-refractory disease (those with progression during receipt of a platinum-containing regimen) and those with clinical or radiological signs of bowel involvement were ineligible. Patients were prescribed one of the following three chemotherapy regimens, on the basis of physician preference:
     1. Pegylated liposomal doxorubicin 40 mg/m² by IV on day 1 every 4 weeks.
     2. Paclitaxel 80 mg/m² by IV on days 1, 8, 15, and 22 every 4 weeks.
     3. Topotecan 4 mg/m² by IV on days 1, 8, and 15 every 4 weeks; or 1.25 mg/m² by IV on days 1 through 5 every 3 weeks.

     Patients were then randomly assigned to receive either chemotherapy alone or chemotherapy with bevacizumab (10 mg/kg every 2 weeks, or 15 mg/kg every 3 weeks if on the 3-week-dosing schedule). Crossover to a bevacizumab-containing regimen was allowed at progression for those patients in the chemotherapy-only arm. PFS was the primary outcome, with response rate, OS, safety, and quality of life used as secondary endpoints. The enrollment included 361 patients with a median follow-up of 13.9 months in the chemotherapy-only arm and 13.0 months in the chemotherapy-plus-bevacizumab arm.

     • Patients in the bevacizumab arm exhibited longer PFS (HR, 0.48; 95% CI, 0.38 to 0.60); median PFS was 3.4 months in the chemotherapy-alone arm versus 6.7 months in the chemotherapy-plus-bevacizumab arm.
     • The objective response rate was 12.6% in the chemotherapy-alone arm versus 30.9% in the chemotherapy-plus-bevacizumab arm.
     • There was no statistically significant difference in OS between the regimens (13.3 months chemotherapy alone vs. 16.6 months chemotherapy plus bevacizumab).
     • Patients in the chemotherapy-plus-bevacizumab arm had an increased incidence of hypertension and proteinuria, when compared with patients in the chemotherapy-only arm.
     • GI perforation occurred in 2% of those receiving chemotherapy plus bevacizumab, which reflects the study's stringent exclusion criteria.
     • The primary endpoint for the quality-of-life portion of the study was a 15% or greater absolute improvement in the abdominal and GI symptom portion of the assessment modules at week 8 to week 9 of the protocol for patients in the chemotherapy-plus-bevacizumab arm.[57 ][Level of Evidence: 1iC] The study used patient-reported outcomes from the European Organization for Research and Treatment of Cancer Ovarian Cancer Module 28 and the Functional Assessment of Cancer Therapy-Ovarian Cancer symptom index at baseline and every 8 to 9 weeks until disease progression.

     Although there were some limitations in study design,[58 ] more patients on the chemotherapy-plus-bevacizumab arm had 15% or greater improvement in their GI scores when compared with baseline. For the chemotherapy-plus-bevacizumab arm, 34 of 115 patients (29.6%) showed improvement versus 15 of 118 (12.7%) patients who showed improvement on the chemotherapy-alone arm (difference, 16.9%; 95% CI, 6.1%–27.6%; P = .002).

     These studies confirm the effect of improving PFS when bevacizumab is added to chemotherapy for ovarian cancer. In the OCEANS trial, the HR for progression was even more prominent than in the first-line trials, and a significant effect was seen when the bevacizumab-chemotherapy combination was extended beyond six cycles until progression.

     In summary, the improvement achieved by bevacizumab in relative risk and PFS rates in platinum-sensitive and platinum-resistant recurrences has been consistently more than the improvement achieved with chemotherapy alone; however, bevacizumab-related toxic effects must be considered.

• Bevacizumab alone.

  Three phase II studies have shown activity for this antibody to vascular endothelial growth factor.

  1. The first study (GOG-0170D) included 62 patients who had received only one or two previous treatments. These last patients had received one additional platinum-based regimen because of an initial interval of 12 months or longer after first-line regimens and also had to have a performance status of 0 or 1.[59 ] Patients received a dose of 15 mg/kg every 21 days.
     • There were two complete responses and 11 partial responses, a median PFS of 4.7 months, and an OS of 17 months. This activity was noted in both platinum-sensitive and platinum-resistant subsets.
  2. The second study included only patients with platinum-resistant disease using an identical dose schedule.
     • The study was stopped because 5 of 44 patients experienced bowel perforations, one of them fatal; seven partial responses had been observed.[60 ] This increased risk of bowel perforations was associated with three or more previous treatments.[61 ,62 ,63 ][Level of evidence: 3iiiDii]
  3. The third study (CCC-PHII-45) included 70 patients who received 50 mg of oral cyclophosphamide daily, in addition to bevacizumab (10 mg/kg q 2 weeks).
     • Partial responses were observed in 17 patients, and 4 patients had intestinal perforations.[64 ]

Other drugs used to treat platinum-refractory or platinum-resistant recurrence (efficacy not well defined)

The drugs shown in Table 10 are not fully confirmed to have activity in a platinum-resistant setting, have a less desirable therapeutic index, and have a level of evidence lower than 3iiiDiv.

Table 10. Other Drugs That Have Been Used in the Setting of Recurrent Ovarian Cancer(Efficacy Not Well Defined After Failure of Platinum-Containing Regimens)

Drugs	Drug Class	Major Toxicities	Comments
Etoposide	Topoisomerase II inhibitor	Myelosuppression; alopecia	Oral administration; rare leukemia lessens acceptability and dampens interest
Cyclophosphamide and several other bis chloroethyl amines	Alkylating agents	Myelosuppression; alopecia (only the oxazaphosphorines)	Leukemia and cystitis; uncertain activity after platinum agents
Hexamethylmelamine (Altretamine)	Unknown but probably alkylating prodrugs	Emesis and neurologic toxic effects	Oral administration; uncertain activity after platinum agents
Irinotecan	Topoisomerase I inhibitor	Diarrhea and other gastrointestinal symptoms	Cross-resistant to topotecan
Oxaliplatin	Platinum	Neuropathy, emesis, myelosuppression	Cross-resistant to usual platinum agents, but less so
Vinorelbine	Mitotic inhibitor	Myelosuppression	Erratic activity
Fluorouracil and capecitabine	Fluoropyrimidine antimetabolites	Gastrointestinal symptoms and myelosuppression	Capecitabine is oral; may be useful in mucinous tumors
Tamoxifen	Antiestrogen	Thromboembolism	Oral administration; minimal activity, perhaps more in subsets

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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64. Garcia AA, Hirte H, Fleming G, et al.: Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol 26 (1): 76-82, 2008.

Changes to This Summary (09 / 03 / 2020)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information About Ovarian Epithelial Cancer, Fallopian Tube Cancer, and Primary Peritoneal Cancer

Updated statistics with estimated new cases and deaths for 2020 (cited American Cancer Society as reference 5).

Revised the clinical presentation list of signs and symptoms.

Stage Information for Ovarian Epithelial Cancer, Fallopian Tube Cancer, and Primary Peritoneal Cancer

Added Prat et al. as reference 2.

Early-Stage Ovarian Epithelial Cancer, FTC, and PPC Treatment

Revised text about the increased risk of recurrence in patients with stage II disease and in those classified as having high-grade serous cancer.

Revised text to state that the following treatments have been largely displaced by the adoption of carboplatin plus paclitaxel for early stages of high-grade ovarian cancers.

Advanced-Stage Ovarian Epithelial Cancer, FTC, and PPC Treatment

This section was extensively revised.

Recurrent or Persistent Ovarian Epithelial Cancer, FTC, and PPC Treatment

Revised Table 8 Chemotherapy Regimens Used in Platinum-Sensitive First Relapse to add a row for carboplatin plus pegylated liposomal doxorubicin (PLD) plus bevacizumab versus carboplatin plus gemcitabine plus bevacizumab (cited Pfisterer et al. as reference 12).

Added text about comparison of serious adverse events of bevacizumab plus PLD/carboplatin versus bevacizumab plus gemcitabine/carboplatin.

Revised text to state that clinical studies with olaparib have been ongoing since 2005 when a phase I study enrolled women with ovarian cancer who were known BRCA mutation carriers. Because of objective responses in this initial trial, olaparib, and subsequently rucaparib and niraparib, have been studied after several lines of treatment for recurrence; these studies lead to an initial approval for olaparib, and then rucaparib and niraparib.

Added Table 9 Indications for PARP Inhibitors in Ovarian Cancer as a new table.

Added text to describe the randomization, objective responses to chemotherapy, and adverse events of the phase III SOLO3 trial (cited Penson et al. as reference 26 and level of evidence 1iiDiii and cited Kaye et al. as reference 27).

Added text to describe an updated outcomes intention-to-treat and safety analysis of the phase III ARIEL 3 trial (cited Ledermann et al. as reference 30 and level of evidence 1iiDiii).

Added text to describe findings in treatment response of the phase II QUADRA trial (cited Moore et al. as reference 31 and level of evidence 3iiiDiii).

Added text about the a subsequent analysis of the ENGOT-OV16/NOVA trial (cited Del Campo et al. as reference 33).

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of ovarian epithelial, fallopian tube, and primary peritoneal cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment are:

• Leslie R. Boyd, MD (New York University Medical Center)
• Franco M. Muggia, MD (New York University Medical Center)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/ovarian/hp/ovarian-epithelial-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389443]

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Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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Last Revised: 2020-09-03