Elsevier

The Lancet

Volume 374, Issue 9698, 17–23 October 2009, Pages 1371-1382
The Lancet

Seminar
Ovarian cancer

https://doi.org/10.1016/S0140-6736(09)61338-6Get rights and content

Summary

The standard initial management of epithelial ovarian cancer consists of surgical staging, operative tumour debulking including total abdominal hysterectomy and bilateral salpingo-oophorectomy, and administration of six cycles of intravenous chemotherapy with carboplatin and paclitaxel. Extensive and largely retrospective experience has shown that optimum surgical debulking to leave residual tumour deposits that are less than 1 cm in size is associated with improved patient outcomes. However, 75% of patients present with advanced (stage III or IV) disease and, although more than 80% of these women benefit from first-line therapy, tumour recurrence occurs in almost all these patients at a median of 15 months from diagnosis. Second-line treatments can improve survival and quality of life but are not curative. Advances in screening and understanding of molecular pathogenesis of ovarian cancer and development of novel targeted therapies (eg, bevacizumab) and practical intraperitoneal techniques for drug delivery are most likely to improve patient outcomes.

Section snippets

Epidemiology and risk factors

Epithelial ovarian cancer results from malignant transformation of the ovarian surface epithelium, which is contiguous with the peritoneal epithelium.1 The disease is the sixth most common cancer in women.2 Most patients present with advanced disease (figure 1) and have a poor prognosis with present therapies. Advances in chemotherapy and improved understanding of genetic risk factors and molecular pathogenesis have provided new treatment possibilities. We describe the clinical and molecular

Pathology

Epithelial ovarian cancers are classified by histopathological grade (1–3) and appearance into serous (most common), mucinous, endometrioid, and, less commonly, clear cell, transitional, squamous, mixed, and undifferentiated subtypes. Additionally, fallopian tube and primary peritoneal cancers occur that morphologically and clinically resemble epithelial ovarian cancers, possibly because the same embryonic precursor is shared by the ovarian surface epithelium and the peritoneal and fallopian

Causes and pathogenesis

Although the subtypes of epithelial ovarian cancer possess unique molecular aberrations (table 1) and transcriptional signatures, their morphological features resemble the specialised epithelia of the reproductive tract that derive from the Müllerian ducts. Research suggests that they might all arise from one surface epithelium precursor cell with specific path of differentiation regulated by embryonic pathways involving HOX genes (figure 3).16, 17, 18 HOX genes are not usually expressed in

Screening

Early detection might substantially improve survival if metastatic disease results from progression of clinically detectable early lesions, and if cancers remain localised for a sufficient interval to allow cost-effective screening.28 In view of the prevalence of epithelial ovarian cancer, strategies for early detection should have high sensitivity (>75%) and very high specificity (99·6%) to attain a positive predictive value of 10% or greater. Serum CA125 concentration does not have the

Staging and diagnosis

Panel 1 shows staging of epithelial ovarian cancers.36 From the primary tumour, propagation can occur throughout the abdominopelvic peritoneal compartment (figure 1) and to retroperitoneal pelvic, periaortic, suprarenal, mesenteric, and mesocolic lymph nodes. The most common extra-abdominal site of disease is the pleural space. Less frequently, distant metastases occur in the parenchyma of the liver, lungs, and other organs. The rates of long-term survival (>10 years) in patients with

Initial surgical therapy

Table 3 summarises treatment strategies. If epithelial ovarian cancer is suspected on the basis of physical examination and imaging, an exploratory laparotomy is usually done for histological confirmation, staging, and tumour debulking.1 The standard comprehensive surgical staging approach consists of a total abdominal hysterectomy and BSO along with examination of all peritoneal surfaces, an infracolic omentectomy, biopsies of pelvic and para-aortic lymph nodes and clinically uninvolved areas,

Novel therapeutics and targets

Novel inhibitors such as epidermal growth factor receptor (EGFR) family inhibitors (eg, cetuximab, erlotinib, trastuzumab) or inhibitors of Kit have not had a major effect on the treatment of epithelial ovarian cancer, probably because EGFR, HER2, and KIT aberrations, which are associated with responsiveness to these therapies in other tumour types, are uncommon in this disease.122, 123 Attempts to replace TP53 have also been unsuccessful.124 However, advances in our understanding of

Conclusion

A plateau has been reached regarding the benefits associated with intravenous administration of cytotoxic chemotherapy in epithelial ovarian cancer. However, advances in screening, novel targeted therapies, and widespread use of practical intraperitoneal drug delivery techniques will probably improve patient outcomes. Although the list of genomic aberrations in this disease is daunting, a systems approach and the integration of therapies targeting multiple component genes of important genetic

References (133)

  • SM Eisenkop et al.

    What are the current surgical objectives, strategies, and technical capabilities of gynecologic oncologists treating advanced epithelial ovarian cancer?

    Gynecol Oncol

    (2001)
  • JM Del Campo et al.

    Long-term survival in advanced ovarian cancer after cytoreduction and chemotherapy treatment

    Gynecol Oncol

    (1994)
  • SM Eisenkop et al.

    “Optimal” cytoreduction for advanced epithelial ovarian cancer: a commentary

    Gynecol Oncol

    (2006)
  • GD Aletti et al.

    Surgical treatment of diaphragm disease correlates with improved survival in optimally debulked advanced stage ovarian cancer

    Gynecol Oncol

    (2006)
  • W Cliby et al.

    Diaphragm resection for ovarian cancer: technique and short-term complications

    Gynecol Oncol

    (2004)
  • F Vernooij et al.

    The outcomes of ovarian cancer treatment are better when provided by gynecologic oncologists and in specialized hospitals: a systematic review

    Gynecol Oncol

    (2007)
  • HE Lambert et al.

    A randomized trial of five versus eight courses of cisplatin or carboplatin in advanced epithelial ovarian carcinoma. A North Thames Ovary Group Study

    Ann Oncol

    (1997)
  • K Bertelsen et al.

    A prospective randomized comparison of 6 and 12 cycles of cyclophosphamide, adriamycin, and cisplatin in advanced epithelial ovarian cancer: a Danish Ovarian Study Group trial (DACOVA)

    Gynecol Oncol

    (1993)
  • TB Hakes et al.

    Randomized prospective trial of 5 versus 10 cycles of cyclophosphamide, doxorubicin, and cisplatin in advanced ovarian carcinoma

    Gynecol Oncol

    (1992)
  • TB Hakes et al.

    Randomized prospective trial of 5 versus 10 cycles of cyclophosphamide, doxorubicin, and cisplatin in advanced ovarian carcinoma

    Gynecol Oncol

    (1992)
  • H Hirte et al.

    A phase III randomized trial of BAY 12-9566 (tanomastat) as maintenance therapy in patients with advanced ovarian cancer responsive to primary surgery and paclitaxel/platinum containing chemotherapy: a National Cancer Institute of Canada Clinical Trials Group Study

    Gynecol Oncol

    (2006)
  • TJ Herzog et al.

    The role of maintenance therapy and novel taxanes in ovarian cancer

    Gynecol Oncol

    (2006)
  • SA Cannistra

    Cancer of the ovary

    N Engl J Med

    (2004)
  • M Garcia et al.

    Global cancer facts and figures 2007

    (2007)
  • HA Risch et al.

    Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada

    J Natl Cancer Inst

    (2006)
  • S Chen et al.

    Characterization of BRCA1 and BRCA2 mutations in a large United States sample

    J Clin Oncol

    (2006)
  • SE Hankinson et al.

    Tubal ligation, hysterectomy, and risk of ovarian cancer. A prospective study

    JAMA

    (1993)
  • Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23 257 women with ovarian cancer and 87 303 controls

    Lancet

    (2008)
  • Cancer stats. Incidence: UK

  • MJ Hayat et al.

    Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program

    Oncologist

    (2007)
  • WR Brewster

    Temporal trends in ovarian cancer: incidence and mortality across Europe

    Nat Clin Pract Oncol

    (2005)
  • DW Cramer et al.

    Determinants of ovarian cancer risk. II. Inferences regarding pathogenesis

    J Natl Cancer Inst

    (1983)
  • C Rodriguez-Burford et al.

    Effects of nonsteroidal anti-inflammatory agents (NSAIDs) on ovarian carcinoma cell lines

    Clin Cancer Res

    (2001)
  • CP Crum et al.

    Lessons from BRCA: the tubal fimbria emerges as an origin for pelvic serous cancer

    Clin Med Res

    (2007)
  • SG Silverberg

    Prognostic significance of pathologic features

    Curr Top Pathol

    (1989)
  • DI Smith

    Transcriptional profiling develops molecular signatures for ovarian tumors

    Cytometry

    (2002)
  • W Cheng et al.

    Lineage infidelity of epithelial ovarian cancers is controlled by HOX genes that specify regional identity in the reproductive tract

    Nat Med

    (2005)
  • IG Campbell et al.

    Mutation of the PIK3CA gene in ovarian and breast cancer

    Cancer Res

    (2004)
  • JD Carpten et al.

    A transforming mutation in the pleckstrin homology domain of AKT1 in cancer

    Nature

    (2007)
  • PA Shaw et al.

    Characteristics of genetically determined ovarian cancer

    Mod Pathol

    (1999)
  • S Suzuki et al.

    An approach to analysis of large-scale correlations between genome changes and clinical endpoints in ovarian cancer

    Cancer Res

    (2000)
  • L Shayesteh et al.

    PIK3CA is implicated as an oncogene in ovarian cancer

    Nat Genet

    (1999)
  • KW Cheng et al.

    The Rab 25 small GTPase determines aggressiveness of ovarian and breast cancers

    Nat Med

    (2004)
  • BT Hennessy et al.

    Ovarian cancer: linking genomics to new target discovery and molecular markers—the way ahead

    Adv Exp Med Biol

    (2008)
  • T Kamikihara et al.

    Epigenetic silencing of the imprinted gene ZAC by DNA methylation is an early event in the progression of human ovarian cancer

    Int J Cancer

    (2005)
  • D Badgwell et al.

    Early detection of ovarian cancer

    Dis Markers

    (2007)
  • DA Berry et al.

    BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes

    J Clin Oncol

    (2002)
  • ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome

    Obstet Gynecol

    (2009)
  • W Burke et al.

    Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium

    JAMA

    (1997)
  • Genetic/familial high-risk assessment: breast and ovarian

  • Cited by (603)

    • Harnessing tumor immunogenomics: Tumor neoantigens in ovarian cancer and beyond

      2023, Biochimica et Biophysica Acta - Reviews on Cancer
    View all citing articles on Scopus
    View full text