The management of ovarian cancer includes a combination of surgery and chemotherapy. The majority of clinical trials have historically addressed questions pertaining to the selection, dosing, and schedule of chemotherapy agents.
Methods
In this report, a comprehensive review of the major clinical trials in ovarian cancer is performed. The increasing data and clinical experience in the management of ovarian cancer, as it sets the stage for currently active protocols and future clinical trial design, are emphasized.
Results
Paclitaxel plus carboplatin is the primary intravenous treatment strategy in the front-line setting. Recent data show an improvement in overall survival for intravenous dose-dense treatment. Multiple randomized controlled trials support the use of intraperitoneal treatment. For recurrent disease, a growing number of new agents including targeted therapeutics are now available. Increasingly, surgical approach, biologic targets, and quality of life endpoints are included in clinical trial design.
Conclusions
Over the last several decades, clinical trials have defined the current therapeutic approach for ovarian cancer. Paclitaxel with a platinum-based agent is currently the preferred front-line therapy, with encouraging data to support either dose-dense or intraperitoneal drug delivery. Future trials will determine the role of biologic agents and vaccine therapies, as well as their impact on quality of life.
References
1.
ArmstrongD.K., BundyB., WenzelL.. Intraperitoneal cisplatin and paclitaxel in ovarian cancer.N Engl J Med.2006; 354(1): 34–43.
2.
McGuireW.P., HoskinsW.J., BradyM.F.. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer.N Engl J Med.1996; 334(1): 1–6.
3.
OzolsR.F., BundyB.N., GreerB.E.. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study.J Clin Oncol.2003; 21(17): 3194–3200.
4.
du BoisA., QuinnM., ThigpenT.. 2004 consensus statements on the management of ovarian cancer: final document of the 3rd International Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference (GCIG OCCC 2004).Ann Oncol.2005; 16(suppl 8): viii7–viii12.
5.
BookmanM.A., BradyM.F., McGuireW.P.. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a phase III trial of the Gynecologic Cancer Intergroup.J Clin Oncol.2009; 27(9): 1419–1425. Erratum in: J Clin Oncol. 2009; 27(13): 2305.
6.
KatsumataN., YasudaM., TakahashiF.. 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.2009; 374(9698): 1331–1338.
7.
BurgerR.A., BradyM.F., BookmanM.A.. Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): a Gynecologic Oncology Group study.J Clin Oncol.2010; 28(18 suppl): LBA1. Abstract.
8.
AlbertsD.S., LiuP.Y., HanniganE.V.. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer.N Engl J Med.1996; 335(26): 1950–1955.
9.
MarkmanM., BundyB.N., AlbertsD.S.. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group.J Clin Oncol.2001; 19(4): 1001–1007.
10.
KirmaniS., BralyP.S., McClayE.F.. A comparison of intravenous versus intraperitoneal chemotherapy for the initial treatment of ovarian cancer.Gynecol Oncol.1994; 54(3): 338–344.
11.
PolyzosA., TsavarisN., KosmasC.. A comparative study of intraperitoneal carboplatin versus intravenous carboplatin with intravenous cyclophosphamide in both arms as initial chemotherapy for stage III ovarian cancer.Oncology.1999; 56(4): 291–296.
12.
GadducciA., CarninoF., ChiaraS.. Intraperitoneal versus intravenous cisplatin in combination with intravenous cyclophosphamide and epidoxorubicin in optimally cytoreduced advanced epithelial ovarian cancer: a randomized trial of the Gruppo Oncologico Nord-Ovest.Gynecol Oncol.2000; 76(2): 157–162.
13.
YenM.S., JuangC.M., LaiC.R.. Intraperitoneal cisplatin-based chemotherapy vs intravenous cisplatin-based chemotherapy for stage III optimally cytoreduced epithelial ovarian cancer.Int J Gynaecol Obstet.2001; 72(1): 55–60.
14.
KonnerJ.A., GrabonD., PezzulliS.. A phase II study of intravenous (IV) and intraperitoneal (IP) paclitaxel, IP cisplatin, and IV bevacizumab as first-line chemotherapy for optimal stage II or III ovarian, primary peritoneal, and fallopian tube cancer.J Clin Oncol (Meeting Abstracts).2009; 27: 5539. Abstract.
15.
HoskinsW.J., McGuireW.P., BradyM.F.. The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma.Am J Obstet Gynecol.1994; 170(4): 974–979; discussion 979-980.
16.
HoskinsW.J., BundyB.N., ThigpenJ.T.. 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.1992; 47(2): 159–166.
17.
BristowR.E., TomacruzR.S., ArmstrongD.K.. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis.J Clin Oncol.2002; 20(5): 1248–1259.
MarkmanM., LiuP.Y., MoonJ.. Impact on survival of 12 versus 3 monthly cycles of paclitaxel (175 mg/m2) administered to patients with advanced ovarian cancer who attained a complete response to primary platinum-paclitaxel: followup of a Southwest Oncology Group and Gynecologic Oncology Group phase 3 trial.Gynecol Oncol.2009; 114(2): 195–198.
20.
PecorelliS., FavalliG., GadducciA.. 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.2009; 27(28): 4642–4648.
21.
A Randomized Phase III Trial of Maintenance Chemotherapy Comparing 12 Monthly Cycles of Single Agent Paclitaxel or Xyotax (CT-2103) (IND# 70177), Versus No Treatment Until Documented Relapse in Women With Advanced Ovarian or Primary Peritoneal or Fallopian Tube Cancer Who Achieve a Complete Clinical Response to Primary Platinum/Taxane Chemotherapy. NCT00108745. http://clinicaltrials.gov/ct2/show/NCT00108745. Accessed August 17, 2010.
22.
ICON7 - A Randomised, Two-Arm, Multi-Centre Gynaecologic Cancer InterGroup Trial of Adding Bevacizumab to Standard Chemotherapy (Carboplatin and Paclitaxel) in Patients With Epithelial Ovarian Cancer. NCT00483782. http://clinicaltrials.gov/ct2/show/NCT00483782?term=NCT00483782&rank=1. Accessed August 17, 2010.
23.
EhlenT.G., HoskinsP.J., MillerD.. A pilot phase 2 study of oregovomab murine monoclonal antibody to CA125 as an immunotherapeutic agent for recurrent ovarian cancer.Int J Gynecol Cancer.2005; 15(6): 1023–1034.
24.
MöbusV.J., BaumR.P., BolleM.. Immune responses to murine monoclonal antibody-B43.13 correlate with prolonged survival of women with recurrent ovarian cancer.Am J Obstet Gynecol.2003; 189(1): 28–36.
25.
BerekJ., TaylorP., McGuireW.. Oregovomab maintenance monoimmunotherapy does not improve outcomes in advanced ovarian cancer.J Clin Oncol.2009; 27(3): 418–425.
26.
SabbatiniP.. Consolidation therapy in ovarian cancer: a clinical update.Int J Gynecol Cancer.2009; 19(suppl 2): S35–S39.
27.
DizonD.S., HensleyM.L., PoynorE.A.. Retrospective analysis of carboplatin and paclitaxel as initial second-line therapy for recurrent epithelial ovarian carcinoma: application toward a dynamic disease state model of ovarian cancer.J Clin Oncol.2002; 20(5): 1238–1247.
28.
ParmarM.K., LedermannJ.A., ColomboN.. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial.Lancet.2003; 361(9375): 2099–2106.
29.
PfistererJ., PlanteM., VergoteI,. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG.J Clin Oncol.2006; 24(29): 4699–4707.
30.
A Phase III, Multicenter, Randomized, Blinded, Placebo-Controlled Trial of Carboplatin and Gemcitabine Plus Bevacizumab in Patients With Platinum-Sensitive Recurrent Ovary, Primary Peritoneal, or Fallopian Tube Carcinoma. NCT00434642. http://clinicaltrials.gov/ct2/show/NCT00434642?term=NCT00434642&rank=1. Accessed August 17, 2010.
31.
A Multi-National, Randomized, Phase III, GCIG Intergroup Study Comparing Pegylated Liposomal Doxorubicin and Carboplatin Versus Paclitaxel and Carboplatin in Patients With Epithelial Ovarian Cancer in Late Relapse (> 6 Months). NCT00189553. http://clinicaltrials.gov/ct2/show/NCT00189553. Accessed August 18, 2010.
32.
MarkmanM., MoonJ., WilczynskiS.. Single agent carboplatin versus carboplatin plus pegylated liposomal doxorubicin in recurrent ovarian cancer: final survival results of a SWOG (S0200) phase 3 randomized trial.Gynecol Oncol.2010; 116(3): 323–325.
33.
ChiD.S., McCaughtyK., DiazJ.P.. Guidelines and selection criteria for secondary cytoreductive surgery in patients with recurrent, platinum-sensitive epithelial ovarian carcinoma.Cancer.2006; 106(9): 1933–1939.
34.
Benedetti PaniciP., De VivoA., BellatiF.. Secondary cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer.Ann Surg Oncol.2007; 14(3): 1136–1142.
35.
A Phase III Randomized Controlled Clinical Trial of Carboplatin and Paclitaxel Alone or in Combination With Bevacizumab (NSC #704865, IND#7921) Followed by Bevacizumab and Secondary Cytoreduction Surgery in Platinum-Sensitive, Recurrent Ovarian, Peritoneal Primary and Fallopian Tube Cancer. NCT00565851. http://clinicaltrials.gov/ct2/show/NCT00565851?term=NCT00565851&rank=1. Accessed August 18, 2010.
36.
BurgerR.A., SillM.W., MonkB.J.. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study.J Clin Oncol.2007; 25(33): 5165–5171.
37.
GarciaA.A., HirteH., FlemingG.. 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.2008; 26(1): 76–82.
38.
CannistraS.A., MatulonisU.A., PensonR.T.. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer.J Clin Oncol.2007; 25(33): 5180–5186. Erratum in: J Clin Oncol. 2008; 26(10): 1773.
39.
LockhartA.C., RothenbergM.L., DupontJ.. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors.J Clin Oncol.2010; 28(2): 207–214.
40.
BurgerR.A.. Role of vascular endothelial growth factor inhibitors in the treatment of gynecologic malignancies.J Gynecol Oncol.2010; 21(1): 3–11.
41.
BehbakhtK., SillM.W., DarcyK.M.. Phase II trial of the mTOR inhibitor temsirolimus and evaluation of circulating tumor cells in persistent or recurrent epithelial ovarian and primary peritoneal malignancies: a Gynecologic Oncology Group study.Gynecol Oncol.2010; 116(3): s1(SGO#7): S5.
42.
FongP.C., BossD.S., YapT.A.. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.N Engl J Med.2009; 361(2): 123–134.
43.
A Phase II Open-Label, Non-Comparative, International, Multicentre Study to Assess the Efficacy and Safety of KU 0059436 Given Orally Twice Daily in Patients With Advanced BRCA1 or BRCA2 Associated Ovarian Cancer. NCT00494442. http://clinicaltrials.gov/ct2/show/NCT00494442?term=NCT00494442&rank=1. Accessed August 18, 2010.
44.
GelmonK.A., HirteH.W., RobidouxA.. Can we define tumors that will respond to PARP inhibitors? A phase II correlative study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer.J Clin Oncol. 2010 ASCO Ann Meet Proc (Post-Meet Ed).2010; 28(15 suppl May 20): 3002.
45.
SandhuS.K., WenhamR.M., WildingG.. First-in-human trial of a poly(ADP-ribose) polymerase (PARP) inhibitor MK-4827 in advanced cancer patients (pts) with antitumor activity in BRCA-deficient and sporadic ovarian cancers.J Clin Oncol. 2010 ASCO Ann Meet Proc (Post-Meet Ed).2010; 28(15 suppl May 20): 3001.
46.
KonstantinopoulosP.A., SpentzosD., KarlanB.Y.. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer.J Clin Oncol.2010; 28(22): 3555–3561.
47.
TurnerN., TuttA., AshworthA.. Hallmarks of ‘BRCAness’ in sporadic cancers.Nat Rev Cancer.2004; 4(10): 814–819.
48.
Hughes-DaviesL., HuntsmanD., RuasM.. EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer.Cell.2003; 115(5): 523–535.
49.
Phase II Randomised, Double Blind, Multicentre Study to Assess the Efficacy of AZD2281 in the Treatment of Patients With Platinum Sensitive Serous Ovarian Cancer Following Treatment With Two or More Platinum Containing Regimens. NCT00753545. http://clinicaltrials.gov/ct2/show/NCT00753545. Accessed August 18, 2010.
50.
QianX., LaRochelleW.J., AraG.. Activity of PXD101, a histone deacetylase inhibitor, in preclinical ovarian cancer studies.Mol Cancer Ther.2006; 5(8): 2086–2095.
51.
SteeleN., FinnP., BrownR.. Combined inhibition of DNA meth-ylation and histone acetylation enhances gene re-expression and drug sensitivity in vivo.Br J Cancer.2009; 100(5): 758–763.
52.
A Phase II Evaluation of Belinostat (NSC #726630, IND #729990) and Carboplatin (NSC #241240) in the Treatment of Recurrent or Persistent Platinum-Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer. NCT00993616. http://clinicaltrials.gov/ct2/show/NCT00993616?term=NCT00993616&rank=1. Accessed August 18, 2010/
53.
Phase II Double Blind Randomized Trial Evaluating the Biologic Effect of Levonorgestrel on the Ovarian Epithelium in Women at High Risk for Ovarian Cancer (IND# 79,610). NCT00445887. http://clinicaltrials.gov/ct2/show/NCT00445887?term=NCT00445887&rank=1. Accessed August 18, 2010.
