Ovarian Cancer Care: It’s Time for “Personalized” Approaches

As outlined in the excellent, comprehensive review by Drs. Liu and Matulonis, ovarian cancer is the most lethal gynecologic malignancy in the United States, with approximately 16,000 deaths and 22,000 new cases yearly.[1] The vast majority of patients present with intra-abdominal spread of disease at the time of diagnosis, resulting in low overall cure rates. As outlined, patients are primarily managed with primary surgical resection and subsequent platinum-based chemotherapy. Unfortunately, most patients at advanced stages eventually develop chemoresistance and finally succumb to their disease. Although the incidence and ultimate cure rate of ovarian cancer have remained unchanged for decades, there have been significant advances in median overall survival, attributed to better surgical management and perioperative care, and new cytotoxic drugs. In addition, there are areas of investigation that hold the promise of improving the overall cure rates. The authors focused their review mainly on select surgical and chemotherapy issues, including the development of new "targeted" agents. Here we summarize the most promising fields of research.

Early Diagnosis: Is It Possible?
Most patients diagnosed with early-stage ovarian cancer have an excellent prognosis. Thus, detection of disease when confined to the ovary/ies could significantly reduce mortality. Unfortunately no effective screening methods have been identified thus far.

The biomarker CA-125 and pelvic ultrasonography (US) are currently the preferred clinical tools for differentiating pelvic masses. Two large, randomized studies are currently ongoing in trying to answer the question of whether CA-125 and pelvic US can detect early-stage ovarian cancer and consequently reduce mortality. The National Institutes of Health Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial[2] enrolled 75,000 women from 1992 to 2001, and preliminary results should be presented in the next few years. The United Kingdom Trial of Ovarian Cancer Screening (UKCTOCS[3]), is currently randomizing 200,000 postmenopausal women. These large prospective studies should be able to help resolve the conflicting retrospective data.

New biomarkers have also been identified for the differentiation of pelvic masses,[4-7] and risk assessment strategies have been proposed using different biomarker panels. Validation of the clinical utilization of these panels is crucial for the possibility of new screening strategies, or for the referral of patients with pelvic masses to a gynecologic oncologist. In fact, primary referral to a gynecologic oncologist can also impact the prognosis of these patients, regardless of stage.[8-9]

As outlined by Drs. Liu and Matulonis, research investigating the correct site of origin of "ovarian cancer"[10,11] could impact not only our understanding of underlying tumor biology but also set the stage for new strategies for early detection of the disease.

Surgical Strategies
The longstanding belief that residual disease after primary cytoreduction is the most important prognostic factor for patients with advanced ovarian cancer has been challenged, at least to some degree, by the recent results of the trial conducted by the European Organisation for Research and Treatment of Cancer-Gynecologic Cancer Group (EORTC-GCG) and the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG).[12] As outlined by Drs. Liu and Matulonis, no difference in survival was noted between the group receiving neo-adjuvant chemotherapy and the group undergoing primary debulking efforts, which experienced more morbidity at the time of surgery. Significantly, the multivariable analysis showed that patients with less residual disease and patients operated on in countries with more favorable surgical outcomes, indeed experienced better prognosis. This represents another argument in favor of the referral of patients with ovarian cancer to expert centers for primary management.

Identification of patients at high risk of complications,[13] or those who might not benefit from aggressive surgical procedures, represents another attempt to "personalize" treatment strategies according to risk variables.

Systemic Therapies: "Does One Size Fit All?"
As thoroughly reported by Drs. Liu and Matulonis, multiple studies are investigating new drugs, novel drug combinations, new "targeted" strategies, and different routes of administration in the setting of primary or recurrent ovarian cancer. Technologic advances now permit us to examine the different molecular pathways that underlie ovarian cancer. The design of new agents that inhibit newly identified pathways is also proceeding rapidly. Several studies are investigating the potential benefit of the new therapeutics either alone or in combination with chemotherapy.

Summarizing, these different fields of investigation include:

• Identification of biomarker indicators of response to different agents

• Studying the efficacy of combination therapies, ie, chemotherapeutics, chemotherapy/biologic agents in the setting of primary tumors versus platinum-sensitive versus platinum-refractory disease

• Development of new drugs in the attempt to overcome platinum resistance

• Determining the best route of drug administration: intravenous versus intraperitoneal versus oral agents

• Identifying the best strategies in the overall plan of care: consolidation therapies after primary treatment, vaccination, when to restart treatment for recurrent tumor (Occurrence of symptoms? Rise in the biomarker? Imaging showing recurrence?)

Advances in our knowledge along the continuum of questions that remain in ovarian cancer-from cell of origin, to improved screening, surgery and systemic therapy-will help us to better identify the varieties of "ovarian cancer" and select the optimal strategy for an individual patient.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

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2. Buys SS, Partridge E, Greene MH, et al, PLCO Project Team: Ovarian cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial: Findings from the initial screen of a randomized trial [published correction appears in Am J Obstet Gynecol 2005;193:2183-2184]. Am J Obstet Gynecol 193:1630-1639, 2005;.

3. UK Collaborative Trial of Ovarian Cancer Screening. Available at: http://www.instituteforwomenshealth. ucl.ac.uk/academic_research/ gynaecologicalcancer/gcrc/ukctocs. Accessed March 29, 2010.

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6. Shah CA, Lowe KA, Paley P, et al: Influence of ovarian cancer risk status on the diagnostic performance of the serum biomarkers mesothelin, HE4, and CA125. Cancer Epidemiol Biomark Prev 18:1365-1372,
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7. Moore RG, MacLaughlan S, Bast RC Jr: Current state of biomarker development for clinical application in epithelial ovarian cancer. Gynecol Oncol 116:240-245, 2010.

8. Earle CC, Schrag D, Neville BA, et al: Effect of surgeon specialty on processes of care and outcomes for ovarian cancer patients. J Natl Cancer Inst 98:172-180, 2006.

9. Guidelines for referral to a gynecologic oncologist: Rationale and benefits. The Society of Gynecologic Oncologists. Gynecol Oncol 78(3 pt. 2): S1-S13, 2000.

10. Levanon K, Crum C, Drapkin R: New insights into the pathogenesis of serous ovarian cancer and its clinical impact. J Clin Oncol 26(32):5284-5293, 2008.

11. Lee Y, Miron A, Drapkin R, et al: A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol 211:26-35, 2007.

12. Vergote I, Tropacup CG, Amant F, et al: EORTC-GCG/NCIC-CTG randomised trial comparing primary debulking surgery with neoadjuvant chemotherapy in stage IIIc-IV ovarian, fallopian tube and peritoneal cancer (OvCa). International Gynecologic Cancer Society 2008 Meeting: Abstract #2008_1767. Available at: http://www.igcs.org/Abstract/meeting_2008_ 1767.html. Accessed March 29, 2010.

13. Aletti GD, Santillan A, Eisenhauer EL, et al: A new frontier for quality of care in gynecologic oncology surgery: Multi-institutional assessment of short-term outcomes for ovarian cancer using a risk-adjusted model. Gynecol Oncol 107:99-106, 2007.