This past year has witnessed several advances in the care of women with ovarian malignancies. The progress has been incremental in that there have been no publications that have profoundly altered the current standard of care. Yet importantly, the continued development of targeted agents and novel biologics has raised the hope that the treatment of ovarian cancer will become more sophisticated with therapies that leverage the genetic vulnerabilities of the tumor while limiting systemic side effects.
Epithelial ovarian cancer patients continue to present at advanced stages, with tumor spread beyond the pelvis in up to three quarters of patients. Ovarian cancer ranks as the fifth most common cancer in women while remaining the most mortal of all gynecologic malignancies in developed countries.
Today's standard is to achieve maximal cytoreduction. Currently optimal cytoreduction is defined as any single tumor measuring less than 1 cm in diameter; however, recently many have postulated that the true goal of radical cytoreduction should be to reduce tumor to no grossly visible disease. Thus, the definition of the “optimally” cytoreduced patient has evolved significantly over time, as originally the cutoff was 2 cm.
Developing an effective screening test has continued to be an elusive goal for ovarian cancer. No one disputes the importance or potential clinical significance of screening given that patients with disease detected at stage I would be potentially curable in almost all cases.
This favorable association is in stark contrast to the current reality of the 70 percent or more of patients who have disease in the upper abdomen at the time of diagnosis resulting in cure rates that approach only 30 percent. Nonetheless, with the ovaries being small internal organs with an undefined latency period in moving from benign to malignant, coupled with ovarian cancer being a low-prevalence disease occurring in approximately one of 70 women, challenges in screening remain daunting.
Recently, Barbara Goff and associates reported survey data that suggested that a Symptom Index would result in earlier diagnosis that in turn may increase. Two publications in the last several months have challenged this premise, including one study from Australia that concluded that once ovarian cancer is symptomatic, reducing the time to diagnosis did not significantly alter the stage at diagnosis or survival.1,2 An ongoing population-based prospective analysis of the Index should clarify the clinical utility of this test.
Screening news over the past year continued to be mixed as the ovarian data from the Prostrate, Lung, Colon and Ovarian Cancer Screening Trial (PLCO) with over 78,000 women randomized to routine care versus annual CA-125 and transvaginal ultrasound showed no decrease in ovarian cancer mortality in the intervention group.3 HE4, however, was introduced as a new potential tool in multi-modal screening.4 The future includes further evaluation of the Risk of Ovarian Cancer (ROCA) algorithm by Karen Lu and associates using CA-125 as an internal control in individuals as well as the development and validation of novel serum proteomic biomarkers.
Surgery remains a critical intervention in the care of ovarian cancer patients. The three goals of surgery are establishing the diagnosis, determining the extent or stage of disease, and removing the maximal amount of tumor possible. As noted above, the new “optimal” has become cytoreduction to no gross disease. Staging is critical in patients who have disease apparently confined to the ovary as microscopic involvement of the lymph nodes, omentum, and other surfaces occurs in up to one third of patients.
The preferred route of frontline therapy has seen continued debate. Intraperitoneal therapy, despite three randomized positive trials that showed significant survival advantages in optimally cytoreduced patients, continues to be underutilized throughout the world. The Japanese Gynecologic Oncology Group (GOG) is conducting a validating randomized trial for intraperitoneal therapy.
Likewise the schedule of frontline therapy continues to evolve. Two GOG trials are attempting to establish the role of administering platinum with paclitaxel in a fractionated weekly schedule at 80 mg/m2 on days 1, 8, and 15 versus standard paclitaxel at 175 mg/m2 every three weeks. This strategy was derived from the results of a Japanese GOG study that demonstrated a survival advantage for the dose-dense schedule. Until confirmatory data in a heterogeneous population are available, this approach remains experimental.
Neoadjuvant chemotherapy (NACT) has taken on an increasingly prominent role, whereby several cycles of chemotherapy is administered prior to cytoreduction. A recent randomized European trial has shown that survival is not impaired with the administration of chemotherapy prior to surgery, and in fact the morbidity of the surgery is reduced with this approach.5
A recent frontline GOG trial had almost 20% of patients enrolled treated with the neoadjuvant approach. While most would agree that NACT i-angiogenic bevacizumab is the preferred approach for patients who are poor surgical candidates, many still advocate upfront surgery in the majority of patients. Further delineation of the profile of patients best treated with upfront debulking versus delayed is required.
In terms of adopting targeted agents into frontline therapy, two major trials were reported recently that examined the role of adding the antiangiogenic bevacizumab to the standard chemotherapy backbone in adjuvant therapy, carboplatin and paclitaxel.6,7
GOG 218 was a placebo-controlled, double-blinded, three-arm trial that examined standard chemotherapy alone versus bevacizumab with chemotherapy versus bevacizumab with chemotherapy followed by prolonged bevacizumab treatment. The latter cohort of bevacizumab with chemotherapy and then prolonged bevacizumab demonstrated a 3.8-month improvement in median progression-free survival (PFS) over standard chemotherapy alone (10.3 vs. 14.1 months). This data, along with the results from the ICON7 trial, using a lower dose of bevacizumab, have presented clinicians with another option for patients requiring front-line adjuvant treatment for epithelial ovarian cancer.
This past year a subset analysis from ICON7 demonstrated an overall survival (OS) advantage for patients with advanced staged disease. The reproducibility and generalizability of these data in poor-prognostic patients are unknown.
This class of compounds may cause significant side effects including bowel perforation, hypertension, and renal toxicity, but these appear to be rare or are usually easily managed based upon phase III data in the front-line setting. Nonetheless, most clinicians are awaiting longer-term safety, quality-of-life, and survival data, including overall survival, prior to routine use.
The cost of this compound can't be ignored either, and cost-effectiveness data have challenged the concept of adding bevacizumab to front-line treatment.8 Clearly the identification of a biomarker is indicated to select those who will or will not benefit from treatment.
The major data reported in this disease setting were from a phase III trial that also examined the role of bevacizumab in platinum-sensitive recurrent ovarian cancer patients.9 The OCEANS trial evaluated bevacizumab in the recurrent disease setting in combination with chemotherapy. Patients were randomized to receive bevacizumab versus placebo until disease progression along with carboplatin and gemcitabine.
OCEANS showed a significant improvement in PFS when bevacizumab is used concurrently with carboplatin and gemcitabine followed by bevacizumab alone until progression compared with use of carboplatin and gemcitabine alone (HR = 0.484, p<0.0001). The objective response increased by 21% in the bevacizumab cohort. Toxicities were similar to previous bevacizumab trials.
Of all the three phase III trials reported on bevacizumb, this was the most impressive in terms of the magnitude of effect. GOG 213, closed to the chemotherapy question this past year, should provide further insights into the role of bevacizumab in the recurrent setting.
Unanswered Questions with Bevacizumab
Subsequent trials will need to answer who are the best candidates for bevacizumab. The dose and duration of treatment remain open inquiries as well. Finally where is this agent best positioned: frontline versus recurrent disease, single-agent after chemotherapy or concomitantly with chemotherapy, or as a single agent alone in recurrent disease? Clearly biomarker discovery is needed to optimize patient selection and provide clarity for the optimal role for this compound.
Novel Areas of Investigation
Among the most provocative data presented this past year focused upon the hope of moving ovarian cancer towards a personalized approach. The loss of homologous repair mechanisms has proven to be a critical target for molecularly based treatments.
Poly (ADP-ribose)-polymerase, or PARP, inhibitors have emerged as a potent new therapy for patients with BRCA mutations or who have a BRCA phenotype, thus exhibiting “BRCAness.” Data on PARP inhibitors in both platinum-resistant and sensitive recurrent ovarian cancer patients were presented.
The most interesting of the studies was with the PARP inhibitor olaparib (AZD2281) in a randomized placebo controlled phase II trial.10 A total of 265 platinum-sensitive recurrent patients who had either maintained a complete or partial response to recent platinum were randomized to olaparib versus placebo. PFS was 8.4 versus 4.8 months with a hazard ratio of 0.35 favoring treatment with the PARP inhibitor. Significant adverse events more common in the olaparib cohort included fatigue, nausea, and anemia.
Interestingly, the entry criteria did not require BRCA mutation, but the protocol did require high-grade serous histology, which essentially serves as an enriching surrogate marker for BRCA.
Phase II data with another PARP inhibitor, iniparib, in combination with carboplatin/gemcitabine were presented in both platinum-sensitive and platinum-resistant patients.11,12 The data appeared promising but the contributory efficacy from the PARP inhibitor was difficult to discern without a comparator arm. The GOG is investigating the role of PARP inhibition in numerous settings with most initiatives studying another agent — veliparib (ABT888).
Developmental initiatives that have progressed in ovarian cancer include investigation of other anti-angiogenic compounds that target alternative pathways. One such compound is AMG 386, which targets the angiopoietin axis by inhibiting the interaction between angiopoietin-1, angiopoietin-2, and their receptor Tie2. Other promising anti-angiogenic compounds under active investigation include aflibercept, cediranib, pazopanib, and sorafenib among others.
Folate receptor targeting, either as a primary therapeutic or as a high-affinity drug-delivery system, has featured farletuzumab and EC145, respectively. Both unique compounds have shown promise in phase II studies tha have generated phase III development.
The key to transitioning ovarian cancer to a personalized care model is further basic science research that identifies the critical proteins and pathways that are expressed in ovarian cancer. Heretofore, most initiatives have investigated compounds that have an impact on critical pathways in other solid tumors. Hopefully with the goal of finding ovarian critical targets, The Cancer Genome Atlas project (TCGA) reported on the sequencing results of all of the protein-coding segments, or exomes, of nearly 500 ovarian tumors.13
Relatedly, despite a uniform adjuvant approach for ovarian cancers, it is now recognized that not all ovarian cancers are the same from a prognostic or genetic perspective. Survival is significantly diminished stage for stage in clear cell and mucinous compared with serous and endometrioid ovarian cancers. The observation of differential response rates and survival outcomes by histologic type has generated interest in developing unique tumor type specific study queues.
At Least Four Subtypes of Papillary Serous Tumors
TCGA and others have now described at least four distinct subtypes of papillary serous tumors. Cooperative group studies are now creating individual queues based upon histology.
As an example of this strategy, GOG 268 combines the mTOR inhibitor temsirolimus with standard front-line chemotherapy in patients with clear-cell histologies. GOG 254 is another active trial for the same histology, which explores the role of sunitinib in recurrent clear-cell patients. Similarly, GOG 241 is a phase III trial in mucinous histologies that compares standard front-line chemotherapy versus oxaliplatin/capecitabine.
So, to summarize the progress in ovarian cancer for this past year, a number of developments have occurred, yet significant milestones remain unmet in the journey towards establishing individualized care for ovarian cancer patients. Basic and clinical research science funding, clinical trial participation, and interrogation of genetic repositories will be critical in identifying the most robust targets and in developing novel compounds for ovarian cancer treatment.
1. Lim AWW, Mesher D, et al. Predictive Value of Symptoms for Ovarian Cancer: Comparison of Symptoms Reported by Questionnaire, Interview, and General Practitioner Notes. JNCI. 2012;104:114–124
2. Nagle CM, Francis JE, et al. Reducing Time to Diagnosis Does Not Improve Outcomes for Women with Symptomatic Ovarian Cancer: A Report From the Australian Ovarian Cancer Study Group. JCO. 2011;29:2253–2258
3. Buys SS, Partridge E, for the PLCO Project Team , et al. Effect of Screening on Ovarian Cancer Mortality. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA. 2011;305:2295–2302
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8. DE Cohn, KH Kim, et al. At What Cost Does a Potential Survival Advantage of Bevacizumab Make Sense for the Primary Treatment of Ovarian Cancer? A Cost-Effectiveness Analysis. JCO. 2011;29:1247–1251
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10. Ledermann J, et al. Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinum-sensitive relapsed serous ovarian cancer. Abstract, 2011 ASCO Annual Meeting, Oral Abstract Session. J Clin Oncol. 2011;29 (suppl; abstr 5003)
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