Faculty Bibliography

The standard platinum-based treatment of previously untreated advanced ovarian cancer continues to evolve because despite high response rates to such first-line treatment, a majority of patients will experience relapse. For many years, the optimal treatment for women with advanced ovarian cancer has been maximum cytoreductive surgery followed by intravenous (IV) platinum and taxane chemotherapy. Later, several randomized multicenter phase III clinical trials demonstrated that intraperitoneal (IP) chemotherapy was superior to standard IV chemotherapy when there was minimal residual disease after primary debulking surgery. The underlying rationale for use of IP therapy is based on the dose-effect relationship for platinum drugs in ovarian cancer. However, barriers to implementation of IP therapy in the routine clinical setting include concern for toxicity, tolerability of planned treatment, and catheter-related complications. In this article, we highlight the key trials and recent directions in IP therapy of ovarian cancer and briefly discuss another approach to the delivery of IP chemotherapy, known as hyperthermic intraperitoneal chemotherapy.

Targeted therapies are increasingly being explored in the treatment of ovarian cancer. The epidermal growth factor receptor (EGFR) has received much attention as this pathway is overexpressed and/or amplified in ovarian cancer. Anti-EGFR tyrosine kinase inhibitors (TKIs) and monoclonal antibodies have been studied in combination with chemotherapy and as single agents in both the first-line and relapsed settings but unfortunately, the results have been disappointing. In this editorial, we review a recently published large randomized phase III trial conducted by Vergote et al. evaluating maintenance erlotinib in patients with ovarian, peritoneal, or fallopian tube cancer who experienced a response or stable disease (SD) after primary therapy. This study did not show a benefit to maintenance erlotinib and moreover, was not able to identify any subgroups that benefited from erlotinib. Testing for EGFR overexpression and/or amplification by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively, and mutation testing were performed on archival tumor tissue. Patients who were EGFR positive did have a worse progression-free survival (PFS) and overall survival (OS) but EGFR positivity or the presence of a mutation was not predictive of erlotinib efficacy. At this time, EGFR inhibition in ovarian cancer has not been successful and further targeting of this pathway requires an understanding of resistance mechanisms and the role of other pathways that interplay with EGFR.

BACKGROUND: Continuous-infusion topotecan with erlotinib has the potential to reverse topotecan resistance due to drug efflux mechanisms. We assessed the activity of such a regimen in ovarian cancer patients previously failing bolus topotecan. Assay for shed collagen epitopes recognized by antibody HU177 during treatment explored its ability to reflect tumor invasion. METHODS: Topotecan 0.4 mg/m(2) per day was administered by continuous infusion for 9-10 days every 3 weeks. Erlotinib, 150 mg orally, was administered on days 1-10 of each cycle. Cycles were repeated until progression or toxicity. Serum for shed HU177 collagen epitopes was collected weekly. This was a two-stage design to detect a CA-125 response rate of at least 20% in 30 patients after completing two treatment cycles. The trial would be terminated early if there were less than two CA-125 responses in 16 patients. Four or more CA-125 responses in 30 patients would justify further study of this regimen in prior topotecan treatment failures. RESULTS: Six patients were enrolled, with four receiving three or more cycles and one achieving a partial response by cancer antigen 125 (CA-125) criteria. Shed epitope levels became undetectable on at least one measurement in all patients who received three or more cycles (Fig. 1A) and reappeared concomitantly with rises in CA-125 and clinical progression (Fig. 1B). After logistical delays, the trial was closed by the sponsor's decision to stop developing erlotinib in ovarian cancer. FIGURE 1: Monitoring of combination treatment. A, B, C, D, and F refer to patients. (A):: Topotecan and erlotinib. (B):: CA-125 in units/mL. CONCLUSION: Continuous-infusion topotecan with erlotinib was found safe in six pretreated ovarian cancer patients; one met CA-125 criteria for partial response. Serial shed epitope levels to reflect invasiveness deserve further study.

OBJECTIVE: The treatment of recurrent epithelial ovarian cancer (rEOC) remains a major challenge because of the development of platinum resistance. To identify treatment regimens associated with better outcomes in BRCA mutation carriers compared with patients with nonhereditary (NH) disease, we summarized the experience after chemotherapy treatment of rEOC in 1 institution and compared the outcome in BRCA mutation carriers versus NH subsets. METHODS: We retrospectively analyzed 256 patient records with rEOC who were treated with second-, third-, and fourth-line treatment with the usual sequential regimens consisting of either pegylated liposomal doxorubicin (PLD), taxanes, gemcitabine, or topotecan (alone or in combination with platinum) between 2002 and 2012 at our institution. The analysis of founder mutations in 8 hotspots was performed. The outcome in BRCA mutation carriers was compared with that of patients with NH disease. RESULTS: BRCA mutation carriers treated with PLD (with or without platinum) or with gemcitabine + platinum had improved progression-free survival (PFS) and a lower risk for disease progression (adjusted for age, line of treatment, and platinum sensitivity) compared with patients with NH disease. By contrast, treatment with taxanes (with or without platinum) or topotecan led to similar PFS in BRCA mutation carriers and in patients with NH disease. Under all treatment regimens, BRCA mutation carriers showed improved overall survival after adjusting for age, line of treatment, and platinum sensitivity. CONCLUSIONS: This single-institution experience provides indications of an enhanced benefit in PFS for BRCA mutation carriers compared with patients with NH disease across a number of drug regimens (PLD, platinum, or gemcitabine + platinum) regardless of platinum sensitivity and line of therapy.

Gynecological carcinomas are major therapeutic targets of platinum-containing regimens. They may be particularly susceptible to these agents if their origins are related to hereditary breast cancer (BRCA) mutations; this implicates defective DNA repair secondary to inherited alterations in BRCA function. The concept of 'BRCAness' was introduced by Ashworth and colleagues in order to identify phenotypic changes in sporadic cancer that would lead to analogous treatment susceptibility. In fact, recent analyses of genetic alterations in ovarian cancer have led to further extending this concept to all women with high-grade serous cancer, the predominant form of ovarian cancer arising in association with hereditary mutations in BRCA genes. Presumably, most serous types of cancer of gynecological origin share BRCA dysfunction to some extent. This renders these types of cancer susceptible to platinum and to other DNA-damaging agents, justifying the general inclusion of this histology in trials of new drugs and therapeutic strategies that have shown activity against hereditary cancer. More recently, however, differences in outcome between BRCA mutation carriers vis-a-vis those with no mutations or those with epigenetic or acquired forms of BRCA genes (somatic mutations) in their respective tumors have been identified. These findings raise additional questions on modifiers of 'BRCAness' and other pathways that appear to contribute to the effects of platinum and other DNA-damaging agents in ovarian cancer. The Cancer Genome Atlas analyses delineate the complexity of genomic alterations in ovarian cancer and other malignancies of Mullerian epithelial origin promising further refinements of the 'BRCAness' concept.

Oxaliplatin and fluoropyrimidines are synergic combinations very active for the treatment of advanced colorectal cancer and for the adjuvant treatment of stage III colon cancer. Oxaliplatin-based regimens can be further strengthened by the addition of a third component, either a traditional drug such as irinotecan or targeted agents such as anti-vascular endothelial growth factor (VEGF) drugs, bevacizumab and aflibercept, or the anti-epidermal growth factor receptor (EGFR), cetuximab and panitumumab. The availabilty of all these active agents prompted several clinical trials on different lines of treatment of advanced colorectal cancer patients and in the adjuvant setting. Clinical studies involving the administration of anti-EGFR drugs also helped identify mutations in KRAS as a negative marker for the activity of these agents. However, positive selection criteria for targeted agents have not been identified. The results of oxaliplatin-containing regimens are critically presented and discussed in this review.

Objective: Treatment of recurrent epithelial ovarian cancer (REOC) remains a major challenge because of development of platinum resistance. Recent evidence has suggested that BRCA mutation carriers may have improved outcome to treatment compared to patients with non-hereditary (NH) disease. We summarized the experience following chemotherapy treatment of REOC in one institution and compared the outcome in BRCA mutation carriers versus NH subsets. Methods: We retrospectively analyzed 256 patient records with REOC who were treated with second-, third-, and fourth-line treatment with the usual sequential regimens consisting of either pegylated liposomal doxorubicin (PLD), taxanes, gemcitabine, or topotecan (alone or in combination with platinum) between 2002 and 2012 at our institution and compared the outcome in BRCA mutation carriers with that of patients with NH disease. Results: BRCA mutation carriers treated with PLD (with or without platinum), gemcitabine plus platinum, or platinum alone had improved progressionfree survival (PFS) and a lower risk for disease progression (adjusted for age, line of treatment and platinum sensitivity) compared with patients with NH disease. By contrast, treatment with taxanes (with or without platinum) or topotecan led to similar PFS in BRCA mutation carriers and in patients with NH disease. Under all treatment regimens, BRCA mutation carriers showed improved overall survival after adjusting for age, line of treatment, and platinum sensitivity. Conclusions: This single-institution experience provides indications of an enhanced benefit in PFS for BRCA mutation carriers compared to patients with NH disease across a number of drug regimens (PLD, platinum, or gemcitabine plus platinum) regardless of platinum sensitivity and line of therapy