Faculty Bibliography

Sensory neuropathy is the dose-limiting toxicity of paclitaxel and also impacts on the use of docetaxel and other taxanes. The cause of this adverse effect has to do with their mechanism of action against microtubules and its interaction with neuronal cytoskeletal components. The variability of this toxicity is defined by several factors including disease type, taxane class, schedule and dose of the specific drug, patient demographics, and use of taxanes in combination regimens (especially with the platinums that are also neurotoxic). Prevention of life-long neuropathy is only produced if the causative drug is halted - treatments to reverse toxicity have shown only minimal improvement. This review investigates trials defining the clinical factors that determine the therapeutic window of taxanes and the enhanced susceptibility to this toxicity. In addition, case vignettes illustrate the range of clinical manifestations of this toxicity during taxane administration.

Since their addition to paclitaxel in the oncologists' armamentarium in the early 1990s, several new taxane formulations have been developed. Besides docetaxel and nab-paclitaxel, new analogs with better therapeutic profiles are being investigated. The goals of this next generation of taxanes are to improve the toxicity profile and efficacy, and to overcome resistance patterns. Several new taxanes, including cabazitaxel, paclitaxel poliglumex, paclitaxel+endotag, and polymeric-micellar paclitaxel, have shown clinical efficacy. These chemotherapeutics are part of many ongoing phase II and III studies on various cancer types. In addition, there are immunotoxins that link key antibodies to mitotic spindle inhibitors (trastuzumab emtansine and brentuximab vedotin). Through this mechanism, novel formulations increase cytotoxicity, improve specificity, and create possibilities for drug enhancement.

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.

BACKGROUND: Ovarian cancer arising in women with BRCA mutations is known to have a more favorable outcome and to be more responsive to platinum-based regimens than in those without a hereditary background. We analyze our previously published intraperitoneal (IP) studies in relation to BRCA mutation status and update their outcomes. METHODS: Among 62 patients with ovarian cancer enrolled in IP platinum doublet studies in clinical trials (with etoposide (n = 18), with floxuridine (n = 30), and with topotecan (n = 14)), a deleterious BRCA mutation was eventually identified in 10 patients. The outcomes in these BRCA mutation carriers are described and compared with survival of others in respective trials. RESULTS: Ten patients that were confirmed to have BRCA mutations-all with high-grade and stages IIC to IV disease-survived a median of 10 years (range: 4-18+) after receiving IP cisplatin-based regimens. Two continue with no evidence of disease since their IP treatment, while four others remain alive with recurrences after 8, 9, 10, and 11 years, respectively. CONCLUSIONS: This experience suggests that IP cisplatin leads to favorable long term outcomes in advanced ovarian cancer in women with defective homologous recombination (i.e., with deleterious BRCA mutations). Whether such cisplatin dose-intensification from IP relative to (intravenous) IV drug administration leads to superior results in these mutation carriers requires 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.