Faculty Bibliography

Background Suppression of neoangiogenesis and pegylated liposomal doxorubicin (PLD) each contribute to the management of platinum-resistant/refractory ovarian cancer. The aim of this study is to test the combination of bevacizumab and PLD in women with resistant or refractory ovarian cancer. Methods Eligibility criteria were no more than two prior treatments with platinum-containing regimens and one additional regimen, without anthracyclines. Treatment was administered every 3 weeks (bevacizumab 15 mg/kg beginning on cycle 2 and PLD 30 mg/m(2)). The primary end point was progression-free survival (PFS) at 6 months; the secondary end points included side-effects, overall response rates (ORR) and survival (OS). Results Forty-six patients were enrolled. The average number of courses administered was 7. The median PFS was 6.6 months (range 1-24.6 months) according to Gynecologic Cancer Intergroup Committee (GCIC) criteria and 7.8 months (range 2-13.3 months) according to Response Evaluation Criteria in Solid Tumors (RECIST). The median OS was 33.2 months (range 3-37.5+ months). The ORR was 30.2% [95% confidence interval (CI) 17.2-46.1] and the clinical benefit rate (CBR) was 86.1% (95% CI 72.1-94.7). Adverse events included mucosal and dermal erosions (30% grade 3) and asymptomatic cardiac dysfunction. Additional toxic effects included hypertension, headache, renal dysfunction and proteinuria, wound healing delay, and one episode each of central nervous system (CNS) ischemia and hemolytic uremic syndrome. Conclusion PLD with bevacizumab has improved activity in recurrent ovarian cancer with increased toxicity.

"Targeted therapy" is becoming the centerpiece of current therapeutic strategies, and is often mentioned as the desirable direction for future progress. Why and how it is replacing past approaches in the management of solid tumors is the subject of this two-part overview. Here, in Part I, we describe areas where major inroads were initially achieved by targeting angiogenesis (central to the biology of renal cell carcinoma and hepatocellular cancer) and by unraveling pathways in the heterogeneous tumors of mesenchymal origin--spurred by the identification of c-Kit-activating mutations in gastrointestinal stromal tumors (GIST) and the regressions that ensued when tumors harboring these mutations were exposed to the tyrosine kinase inhibitor imatinib (Gleevec). More recently, the successes in the treatment of the notoriously refractory malignant melanoma via the targeting of a specific BRAF mutation and via immune activation represent an unprecedented achievement of this new therapeutic direction. For each cancer discussed in the first part of our overview, as well as in Part II, which will deal with more common cancers, we briefly cover the tumor biology, how targeting was achieved, the introduction of immune modulation or immune-conjugates, and the impact these therapies are having in the disease.

AIM: Trabectedin in combination with pegylated liposomal doxorubicin (PLD) improves progression-free survival (PFS) compared to PLD alone in recurrent ovarian cancer (J Clin Oncol 2010;28:3107-14). METHODS: Women, stratified by performance status (0-1 versus 2) and platinum sensitivity (platinum-free interval [PFI]<6 versus 6months), were randomly assigned to receive PLD 30mg/m(2) IV followed by a 3-h infusion of trabectedin 1.1mg/m(2) every 3weeks or PLD 50mg/m(2) every 4weeks. The study was powered to show a 33% increase in overall survival (OS) after 520 deaths had occurred. RESULTS: After a median follow-up of 47.4months, there were 522 deaths among 672 subjects. The median OS for trabectedin+PLD and PLD arms was 22.2 and 18.9months, respectively (hazard ratio [HR]=0.86; 95% confidence interval [CI]: 0.72-1.02; p=0.0835). An unexpected but significant imbalance in the PFI favouring the PLD arm (mean PFI: PLD=13.3months, trabectedin+PLD=10.6months) was identified. On the basis of this finding, an unplanned hypothesis generating analysis adjusting for the PFI imbalance and other prognostic factors suggested an improvement in OS associated with the trabectedin+PLD arm (HR=0.82; 95%CI: 0.69-0.98; p=0.0285). In another unplanned exploratory analysis, the subset of patients with a PFI of 6-12months had the largest difference in OS (HR=0.64; 95%CI: 0.47-0.86; p=0.0027). CONCLUSIONS: The final OS analysis did not meet the protocol-defined criterion for statistical significance. Despite stratification on platinum sensitivity, there was an imbalance in mean platinum free interval that had an effect on OS.

AbstractBackground and Objective.Ovarian cancer is usually diagnosed at an advanced stage, with most patients undergoing surgery followed by platinum- and taxane-based chemotherapy. After initial clinical remission, the majority recur, leading to additional treatments, including not only platinums and taxanes but also pegylated liposomal doxorubicin (PLD), gemcitabine, topotecan, and, more recently, bevacizumab, which may extend survival times. PLD, in particular, has been extensively studied by our group, with encouraging therapeutic results. We, however, observed instances of chronic kidney disease (CKD) developing among patients who received long-term treatment for recurrent ovarian cancer. To document the frequency and contributing factors to the emergence of CKD, we initiated a retrospective review at two institutions.Patients and Methods.Fifty-six consecutive patients with recurrent ovarian cancer receiving treatment at New York University Cancer Institute were reviewed for the presence of renal disease in 1997-2010. At Shaare Zedek Medical Center, 73 consecutive patients with ovarian cancer were reviewed in 2002-2010. Patients were diagnosed with CKD if they had an estimated GFR <60 mL/minute per 1.73 m(2) for >3 months and were staged according to the National Kidney Foundation guidelines.Results.Thirteen patients (23%) developed stage >/=3 CKD. Three patients had renal biopsies performed that showed thrombotic microangiopathy.Conclusions.CKD is emerging as a potential long-term consequence of current chemotherapy for recurrent ovarian cancer.

Well-to-moderately differentiated neuroendocrine tumors of gastroesophageal and pancreatic origin (GEP-NETs) with liver metastasis are a heterogeneous group of malignancies for which a range of therapeutic options have been employed. Surgical resection of hepatic metastases or hepatic artery embolization may be beneficial in patients with hepatic-predominant metastatic disease. Patients with "carcinoid" syndrome and syndromes associated with functional pancreatic NET (PNET) can be effectively treated with somatostatin analogs. On the other hand, the efficacy of systemic chemotherapy for these patients is limited. A placebo-controlled, double-blind, prospective, and randomized study showed that octreotide LAR improves progression-free survival in patients with advanced midgut functional "carcinoids." In patients with advanced pancreatic NET, randomized, placebo-controlled studies have recently demonstrated that treatment with the tyrosine kinase inhibitor sunitinib or with mTOR inhibitor everolimus is associated with improved progression-free survival. Based on these studies, octreotide LAR, sunitinib, or everolimus are now considered as first-line therapeutic options in patients with advanced NET. Future studies will likely further define the role of these agents in patients with carcinoid liver metastasis and pancreatic NET liver metastasis.

AbstractPurpose. To describe occurrences of oral squamous cell carcinoma (SCC) in patients who had received long-term pegylated liposomal doxorubicin (PLD) for ovarian cancer.Patients and Methods. In our cohort of patients on maintenance PLD for ovarian and related mullerian epithelial malignancies, we encountered two patients with invasive SCC of the oral cavity (one of them multifocal) and one with high-grade squamous dysplasia. Review of patients at our institution receiving PLD for recurrent ovarian cancer identified three additional patients. The duration of treatment, cumulative PLD dose, human papillomavirus (HPV) positivity, BRCA status, stage at diagnosis, outcome, and other characteristics are reviewed.Results. All five cases were nonsmokers with no known risk factors for HPV and four were negative for p16 expression. Four of the patients had known BRCA mutations whereas one tested negative. Cumulative doses of PLD were >1,600 mg/m(2) given over 30-132 months. Three had SCCs staged as T1N0 oral tongue, alveolar ridge (gingival), and multifocal oral mucosa; one had a T2N0 oral tongue; and one had dysplasia. After excision, two were given radiation but recurred shortly thereafter; the others remain well and have had no further exposure to cytotoxic drugs, including PLD.Conclusion. Awareness of this possible long-term complication during PLD treatment should enhance the likelihood of early detection of oral lesions in these patients. Decisions to continue maintenance PLD after complete response of the original cancer should perhaps consider the benefits of delaying ovarian cancer recurrence versus the possible risk for a secondary cancer.