Faculty Bibliography

Introduction: Topotecan was initially approved for the treatment of recurrent ovarian cancer. In cervical cancer, it has been investigated for its potential as part of systemic therapy for advanced and/or recurrent disease and in combination with cisplatin and radiation as a first-line treatment for advanced disease. As a topoisomerase I (topo I) inhibitor, its activity is predicted to be schedule-dependent and potentiated in a schedule-dependent manner by its interaction with DNA damaging agents. Areas covered: The cytotoxicity of topotecan is believed to be due to double-stranded DNA damage produced when the DNA replication 'fork' on the opposing DNA strand is interrupted by the ternary complex formed by topotecan, topoisomerase I and DNA. This review focuses on: i) combination studies of cisplatin + topotecan both as neoadjuvant and with concomitant radiation; ii) adding this drug as a radiosensitizer in pilot studies for locally advanced disease and iii) topotecan as part of non-cisplatin combinations in metastatic disease. Expert opinion: Cervical cancer continues to claim many victims among parts of the world where early detection and/or vaccination programs are not systemically applied. Topotecan is an attractive building block for improving therapy against advanced disease.

Gonadotropin-releasing hormone (GnRH) agonists are used for gonadal suppression in the treatment of breast and prostate cancers. In older men, their use has occasionally been associated with cardiovascular side effects such as supraventricular tachyarrhythmias (SVTs). Several reports document their occurrence in men receiving leuprolide for prostate cancer. We now report this complication with concomitant occurrence of migratory trunk and extremity urticaria in a young woman receiving this treatment after diagnosis of a T1cN0 premenopausal breast cancer. Changing from leuprolide to another GnRH agonist, goserelin, no additional problems with SVT or accompanying urticaria were encountered during the nearly two years of treatment and three subsequent years of follow-up.

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.

This second article in our two-part series on targeted therapies in solid tumors covers the emergence of targeted therapies for the treatment of two common malignancies: lung cancer and breast cancer. In these two tumors, the identification of a promising target has led to successful preliminary applications, and eventually to further advances through drug development and the fine tuning of patient selection. As a result, the percentage of patients with breast or lung cancer who are benefiting from targeted agents has steadily increased, even if the majority are still treated with conventional cytotoxic regimens. We also review the latest therapeutic strategies for colorectal and gynecologic cancers--because these offer an instructive contrast. The curative regimens that have been developed for these two tumors--even those in more advanced stages--have included combinations of surgery and/or radiation with chemotherapy. The Cancer Genome Atlas has revealed complexities in the biology of these tumors that underscore the fact that reliance on selective DNA-damaging agents such as platinums, antimetabolites, and antimitotic agents will continue for some time. We conclude that the therapeutic progress that may arise from the study of molecular pathways will be due not only to the development of new targeted therapies, but also to a better understanding of older drugs developed empirically in the past. Taken together, these two types of advance illustrate the remarkable overall effect of modern cancer therapeutics' focus on tumor biology and tumor immunology.

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.

"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.