Faculty Bibliography

Author Summary BACKGROUND: Transcatheter arterial chemoembolization (TACE) has been used to curtail tumor vasculature and delay tumor progression in hepatocellular carcinoma (HCC). We conducted a phase I trial to evaluate the efficacy and toxicity of thalidomide when combined with TACE in patients with advanced HCC. METHODS: Between June 2000 and November 2003, 56 patients with unresectable HCC and amenable to TACE were enrolled. The starting dose of thalidomide was 200 mg/day and was escalated every 2 weeks as tolerated to a maximum dose of 1,000 mg/day. Dose reductions and discontinuation were determined by toxicity. TACE was performed 4 weeks after initiation of thalidomide therapy and repeated as necessary. RESULTS: Overall, 47 and 55 patients were evaluable for response and toxicity, respectively; the median dose of thalidomide given was 200 mg/day. Three patients (6.38%) patients achieved complete responses, whereas 10 (21.3%) had partial responses, for an overall response rate of 27.7%, and 27 (57.5%) had stable disease. Median progression-free survival was 7 months (95% confidence interval [CI]: 5-10 months), and median OS was 21 months (95% CI: 16-28 months) (Fig. 1). Fatigue and lethargy (49.1%), constipation (47.3%), and nausea (43.6%) were common. Grade 3-4 toxicities consisted mostly of increased aspartate aminotransferase (43.6%) and elevated alanine aminotransferase (38.2%) (Table 1). CONCLUSION: Thalidomide and TACE were commonly associated with nonhematologic side effects, with fatigue and constipation being prominent. With a lack of clear therapeutic benefit, this combination is unlikely to be pursued for HCC.

BACKGROUND: Outbreaks of hepatitis C virus (HCV) infection have been reported in HIV-positive men who have sex with men (MSM) in North America, Europe and Asia. Transmission is believed to be the result of exposure to blood during sexual contact. In those infected with HIV, acute HCV infection is more likely to become chronic, treatment for both HIV and HCV is more complicated and HCV disease progression may be accelerated. There is a need for systematic reviews and meta-analyses to synthesize the epidemiology, prevention and methods to control HCV infection in this population. METHODS/DESIGN: Eligible studies will include quantitative empirical data related to sexual transmission of HCV in HIV-positive MSM, including data describing incidence or prevalence, and associations between risk factors or interventions and the occurrence or progression of HCV disease. Care will be taken to ensure that HCV transmission related to injection drug use is excluded from the incidence estimates. Scientific databases will be searched using a comprehensive search strategy. Proceedings of scientific conferences, reference lists and personal files will also be searched. Quality ratings will be assigned to each eligible report using the Newcastle-Ottawa scale. Pooled estimates of incidence rates and measures of association will be calculated using random effects models. Heterogeneity will be assessed at each stage of data synthesis. DISCUSSION: HIV-positive MSM are a key HCV-affected population in the US and other high-income countries. This review seeks to identify modifiable risk factors and settings that will be the target of interventions, and will consider how to constitute a portfolio of interventions to deliver the greatest health benefit. This question must be considered in relation to the magnitude of HCV infection and its consequences in other key affected populations, namely, young prescription opioid users who have transitioned to illicit opiate injection, and older injection drug users among whom HCV prevalence and incidence are extremely high. This review is part of a series of systematic reviews and meta-analyses that will synthesize the evidence across all these population groups and develop recommendations and decision tools to guide public health resource allocation. TRIAL REGISTRATION: PROSPERO registration number: CRD42013006462.

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.

"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.

CONTEXT: Hepatitis B and Hepatitis C (HBV and HCV) infections are both major causes of hepatocellular carcinoma (HCC). However, HCC caused by each of these two viruses has unique characteristics that should be studied independently to that of another one. While HBV- and HCV-related HCCs share similar host and environmental risk factors such as male gender, age above 50 years old, family history of HCC, cirrhosis, obesity, and concomitant alcohol/tobacco use, they differ in their viral risk factors. EVIDENCE ACQUISITION: The actual level of HBV DNA, the presence of HBV e antigen (HBeAg), and mutations in the viral genome are important predisposing factors to HCC development in HBV, whereas in HCV, viremia of any amount denotes an elevated risk. HBV and HCV also differ in their mechanisms of carcinogenesis. For example, HBV can integrate into the host genome and induce many different genetic alterations/mutations. Ultimately, though, both viruses act on similar pathways to produce HCC. RESULT: HBV and HCV are often transmitted differently - vertically (HBV) and horizontally (HCV), which may play a role in their distinct clinical presentations: HBV patients are younger and more frequently have larger/ bilobar tumors as opposed to HCV patients, who have worse liver function on diagnosis of HCC. Even the way they respond to treatment seems to be different. HBV-related HCC patients tend to progress faster after sorafenib treatments. CONCLUSIONS: Future studies should investigate the ways in which these differences between HBV- and HCV-related HCC can translate into more tailored treatment strategies for each etiology of HCC in order to improve outcomes of both.

Cancer stem cells (CSC) are chemoresistant and implicated in tumor recurrence, metastasis and high patient mortality; thus substances impairing CSC activity, could be invaluable as novel cancer therapeutics. We previously showed that CAPE (caffeic acid phenethyl ester), a component of propolis, a honeybee product, inhibits growth of MDA-MB-231 (MDA-231) cells, mdr gene expression, NF-kappaB, EGFR, and VEGF. We hypothesized that CAPE also acts by interfering with CSC-mediated effects. We isolated breast CSC (bCSC) from MDA-231 cells, a model of human triple-negative breast cancer, and mouse xenografts. bCSC grow as mammospheres (MMS) and when dissociated into single cells, form MMS again, a sign of self-renewal. bCSC exhibited the characteristic CD44(+)/CD24(-/low) phenotype and generated progenitors in the presence of serum, a CSC trait responsible for regenerating tumor mass. CAPE caused dose-dependent bCSC self-renewal inhibition and progenitor formation. Clonal growth on soft agar was inhibited dose-dependently, but apoptosis was not induced as determined by Annexin-V/PI assay. Instead, bCSC were noted to significantly progress from a quiescent cell cycle state in G0/G1 (82%), S phase (12%) to a cycling state with an increase in S phase (41%) and subsequent decrease in G0/G1 (54%). Treatment of bCSC with CAPE (4.5-days) decreased CD44 levels by 95%, while another cell population containing 10-100-fold lower CD44 content concurrently increased. Results suggest that CAPE causes pronounced changes in bCSC characteristics manifested by inhibition of self renewal, progenitor formation, clonal growth in soft agar, and concurrent significant decrease in CD44 content, all signs of decreased malignancy potential

BACKGROUND: Capecitabine is an oral prodrug of flurouracil with broad activity against various malignancies. We explored its tolerance and preliminary efficacy when given together with cisplatin in a phase I/II study preferentially enrolling gastric cancer patients. PATIENTS AND METHODS: The study was a 3+3 dose escalation design and at the recommended phase II dose it included an expanded cohort of patients with upper gastrointestinal cancer. The dose of cisplatin was escalated from 40 to 50 mg/m(2) on day 1, and capecitabine of 2,500 mg/m(2)/day starting on day 2, was escalated from 5 days to 10 and then to 14 days, with the cycle repeated every 21 days. Prolonged maintenance with capecitabine was offered to selected patients completing three to six cycles. RESULTS: A total of 34 patients were enrolled, and 27 patients were also evaluable for response. Dose limiting toxicities were palmar plantar erythrodyesthesia (PPE) and diarrhea; grade 3 and 4 neutropenia occurred in 8.8% and grade 3 PPE in 5.9%, while the most common grade 1-2 toxicities were anemia, neutropenia, fatigue and PPE (11.7% each). There were no treatment related deaths. With cisplatin at 40-50 mg/m(2) day 1 and capecitabine at 2,500 mg/m(2)/day for 5 -14 days every 21 days, 18 patients with gastric cancer were treated and 7 had partial responses. CONCLUSION: A regimen of capecitabine and cisplatin at the doses and schedules explored was safe and active in patients with gastric cancer. Moreover, a 6-month administration of adjuvant capecitabine proved feasible, yielding favorable results after treatment completion and surgery, and should be investigated further.

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.