Antiangiogenic strategies in neuroblastoma

Promising new antiangiogenic strategies are emerging for the treatment of cancer and the inhibition of angiogenesis could represent a powerful adjunct to traditional therapy of malignant tumors. Over the last ten years several reports have been published concerning the relationship between tumor progression and angiogenesis in neuroblastoma in experimental models in vitro and in vivo. Moreover, a high vascular index in neuroblastoma correlates with poor prognosis, suggesting dependence of aggressive tumor growth on active angiogenesis. Here, we present an overview of recent advances in antiangiogenesis in neuroblastoma and describe the most important active substances, preclinical and clinical data, as well as future perspectives.     

Antiangiogenic agents and late anastomotic complications

Anticancer agents targeting circulating vascular endothelial growth factor (VEGF) (e.g., bevacizumab and aflibercept) are strong angiogenesis inhibitors. As such, they may hamper the healing process, notably in the early postoperative period. Whether antiangiogenic agents may be associated with late postoperative healing complications is less known. We reviewed three cases of patients with anastomotic complications under antiangiogenic treatment occurring more than 1 year after initial surgery and we conducted a review of the literature. We report the first case of delayed anastomotic leakage which occurred under aflibercept therapy 13 months after a bilioenteric anastomosis and two cases of delayed rectal anastomotic complications associated with bevacizumab treatment 18 and 78 months after surgery. Fifteen similar cases of late gastrointestinal anastomotic complications were found in the English literature. Antiangiogenic agents are probably not deleterious to a healed wound. However, they appear to be associated with an increased risk of complications in a subgroup of patients. According to the 18 cases reported, the main risk factors appear to be low anterior resection for rectal cancer, perioperative radiotherapy, and early postoperative leak which heals through the formation of abundant and hypervascularized granulation tissue. J. Surg. Oncol. 2010;101:180–183. © 2009 Wiley‐Liss, Inc.     

Antiangiogenic agents and chemotherapy in advanced non-small cell lung cancer: a clinical perspective

Antiangiogenic agents represent a major advance in the management of patients with advanced non-small-cell lung cancer receiving chemotherapy. While bevacizumab has been available for first-line treatment, other drugs, such as nintedanib, recently demontrated significant activity in the second-line setting. This review covers most recent results with antiangiogenic treatments, focusing on data relevant for routine clinical practice; recent results potentially leading to new agents approval are discussed. While biomarkers are still awaited to better-select patients for these approaches, the development of antiangiogenic agents represent a model for implementation in thoracic oncology, while highlighting the promise of a better outcome for patients with advanced lung cancer.     

Assessing oncologic benefit in clinical trials of immunotherapy agents

Background: USA Food and Drug Administration approval for cancer therapy requires demonstration of patient benefit as a marker of clinical efficacy. Prolonged survival is the gold standard for demonstration of efficacy, but other end points such as antitumor response, progression-free survival, quality of life, or surrogate end points may be used.Design: This study was developed based on discussion during a roundtable meeting of experts in the field of immunotherapy.Results: In most clinical trials involving cytotoxic agents, response end points use RECIST based on the premise that ‘effective’ therapy causes tumor destruction, target lesion shrinkage, and prevention of new lesions. However, RECIST may not be appropriate in trials of immunotherapy. Like other targeted agents, immunotherapies may mediate cytostatic rather than direct cytotoxic effects, and these may be difficult to quantify with RECIST. Furthermore, significant time may elapse before clinical effects are quantifiable because of complex response pathways. Effective immunotherapy may even mediate transient lesion growth secondary to immune cell infiltration.Conclusions: RECIST may not be an optimal indicator of clinical benefit in immunotherapy trials. This article discusses alternative clinical trial designs and end points that may be more relevant for immunotherapy trials and may offer more effective prediction of survival in pivotal phase III studies.     

Antiangiogenic strategies in hepatocellular carcinoma: current status

Hepatocellular carcinoma is a leading cause of cancer death worldwide in both adult and pediatric patients. Despite many options, no ideal treatment exists for this highly malignant tumor, and management strategies have varied accordingly. Angiogenesis, the formation of new blood vessels, is an essential component of hepatocellular carcinoma biology. Innovative approaches such as targeting the nontransformed, less resistant, tumor-supporting endothelial cells are currently under investigation in hepatocellular carcinoma. This review will focus on the current knowledge of the pathophysiology of hepatocellular carcinoma angiogenesis, as well as the reported data with angiogenesis inhibitors against hepatocellular carcinoma.     

Antiangiogenic strategies in hepatocellular carcinoma: current status

Hepatocellular carcinoma is a leading cause of cancer death worldwide in both adult and pediatric patients. Despite many options, no ideal treatment exists for this highly malignant tumor, and management strategies have varied accordingly. Angiogenesis, the formation of new blood vessels, is an essential component of hepatocellular carcinoma biology. Innovative approaches such as targeting the nontransformed, less resistant, tumor-supporting endothelial cells are currently under investigation in hepatocellular carcinoma. This review will focus on the current knowledge of the pathophysiology of hepatocellular carcinoma angiogenesis, as well as the reported data with angiogenesis inhibitors against hepatocellular carcinoma.     

Adaptive designs for clinical trials assessing biomarker-guided treatment strategies

Background:

The Biomarker Strategy Design has been proposed for trials assessing the value of a biomarker in guiding treatment in oncology. In such trials, patients are randomised to either receive the standard chemotherapy treatment or a biomarker-directed treatment arm, in which biomarker status is used to guide treatment.

Methods:

Motivated by a current trial, we consider an adaptive design in which two biomarkers are assessed. The trial is conducted in two stages. In the first stage, patients in the biomarker-guided arm are assessed using a standard and an alternative cheaper biomarker, with the standard biomarker guiding treatment. An analysis comparing biomarker results is then used to choose the biomarker to use for the remainder of the trial. The new biomarker is used if the results for the two biomarkers are sufficiently similar.

Results:

We show that in practical situations the first-stage results can be used to adapt the trial without type I error rate inflation. We also show that there can be considerable cost gains with only a small loss in power in the case where the alternative biomarker is highly concordant with the standard one.

Conclusions:

Adaptive designs have an important role in reducing the cost and increasing the clinical utility of trials evaluating biomarker-guided treatment strategies.     

Search strategies for retrieving complementary and alternative medicine clinical trials in oncology

PURPOSE: Several Medline search strategies exist to retrieve complementary and alternative medicine (CAM) literature related to oncology. The objective of this study was to compare different search methods to ascertain the most optimal strategy. METHODS: All clinical trials with CAM interventions in patients with cancer, published from 1965 to 2004, were abstracted using 4 different approaches. In the CAM filter search, the PubMed complementary medicine filter was used. The Ovid search was performed using a complex search strategy with the Ovid search engine. CAM keyword and not phytogenic searches involved the CAM filter search with the addition of the search terms "AND (complementary OR alternative)" and "NOT (antineoplastic agents, phytogenic), respectively. Articles were evaluated by 3 reviewers to ascertain whether they were clinical trials, the study intervention was related to CAM, and the condition prevented/treated was cancer related (inclusion criteria). RESULTS: The CAM filter search retrieved 10 718 citations, Ovid retrieved 1190, CAM keyword retrieved 2895, and not phytogenic retrieved 1806. Compared to the CAM filter search, all other methods had significantly lower sensitivity (Ovid 48.3% +/- 3.2%, CAM keyword 5.8% +/- 1.5%, and not phytogenic 77.9% +/- 2.7%, P < .001). The specificity of Ovid (38.4% +/- 2.8%) and not phytogenic (40.8% +/- 2.3%) searches was significantly higher (P < .001) compared to CAM filter (8.8% +/- 0.5%) and CAM keyword searches (1.9% +/- 0.5%). CONCLUSION: The search strategy using PubMed's complementary medicine filter, although comprehensive, lacks specificity; other methods, although more specific, lack sensitivity. Future indexing of all CAM clinical trials with a common medical subject heading term complementary medicine would enhance efficient retrieval of relevant citations.     

Intravascular adenoviral agents in cancer patients: lessons from clinical trials

A large number of adenoviral agents are being developed for the treatment of cancer. However, the treatment-related death of a patient with ornithine transcarbamylase deficiency following adenovirus administration by hepatic artery has led to serious concerns regarding the safety of intravascular adenovirus. Both replication-incompetent (rAd.p53, e.g., SCH58500) and replication-selective (dl1520, aka Onyx-015; CG7870) oncolytic adenoviruses, by intravascular administration, are in clinical trials. We review Phases I and I/II results from these clinical trials. dl1520 and rAd.p53 were well-tolerated following hepatic artery infusion at doses of up to 2x10(12) and 2.5x10(13) particles, respectively. At a dose of 7.5x10(13) particles, rAd.p53 was associated with dose-limiting cardiac output suppression; dl1520 dose escalation did not proceed higher than 2x10(12). Intravenous (i.v.) infusions of dl1520 and CG7870 have been well tolerated by i.v. infusion at doses of 2x10(13) and 6x10(12), respectively, without identification of a maximally tolerated dose to date. Mild/moderate transaminitis was demonstrated in some patients on both the hepatic arterial and i.v. trials at doses >or=10(12) particles. Interleukin (IL)-6 and IL-10 were induced in a dose-dependent manner in most patients, but significant interpatient and intrapatient (on repeat doses) variabilities were demonstrated. Evidence of p53 gene expression (Ad.p53) or viral replication (dl1520) was demonstrated in the majority of patients receiving >or=10(12) particles. Over 100 cancer patients have been treated with intravascular adenovirus constructs to date with an acceptable toxicity profile; further clinical trial testing appears appropriate in cancer patients.     

Progression-free survival as an end-point in clinical trials of biotherapeutic agents

Progression-free survival (PFS), the time from registration or randomisation of a patient until objective disease progression or death, can be considered as an outcome for clinical research and also as a basis for regulatory approval. Current experience suggests that greater standardisation and consistency are needed for clinical trials utilising PFS endpoints. To this end, the Biotherapy Development Association (BDA) convened a breakout session on the topic of PFS during its Third Alpine Meeting held 14–16 March 2007. Representatives of the pharmaceutical industry, regulatory agencies, academia, and patient advocacy groups identified challenges, developed recommendations, and worked to build consensus regarding the conduct of clinical trials utilising PFS as an end-point to help speed new targeted biologics to the patient bedside.     

Antiangiogenic agents and endothelin antagonists in advanced castration resistant prostate cancer

Despite multiple advances in prostate cancer therapy, treatment options for castration resistant disease are very limited. While data from recent studies are encouraging, there is no drug that has significantly improved results of standard chemotherapy. Some of the most consistent results are provided by antiangiogenic agents, showing high response rates and manageable toxicity. We describe some of the main therapeutic angiogenesis inhibitors in metastatic castration resistant prostate cancer. These agents include vascular endothelial growth factor inhibitors, tyrosine kinase inhibitors, antiangiogenic and inmunomodulatory agents and endothelin receptor antagonists.     

Antiangiogenic agents combined with chemotherapy in non-small cell lung cancer

As a targeted therapy, antiangiogenic treatment has been increasingly studied for advanced non-small cell lung cancer(NSCLC) and has proven effective for the treatment of advanced NSCLC. Bevacizumab, a monoclonal antibody targeting angiogenesis, is the only antiangiogenic agent approved for use in combination with first-line chemotherapy for non-squamous NSCLC. Small-molecule inhibitors targeting the tyrosine kinase receptor have also shown promise when combined with standard chemotherapeutic agents in patients with advanced NSCLC. However, unlike bevacizumab, not all other antiangiogenic agents show significant benefits when combined with chemotherapy. As for the failures of most other combinations, the combination schedule may be an important reason that has so far been overlooked in clinical trials. This article reviews the combination of angiogenic agents with chemotherapy in the treatment of NSCLC.