Reviews on Recent Clinical Trials - Volume 2, Issue 3, 2007

Angiogenesis inhibition by monoclonal antibodies against vascular endothelial growth factor receptor (VEGFR) combined with cytotoxic chemotherapy has shown encouraging potential for improvement of cancer treatment. Several rationales exist for combining VEGFR antibodies with ionizing radiation, a primary curative cancer treatment, either in bimodal or trimodal fashion, i.e. with or without additional chemotherapy. This systematic review compares the results of preclinical and clinical studies published before December 2006. The combination of VEGFR inhibitors with irradiation in animal models consistently resulted in improved tumor growth delay (at least additive effects), despite different treatment schedules. Only one study evaluated tumor control dose (TCD)50 as a measure of tumor cure (radiation dose yielding permanent local control in 50% of the tumors). Also in this setting, anti-VEGFR antibody treatment improved the outcome. Importantly, both radiotherapy schedule and sequence of the modalities in combined treatment may impact on the outcome. Hence, further preclinical studies examining these parameters need to be conducted. While preclinical research is ongoing, phase I and II clinical trials with bevacizumab, usually combined with radio- and chemotherapy, have been designed. Early results suggest that acute toxicity is acceptable, planned surgery after such treatment is feasible, and that further evaluation of such combined modality treatment is warranted.

Three U.S. National Cancer Institute cooperative group randomized phase 3 trials have demonstrated that the intraperitoneal delivery of cisplatin-based chemotherapy as primary treatment of small-volume residual advanced ovarian cancer improves survival compared to the administration of all agents by the intravenous route. As use of intraperitoneal chemotherapy requires additional resources and expertise beyond that associated with routine intravenous treatment, and unique side effects may be observed (e.g., catheter malfunction, intra-abdominal infection), some have questioned the utility of this approach, despite the documented survival advantage. This review outlines the data supporting intraperitoneal delivery in ovarian cancer, discusses strategies to safely and effectively employ regional therapy, and highlights areas where future trials are required to optimize this novel method for treatment of this malignancy.

Intracerebral hemorrhage (ICH) accounts for 15% of all strokes in the US and Europe and 20% to 30% in Asian populations. ICH is associated with a higher morbidity, disability and mortality than ischemic strokes. Primary ICH originates from spontaneous rupture of small arteries and arterioles previously damaged by chronic hypertension or amyloid angiopathy. Secondary ICH is associated with underlying vascular abnormalities or other pathologies. Manifestation is acute with focal neurological signs and features of raised intracranial pressure. Despite our improved understanding of the pathophysiology of hematoma expansion and edema formation, management is primarily supportive, and outcomes remain poor. A recently published report has confirmed that there is no overall benefit from early surgery when compared with initial conservative treatment. In contrast, treatment with recombinant activated factor VII within 4 hours of onset limits hematoma growth at 24 hours, and reduces mortality and improves functional outcomes at 90 days. Several ICH scoring methods have recently been proposed for better prediction of outcome. These scoring methods may be useful in selecting suitable patients for clinical trials. Microbleeds are commonly seen on magnetic resonance imaging. Further studies are awaited to clarify the association between microbleeds and the future risk of ICH.

Prostate cancer is the most common non-cutaneous cancer of men in the United States and represents their second-leading cause of cancer-related death. Metastatic disease is largely resistant to conventional chemotherapies, and targeted therapies are urgently needed. Prostate-specific membrane antigen (PSMA) is a prototypical cell-surface marker of prostate cancer. PSMA is an integral, nonshed, type 2 membrane protein with abundant and nearly universal expression in prostate carcinoma, but has limited extra-prostatic expression. In addition, PSMA is expressed in the neovasculature of other solid tumors. These findings have spurred development of PSMA-targeted therapies for cancer, and first-generation products have entered clinical testing. Vaccine approaches have included recombinant protein, nucleic acid and cell-based strategies, and anti-PSMA immune responses have been demonstrated in the absence of significant toxicity. Therapy with drug-conjugated and radiolabeled antibodies has yielded objective clinical responses as measured by reductions in serum prostate-specific antigen and/or imageable tumor volume. However, responses were observed in a minor fraction of patients and at doses near the maximum tolerated dose. Overall, these initial studies have provided measured proof of concept for PSMAbased therapies, and second-generation antibody and vaccine products may hold the key to exploit PSMA for molecularly targeted therapy of prostate and other cancers.

Progress in the systemic therapy of thymic malignancies has been hampered in the past by the rarity of this disease entity and the lack of a global collaborative effort in conducting phase II studies. Cisplatin-based therapy has been considered the standard of care, though data typically has been derived from a retrospective case-series approach. However, the arrival of novel cytotoxic agents and molecularly targeted agents into the clinic has helped provide the impetus for improved methodology in thymic malignancy research with an emphasis on more prospective phase II studies. This review discusses the results of traditional cytotoxic agents, novel cytotoxic agents, biologic therapy and the initial evaluation of molecularly targeted therapeutics, such as epidermal growth factor receptor inhibitors, for the treatment of thymic malignancies. In addition, potential novel targets such as VEGF, Bcl-2 and c-KIT are assessed.

Soft tissue sarcomas are a heterogeneous group of tumours arising predominantly from the embryonic mesoderm. They account for less than 1 % of all adult malignancies. The prognosis of patients with advanced metastatic soft tissue sarcoma remains poor with a disease-free survival at 5 years less than 10 %. Despite improvements in local tumour control due to surgery and radiotherapy, distant metastasis and death remain a significant problem in 50 % of patients. Complete resection remains the major factor in providing cure with limited benefits in local tumour control by radiotherapy and only minimal benefit of systemic therapy for metastatic disease. Only few chemotherapeutic agents have been identified to be active with reported response rates for doxorubicin and ifosfamide around 20 %. New strategies are urgently needed to improve patients' outcome. Progress in the molecular characteristics, the understanding of biology and pathogenesis of these tumours has been made and should in the near future translate into molecularly based therapies. We describe current treatment strategies and existing standards. Moreover, we give an overview on the emerging compounds for patients with soft tissue sarcoma including recent developments of targeted therapy focusing on antiangiogenic and immunomodulatory drugs, Bcl-2 antisense therapy, raf kinase and mTOR inhibition, minor groove binders, and other agents being developed.

Primary and secondary liver tumours are common malignancies that are being treated more aggressively nowadays than decades ago. Surgery is the most effective method of treatment but is only suitable for a minority of patients with well-defined and easily accessible tumours. Surgical resection is contraindicated in patients with massive involvement of the liver or in cases where the disease involves the confluence of vessels at the porta hepatis. These patients may benefit from a variety of ablative and embolic therapies including selective internal radiation therapy (SIRT) with Yttrium-90 microspheres. SIRT has been introduced in the 1980's but the technology has been refined and made more available only recently. The microspheres are injected directly into the hepatic arteries, through a trans-femoral angiographic approach, and are delivered selectively to tumours due to their preferential blood supply by hepatic arteries. SIRT can therefore target small volumes disease with a higher dose of radiation compared with external-beam radiation and is associated the relatively low toxicity and a good response irrespective of tumor origin. Assessment of response to therapy is best performed with metabolic imaging using 18F-FDG PET scanning. Although it is not considered as a cure, it has been shown to improve quality of life and prolong survival, with the main cause of death being extra-hepatic spread. The technical and clinical demands of patient selection, treatment planning, administration, and clinical follow-up require an interdisciplinary team willing to work cooperatively to achieve the best result for the patient.

Genomic instability during hepatocarcinogenesis causes changes in signal transduction network. Strategies for identification of new markers/therapeutic targets include discovery of early molecular changes during hepatocarcinogenesis, relevant to preneoplastic lesions progression to full malignancy in rodent models, and evaluation of these changes in human hepatocellular carcinomas (HCCs). Activation of ERB receptor family, MAPK, JAK-STAT, β-Catenin cascades, c-Myc targets, iNOS-IKK/MAT1A-NF-kB axis, Ornithine decarboxylase, Cyclins and CDKs occurs in human and rodent hepatocarcinogenesis. This is associated with downregulation of the cell cycle inhibitors p16INK4A and p53 and TGF-β/SMAD signaling. Oncosuppressor genes, including p16INK4A, E-CAD, and DLC-1 are often hypermethylated in humans and rodents. Moreover, protection of cell cycle from p16INK4A inhibition by upregulation of CDC37, HSP90, and CRM1 correlates to HCC progression. A body of evidence indicates that inhibition of key genes of aforementioned signaling pathways by antisense or siRNA approaches or specific inhibitors restraints growth of in vitro cultured or in vivo xenografted HCCs. Efforts are currently dedicated to improve transduction efficiency. HCC cells may escape gene therapy by various mechanisms. Attempts to overcome this difficulty include discovery of new therapeutic targets, gene therapy directed to different molecular targets essential for tumor cell survival and specifically directed to HCC subtypes.