Phase 0 clinical trials in oncology: a paradigm shift for early drug development?

Purpose  To review the potential impact of Phase 0 trials conducted under the United States Food and Drug Administration (FDA) exploratory IND guidance on oncology drug development. Methods  The FDA’s exploratory IND guidance document is examined in detail and its practical application to specific first-in-human proof of concept clinical studies called Phase 0 trials is discussed. Results  Phase 0 trials represent a novel strategy for accelerating the development of the next generation of anticancer treatments. Phase 0 studies are conducted prior to conventional toxicity-defined dose-escalation studies and these trials do not explore maximum toxicity levels and by definition are devoid of any therapeutic or diagnostic intent. They require less extensive formulation and non-clinical toxicity testing than conventional first-in-human Phase I trials. This pathway may be valuable in reducing the time and resources required to initiate clinical testing and it may also be useful in guiding the later stages of drug development. Alternatively, the early termination of a less than promising lead compounds could help in selecting the best agents for later clinical development. Possible disadvantages include the ethical challenge of testing non-therapeutic drug regimens in cancer patients and the need to conduct standard dose-escalation Phase I studies later in development. Conclusions  The potential of this novel pathway to accelerate drug development makes it worthy of further exploration, and National Cancer Institute has recently completed a Phase 0 trial demonstrating its applicability to targeted anticancer agents.     

Thalidomide: a role in oral oncology?

Thalidomide is having increasing application in the management of a wide spectrum of immunologically-mediated and infectious disorders. It is also suggested that this agent may also have be of importance in the treatment of solid and non-solid malignancies. The present article reviews the role of thalidomide in the management of malignancy and outlines its possible potential in the treatment of malignancy of the mouth.     

How has acute oncology improved care for patients?

A United Kingdom–wide appreciation of the systemic failings of emergency cancer care led to the creation of a new subspecialty, acute oncology. It was meant to bridge the gap between admitting teams, oncology, and palliative care, providing support to manage the symptoms of cancer, the side effects of cancer treatment, and people presenting with cancer of unknown primary origin. This article identifies the reasons for the creation of acute oncology and explores various models for this aspect of cancer care worldwide. With health care budgets static and demand increasing, the article also identifies ways in which acute oncology can contribute to an efficient and caring health system.     

Targeted therapies in oncology: in the crosshairs or at the crossroads?

Normal cellular behavior depends on functional integration of extracellular stimuli with intracellular signal transduction pathways. Coupling cell surface message reception to nuclear gene expression is no longer a linear model constructed with molecular components acting merely as conduits to relay signals that cascade toward the nucleus. What has emerged instead is a highly integrated circuit comprised of numerous molecular components harmoniously programmed to communicate a multitude of internal signals that controls cellular response. Despite increasing understanding of cell signaling, mutinous elements embedded in these pathways have defied complete resolution. Research indicates that propagation of signals emanating from the extracellular environment to the cell nucleus follows a complex internal circuit equipped with sophisticated molecular components that provide rigid control over a variety of cellular responses. Although increasing understanding of genetic aberrations and signaling pathway transgressions can lead to novel strategies for targeting cancer cells, the disappointing results from clinical trials suggest that the occult processes responsible for neoplastic transformation remain largely unexplained.     

Biomarkers of angiogenesis for the development of antiangiogenic therapies in oncology: tools or decorations?

Since 2004, four antiangiogenic drugs have been approved for clinical use in patients with advanced solid cancers, on the basis of their capacity to improve survival in phase III clinical studies. These achievements validated the concept introduced by Judah Folkman that the inhibition of tumor angiogenesis could control tumor growth. It has been suggested that biomarkers of angiogenesis would greatly facilitate the clinical development of antiangiogenic therapies. For these four drugs, the pharmacodynamic effects observed in early clinical studies were important to corroborate activities, but were not essential for the continuation of clinical development and approval. Furthermore, no validated biomarkers of angiogenesis or antiangiogenesis are available for routine clinical use. Thus, the quest for biomarkers of angiogenesis and their successful use in the development of antiangiogenic therapies are challenges in clinical oncology and translational cancer research. We review critical points resulting from the successful clinical trials, review current biomarkers, and discuss their potential impact on improving the clinical use of available antiangiogenic drugs and the development of new ones.     

High-tech in radiation oncology: should there be a ceiling?

PURPOSE: To analyze some of the limitations to improvement of the outcome of radiotherapy (RT) expected from the introduction of sophisticated treatment planning and delivery technology. METHODS AND MATERIALS: Several recent examples from the literature were analyzed in some detail. Mathematical modeling techniques were used to assess the likely clinical impact of new technologies or biologic principles. The findings of recent randomized controlled trials of RT for prostate, breast, and rectal cancer were analyzed from the perspective of cost-effectiveness and therapeutic gain. RESULTS: The main findings of the analyses may be summarized as follows. Dosimetric precision should aim for a <2% patient-to-patient variability in the delivered dose. Imprecision in clinical target volume definition remains an obstacle for high-precision RT. Functional imaging and novel biologic assays may facilitate a move from a clinical target volume to the real target volume. Improved target volume coverage is mainly important if RT has high effectiveness. Radiation oncology is increasingly becoming evidence based. However, there is still a long way to go. Hypofractionation in adjuvant RT for breast cancer may represent a favorable balance between cost and benefit. Treatment complications are potentially associated with both suffering and high cost. The identification of high-risk patients would improve the cost-effectiveness of high-tech RT aimed at avoiding complications. Conformal RT may allow the introduction of hypofractionation, which, again, could potentially save resources. With improvement in surgery and more screening-detected cancer cases, the number needed to treat increases, and this will directly affect the cost-effectiveness of high-tech RT unless efficient patient selection can be developed. CONCLUSION: Sustained technological refinement is only likely to be cost-effective if the clinical and biologic understanding of patient-to-patient variability in the risk of specific types of failure and the optimal multimodality approach to handle these risks is developed at the same time. Mathematical modeling together with methods from health technology assessment and health economics are useful complements to standard methods from evidence-based medicine. Progress in functional imaging and in basic and clinical cancer biology is likely to provide the tools required for individualized risk-adapted RT.