Roger Ove

TUMOR CONTROL PROBABILITY FOR SELECTIVE BOOSTING OF HYPOXIC SUBVOLUMES, INCLUDING THE EFFECT OF REOXYGENATION

PURPOSE To study the effect on tumor control probability of selectively boosting the dose to hypoxic subvolumes. METHODS AND MATERIALS A Monte Carlo model was developed that separates the tumor into two compartments, one of which receives a primary dose, and one of which receives a higher boost dose. During radiation delivery, each compartment consists of three clonogen subpopulations: those that are well oxygenated, those that are temporarily hypoxic (geometrically transient hypoxia), and those that are permanently hypoxic (geometrically stable hypoxia). The spatial location of temporary hypoxia within the tumor volume varies over time, whereas, the spatial location of permanent hypoxia does not. The effect of reoxygenation was included. Clonogen proliferation was not included in the model. RESULTS A modest boost dose (120%-150% of the primary dose) increases tumor control probability to that found in the absence of permanent hypoxia. The entire hypoxic subvolume need not be included to obtain a significant benefit. However, only tumors with a geometrically stable hypoxic volume will have an improved control rate. CONCLUSIONS Tumors with an identifiable geometrically stable hypoxic volume will have an improved control rate if the dose to the hypoxic volume is escalated. Further work is required to determine the spatiotemporal evolution of the hypoxic volumes before and during the course of radiotherapy.

Molecular targets as therapeutic strategies in the management of breast cancer.

Although the molecular and genetic determinants of most sporadic breast cancers remain unknown, increasing understanding of molecular and genetic events affecting breast carcinogenesis has provided information about the potential roles of specific biomarkers in tumour development and spread. It is now recognised that mutations of some tumour suppressor genes appear to play important early roles in the formation of some breast cancers. In addition, alterations in proto-oncogenes may contribute to the development of some breast cancers. The study of breast tumour biology at the molecular level has led to the development of targeted drug design, which provides a variety of agents targeted at specific molecules for the prevention, diagnosis and treatment of breast cancer. This review will describe the recognised molecular targets in breast cancer.

Sequential annealing–gradient Gamma-Knife radiosurgery optimization

Simulated annealing and gradient methods are commonly employed for inverse planning of radiotherapy delivery schemes. Annealing is effective in finding an approximation of the global solution, suffering from slow late convergence and in some cases poor dose homogeneity. Gradient methods converge well but not necessarily to the global minimum. We explored simulated annealing followed by gradient optimization to improve on either method alone, using radiosurgery as the model system. Simulated annealing and gradient inverse planning programs using the same objective function were adapted for radiosurgical optimization. The objective function chosen is a least-squares dose-matching function, with differential weighting of tissues. A simple test target allowing local minima in the objective function was evaluated. Two hundred trials using the gradient method were done. The gradient method approximated the global solution only 12% of the time, commonly finding a local minimum. The annealing-gradient technique converged to the global minimum in 78 out of 80 trials, more efficiently than annealing alone. Dose homogeneity was improved. In conclusion, sequential annealing-gradient optimization can improve on either method alone. The technique may be extensible to radiotherapy inverse planning in general, with benefit expected for problems characterized by slow gradient method convergence and local minima.

MOLECULAR TARGETS FOR RADIOSENSITIZATION

Publisher Summary This chapter discusses molecular targets for radiosensitization that have reached clinical trial or that are likely to form the basis of clinical trials in the future. The chapter explores several approaches to create radiosensitization through various interactions with EGFr. The receptor can be blocked by a specific antibody, such as cetuximab in the case of EGFr or trastuzumab in the case of Her2. Another approach is to interfere with the tyrosine kinase cytoplasmic component of EGFr, as is currently being explored with the small molecule gefitinib. Anti-EGFr-induced radiosensitization may also be intimately involved with DNA double-strand break repair. Angiogenesis inhibitors show considerable promise as possible synergistic agents for use with radiotherapy, which complements their potential systemic activity. Cetuximab and other agents targeting the EGFr appear to act in part through the anti-angiogenesis pathway, which may contribute to synergy with radiation. Various cell lines with Ras mutations have been shown to exhibit radioresistance. The first attempt to induce enhanced radiosensitivity through interference with the membrane binding of Ras was undertaken with lovastatin, a drug that non-specifically interferes with lipid metabolism. The importance of angiogenesis suggests that the standard measure of radiosensitization, the clonogenic assay, may be inadequate and more clinically relevant in vivo assays are required.