Introduction

Radiation therapy has more than 100 years of exciting history. Soon after Röntgen discovered x-rays in 1895, the biologic effects of radiation were described: skin burns, epilation and eye irritation. Radiation induced cancer was reported first in 1902--a topic of great relevance today, with more cures and long survival after cancer therapy. Bergonie and Tribondeau related radiosensitivity to mitotic activity and in 1903 there was the first suggestion to treat cancer with implanting radium. The famous testes experiments, in which it was noted, that with a single dose of radiation a ram's testes could not be sterilized without severe skin reactions. However, applying the dose in small fractions, allowing increasing the total dose without causing skin irritation, resulted in sterilizing the ram. The testes were obviously used as a model tissue for a tumor. These early experiments led to the still practiced fractionated radiation therapy.

A major step forward was the development of modern imaging techniques, mainly the introduction of computed tomography in 1972. The tumor could not only be visualized, it soon became possible to calculate the dose prescribed to a tumor in a 3D setting. From the biology aspect, the important role of tumor hypoxia and the tumor environment became apparent in the 1990s. Today, the therapeutic use of radiation-activated signal transduction pathways is being exploited.

However, the biggest contribution to increased cancer cure and survival after radiation therapy has been achieved by the introduction of computational sciences which made modern treatment planning systems, on board imaging, and precise dose application possible.

Tumor Biology

The biologic effects of radiation result principally from damage to DNA. Most of this damage is created after interaction of ionizing radiation with water, and hydroxyl radicals are formed, which cause DNA-breakage. The biologic effect will become apparent once the cell attempts division. It has been shown with the comet assays that cell killing correlates with double strand breaks. Interestingly, various research studies have documented that the larger the mean chromosome volume, the greater the radiosensitivity. In addition, even cell not directly hit by radiation may get killed, by the so called "bystander-effect".

Hemopoietic and lymphoid cells are particularly prone to rapid cell death after radiation by the apoptotic pathway. In most tumor cells mitotic cell death is more important or the only mode of death. Cells die attempting to divide because of damaged chromosomes. Mammalian cells vary considerably in their sensitivity to killing by radiation. Among the most resistant cells are glioblastoma cells. Sinclair measured the number of cell surviving dose of radiation while at discrete time points of the cell cycle. The most sensitive cells are in M and G2 phase, whereas cells in the late S phase appear more radioresistant.

Fractionation Protocols

Fractionation of the radiation dose produces better tumor control for a given level of normal tissue toxicity than a single large dose. We can now account for the efficacy of fractionation based on more relevant biologic experiments and appeal to the four R's of radiobiology: Repair of sublethal damage, Re-assortment of cell within the cell cycle, Re-population and Re-oxygenation. While over the course of fractionated radiation therapy, repair and re-population spare normal tissue, re-assortment and re-oxygenation increased damage to tumor cells. Early reactions of skin or mucosa profit from prolonging overall treatment time, whereas there is little sparing of late responding tissue such as nervous tissue. Treatment with a cytotoxic agent, chemotherapy or radiation therapy, may trigger surviving cells to divide faster than before. This is known as accelerated re-population. In head and neck cancer of human patients, the overall treatment time had an impact on local tumor control. This is why treatment should be completed as rapidly as possible after it starts, at least in head and neck cancer. There is evidence, that this is true also in animal carcinomas. There are some reports, that radiation preceded by a course of chemotherapy produces poorer results.

In animal tumors, known to have doubling times of less than 10 days (most carcinomas), it is suggested to use a rapid delivery of the total dose. This means daily fractionation, or even hyperfractionation, which means two fractions per days. Sarcomas are more "forgiving" in this regard, and may be treated over a longer time period. As sarcomas generally need higher total doses for local control, prolongation of overall treatment time is normally done in combination with increasing overall tumor dose, without an increase of acute side effects of skin or mucosa.

Imaging, Tumor Volume Definition, Dose Application

While it is easy to apply a dose to a tumor in the skin, precise dose delivery in a complex anatomic location, such as for example in a nasal tumor, becomes much more difficult. The first step is always to visualize the location and extent of a tumor. It is a radiation oncologist's nightmare to miss a part of the tumor, called geographic miss, a mistake which will result in local recurrence of a tumor. While in the early days plans were hand calculated and based on two orthogonal radiographs, computed tomography is now largely being used for treatment planning. A 3D view of the tumor is visualized and the gross tumor is contoured on the CT-study, as well as the organ at risk. Computed tomography is often combined with functional imaging, Positron emission tomography is used to further define the tumor burden within a gross tumor mass. While the early treatment plans were large "boxes", usually making use of a few beams, modern treatment planning uses a conformal dose planning, with the goal of applying the radiation dose homogenously to the target, while minimizing the dose to the surrounding tissue. This is achieved with complex 3D target volumes and complex beam configurations. The availability of functional imaging makes it possible to even deliver higher doses to subvolumes of a tumor target, thought of having an extra high tumor cell burden or hypoxic regions in need of an extra dose. The rapid progress of imaging technology has a direct impact on dose distribution and eventually tumor control and survival.

Treatment plan of a dog with tumor in the nose and nasopharynx.