Radiobiology of Lung Cancer

Summary of Key Points

The hallmarks of radiobiology are the “4 Rs”: r epair, r eassortment, r eoxygenation, r epopulation.
Radiation exerts its biologic effects by causing damage to DNA.
The linear–quadratic model provides a convenient method to compare different radiation dose and fractionation schedules.
Radiobiologic principles have underpinned the rationale for many early clinical trials in lung cancer testing including the use of alternative fractionation schedules.
Ultra-high doses of radiation may have other mechanisms of cell killing in addition to causing DNA damage.
Chemotherapy is most often used to sensitize the effects of radiation and improve local control in patients with locally advanced lung cancer.
Tumor hypoxia is a major problem in treating lung tumors; clinical trials that have tried to reverse hypoxia have shown mixed results.
Predictive biomarkers of radiation response are the subject of continued research.

Radiobiology is central to an understanding of the principles of radiotherapy today. In the early 20th century, the use of large, single doses of radiation declined as scientists and clinicians recognized that these doses caused considerable damage to normal tissues. Radiation oncologists then began applying smaller daily doses over a period of several weeks as a way to reduce this damage yet still achieve tumor control. In the 21st century, radiation oncologists have again been using large doses of radiation, over one to several days, as advances in technology now enable them to more precisely target the tumor while minimizing the amount of normal tissue exposed. In this chapter, we explore the basic tenets of radiation biology in order to understand the rationale behind these vastly different approaches as they apply specifically to the treatment of lung cancer. We also examine ways to exploit the radiobiology of lung cancer by using various strategies, including alternative fractionation schedules, concurrent chemotherapy with radiation, and modifiers of tumor hypoxia. We conclude with a look toward the future of personalized care, by examining potential biomarkers that may be used to predict response to radiotherapy.

Radiobiologic Basis of Conventionally Fractionated Radiotherapy

This section provides a review of the basic principles of radiobiology, including the mechanism of action of x-rays, the linear–quadratic (LQ) model of cell survival, and the four Rs of radiobiology. Taken together, these fundamentals help explain why radiation is most commonly delivered as a fractionated course over 5 weeks to 6 weeks.

DNA: The Critical Target for the Biologic Effects of Radiation Damage

The biologic effects of radiation result principally from damage to a cell’s DNA. The damage induced by radiation can be direct or indirect. Direct DNA damage occurs when the absorption of a photon by an atom releases an electron (a secondary electron) that then directly interacts with the DNA molecule. Indirect damage occurs when the secondary electron reacts with a water molecule to produce a free radical. It is the production of this free radical that leads to the DNA damage. Most of the DNA damage produced by the high-energy photons used in most medical linear accelerators is indirect damage.

The types of DNA damage produced by radiation include base damage (>1000 lesions per cell per Gy), single-strand breaks (approximately 1000 per Gy), and double-strand breaks (approximately 20–40 per Gy). Among these lesions, DNA double-strand breaks correlate best with cell killing, because they can lead to certain chromosomal aberrations (dicentrics, rings, anaphase bridges) that are lethal to the cell. Lethality, from the perspective of radiation biology, means the loss of reproductive integrity of tumor clonogens; that is, the tumor cells may still be physically present or intact and may still be able to undergo a few cell divisions, but they are no longer able to form a colony of cells.

The Linear–Quadratic Model

Cell survival curves have a characteristic shape when plotted on a log-linear scale with radiation dose on the x-axis and the log of cell survival on the y-axis. At low doses, the curve tends to be straight (linear). As the dose increases, the curve bends over a region of several Gy; this region is often referred to as the shoulder of the survival curve. At very high doses, the curve tends to straighten out again.

Many biophysical models have been proposed to mathematically capture this relationship between radiation dose and cell survival. A comprehensive review of all of these models is beyond the scope of this chapter but can be found in Hall and Giaccia and Brenner et al. The most commonly used model is the LQ model, which assumes that there are two components to cell killing: one that is proportional to the radiation dose and another that is proportional to the square of the dose. Cell survival in this model is represented by the following exponential function:

S (D) = e^{- (α D + β D^{2})}

$S (D) = e^{- (α D + β D^{2})}$

where S is the fraction of cells surviving a dose, D ; e is the mathematical constant approximately equal to 2.71828; and α and β are constants that represent the linear and quadratic components of cell killing, respectively. At dose D = α/β , the contributions from the linear and quadratic components of cell killing are equal.

The LQ model is convenient in that it depends on only two parameters ( α and β ) and it is relatively easy to manipulate mathematically. However, there is also a biologic rationale for using this model. As mentioned earlier, DNA double-strand breaks are believed to be the primary mechanism leading to cell death. A single hit of radiation (one electron) can cause lethal injury by inducing breaks on two adjacent chromosomes ( αD component). However, when two separate electrons cause the two chromosome breaks, cumulative injury can occur, and the probability of this occurrence is proportional to the square of the dose ( βD ² ).

The Four Rs of Radiobiology

The principles underlying fractionated radiotherapy can best be understood in terms of the classical four Rs of radiobiology: r epair, r eassortment, r eoxygenation, and r epopulation.

Repair

Repair refers primarily to the ability of normal tissues to recover from sublethal DNA damage. Sublethal damage repair is the operational term for the increase in cell survival that is seen when a given radiation dose is split into two fractions separated by a time interval. Sublethal damage repair is simply the repair of DNA double-strand breaks. In terms of the LQ model, tissues that have a greater capacity for DNA double-strand break repair have larger values for β and, therefore, a low α/β ratio. By contrast, most tumors and acutely responding tissues have a low capacity for repair and, therefore, a high α/β ratio.

Reassortment

Experiments have demonstrated that the most radiosensitive phases of the cell cycle are the M and G ₂ phases and the most radioresistant phase is the late S phase. Reassortment is the principle that cells progress through the cell cycle during the interval between two doses of radiation. Cells that were not killed by the first dose of radiation were likely in a radioresistant phase of the cell cycle at that time. Between the first and second doses of radiation, these cells would have time to progress to the M or G ₂ phase, and thus they would be more sensitive to the second dose of radiation.

Reoxygenation

The presence of oxygen within microseconds of radiation exposure is crucial for radiation-induced cell killing. Oxygen acts at the level of free radicals to effectively fix the radiation damage by inducing a permanent conformational change in the DNA molecule.

In the absence of oxygen (hypoxic conditions), as much as triple the amount of radiation may be needed to induce as much cell killing as would occur in the presence of oxygen. Most tumors have areas of hypoxia. Hypoxia can be acute or chronic: acute hypoxia results from the temporary closing or blockage of a blood vessel, whereas chronic hypoxia results from the limited diffusion distance (70 μ) of oxygen.

In the late 1960s, Van Putten and Kallman performed a set of experiments to determine the proportion of hypoxic cells in a transplantable sarcoma in a mouse model. They measured the proportion of hypoxic cells in the untreated tumor at 14%. They then administered five fractions of daily radiotherapy (1.9 Gy per fraction) to the tumor on Monday through Friday. The subsequent Monday, the hypoxic fraction was nearly the same, at 18%. They repeated the experiment except that they administered four fractions of 1.9 Gy each to the tumor on Monday through Thursday, and the hypoxic fraction measured on Friday was again constant at 14%.

These experiments provided some of the first evidence that reoxygenation occurs between deliveries of fractions of radiation. If reoxygenation did not occur, the proportion of hypoxic tumor cells would be expected to increase by the end of a fractionated course of treatment. Therefore if enough time is allowed for reoxygenation to occur, the negative effects of hypoxia can be overcome.

Repopulation

Fractionation of radiation can lead to an increase in the surviving fraction of cancer cells if the interval between the two doses of radiation exceeds the length of the cell cycle time needed for the tumor cells to divide. Therefore repopulation of tumor cells as a result of fractionation can be detrimental. In addition, treatment with any cytotoxic agent (e.g., chemotherapy drug or radiation) can trigger surviving tumor cells to divide faster than their normal cell cycle time or can reduce the number of cells lost; this phenomenon is known as accelerated repopulation. A high level of evidence supports this phenomenon in human tumors, including tumors of the lung and squamous cell carcinomas of the head and neck and the cervix. Because of this phenomenon, it is recommended that radiotherapy courses be completed without interruption.

Summary

The use of conventionally fractionated radiotherapy can now be understood in terms of the four Rs of radiobiology. Advantages of fractionation include reoxygenation of tumor cells to overcome hypoxia, reassortment of tumor cells into more sensitive phases of the cell cycle, and repair of sublethal damage in normal tissues to help reduce radiation toxicity. The main disadvantage of a fractionated course of radiation is that repopulation of tumor cells may occur, especially if the treatment course is prolonged beyond the expected time frame for completion.

Biologically Effective Dose (BED)

The biologically effective dose is a single dose value that can be used to compare the effectiveness of different fractionation schemes. This quantity is derived from the LQ model. For a treatment schedule of n fractions each of size D , Eq. 35.1 can be rewritten as

\begin{matrix} S = e^{- (α D + β D^{2})} or, alternatively, \\ as \frac{1 ns}{α} = nD (1 + \begin{matrix} D \\ α \\ β \end{matrix}) \end{matrix}

$\begin{matrix} S = e^{- (α D + β D^{2})} or, alternatively, \\ as \frac{1 ns}{α} = nD (1 + \begin{matrix} D \\ α \\ β \end{matrix}) \end{matrix}$

The quantity 1 nS is referred to as the biologically effective dose. When calculating the biologically effective dose for most tumors and tissues that respond acutely to radiation injury, the α / β ratio is usually set at 10 Gy; these tumors and tissues have a low capacity for repair, so the α term dominates the ratio. Late-responding tissues (e.g., the spinal cord) have a greater capacity for repair between fractions of radiation, so the β term dominates the ratio α / β ; when calculating the biologically effective dose for these tissues, α / β = 3 Gy is the most common convention.

As an example, a common fractionation schedule used to treat nonsmall cell lung cancer (NSCLC) is 60 Gy in 30 fractions of 2 Gy each. Assuming α / β = 10 for the tumor and α / β = 3 for late-responding tissue, the biologically effective dose for this schedule would be given as follows:

\begin{matrix} {BED}_{tumor} = (30 fractions) (2 Gy / fraction) \\ 1 + \frac{2 Gy}{10 Gy} = 72 Gy \end{matrix}

$\begin{matrix} {BED}_{tumor} = (30 fractions) (2 Gy / fraction) \\ 1 + \frac{2 Gy}{10 Gy} = 72 Gy \end{matrix}$

{BED}_{late - responding tissue} = (30 fractions) (2 Gy / fractions) 1 + \frac{2 Gy}{3 Gy} = 100 Gy

${BED}_{late - responding tissue} = (30 fractions) (2 Gy / fractions) 1 + \frac{2 Gy}{3 Gy} = 100 Gy$

Alternatively, a fractionation schedule now used to treat patients who have a poor performance status or who are not candidates for concurrent chemotherapy is 60 Gy in 15 fractions of 4 Gy each. Again assuming α / β = 10 for the tumor and α / β = 3 for late-responding tissue, the biologically effective dose for this approach is

\begin{matrix} {BED}_{tumor} = (15 fractions) (4 Gy / fractions) \\ 1 + \frac{4 Gy}{10 Gy} = 72 Gy \end{matrix}

$\begin{matrix} {BED}_{tumor} = (15 fractions) (4 Gy / fractions) \\ 1 + \frac{4 Gy}{10 Gy} = 72 Gy \end{matrix}$

\begin{matrix} {BED}_{late - responding tissue} = (15 fractions) (4 Gy fraction) \\ 1 + \frac{4 Gy}{3 Gy} = 100 Gy \end{matrix}

$\begin{matrix} {BED}_{late - responding tissue} = (15 fractions) (4 Gy fraction) \\ 1 + \frac{4 Gy}{3 Gy} = 100 Gy \end{matrix}$

Although the total dose was the same in both cases (60 Gy), the treatment schedule of 15 fractions of 4 Gy each has a higher tumor effective dose than the schedule of 30 fractions of 2 Gy each, but the 15-fraction schedule confers a higher risk to the late-responding tissue, such as the spinal cord if it is kept in the high-dose areas. The biologically effective dose is therefore a very useful tool that radiation oncologists often use when varying the fraction size from the standard 2 Gy/d. However, this simple concept does not take into account other factors that affect the biologically effective dose, such as repopulation, reassortment, and reoxygenation. In addition, the applicability of the LQ model for estimating the biologically effective dose at larger doses per fraction is under debate, as will be discussed.

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