Principles and Management of Cancer Tejinder Kataria, Hemant Singhal , Dinesh Chand Doval
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Radiobiology of Radiation TherapyCHAPTER 1

Govardhan HB,
Anurita Srivastava,
Tejinder Kataria
 
INTRODUCTION
Radiobiology is the science that evaluates the effects of radiation in living organisms. “X-rays and Gamma rays are the two important radiation sources that interact with biologic material through Compton effect mainly and result in energetic recoil electrons which traverse through cell and cause ionization along with creation of tracks that remove electrons through a double action. The first one is a “direct effect” where the electrons act on the critical molecules by a straight hit and an “indirect effect” whereby the water molecules are denatured with the production of free radicals to act on critical molecules leading to lethal effects.1,2
 
THE TIME-SCALE OF EFFECTS IN RADIATION BIOLOGY
Irradiation of a tissue generates processes that differ enormously in time-scale and these processes are divided into three phases.3
 
Physical Phase
It consists of interactions between charged particles and the atoms of which the tissue is composed. Physical phase is complete between 10–18s and 10–14s. It includes the interaction of X-ray with orbital electrons, and ejecting some of them from atoms (ionization) and raising others to higher energy levels within an atom or molecule excitation. For 1 Gy of absorbed radiation dose, there will be 105 ionizations within 10 μm within cells.
 
Chemical Phase
It is a period in which the ejected electrons act over water molecules and produce free radicals with a very short half- life. These free radicals are highly reactive and they eventually lead to the restoration of electronic charge equilibrium. This phase is completed within approximately 1 ms of radiation exposure.
 
Biological Phase
After the physical and chemical phase is the important subsequent process, basically it starts with enzymatic reactions that act on the residual chemical damage. After the radiation effect these cells take time to die and may undergo a number of mitotic divisions before dying. The early manifestations of normal-tissue damage after radiation exposure are the killing of stem cells and the subsequent loss of the progenitor progenies.
After a finite time lag (months to years) from irradiation of normal tissues “late reactions” may appear. Fibrosis and telangiectasia of skin, spinal cord damage (myelitis) and blood vessel damage (endarteritis) are a few of such effects. Appearance of a second primary cancer from 7 to 20 years has also been recorded as a late effect of radiation, although the incidence is <1%. Also the risk versus benefit of cure of first primary cancer needs to be accounted for at the time of giving curative radiation treatment.
 
DNA DAMAGE
The level and type of DNA damage is established within seconds of irradiation, so that at this point cell signaling pathways are triggered and the biological repair pathways can recognize the problem they have to deal with. The nature and level of initial damage therefore has important implications for the overall biological effects of radiation.
 
DIRECT ACTION
If any form of radiation (X-rays or Gamma rays), charged or uncharged particles are absorbed in biological material and there is a possibility that it will interact directly with 2critical target in the cells. The atoms of the target tissue are ionized leading to a biological change called direct action of radiation. It is the dominant process in the high linear energy transfer (LET) radiations like neutrons and alpha particles. It is the dominant process in the high “linear energy transfer” (LET) like neutron and a particle.
 
INDIRECT ACTION
Alternatively, the radiation may interact with other atom or molecules in the cell, mainly water, to produce the free radicals that are able to diffuse far enough to reach and damage the critical target called “indirect action” on radiation.
 
Types of Damage
A variety of lesions are produced in DNA by ionizing radiation, including base or sugar damage, DNA single-strand and double-strand breaks (DSB), DNA-protein crosslinks and DNA-DNA crosslinks (Table 1). For most cells it appears that the DNA DSB is the critical lesion, causing cell death by ionizing radiation.4
However, DSBs are not a uniform category of lesion. They may vary by virtue of the termini on the free ends of the molecule, also the proximity of other lesions. It has been suggested that a significant number of DSB will have other types of DNA damage nearby. These lesions have been termed clustered damage or locally multiply damaged sites, and they may be particularly significant for radiation cell killing. It is hypothesized that the complexity of these clusters will increase with increasing LET of the radiation. The potential significance of these is that they are formed by single tracks and that they will be more difficult to repair as the complexity of the cluster increases.4 At the present time, we are unable to distinguish these different kinds of DSB experimentally, however, the reparability of DSB is known to decrease with an increase in LET.5
 
DNA REPAIR
Once damaged, a primary aim for a cell has to be to restore as accurately as possible the structural and functional integrity of the DNA. DNA can be repaired by any one of the following mechanism: Base excision repair, nucleotide excision repair, DNA DSB repair, nonhomologous end joining, homologous recombination repair, single strand annealing, cross link repair and mismatch repair.4,5
Table 1   Radiation-induced DNA damage
DNA double-strand breaks
40
DNA single-strand breaks
1,000
DNA-protein crosslinks
150
DNA-DNA crosslinks
30
Base damage
2,000
Sugar damage
1,500
 
ACUTE AND LATE EFFECTS OF RADIATION
Acute effects of radiation are dose limiting for normal tissues and involve effects on mucosa and hematopoitic system. The effects are predominantly due to apoptosis and loss of reproductive capacity of the cellular systems. Tissues with a rapid cell turnover comprise the early reacting tissues and they recover from the effect of radiation also early as compared to late reacting tissues (spinal cord). The time to recovery is dependent upon the dose delivered and the speed of recovery depends upon the level of stem cell depletion and it may vary from a few days to several months. If the number of surviving stem cells is too low, these acute reaction may turn into sequential late effect. The acute effect depends on the total dose, duration of the treatment and the dose per fraction.
Late effects following radiation occur after months to years and affect the slowly proliferating tissues (lung, kidney, heart, liver and central nervous system). They may also affect the slowly renewing systems like skin causing fibrosis, atrophy or telangiectasia after many years. The most important factor for late effects is the total dose of radiation, dose of radiation per fraction of treatment. The duration of the late effect is not related to the radiosensitivity or tolerance of the relevant normal tissue.
The differentiation between acute and late effects has important clinical implications. The acute reactions are usually observed during conventionally fractionated radiotherapy schedule. The severity depends on the effect on stem cell. It is possible to adjust the dose in the event of unexpectedly severe reactions, allowing a sufficient number of stem cells to survive. Whenever the remaining stem cells are reduced either by reducing overall treatment time or reducing the healing replacing capacity of stem cell, it results in acute reactions which may persist as chronic injury, called consequential late complications.
 
CELL DEATH
The use of radiation to treat cancer results from its ability to cause the death of tumor cells and its biological consequences are influenced by DNA damage response. The DNA damage response determines both the sensitivity of cells to die following irradiation and type of cell death that occurs and the timing of cell death. The cause of the cell death after irradiation complex process as described below.
 
Programmed Cell Death (Apoptosis)
Apoptosis is a regulated form of cell death. It can be initiated either as a result of conditions occurring within the cell 3(DNA damage) or external signal from a surrounding tissue or immune cell.6
 
Mitotic Catastrophe
Mitotic catastrophe is associated with the accumulation of multinucleated, giant cells with uncondensed chromosomes, chromosome aberrations and micronuclei. This will occur when cells proceed through mitosis in an inappropriate manner and cause entry of cells into mitosis with unrepaired or misrepaired DNA damage. The cells lose their replicative potential called death. This can occur either due to loss of genetic material associated with this process or from a physical inability to replicate and separate the genetic material correctly.7
 
Necrosis
Necrosis is “death by injury”. It is most frequently observed in human tumors and can occur following treatment with certain DNA-damaging agents, including radiation.
 
Senescence
It can be elicited by various cellular stresses, such as those caused by oncogene activation or by radiation-induced DNA damage.8 In both cases, the cells enter a permanent cell cycle arrest. Senescence does not occur by shortening of the telomeres, but instead are controlled by a number of molecular pathways.
 
Bystander Death
It is a mechanism in which cell death can occur in cells with irradiation of neighboring cells. The evidences come from studies using high LET α-particles in which a larger fraction of cells die than are estimated. The bystander effects have also been observed for other known biological effects of irradiation, including DNA damage, chromosomal aberrations, mutation, transformation and gene expression.9
 
THE FIVE “RS” OF RADIOBIOLOGY
Clinical observation and experimental radiobiology have identified five factors that are clearly influential in the determination of the outcome of a course of fractionated radiotherapy. These are the five “Rs” of radiobiology and they form the fundamental basis for the application of our molecular knowledge.
 
Repair
Repair is the increase in surviving fraction of cells when radiation exposure is prolonged or fractionated. It is because of the sublethal damage repair (SLDR). In addition, cells held in a nonproliferating state after irradiation in suboptimal conditions show a reduced sensitivity compared to proliferating cells. This is potentially lethal damage recovery (PLDR). Both of these processes are believed to be a consequence of the repair of radiation damage to DNA. However, SLDR and PLDR are apparently not controlled by the same processes, since they have differing effects on the number of gene mutations that are induced by radiation.10 The molecular dissection of these processes is still in its infancy but there are data to link the gene TP53 to PLDR.11 Of recent interest is the finding that clonogenic cell survival curves may have a steep component at low doses and that some radioprotective processes might be induced by radiation. This could have important implications for cellular recovery in different fractionation regimes and attempts are being made to exploit this in the clinic.
 
Reassortment
Cells vary in their radiosensitivity as they progress through the cell cycle. For example, cells in mitosis have been found to be approximately twice as sensitive as cells in the latter part of the DNA synthesis phase. Radiation therefore exerts selective damage of cells in the sensitive phase of the cell cycle. If there were no cell cycle progression, then a second radiation dose would be less effective than the first. The effect of cells progressing through the cell cycle in between treatments is that cells that survive the first treatment because of their presence in a resistant phase move into a more sensitive phase before the next fraction is delivered. This movement and redistribution of cells to sensitive phase is called reassortment. Importantly, one of the key cellular responses to DNA damage is the triggering of cell-cycle checkpoints toward the end of G1 and in G2. These have been examined extensively in relation to cellular radiosensitivity but their influence on cell-cycle reassortment during radiotherapy has not been well characterized.
 
Repopulation
Proliferation of tumor cells during a course of radiotherapy is potentially a major obstacle to the success of treatment. It is apparent that the proliferation of tumor cells can be faster in a treated tumor than in an untreated tumor, and this “accelerated-repopulation” appears to have a significant bearing on the efficacy of radiotherapy.12 Acceleration may partly be due to physical effects, i.e. the removal of dead cells may lead to an improved nutrient supply to surviving cells. If depopulation within the tumor leads to reduced cell loss, then survivors may proliferate with a doubling time that approaches the “potential doubling time”, a process that has been described as the “unmasking” of the high proliferation rate of clonogenic tumor cells.4
 
Reoxygenation
Low oxygen levels render cells relatively resistant to ionizing radiation, largely because of a decreased induction of DNA damage. In some tumors, and to a minor extent in normal tissues such as cartilage, vascular supply is inadequate to maintain good oxygen supply to all regions, so there are cells that are hypoxic and therefore resistant to radiation. Clinically this has been demonstrated to limit the success of therapy.13 but its influence is reduced when the radiation is fractionated, due to the process of reoxygenation. The death of some tumor cells may lead to improved oxygen supply to others, and thus to an increase in their radiosensitivity. Furthermore, the opening and closing of blood vessels in a tumor is a dynamic process, so that cells adjacent to a closed vessel at the time of one fraction may be oxygenated at the next fraction if the vessel has opened. The effect of a subpopulation of resistant cells at each treatment time may be quite small in some cases, but when amplified over a multiple fraction regime it can result in a significant reduction in the theoretical tumor curability.14
 
Radiosensitivity
It is intuitively reasonable to expect that the inherent radiosensitivity of tumor cells can be a significant factor in the overall level of cell killing induced by radiation. The clinical radioresponsiveness of tumors of different histological origins correlates strongly with radiosensitivity of cells taken from those tumors. To take this one step further, the radiosensitivity of tumor cells from cervix carcinomas has been demonstrated to be predictive of local tumor control.15 In cervix cancer it therefore appears that cellular sensitivity is a major determinant of the overall response. Not all studies have shown this relationship in other tumor types, and there is still work to be done to determine whether these results are a true reflection of a varied influence of inherent sensitivity or whether technical problems in the assay systems have blurred the situation.
 
LINEAR ENERGY TRANSFER
Linear energy transfer (LET) is defined as the energy transferred per unit length of the track of radiation passes through. The special unit of LET is kiloelectron volt per micrometer (keV/µm). The International Commission on Radiological Units (ICRU) defined LET as, the charged particles in medium is the quotient of dE/dL, where dE is the average energy locally imparted to the medium by a charged particle of specified energy in traversing a distance of dL.16
That is, LET = dE/dL
Table 2   Linear energy transfer values for various radiation types
Type and energy of radiation
Linear energy transfer
250 kV X-ray (250 kV)
2
3 MV X-ray (3 MV)
0.2
Cobalt 60 (1.17–133 MV)
0.2
Beta 10 kV (10 kV)
2.3
Beta 1 MV (1 MV)
0.25
Neutron 2.5 MV (2.5 MV)
20
Neutron 19 MV (19 MV)
7
Proton 10 MeV
4.7
Proton 50 MeV
0.5
Alpha 2.5 MeV
166
As radiation is an act over at the microscopic level, LET is an average and the energy per unit length of track varies over such a wide range. There are 2 methods to calculate LET; the most commonly used method is to calculate
  • Track average, which is obtained by dividing the track into equal lengths, calculating the energy deposited in each length, and finding the mean
  • Energy average is obtained by dividing the track into equal energy increments and averaging the lengths of track over which these energy increments are deposited.17 The LET for various radiations are given in Table 2.
 
RELATIVE BIOLOGIC EFFECTIVENESS
In comparing different radiations, it is customary to use X-rays as the standard. The National Bureau of Standards in 1954 defined relative biologic effectiveness (RBE) as follows:
The RBE of test radiation (r) compared with X-rays is defined by the ratio D250/Dr, where D250 and Dr are, respectively, the doses of X-rays and the test radiation required for equal biological effect.
This is explained further by the following example. To measure the RBE of some test radiation, one first chooses a biologic system in which the effect of radiations may be scored quantitatively. Suppose, we are measuring the RBE of fast neutrons compared with 250-kV X-rays, using the lethality of plant seedlings as a test system. Groups of plants are exposed to graded doses of X-rays; parallel groups are exposed to a range of neutron doses. At the end of the period of observation, it is possible to calculate the doses of X-rays and that of neutrons that result in the death of half of the plants in a group. This quantity is known as the LD50, the mean lethal dose. Suppose that for X-rays the LD50 turns out to be 6 Gy (600 rad) and that for neutrons the corresponding quantity is 4 Gy (400 rad). The RBE of neutrons compared with X-rays is then simply the ratio 6:4, or 1.5. RBE depends on the following: radiation quality (LET), radiation dose, number of dose fractions, dose rate and biologic system or end point.18–205
Relative biological effect (RBE) increases with LET to a maximum to 100 keV/µm, then it start decreases with increasing the LET. At LET of 100 keV/µm, the ionizing events is similar to the diameter of the DNA double helix (2 nm) and can most efficiently produce DSB by a single track. As the dose per fraction decreases, the RBE of high-LET radiations compared with that of low-LET radiations increases. This is a direct consequence of the fact that the dose-response curve for low-LET radiations has a broader shoulder than for high-LET radiations. The RBE values are high for cells or tissues that accumulate and repair a great deal of sublethal damage.19,20
 
OXYGEN ENHANCEMENT RATIO
It is defined as the ratio of radiation doses under hypoxic to aerated conditions to achieve the same biological effect is called the oxygen enhancement ratio (OER). The OER for sparsely ionizing radiations, such as X- and γ-rays is between 2.5 and 3.5. There is some evidence that for rapidly growing cells cultured in vitro, the OER has a smaller value of about 2.5 at lower doses, on the order of the daily dose per fraction generally used in radiotherapy.21 This is believed to result from the variation of OER with the phase of the cell cycle: cells in G1 phase have a lower OER than those in S, and because G1 cells are more radiosensitive, they dominate the low-dose region of the survival curve. For this reason, the OER of an asynchronous population is slightly smaller at low doses than at high doses. The oxygen enhancement ratio has a value of about 3 for low-LET radiations, falls when the LET rises above about 30 keV/µm and reaches unity by an LET of about 200 keV/µm.22
 
DOSE RATE EFFECT IN RADIOTHERAPY
In many experimental model systems it has been demonstrated that irradiations at lower dose rates are less effective for cell killing as compared to high dose rate irradiations. Effectiveness of radiations (in causing cell death) varies remarkably in the dose rate range of 1 mGy min–1 to 1 Gy min–1. Ability to recover from sublethal damage has been suggested to be the most important mechanism underlying the dose rate effect.23
In radiotherapy a wide range of dose rates are used depending upon the technique of treatment. High dose rates of several Gy min–1 is used in external beam therapy, whereas, dose rates as low as 0.5 Gy/hr used in brachytherapy. The dose rate can be as low as 1.3 Gy/day when 125I seeds are used as permanent implants. Response of normal tissues and tumors to variations in dose rate must be clearly understood for designing appropriate strategies for low-dose rate radiotherapy.
 
Mechanism of Dose Rate Effect and Inverse Dose Rate Effect
Response of the biological system to low-dose rate irradiation is influenced by different complex events, which occur simultaneously. These events include repair from sublethal damage, cell proliferation, redistribution of cells in the cell cycle (G2 block) and reoxygenation. The magnitude of contributions from these different events depends to a great extent on the dose rate used as well as the type of the tissues involved. Final response of the tissue to radiation is a resultant of contributions of these factors. Repair of sublethal damage occurs both in the normal as well as in tumor tissues, but the extent of recovery is generally higher in normal tissues, due to the free availability of nutrients and oxygen. Larger tumors show a lesser repair from sublethal damage compared to smaller tumors.
Repopulation occurs very actively in normal tissues at low-dose rates. Normal cell population can be maintained in intestines up to a dose rate of 14 Gy/day, in bone marrow up to 0.5 Gy/day, and the testis is more sensitive and can maintain normal functioning up to a dose rate of 120 mGy per day. Generally, the repopulation in tumors can be inhibited by a dose rate of 0.3 Gy/hr. On the basis of experimental studies with various cell lines it has been established that the dose required to inhibit repopulation depends upon the cell cycle duration. A dose of 7.5–10 Gy per cell cycle is adequate to inhibit cell division. Since most tumor cells have generation times larger than of 24 hours, repopulation is easily inhibited by a dose rate of 0.3–0.5 Gy/hr. At higher dose rates above 0.5 Gy/hr, the problem of repopulation does not arise. At a critical dose rate 0.37 Gy/hr cells do progress very slowly and tend to accumulate in G2 phase of the cell cycle. They do not progress further and are effectively killed by radiations. This could possibly be one of the reasons for the less pronounced dose rate effect seen in tumors. Further, in cell cultures (HeLa) it has been demonstrated that a dose rate of 0.37 Gy/hr is more effective than higher dose rates of 0.55, 0.74 or 1.54 Gy/hr. At higher dose rates the cells do not progress in the cell cycle and hence the advantage of cell synchrony and accumulation in the radiosensitive G2 phase does not occur. This phenomenon is termed as “inverse dose rate effect”.23,24
In tumors, such as KHT sarcomas, there is no significant dose rate effect in the dose rate range of 1 Gy min–1 to 0.41 Gy/hr. It has been suggested that in tumors high-dose rate irradiation may encounter hypoxic cell radioresistance. On the other hand low-dose rates may permit adequate reoxygenation. Hence, the disadvantage of SLD repair occurring in tumors may well be compensated by the reoxygenation and concomitant sensitization of tumor cells.25
As compared to the response of tumors, to low-dose rates, normal tissues like the small intestines show an enormous 6amount of sparing. This forms of biological rationale for brachytherapy at low-dose rates as well as multiple dose fractions daily regimens.25
 
DOSE FRACTIONATION IN RADIOTHERAPY
In radiotherapy, fractionation of the dose was introduced with objective of sparing the normal tissue damage and at the same time eradicating the tumor. Fractionation facilitates repair and repopulation in normal tissues, redistribution of radioresistant cells in the sensitive phases of the cell cycle, and reoxygenation of hypoxic cell fraction which survive the earlier dose fractions.26–28 Furthermore, quiescent (G0) cells not in the division cycle are recruited into the proliferating compartment. These advantages associated with dose fractionation are generally referred as 4R's of radiotherapy.
Generally, the normal tissue damage is of two types, early reaction and late injury. Late responding normal tissue may have a large number of cells in resting phase. Early responding tissues generally constitute fast proliferating cells. Skin, mucosa, interstitial epithelium, bone marrow, colon, testis, etc. constitute early responding tissues, whereas spinal cord, bladder, lung, and kidneys are late responding tissues. In the recent years there is an improvement in the understanding of proliferation of normal tissues following radiotherapy. Acutely reacting tissues proliferate to compensate the cell loss in these tissues. Tissues like skin and mucosa begin to proliferate 2 or 3 weeks after the start of radiotherapy. In late responding tissues, this type of proliferation occurs only after the end of therapy. As a result, prolongation of therapy could decrease the acute normal tissue reactions without sparing the late damages. However, one of the positive benefits of increasing the intervals between fractions is to allow for adequate reoxygenation. Hence, the use of hypoxic sensitizers and high LET radiations to overcome the hypoxic cell radioresistance may play a critical role in shorter schedules. Since it has been observed that use of large fraction in shorter schedules result in unacceptable levels of late injury, large number of smaller dose fractions (hyperfractionation) can effectively bring about cure, while not increasing the late tissue damage. Hyperfractionation may increase the early tissue damage but not to an unacceptable level.29,30
 
Rationale for Multiple Fractionation Daily
Survival curve of the cells involved in early and late response have different shapes. Survival response of late responding tissues are more curved with a lower response at lower doses, as compared to the sharp fall in surviving fraction with dose observed for early responding tissue. Response curve can be adequately explained on the basis of linear quadratic relationship.
An adequate knowledge of the tissue response enables us to evolve new schemes of fractionation to improve radiotherapy. One of the most important considerations is to understand the tolerance levels of dose for early and late injury for different fractionation schedules. Effect of dose fractionation on the level of damage induced in fast and slow responding tissues. Dose is delivered acutely (single doses) or in fractions of 1,2,3 or 4 Gy each. Fractionation spares both the slow and fast reactions. However, the extent of the sparing is remarkably higher for the late reacting tissues. Further, smaller the fraction size the greater is sparing of damage, particularly so, for the late reacting tissues.28,31
 
Linear Quadratic Model
Concepts of early and late response can be clearly understood by the cell survival response of these tissues. Survival response can be explained on the basis of linear quadratic model. Survival curves have two components, the a component which predominantly operates at low doses and the β component dominates at higher doses. This can be attributed to one hit and two hit mechanisms associated with cell killing. As per this model survival “S” varies with the dose “D”.32
The α and β are linear and quadratic coefficients. Cells which respond early have a large α value whereas the more curvy late responding cells have a small α value and large β values. Dose at which the linear and the quadratic components contribute equally to the effect is called the α/β value. α/β dose provides a good description of the tissue response. Late responding tissues are characterized by small α/β values 1–3 Gy, whereas the early reacting tissues have large α/β values in the range of 8–10 Gy.
Linear quadratic model can also predict the response for fractionated irradiation. Survival Sn for n fractions of dose “d” equals then, the dose per fraction on X-axis and inverse of the total dose required for a definite level of damage yields a straight line with slope equal to –β/ln Sn and intercept –α/ln Sn. Hence, α/β is the ratio of the intercept to slope. In practice total dose required to produce the same level of damage with different fraction sizes is determined. Such determination is available for skin where it is convenient to score the level of damage. For mouse skin reaction the α/β value is ≈ 10. α/β values available from animal experimental systems for the early and late responding tissues are as shown in Table 3.
There is no reason to believe that the values can be very different for human tissues.
 
Isoeffect and Dose Fractionation
Using many experimental animal systems and various fraction sizes, variation of the total dose required to produce the same level of injury (isoeffect doses) has been determined 7for different fraction sizes. The end points scored are response of skin, bone marrow, vertebral growth, fibro sarcoma, small intestine, lung, testis, kidney, colon and spinal cord. The general conclusion from these studies is that for late effects the decrease in dose fraction rapidly increases the isodose. Increase in isodose for many fast responding injuries (and tissues) occur more slowly as compared to that for late injury. From these response curves it is clear that where late damage is the limiting factor in radiotherapy, small dose fractions enable to deliver a higher total dose. Further, large dose per fractions limits the total dose drastically more due to late tissue damage rather than early damage. Hence, large dose fractions can be of use only where small total doses are required for palliation.
Table 3   α/β values available from animal experimental systems for the early and late responding tissues33
A. α/β values for some of the animal tissues*
Early responding tissues
α/β (Gy)
Late responding† tissues
α/β (Gy)
Skin (epithelium)
9–12
Lung
2.3–6.0
Testis
12–13
Kidney
1.9–6.4
Callus
9–10
Spinal cord
1.7–4.9
Colon
10–11
Dermis
1.4–6.2
Jejunum
6–10
Bladder
3.1–7
B. α/β values for medium term reactions
Reactions
α/β value (Gy)
Pneumonitis of mouse lung (50% mortality)
2.5–6.0
Breathing rate
3.0–6.0
*α/β values for tumors range from 2.5 to 100
†α/β values for late responding tissues are not very reliable.
Source: Data based on the experiments using rat, mouse, pig and rabbits. Withers 1983 et.al.33
 
α/β Values and Dose Per Fraction
Many efforts have been made to improve the therapeutic gain, viz. by manipulating the biological parameters, selective chemical modifiers, use of high LET radiations, accelerated photon and electron beams. Introduction of fractionation has been one of the most successful methods for improving tumor cure. At present, it is well-known that a standard fractionation schedule may not be adequate for treatment of all the tumors.28 This is because of the wide variations in the proliferation kinetics of different tumors and also of the surrounding normal tissues. Hence, it should be possible to adopt an appropriate fractionation scheme depending upon the type of neoplasms and improve the therapeutic response.
Choice of the size of fraction should be based on the α/β values of the normal tissues to be spared. Generally, the response curve begins to bend at dose one-tenth of the D/E (flexure dose). Hence, the flexure doses for fast responding tissues range from 0.8 to 1.2 Gy, whereas the same is as low as 0.1–0.5 Gy for late responding tissues such as the spinal cord, kidney, lung and skin contraction. Hence, it must be emphasized that the dose per fraction must be reduced to the lowest possible level and the number of fractions increased up to 4 fractions if possible, to achieve maximum sparing of the late effects. Reducing the dose per fraction to less than 0.8 Gy does not spare either the fast responding tissues or the tumor to the same extent.34,35
 
THE CONCEPT OF THERAPEUTIC INDEX
The “therapeutic index” defined as the tumor control probability (TCP) for a fixed normal tissue complication probability (NTCP) for different doses and type of radiation.36 First, normal tissues may get more radiation doses that cause more reaction but same dose required to control the tumor; on the other hand, tumor may receive an inadequate dose if, radiation dose is restricted below the normal tissue tolerance. Thus, the main aim in radiotherapy is to achieving the optimal balance between TCP and NTCP, all the recent technologies are directed toward to achieve these aims. TCP and NTCP curves are sigmoid in shape, left curve is TCP and right side is NTCP. The main purpose of radiotherapy treatment is to shift the TCP to the left and the NTCP curve toward right. The therapeutic index also called therapeutic window increases, if the area between the two curves becomes too large then the expected benefit from treatment will increases.
 
Tumor Control Probability
The effectiveness of radiation-therapy treatment is evaluated by the locoregional TCP and treatment related NTCP.37 TCP is directly proportional to the dose of radiation and inversely proportional to the number of cells in the tumor tissue or volume of the tumor. The total radiation doses required to control subclinical disease is 40–50 Gy and 60–70 Gy for gross disease. The dose-limiting factor in effectiveness in radiotherapy is the tolerance of the surrounding tissues to radiation.
The factor affecting TCP were divided into:
  • Tumoral factors affecting the TCP: Intrinsic radio-sensitivity, location and size of tumor, cellular type of tumor and effect of oxygen.
  • Treatment-related factors affecting the TCP: Dose-time fractionation, radiation quality (RBE, LET), dose rate, 8use of radiosensitizers, combination of radiotherapy with surgery and/or chemotherapy, technique (e.g., small field sizes), treatment modality.
 
Normal Tissue Complication Probability
The NTCP is a function of the total dose (TD), fraction dose (d), fraction number (N) and the volume of normal tissue exposed to the radiation.37,38
The Lyman model is used in NTCP calculation and is highly complex mathematical model of biological effects based on the use of algebraic definitions. The tissue types (parallel or serial organs), volume of irradiated normal tissue, its radiosensitivity and functional subunits of tissues make this model more complex.39
The factor affecting NTCP were:
Factors related to organ tissue: Tissue radiosensitivity, the volume of organ tissue within the radiotherapy portal and organ type; serial or parallel.
Factors related to treatment: Dose-time fractionation, quality of radiation (RBE, LET), dose rate, use of radioprotectors, combination of RT with surgery and/or chemotherapy, technique (e.g., addition of boost field), treatment modality.
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