6

Linear energy transfer and relative biological effectiveness

MICHAEL C. JOINER

6.1	Introduction	68	6.6 The physical basis for charged-particle
6.2	Microdosimetry	68	therapy	74
6.3	Biological effects depend upon LET	69	Key points	76
6.4	Relative biological effectiveness		Bibliography	77
	depends on dose	71	Further reading	77
6.5	The biological basis for high-LET
	radiotherapy	72

6.1 INTRODUCTION

Modern radiotherapy is usually given by linear accelerators producing X-rays with high-energy of 4–25 MV which have generally superseded therapy with lower energy 60Co or 137Cs γ-rays. X-rays and γ-rays are uncharged electromagnetic radiations, physically similar in nature to radio waves or visible light except that their wavelength is less than 10 picometres (10 12 m) so that the individual photons (‘packets’ of energy) are energetic enough to ionize molecules in tissues that they penetrate. It is this ionization that results in the biological effects seen in radiotherapy. These X- and γ-rays all have roughly the same biological effect per unit dose, although there is a small dependence on the energy with lower energies being slightly more effective. Electron beams are quantum-mechanically similar to X-rays and produce similar biological effects. Two other classes of radiations that are being increasingly adopted in radiotherapy are often referred to as:

●Light particles – e.g. protons, neutrons and

α-particles.

●Heavy particles – e.g. fully stripped carbon, neon, silicon or argon ions.

These light and heavy particles may have a greater biological effect per unit dose than conventional X- and γ-rays. The charged particles have, in addition, very different depth–dose absorption profiles compared with uncharged particles (i.e. neutrons) or conventional electromagnetic radiations (X- and γ-rays) and this enables more precise dose distributions to be achieved in radiotherapy (see Chapter 24). This chapter explains the basic physics and radiobiology of these different types of radiation used in cancer therapy.

6.2 MICRODOSIMETRY

It is possible to build up a picture of the submicroscopic pattern of ionizations produced by radiation within a cell nucleus using special techniques for measuring ionization in very small volumes, together with computer simulations: this is the field of microdosimetry. Figure 6.1 shows

Biological effects depend upon LET 69

Low-LET tracks in cell nucleus e.g. from X-rays

A dose of 1 Gy corresponds to approx. 1000 tracks

High-LET tracks in cell nucleus,

e.g. alpha

	A dose of 1 Gy
	corresponds to	1	μ
	approx. 4 tracks

Figure 6.1 The structure of particle tracks for low-linear energy transfer (LET) radiation (left) and α-particles (right). The circles indicate the typical size of mammalian cell nuclei. Note the tortuous tracks of low-energy secondary electrons, greatly magnified in this illustration. From Goodhead (1988), with permission.

examples of microdosimetric calculations of ionization tracks from γ-rays or α-particles passing through a cell nucleus (Goodhead, 1988). At the scale of the cell nucleus, the γ-rays deposit much of their energy as single isolated ionizations or excitations and much of the resulting DNA damage is efficiently repaired by enzymes within the nucleus (see Chapter 2). About 1000 of these sparse tracks are produced per gray of absorbed radiation dose. The α-particles produce fewer tracks but the intense ionization within each track leads to more severe damage where the track intersects vital structures such as DNA. The resulting DNA damage may involve several adjacent base pairs and will be much more difficult or even impossible to repair; this is the reason why these radiations produce steeper cell survival curves and allow less cellular recovery than X-rays. At the low doses of α-particle irradiation that are encountered in environmental exposures, only some cells will be traversed by a particle and many cells will be unexposed.

Linear energy transfer (LET) is the term used to describe the density of ionization in particle tracks. LET is the average energy (in keV) given up by a charged particle traversing a distance of 1 μm. In Fig. 6.1, the γ-rays have an LET of about 0.3 keV/μm and are described as low-LET radiation. The α-particles have an LET of about 100 keV/μm and are an example of high-LET radiation.

Why are neutrons described as high-LET radiation when they are uncharged particles? Neutrons do not interact with the orbital electrons in the tissues through which they pass and they do not directly produce ionization. They do, however, interact with atomic nuclei from which they eject slow,

	1
cells	10
surviving	10
of
Fraction	10
	10

0	2		4	6	8	10	12	14
				Dose (Gy)
			2.5 MeV					μ
			4 MeV					μ
			5.1 MeV					μ
			8.3 MeV					μ
			26 MeV					μ
			3 MeV					μ
			14.9 MeV deuterons				5.6 keV/μ
			250 kVp X-rays

Figure 6.2 Survival of human kidney cells exposed

in vitro to radiations of different linear energy transfer. From Barendsen (1968), with permission.

densely ionizing protons. It is this secondary production of knock-on protons that confers high LET.

6.3 BIOLOGICAL EFFECTS DEPEND UPON LET

As LET increases, radiation produces more cell killing per gray. Figure 6.2 shows the survival of human T1g kidney cells plotted against dose for eight different radiations, with LET varying from 2 keV/μm (250 kVp X-rays) to 165 keV/μm (2.5 MeV α-particles). As LET increases, the

70 Linear energy transfer and relative biological effectiveness

				Optimum
				LET
	8	Less efficient			Overkill
		cell killing
	7
	6
	5				SF
RBE
	4
	3				SF
	2				SF
	1
	0
	0.1	1	10	100	1000

Linear energy transfer (keV/μ

Figure 6.3 Dependence of relative biological effectiveness (RBE) on linear energy transfer (LET) and the phenomenon of overkill by very high LET radiations. The RBE has been calculated from Fig. 6.2 at cell surviving fraction (SF) levels of 0.8, 0.1 and 0.01. From Barendsen (1968), with permission.

survival curves become steeper; they also become straighter with less shoulder, which indicates either a higher ratio of lethal to potentially lethal lesions (in lesion-interaction models; Chapter 4, Section 4.11) or that high-LET radiation damage is less likely to be repaired correctly (in repair saturation models; Chapter 4, Section 4.12). In the linearquadratic (LQ) description, these straighter cellsurvival curves have a higher α/βratio, thus higher LET radiations usually give responses with higher α/β. For particles of identical atomic composition, LET generally increases with decreasing particle energy. However, notice that 2.5 MeV α-particles are less efficient than 4.0 MeV α-particles even though they have a higher LET; this is because of the phenomenon of overkill shown in Fig. 6.3.

The relative biological effectiveness (RBE) of a radiation under test (e.g. a high-LET radiation) is defined as:

	RBE	dose of reference radiation	(6.1)
		dose of test radiation

to give the same biological effect. The reference low-LET radiation is commonly 250 kVp X-rays or 60Co γ-rays since these radiations are usually available whenever RBE is being evaluated. Figure 6.3

3.0

OER	2.0

1.0

1

10

100

1000

LET (keV/ m)

Figure 6.4 The oxygen enhancement ratio (OER) decreases with increasing linear energy transfer (LET). Closed circles refer to monoenergetic α-particles and deuterons and the open triangle to 250 kVp X-rays. From Barendsen (1968), with permission.

shows RBE values for the T1g cells featured in Fig. 6.2. RBE has been calculated at cell survival levels of 0.8, 0.1 and 0.01, illustrating the fact that RBE is not constant but depends on the level of biological damage and hence on the dose level. The RBE also depends on LET, and rises to a maximum at an LET of about 100 keV/μm, then falls for higher values of LET because of overkill. For a cell to be killed, enough energy must be deposited in the DNA to produce a sufficient number of dou- ble-strand breaks (see Chapter 4, Section 4.8). Sparsely ionizing, low-LET radiation is inefficient because more than one particle may have to pass through the cell to produce enough DNA doublestrand breaks. Densely ionizing, very high-LET radiation is also inefficient because it deposits more energy per cell, and hence produces more DNA double-strand breaks than are actually needed to kill the cell. These cells are ‘overkilled’, and per gray there is then less likelihood that other cells will be killed, leading to a reduced biological effect. Radiation of optimal LET deposits the right amount of energy per cell, which produces just enough DNA double-strand breaks to kill the cell. This optimum LET is usually around 100 keV/μm but does vary between different cell types and depends on the spectrum of LET values in the radiation beam as well as the mean LET.

Relative biological effectiveness depends on dose 71

As LET increases, the oxygen enhancement ratio (OER; Chapter 15, Section 15.1) decreases. The measurements shown as an example in Fig. 6.4 were also made with cultured T1g cells of human origin (Barendsen, 1968). The sharp reduction in OER occurs over the same range of LET as the sharp increase in RBE (Fig. 6.3).

6.4 RELATIVE BIOLOGICAL EFFECTIVENESS DEPENDS ON DOSE

As indicated in Fig. 6.3, the RBE is higher if measured at lower radiation doses, corresponding to higher levels of cell survival (less effect). Figure 6.5 shows in more detail the RBE for test doses of 4 MeV α-particles plotted against a reference dose of 250 kVp X-rays, for the T1g human cells irradiated in vitro. The data points were derived from Fig. 6.2 by reading off from the α-particle survival curve the dose required to achieve the same cell survival as obtained for each X-ray dose evaluated. The RBE for the 4.0 MeV α-particles increases with decreasing dose because the low-LET X-ray survival response is more curved and has a bigger shoulder than the high-LET survival response. If LQ equations are used to model both the low-LET (reference) and the high-LET (test) responses, RBE can be predicted mathematically as a function of the reference dose (dR) or the test dose (dT) using formulae containing the α/β ratios and the ratio αT/αR (Joiner, 1988). The formulae are:

RBE K K 2 4KdR (1 dR /V )/C (6.2) 2(1 dR /V )

RBE V V 2 4VKdT (1 dT /C) (6.3) 2dT

where K αT/αR, V α/βfor the reference radiation and C α/β for the test radiation.

In Fig. 6.5, the solid line shows the prediction of equation 6.2, which gives RBE as a function of the reference dose, in this case X-rays.

The RBE can also be measured in vivo. In normal tissues this may be done by comparing the relationships between damage and dose for both highand low-LET radiations. This may be done for any endpoint of damage, including tissue breakdown

	6
RBE	4
	2
	0

0

4

8

12

X-ray dose (Gy)

Figure 6.5 Relative biological effectiveness (RBE) of 4 MeV α-particles increases with decreasing dose for

cell lines irradiated in vitro. RBE values were calculated from the cell survival data shown in Fig. 6.2. The full line is calculated as described in the text.

or loss of tissue function. As an example, Fig. 6.6a shows the results of an experiment to study the loss of renal function in mice after external-beam radiotherapy. This was done by measuring the increased retention of 51Cr-radiolabelled ethylenediaminetetraacetic acid (EDTA) in the plasma 1 hour after injection; normally functioning kidneys completely clear this substance from the body within this time. For neutrons (in this example produced by bombarding beryllium with 4 MeV deuterons, designated d(4)-Be), fractionation makes almost no difference to the tolerance dose but for X-rays a much higher total dose is required to produce renal damage when the treatment is split into two, five or ten fractions. This difference in the fractionation response for highand lowLET radiations in vivo reflects the shape of the survival curves for the putative target cells in the tissue: almost straight for neutrons with a high α/β ratio, and downwards bending for X-rays (Fig. 6.2) with a low α/βratio. In this in vivo situation, RBE is calculated from the ratio of X-ray to neutron total doses required to produce the same biological effect in the same number of fractions. This is plotted against X-ray dose per fraction in Fig. 6.6b. It can be seen that, in vivo, RBE increases with decreasing dose per fraction in exactly the same way as RBE increases with decreasing single dose for the cells in vitro shown in Fig. 6.5. In vivo, RBE versus dose can also be modelled using equations

72 Linear energy transfer and relative biological effectiveness

Per cent injected activity per mL plasma

(a)

14

12

10

8

6

4

2

0

0

Neutrons

X-rays

	2F	5F		RBE
				10F
	1F
10	20	30	40	50
Total radiation dose (Gy)				(b)

6					10 fractions
5									5 fractions
4
3															2 fractions
2																	1 fractions
1
		4			6				8			10			15			20
2

X-ray dose per fraction (Gy)

Figure 6.6 The relative biological effectiveness (RBE) for kidney damage increases with decreasing dose per fraction. The RBE values are derived from graphs similar to (a), which shows dose–effect curves for 51Cr-

ethylenediaminetetraacetic acid (EDTA) clearance following irradiation with 1, 2, 3, 5 and 10 fractions of neutrons or 1, 2, 5 and 10 fractions of X-rays. The RBE values in (b) were obtained with various renal-damage endpoints: isotope clearance (circles); reduction in haematocrit (squares); and increase in urine output (triangles). From Joiner and Johns (1987), with permission.

6.2 and 6.3. The solid line in Fig. 6.6b shows the mathematical fit of equation 6.2 to the data, from

which it is possible to obtain αNeutrons/αXrays, and α/βfor X-rays and for neutrons, directly from these

RBE versus dose data.

6.5 THE BIOLOGICAL BASIS FOR HIGH-LET RADIOTHERAPY

We have seen (Fig. 6.4) that the differential radiosensitivity between poorly oxygenated (more resistant) and well-oxygenated (more sensitive) cells is reduced with high-LET radiations. Therefore, tumour sites in which hypoxia is a problem in radiotherapy (some head and neck tumours and prostate cancer, for example) might benefit from high-LET radiotherapy in the same way as from chemical hypoxic-cell sensitizers (see Chapter 17, Section 17.3).

The effect of low-LET radiation on cells is strongly influenced by their position in the cell cycle, with cells in S-phase being more radioresistant than cells in G2 or mitosis (see Chapter 7, Section 7.3). Cells in stationary (i.e. plateau) phase also tend to be more radioresistant than cells in active proliferation. Both of these factors act to increase the effect of fractionated radiotherapy on

more rapidly cycling cells compared with those cycling slowly or not at all, because the rapidly cycling cells that survive the first few fractions are statistically more likely to be caught later in a sensitive phase and so be killed by a subsequent dose – a process termed ‘cell-cycle resensitization’. This differential radiosensitivity due to cell-cycle position is considerably reduced with high-LET radiation (Chapman, 1980) and is a reason why we might expect high-LET radiotherapy to be beneficial in some slowly growing, X-ray-resistant tumours.

A third biological rationale for high-LET therapy is based on the observation that the range of radiation response of different cell types is reduced with high-LET radiation compared with X-rays. This is shown in Fig. 6.7, which summarizes the in vitro response of 20 human cell lines to photon and neutron irradiation (Britten et al., 1992). This reduced range of response affects the benefit expected, which is the balance between tumour and normal-tissue responses. Thus, if tumour cells are already more radiosensitive to X-rays than the critical normal-cell population, high-LET radiation should not be used since this would reduce an already favourable differential. Possible examples are seminomas, lymphomas and Hodgkin’s disease. However, if the tumour cells are more resistant to

The biological basis for high-LET radiotherapy 73

	1.0
	0.6
	0.4
fraction	0.2		fraction
	0.1
Surviving			Surviving
	0.06
	0.04		Photons
	0.02

0.01
							1				2								3				4
	0
(a)												Dose (Gy)																			(b)
	1.0
2	0.6																														fractionSurviving
SFPhotons	0.4
	0.2
	0.1
	0.1						0.2				0.4								0.6				1
(c)											Neutrons SF0.68																				(d)

1.0

0.6

0.4

0.2

0.1

0.06

0.04

0.02

0.01

0

1.0

0.6

0.4

0.2

0.1

Neutrons

0.2

0.4

0.6

0.8

1

1.2

1.4

Dose (Gy)

Photons	Neutrons
SF2	SF0.68

Figure 6.7 Response of 20 human tumour cell lines to (a) 4 MVp photons or (b) p(62.5)-Be neutrons. The vertical lines show the photon (2 Gy) and neutron (0.68 Gy) doses that give the same median cell survival; the average relative biological effectiveness (RBE) is therefore 2/0.68 2.94. (c) The range of cell survival at the reference neutron dose of 0.68 Gy (SF0.68) is less than the range of survival at a photon dose of 2 Gy (SF2). In 9/20 of the cell lines neutrons gave lower cell survival than photons at these doses (d).

X-rays than the critical normal cells, high-LET radiation might reduce this difference in radiosensitivity and thus would effectively ‘sensitize’ the tumour cell population relative to a fixed level of

damage to normal tissue; high-LET radiation would be advantageous in this case.

In Chapter 24, we summarize the clinical experience with high-LET radiations.

74 Linear energy transfer and relative biological effectiveness

Relative dose (%)

(a)

100												Sum
					6 MVp X-rays
														1
50			60Co γ
												5	4	3	2
0
	2	4	6	8	10	12	14	16	8	9	10	11		12	13
0
			Depth in water (cm)						(b)		Depth in water (cm)

Figure 6.8 The different depth–dose characteristics of (a) photons and (b) proton beams of different intensities and ranges, achieved by passing a primary beam (1) through plastic absorbers (see text).

					1
50	90			40	60		3
60	100
70				20
		90			TARGET		40
	100		50	70
					95		90
50		60	60
				4	80	60
		80	50
60	70		60
50	60	70	70	2040			20
	80	60
					2
250 kV X-rays 6 fields				18 MV X-rays 4 fields

	40	50	40
40
	TARGET	40	TARGET	10
			100
50	100
				3020

10

He ions

C ions

Figure 6.9 Comparison of treatment plans for the radiotherapy of a case of pancreas carcinoma using charged particle beams or photons. From Bewley (1989), with permission.

6.6 THE PHYSICAL BASIS FOR CHARGED-PARTICLE THERAPY

With conventional X-ray therapy, absorbed dose increases very rapidly within the short distance in which electronic equilibrium (‘build-up’) occurs,

and then decreases exponentially with increasing penetration. Figure 6.8a shows central-axis depth doses from 60Co γ-rays and from X-rays generated by a 6-MV linear accelerator (Fowler, 1981). Neutrons are also uncharged and their depth–dose characteristics are similar: modern

The physical basis for charged-particle therapy 75

		approx. 14 cm range						approx.
		4 cm spread peak						10 cm spread peak
	0	4	8	12	16	20	4	8	12	16	20	24	28
	2.2	Carbon					Carbon						2.2
	1.8												1.8
	1.4												1.4
	1.0					OER							1.0
						3
	0.6												0.6
	0.2					2
													0.2
	2.2	Neon					Neon						2.2
dose	1.8												1.8	Figure 6.10 The biological
	1.4												1.4	effect of charged particle
Relative						3								beams is increased further in
	1.0												1.0	curves are shown for three
						OER								the Bragg peak. Depth–dose
	0.6												0.6	types of ion beam, each with a
						2
	0.2													4-cm or 10-cm spread peak.
													0.2
														Full lines show the dose
	1.8	Argon											1.8	distribution; upper broken
														lines (full symbols) show the
									RBE
														biologically effective dose (i.e.
	1.4												1.4
									Dose					dose relative biological
						OER
	1.0								OER				1.0	effectiveness, RBE). The lower
						3								broken lines (open symbols)
	0.6												0.6
														show the reduction in oxygen
						2
	0.2													enhancement ratio (OER)
													0.2
														within the spread peak. From
	0	4	8	12	16	20	4	8	12	16	20	24	28
														Blakely (1982), with
						Depth in water (cm)								permission.

high-energy neutron therapy beams have a penetration that is comparable to 4 MV X-rays. The only rationale for neutron therapy is therefore radiobiological, as discussed in Section 6.5.

In contrast, ion beams (i.e. incident beams of charged particles) increase their rate of energy deposition as they slow down with increasing penetration, finally stopping and releasing an intense burst of ionization called the Bragg peak. As an example, curve 1 in Fig. 6.8b shows the depth–dose distribution of a primary beam of 160 MeV protons. The broad peak is obtained by superimposing on curve 1 four other beams of different

intensities and ranges (curves 2, 3, 4 and 5), achieved by passing the primary beam through a rotating wheel with sectors of different thickness of plastic sheet. This spread-out peak (Sum) can be adjusted to cover the tumour volume and therefore increase the ratio of tumour-to-normal-tissue dose compared with conventional photon therapy (Raju, 1980). In modern beam delivery systems, this same scanning of the Bragg peak over a range of depths is achieved by directly modulating the particle energy in variable-energy accelerators.

Figure 6.9 shows some possible treatment plans with heavy-ion beams of helium and carbon

76 Linear energy transfer and relative biological effectiveness

nuclei, using carcinoma of the pancreas as an example. The improvement given by the He ions over 18 MV X-rays is as dramatic as the comparison between 18 MV and 250 kVp X-rays. The mean doses to the spinal cord and kidney are almost zero for He ions, 50 per cent for 18 MV X-rays and 70 per cent for 250 kVp X-rays. Uniformity over the tumour is 2–3 per cent, 5 per cent and 15 per cent, respectively.

Carbon ions give a similar dose distribution to He ions but in addition they have a higher LET and RBE in the Bragg peak, which in suitable tumours (see above) might confer an additional radiobiological advantage. The LET of a charged particle is proportional to the square of its charge divided by the square of its velocity. Therefore, in the Bragg peak, where the particles are slowing down rapidly, heavy ions such as carbon, neon and argon have very high LET, with the potential for a greatly increased biological effect. To illustrate this, Fig. 6.10 shows depth–dose curves for beams of heavy ions accelerated to two different energies giving maximum penetrations in tissue of about 14 or 24 cm. In each case the solid line represents the pattern of dose produced by a ridge filter designed to spread out the Bragg peak to cover imaginary tumours of 4 or 10 cm, respectively. This is a similar ‘peak-spreading’ technique to that described in Fig. 6.8b. However, the dotted line shows the distribution of biologically effective dose, which is physical dose multiplied by RBE. The RBE values are those for Chinese hamster cells corresponding to an X-ray dose of about 2 Gy. This demonstrates that for heavy ions (not high-energy protons or helium ions) the physical advantage of better dose distribution in the spread-out Bragg peak can be further enhanced by the radiobiological advantage from the higher LET.

Figure 6.11 conveniently summarizes the relative physical and radiobiological properties of different radiations and charged particles (Fowler, 1981). Protons have excellent depth–dose distributions and have radiobiological properties similar to orthovoltage X-rays: it is highly probable that light-ion beams of protons and perhaps helium will play a key role in better radiotherapy during the next 20 years. Neutrons have no dose distribution advantage over megavoltage X-rays

		Ar
		Si
	Neutrons	Ne
				RBE
LET		Pions	C
250			He
kV		Megavoltage
	60Co		P
X rays
		X rays

Quality of dose distribution

Figure 6.11 The radiations available for radiation therapy differ in the quality of beam that they produce, also in relative biological effectiveness (RBE). LET, linear energy transfer. Based on Fowler (1981).

but may be useful because of their high LET. The heavy ions give better dose distributions than X- rays and a higher LET, depending on the particle. Argon ions have a high LET but in practice they break up so readily that only limited penetration can be obtained. Carbon, neon and silicon ions are the most promising of the heavy ions at the present time and where heavy-ion therapy is adopted it will probably be with these particles (Castro, 1995).

Key points

1.Both X-rays and γ-rays are sparsely ionizing

radiations with a low LET. Some particle radiations (e.g. neutrons, α-particles or heavy ions) have a high LET.

2.High-LET radiations are biologically more effective per gray than low-LET radiations. This is measured by the RBE. For most high-LET radiations at therapeutic dose levels, RBE is in the range of 2–10.

3.RBE increases as the LET increases up to about 100 keV/μm, above which RBE decreases because of cellular overkill. The OER also decreases rapidly over the same range of LET.

Further reading 77

4.RBE increases as the dose is reduced in vitro, or the dose per fraction is reduced in vivo. In late-responding tissues, this increase occurs more rapidly than in early-responding tissues.

6.Heavy particles such as He, C and Ne ions have a high-LET and in addition they have improved physical depth–dose distributions.

7.Proton beams provide the best improvement in dose distribution for the lowest cost; their RBE is similar to low-energy photons.

■BIBLIOGRAPHY

Barendsen GW (1968). Responses of cultured cells, tumours and normal tissues to radiations of different linear energy transfer. Curr Topics Radiat Res Q 4: 293–356.

Bewley DK (1989). The physics and radiobiology of fast neutron beams. Bristol: Adam Hilger.

Blakely EA (1982). Biology of bevalac beams: cellular studies. In: Skarsgard LD (ed.) Pion and heavy ion radiotherapy: pre-clinical and clinical studies.

Amsterdam: Elsevier, 229–250.

Britten RA, Warenius HM, Parkins C, Peacock JH (1992). The inherent cellular sensitivity to 62.5 MeV(p-Be) neutrons of human cells differing in photon sensitivity. Int J Radiat Biol 61: 805–12.

Castro JR (1995). Results of heavy ion radiotherapy.

Radiat Environ Biophys 34: 45–8.

Chapman JD (1980). Biophysical models of mammalian cell inactivation by radiation. In: Meyn RE, Withers HR (eds) Radiation biology in cancer research.

New York: Raven Press, 21–32.

Fowler JF (1981). Nuclear particles in cancer treatment. Bristol: Adam Hilger.

Goodhead DT (1988). Spatial and temporal distribution of energy. Health Phys 55: 231–40.

Joiner MC (1988). A comparison of the effects of p(62)-Be and d(16)-Be neutrons in the mouse kidney. Radiother Oncol 13: 211–24.

Joiner MC, Johns H (1987). Renal damage in the mouse: the effect of d(4)-Be neutrons. Radiat Res 109: 456–68.

Raju MR (1980). Heavy particle radiotherapy. New York: Academic Press.

■ FURTHER READING

Alpen EL (1998). Radiation biophysics, 2nd edn. San Diego: Academic Press.

Conference Proceedings (1994). Nordic conference on neutrons in research and cancer therapy. Linkoping, April 29–30, 1993. Acta Oncol 33: 225–327.

Engenhart-Cabillic R, Wambersie A (eds) (1998). Fast neutrons and high-LET particles in cancer therapy. Recent results in cancer research, Vol. 150. New York: Springer-Verlag.

Goodhead DT (1989). The initial physical damage produced by ionizing radiations. Int J Radiat Biol 56: 623–34.

Noda K, Furukawa T, Fujisawa T et al. (2007). New accelerator facility for carbon-ion cancer-therapy.

J Radiat Res (Tokyo) 48(Suppl A): A43–54. Wambersie A, Richard F, Breteau N (1994).

Development of fast neutron therapy worldwide. Radiobiological, clinical and technical aspects. Acta Oncol 33: 261–74.

Wambersie A, Auberger T, Gahbauer RA, Jones DT, Potter R (1999). A challenge for high-precision radiation therapy: the case for hadrons. Strahlenther Onkol 175(Suppl 2): 122–8.

Withers HR, Thames HD Jr, Peters LJ (1982). Biological bases for high RBE values for late effects of neutron irradiation. Int J Radiat Oncol Biol Phys 8: 2071–6.