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The Clinical Radiobiology of High LET Radiotherapy with Particular Reference to Proton Radiotherapy
Clinical Oncology (2003) 15: S16–S22 doi:10.1053/clon.2002.0181
The Clinical Radiobiology of High LET Radiotherapy with Particular Reference to Proton Radiotherapy B. Jones*, R. Dale† *Department of Clinical Oncology, Imperial College School of Medicine, Hammersmith Hospital, London W12 0HS; †Department of Radiotherapy Physics and Radiobiology, Charing Cross Hospital, London W6 8RF, U.K. Received: 9 October 2002
Many countries throughout the world will soon possess high linear energy transfer (LET) charged particle radiotherapy facilities. These have the advantage of a superior dose distribution, due to the Bragg peak effect, when compared with conventional X-ray based radiotherapy of equal complexity in terms of field arrangements and treatment planning sophistication. This paper concentrates on the subtle effects caused by relative biological efficiency or effect (RBE) that can occur in the context of high LET therapy. Higher RBE values than those associated with protons are found with light ions, which also have the potential advantage of a reduced oxygen enhancement ratio. Clinicians should remember that although neutrons are high LET particles, they are uncharged and do not possess the dose localizing advantages of a Bragg peak. Radioresistance, from whatever cause, will be opposed by an increase in tumour dose. The sigmoidal shapes of radiation dose–response curves show that increasing the total dose will produce an enhanced tumour cure probability (TCP), but with diminishing returns at the very highest doses [1]. If the normal tissue receives the same dose as the tumour then normal tissue complications (NTCPs) also escalate. However, if tumour dose can be increased whilst normal tissue doses are simultaneously reduced we effectively follow the normal tissue curve downwards and to the left, and beneficially increase the cure:complication ratio. The ratio of cure:complication is a measure of the therapeutic ratio associated with a given treatment. The advantage of proton therapy stems from the extra tumour dose that can be delivered in association with a reduced dose to normal tissues [2]. Newer forms of X-ray therapy [e.g., intensity-modulated radiation therapy (IMRT) or X-ray IMRT (IMXT)] may also facilitate a similar degree of dose escalation, but proton dose distributions are usually better due to the absence of any dose beyond the Bragg peak. Proton IMRT techniques may also be used to further improve the dose Author for correspondence: Dr Jones Department of Clinical Oncology, Imperial College School of Medicine, Hammersmith Hospital, London W12 OHS, U.K. Tel: 0208-383-3059; Fax: 0208383-3054; E-mail: [email protected] 0936–6555/03/010S16+07 $30.00/0
Accepted: 16 October 2002
distribution. Such progressive dose reduction in normal tissues should produce benefits to patients in terms of reduced low-grade, radiation-related morbidity, e.g., specific organ dysfunction related to stem cell depletion, reduced vascular function, fibrosis and a reduction in stochastic effects such as second malignancies. Both short- and long-term quality of life is expected to be superior in proton-irradiated patients than after X-ray therapy, although this difference needs to be measured in comparative studies. High LET Particle Radiobiology
Charged particle beams have a higher LET and thus deposit more energy per unit length of beam than megavoltage X-rays [3]. The additional biological effect is quantified in terms of RBE, the ratio of the iso-effect dose for a high-LET radiation to that required with low-LET cobalt gamma rays or orthovoltage X-rays. RBE increases with LET until the phenomenon of overkill occurs. LET and RBE values vary along the path of a proton beam [2,3]. They are initially low and increase to the highest value at the terminal part of the Bragg peak. Modulation of the peak should effectively spread out the region over which the higher RBE is operative, and this is confirmed experimentally, but highest values of RBE are predicted and continue to be found at the end or beyond the plateau region [4,5]. Higher proton energies have a lower average LET and therefore a lower ‘average’ RBE than lower proton energies [3,4]. Thus 60 MV protons will have a higher RBE than 200 MV protons. From a theoretical perspective, RBE is expected to increase with decreasing dose per fraction. This fractionation effect is due to more repair of sub-lethal DNA damage at small doses per fractions with the low-LET reference radiation than with higher LET test radiation [3]. The standard definition for RBE is the ratio of doses for each radiation type at an experimental surviving fraction of 0.1 [3,4]. This is a restrictive definition and probably inappropriate for use over a wide range of dose per fraction, particularly if the RBE is greater than 1.1. The maximum RBE (RBEmax) is defined as the ratio of the initial slopes of the low- and high-LET cell survival
2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved.
Table 1 – Estimates of sample size (n) in each treatment arm to show various outcome differences for a significance level of 5% (0.05) for two study powers Percentage differences in outcomes Power of study 80% 90%
5%
10%
25%
n=1100 n=1200
n=420 n=600
n=60 n=90
S17
are generally larger but equal for late and early normal tissue effects in skin. Significantly higher neutron RBEs in the central nervous system (CNS) are probably caused by enhanced neutron dose due to the increase in hydrogen density of myelin-rich tissue. Such effects are not expected to be significant in proton therapy, where electron density is the main cause of absorption as in the case of X-rays. Inclusion of RBE with the biological effective dose (BED) Concept
Modified from Bentzen [12].
curves: this can be interpreted as the ratio of the radiosensitivity values of the low and high LET radiations. In proton radiotherapy, generic values of proton RBE (usually 1.1) are used to convert absorbed dose in Grays to cobalt Gray equivalent: the X-ray dose is divided by 1.1 to give the equivalent proton dose, regardless of the dose per fraction used. Estimations of proton RBE have been reported in the literature. At Boston, one late reacting tissue and a wide range of acute responding tissues were studied and a relatively uniform RBE of 1.1 was found by Urano et al. [6]. More recently, Paganetti et al. [7], using an intestinal crypt assay, found RBEs of 1.1–1.2 and the variation with depth was found to be larger for lower proton energies. Some interesting inter-relationships have been tested: (1) Monte Carlo techniques suggests that RBE is independent from the tissue / ratio [8]. (2) Lung radiation experiments in mice show that the late reaction RBE is no different from acute reactions although RBE appears to vary with the time period following exposure [9]. (3) Neutron studies provide supporting evidence that values increase in the same ratio for both early and late tissues [10]. More recently, the Boston group [11] have collected the data on in vitro and in vivo experiments and found a less marked inverse relationship between dose per fraction and RBE for doses that range as low as 1.1 Gy per fraction in a variety of tissues. Because of biological variation, it is probably unrealistic to expect that studies of this type will estimate RBE accurately enough to distinguish a 2–5% change in RBE, such as between 1.1 and a 5% increase 1.11.05=1.155. For statistical precision, very large numbers of syngeneic animals would be required, probably between 500 and 1000 per point estimate of the RBE. For clinical trials, because of heterogeneity, the numbers of patients given in Table 1 are required to confirm differences in outcomes. There is a further concern in that there are no reported in vivo data where tumour control and a normal tissue iso-effect are studied simultaneously after proton therapy, that is a true therapeutic ratio (TR) has not been studied. The RBE values are small for the dose schedules used in proton radiotherapy. For neutrons, the RBE values
The BED concept is increasingly useful in clinical radiobiology [13]. RBE effects can be included within BED equations [14,15]. RBEMax is the ratio of the non-repairable () radiosensitivity parameters
at near zero dose, where the
subscripts H and L refer to high and low LET radiations respectively. Consequently, H =L · RBEMax
(1)
It is assumed that the radiosensitivity parameter is relatively unchanged by LET, i.e.H =L. Within the LQ model, radiation effect (E) can be expressed as E=n(d+d2) where n is the number of fractions of dose d such that D, the total dose will equal nd. The BED for low LET radiation (BEDL) may be written as:
The BED for high LET (BEDH) radiation will be obtained by dividing E instead by H and multiplying throughout by RBEM so that,
where (/)L is the late normal tissue fractionation sensitivity for megavoltage photons: the same as that utilized in more common (low-LET) applications of the model. The inclusion of RBEMax ensures that the high LET BED is expressed in the same biological units as the low-LET value. Low-LET / ratios, which are increasingly known for a variety of tissues and tumours, can then be used to derive high-LET BEDs. The RBEMax dominates the bracketed portion of the equation when dose per fraction is low but becomes less important when dose per fraction is high. The low LET / ratio influences the balance between the RBE effect and the dose per fraction effect. Equation 3 also allows estimation of the RBEmax from existing in vivo data for which the low-LET / ratio is known. Results Use of Simple BED Calculations in Proton Therapy
Until now, generic RBE values, such as 1.1, have been used to modify the proton dose. Subsequent estimation
S18
of BED will use a modified dose per fraction parameter, which will introduce errors mostly in the quadratic term. Alternatively, a more accurate method would be to use the modified BED equations with RBEmax. Simple BED-RBEmax calculations are presented for cases where the protons are initially assumed not to posses normal tissue sparing properties. If we assume that the low-LET normal tissue tolerance is 60 Gy in 30 fractions then (from Equation 4) BED=100 Gy3. Similarly, the tumour BED is determined as being 72 Gy10. This value is to be compared with the calculation results presented below. Using Equation 6, it is found that, for protons with RBEmax of 1.4 (as found for the Clatterbridge 60 MeV proton beam), only 242 Gy fractions are required to obtain the same normal tissue effect for /=3Gy. The associated tumour BED, for /=10Gy, is then found to be 76.8 Gy: 100=2n(1.4+2/3) n=24, proton BEDtum =48(1.4+2/10) =76.8 Gy10 This is larger than the BED of 72 Gy10 for X-rays. A further increase in tumour BED is found on calculating a new smaller proton dose per fraction. The tumour proton BED is 80.7 Gy (c.f. 72 Gy10 for the X-rays at 2 Gy per fraction). The predicted tumour kill is enhanced for protons and the therapeutic ratio (TR) is improved as follows: 100=30d(1.4+d/3) d=1.7 Gy proton BEDtum =301.7(1.4+1.7/10) =80.7 Gy10. Should the RBEmax increase, for example to 1.7 for late effects, a smaller tumour BED is found compared with X-rays, regardless of whether a new dose per fraction is used, or if the number of fractions remains the same. Then we have 100=2n(1.7+2/3) n=21, proton BEDtum =212(1.4+2/10) proton BEDtum =67.2 Gy10 This result is less than 72 Gy10, indicating a decreased TR. For a fixed number of 30 fractions and changing dose per fraction and total dose, we have 100=30d(1.7+d/3) d=1.5 Gy proton BEDtum =301.5(1.4+1.5/10) proton BEDtum =69.75 Gy10 The predicted tumour BED is smaller for protons if the / ratio for the late effect exceeds that of the acute effect. A reduction in the TR is then predicted. These differences in BED will be much smaller for higher energy protons (where RBEmax is smaller), but will be generally improved when we include a specific dose reduction for normal tissues. For example, if the
normal tissue dose is 65% for protons and 75% for X-rays relative to 100% at tumour, for a normal tissue iso-effect we obtain for 1.65 Gy per fraction in the normal tissue 100=n1.65 (1+1.1.65/3) n=39 The tumour BED for X-rays will be 391.651/ 0.8(1+1.65/(0.810))=97 Gy10. This is significantly greater than the original value of 72 Gy10. For protons with RBEmax of 1.2 and for the same dose per fraction, we have 100=n1.65(1.2+1.65/3) and n=34.6 The proton tumour BED will then be =100.4 Gy10. This value is substantially greater than the original 72 Gy10 and also far exceeds that for the X-rays. The TR is likely to further improve. Some recent conclusions of further modelling are as follows: (1) If tumour />late normal tissue /, i.e. the majority of clinical situations, improved outcomes are predicted providing dose per fraction is kept below critical values which may be calculated. If the late-responding tissues have a higher RBEmax there is a more severe upper constraint on the dose per fraction that may be used. (2) If tumour /
Graphical Methods Optimum dose per fraction
The optimum dose per fraction, which provides the maximum tumour cell kill for the same degree of normal tissue effect, can be estimated [15–17]. The effects of normal tissue sparing, which can accrue from the beam geometry, can also be crudely incorporated. This is achieved through use of a fractional sparing parameter (g) such that if the modal tumour dose is 100% and the normal tissue critical volume modal dose is 75% then g is 0.75. The BED formulations given above are used with an RBEmax of 1.4 in these examples. The method does not use the generic RBE values, which if used do not produce the same gains in TR. Initially, if no geometric advantage is assumed (normal tissue dose=tumour dose; g =1) and there is a uniform normal tissue RBEmax in normal tissue and tumour. The values of K refer to the daily dose equivalent of tumour cell repopulation in units of Gy10/day. A value of 0.3 Gy10 per day is used to represent relatively
Fig. 1 – Plot of tumour BED (Gy10) for the same normal tissue iso-effect as 50 Gy in 25 fractions at increasing dose per fraction for X-rays and protons with an RBEmax of 1.4. Here, g=1, which signifies no normal tissue sparing.
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Fig. 3 – Plot of tumour BED (Gy10) for the same normal tissue iso-effect as 50 Gy in 25 fractions at increasing dose per fraction for X-rays and protons with an RBEmax of 1.4. Here, g=0.7, which signifies 70% sparing of dose for protons and 0.8, which signifies 80% sparing for X-rays.
BED is increased from 10 Gy10 to be 23 Gy10. These differences will be smaller for higher energy protons, but will still depend on the RBEmax and the geometrical sparing achieved. RBEmax values
Fig. 2 – Plot of tumour BED (Gy10) for the same normal tissue iso-effect as 50 Gy in 25 fractions at increasing dose per fraction for X-rays and protons with an RBEmax of 1.4. Here, g=0.75, which signifies 75% sparing of dose for protons but sparing for X-rays.
slow tumour repopulation and the normal tissue isoeffect is taken to be 50 Gy in 25 fractions for X-rays, as would be appropriate for the brainstem. The turnover points in Figs 1–3 represent the optimum dose per fraction for each modality and the tumour kill is uniformly better with protons when the same absolute dose per fraction is used for each class of radiation. The difference in BED due to the RBE is over 10 Gy10 at 1 Gy per fraction and around 8 Gy10 at the turnover points, with decreasing differences at higher doses per fraction. When the normal tissue sparing improves (g=0.75) for both modalities the tumour BED increases and the differences between the radiation types are similar to the first case. The increment of tumour
Fig. 4 contains plots of the RBE variation with dose per fraction for three different RBEmax values, 1.4, 1.2 and 1.15. It can be seen that for the cases where RBEmax =1.15–1.2, as would be expected for relatively high-energy protons, say greater than 150 MeV, it would be very difficult to detect such small changes from biological experiments. For example, a value different from a ‘rounded’ 1.1 in the range of fractionation between 1–3 Gy would be unlikely if the biological system used can only provide a 10% level of accuracy. A further example of the difficulty inherent in the assessment of marginal changes in RBE at low doses per fraction is shown in Fig. 5. This shows the relatively wide 95% confidence limits for RBE in a group of 250 individuals (with a mean / of 3 Gy (with standard deviation=0.3 Gy), for a mean RBEmax of 1.2 (standard deviate=0.025). Investigation of the variable / ratios and the resultant RBEs (see Fig. 6), using the BED-Rmax equations given above, provides interesting results. The change in RBE with dose per fraction depends on the tissue or tumour / ratio, with lower ratios for late-reacting tissues having the lower RBEs, although there is a common RBEmax. This suggests that RBE values should differ between tissue and tumour types, while RBEmax remains constant for a particular proton beam. RBE values are predicted to be lower for tissues with small / ratios.
S20
Fig. 4 – The predicted relationship between dose per fraction and RBE for three different values of RBEmax (1.15, 1.2 and 1.4).
Fig. 5 – Plot of mean RBE (bold line), with 95% confidence limits (feint lines), against dose per fraction for 250 individuals.
Differential normal tissue sparing ratios
The extent of the tumour BED improvement ratio can be impressive but in practical situations the g values will not be extreme and more modest differences will occur. Fig. 7 shows the tumour BED improvement ratio for protons versus X-rays (proton sparing=g1, proton sparing=g2). The ratio of g1/g2 will exceed unity when the proton sparing is superior. It can be seen that when tissue sparing is extremely good, and is equally good for protons and X-rays (g1/g2=1), there is no advantage – a slight detriment is actually seen because of the extreme hypofractionation. However, at most practical values of tissue sparing and where there is a slight advantage for protons, then the potential benefits appear to be considerable. It should be remembered in this context
Fig. 6 – Predicted relationship between RBE and dose per fraction for different / ratios of cells or tissues.
Fig. 7 – Plot of predicted tumour BED ratios for protons and X-rays against the g1 parameter, the treatment being limited by the constraints of a g1 parameter for protons and a g2 parameter for X-rays. A larger tumour BED ratio indicates improved outcomes for protons.
that tumour BED increments of say 20 Gy10 may result in a 20–40% increase in tumour control, depending on the gradients of the dose–response curves and the tumour control probability expected from the X-ray treatment. Correspondingly, should it be possible to deliver the same tumour BED by X-rays or protons, then the normal tissue effects would be reduced for the proton therapy. Implications for high LET radiotherapy
Inclusion of RBEmax values within standard BED equations allows more refinement of high-LET isoeffective calculations, and puts them on an equal footing with
S21
those for X-ray therapy. The RBEmax represents a ‘latent’ RBE factor that manifests itself subtly as dose per fraction is varied and should be protective with respect to the normal tissues providing that iso-effect calculations are adhered to. For proton beams, the changes in overall RBE may not be large and will therefore be extremely difficult to identify in clinical studies or animal experiments. However, small changes in the RBE of say 2–4% would have significant clinical impact on normal tissues, particularly as their dose– response curves have steeper slopes. If treatment is planned with a constraint in terms of normal tissue dose, as in the optic nerve and brainstem for chordoma treatments, the use of a slightly incorrect generic RBE could produce a significant clinical error. For example, to equate a dose of 55 Gy in 30 fractions, we have
Conclusions
NT BED=55 (1+1.83/2)=105.3 Gy2
+ Appropriate tumour types may be identified for proton therapy from the known low LET parameters that are increasingly available from clinical data sets. + The RBEmax estimates and estimates of improvement based on BEDs will be smaller for higher proton energies. + Modelling may identify areas where more basic research can provide further specific information to identify optimal use of protons, that is safer treatments and substantial potential gains for the selective use of protons. + More studies are required of & values for X-rays and protons in log and plateau growth phases to determine if RBEmax changes with cell cycle time. + More in vivo experiments could test if changes in RBEmax occurs by use of BED equations in tissues where / parameter is known.
For protons using RBE=1.1, we would divide the dose per fraction by 1.1 to give 1.83/1.1=1.66 Gy protons. Now if we use 1.66 Gy per fraction protons and the RBE is actually 1.125, we would obtain (using the standard BED equations without RBEmax: BED=1.66301.125 (1+1.1251.66/2) =108.34 Gy2. This represents a 108/105=nearly 3% increase in the NT BED, which could result in a larger NTCP (normal tissue complication probability) of say 3–10%. Alternatively, the RBEmax BED method could be used. This would be as follows: 105.325=n d (RBEmax +d/(/)) where for the same number of fractions (30), we obtain, for RBEmax =1.2, 105.33=30 d (1.2+d/2) d=1.71 Gy For this dose per fraction we obtain BED=301.71 (1.2+1.71/2)=105.4 Gy2. This result is the same as that for the X-ray BED. This example is a single illustration that the BED-RBEmax method ‘falls safe’ with respect to normal tissue tolerance when compared with the generic RBE method. The use of the RBEmax effectively provides a sliding scale of RBE, which is protective on normal tissues when compared to the generic RBE methodology. RBEmax can itself be derived from in vivo isoeffect data where the low-LET / is known. This will be given by:
or
This exploratory paper has presented a prospectus for further fundamental research with important clinical applications. The modelling predictions are testable within scientific experiments and in developmental clinical trials. The recent recommendations from Boston that the generic RBE method should be preserved is very practical but does miss an opportunity to further improve the results of proton therapy, which has an associated morbidity [18–20]. The future work necessary can be summarized as follows:
Radiobiology
Clinical
+ Future clinical objectives should recognize the potential of modern radiobiological models and seek to integrate these with the treatment planning process. There is no justification for continued use of oversimplistic concepts such as co-equivalent Grays. + Studies of volume effects and changes in RBE as Bragg peak is modulated; translation to equivalent uniform dose (EUD), as defined by Niemierko in Boston [21]. By means of BED dose volume histograms, as advocated by Wheldon et al. in the U.K. [22], EUD may be converted to equivalent uniform BED (EUBED). + Comparisons of the best available X-ray IMRT and proton plans in terms of the physical and likely BED. + Optimize dose per fraction for photon and proton therapies based on the likely tumour radiobiological parameters as obtained from clinical data sets. In these ways scientific principles can be used to decide which tumour type and anatomical sites that are best treated by protons. The further investigation of RBE effects could also have important conclusions in other areas of radiotherapy, e.g. iodine and palladium
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seed implants in prostate cancer etc. The use of optimization techniques for protons in parallel with conventional X-ray therapy may also yield significant benefits. References 1 Fowler JF. What can we expect from dose escalation using proton beams? Clin Oncol 2003;15:S10–S15. 2 Suit H, Urie M. Proton beams in radiation therapy. J Nat Cancer Institute 1992;84:155–164. 3 Hall E. Alternative Radiation Modalities. In Radiobiology for the Radiologist, 5th Edn. Philadelphia: Lippincott, Williams & Wilkins, 2000;432 – 445. 4 Gerweck LE, Kosin SV. Relative biological effectiveness of proton beams in clinical therapy. Radiother Oncol 1999;50:135–142. 5 Paganetti H, Goitein M. Radiobiological significance of beam-line dependent proton energy distribution in a spread out Bragg peak. Med Phys 2000;27:1119–1126. 6 Urano M, Verhey LJ, Goitein M, et al. Relative biological effectiveness of modulated proton beams in various murine tissues. Int J Radiat Oncol Biol Phys 1984;10:509–514. 7 Paganetti H, Olko P, Kobus H, et al. Calculation of relative biological effectiveness for proton beams using biological weighting functions. Int J Radiat Oncol Biol Phys 1997;37:719–729. 8 Paganetti H, Gerweck LE, Goitein M. The general relation between tissue response to x-irradiation (alpha/beta-values) and the relative biological effectiveness (RBE) of protons: prediction by the K track-structure model. Int J Radiat Biol 2000;76:985–998. 9 Guellette J, Bohm L, Slabbert JP, et al. Proton relative biological effectiveness (RBE) for survival in mice after thoracic irradiation with fractionated doses. Int J Rad Oncol Biol Phys 2000;47:1051– 1058. 10 Joiner MC, Bremner JC, Denekamp J, Maughan RL. The interaction between X-rays and 3 MeV neutrons in the skin of the mouse foot. Int J Radiat Biol 1984;46:625–638.
11 Paganetti H, Niemierko A, Ancukiewicz M, et al. Relative biological effectiveness (RBE) values for proton beam therapy. Int J Radiat Oncol Biol Phys 2002;53:407–421. 12 Bentzen S. Towards evidence based radiation oncology: improving the design, analysis, and reporting of clinical outcome studies in radiotherapy. Radiother Oncol 1998;46:5–18. 13 Jones B, Dale RG, Deehan C, Hopkins KI, Morgan DAL. The role of biologically effective dose (BED) in Clinical Oncology. Clin Oncol 2001;13:71–81. 14 Dale RG, Jones B. The assessment of RBE effects using the concept of biologically effective dose. Int J Radiat Oncol Biol Phys 1999;43:639–645. 15 Jones B, Dale RG. Estimation of optimum dose per fraction for high LET radiations: implications for proton radiotherapy. Int J Radiat Oncol Biol Phys 2000;48:1549–1557. 16 Jones B, Tan LT, Dale RG. Derivation of the optimum dose per fraction from the Linear Quadratic model. Br J Radiol 1995;68: 894–902. 17 Jones B, Dale RG. Radiobiologically based assessments of the net costs of fractionated focal radiotherapy. Int J Radiat Oncol Biol Phys 1998;41:1139–1148. 18 Urie MM, Fullerton B, Tatsuzaki H et al. A dose–response analysis of injury to cranial nerves and/or nuclei following proton beam radiation therapy. Int J Radiat Oncol Biol Phys 1992;23:27– 39. 19 Santoni R, Liebsch N, Finkelstein DM, et al. Temporal lobe (TL) damage following surgery and high-dose photon and proton irradiation in 96 patients affected by chordomas and chondrosarcomas of the base of the skull. Int J Radiat Oncol Biol Phys 1998;41:59–68. 20 Jones B, Errington RD. Commentary: proton beam therapy. Br J Radiol 2000;73:802–805. 21 Niemierko A. Reporting and analysing dose distributions: a concept of equivalent uniform dose. Med Phys 1997;24:103–110. 22 Wheldon TE, Deehan C, Wheldon EG, Barrett A. The linear quadratic transformation of dose volume histograms in fractionated radiotherapy. Radiother Oncol 1998;46:285–295.
The Clinical Radiobiology of High LET Radiotherapy with Particular Reference to Proton Radiotherapy B. Jones*, R. Dale† *Department of Clinical Oncology, Imperial College School of Medicine, Hammersmith Hospital, London W12 0HS; †Department of Radiotherapy Physics and Radiobiology, Charing Cross Hospital, London W6 8RF, U.K. Received: 9 October 2002
Many countries throughout the world will soon possess high linear energy transfer (LET) charged particle radiotherapy facilities. These have the advantage of a superior dose distribution, due to the Bragg peak effect, when compared with conventional X-ray based radiotherapy of equal complexity in terms of field arrangements and treatment planning sophistication. This paper concentrates on the subtle effects caused by relative biological efficiency or effect (RBE) that can occur in the context of high LET therapy. Higher RBE values than those associated with protons are found with light ions, which also have the potential advantage of a reduced oxygen enhancement ratio. Clinicians should remember that although neutrons are high LET particles, they are uncharged and do not possess the dose localizing advantages of a Bragg peak. Radioresistance, from whatever cause, will be opposed by an increase in tumour dose. The sigmoidal shapes of radiation dose–response curves show that increasing the total dose will produce an enhanced tumour cure probability (TCP), but with diminishing returns at the very highest doses [1]. If the normal tissue receives the same dose as the tumour then normal tissue complications (NTCPs) also escalate. However, if tumour dose can be increased whilst normal tissue doses are simultaneously reduced we effectively follow the normal tissue curve downwards and to the left, and beneficially increase the cure:complication ratio. The ratio of cure:complication is a measure of the therapeutic ratio associated with a given treatment. The advantage of proton therapy stems from the extra tumour dose that can be delivered in association with a reduced dose to normal tissues [2]. Newer forms of X-ray therapy [e.g., intensity-modulated radiation therapy (IMRT) or X-ray IMRT (IMXT)] may also facilitate a similar degree of dose escalation, but proton dose distributions are usually better due to the absence of any dose beyond the Bragg peak. Proton IMRT techniques may also be used to further improve the dose Author for correspondence: Dr Jones Department of Clinical Oncology, Imperial College School of Medicine, Hammersmith Hospital, London W12 OHS, U.K. Tel: 0208-383-3059; Fax: 0208383-3054; E-mail: [email protected] 0936–6555/03/010S16+07 $30.00/0
Accepted: 16 October 2002
distribution. Such progressive dose reduction in normal tissues should produce benefits to patients in terms of reduced low-grade, radiation-related morbidity, e.g., specific organ dysfunction related to stem cell depletion, reduced vascular function, fibrosis and a reduction in stochastic effects such as second malignancies. Both short- and long-term quality of life is expected to be superior in proton-irradiated patients than after X-ray therapy, although this difference needs to be measured in comparative studies. High LET Particle Radiobiology
Charged particle beams have a higher LET and thus deposit more energy per unit length of beam than megavoltage X-rays [3]. The additional biological effect is quantified in terms of RBE, the ratio of the iso-effect dose for a high-LET radiation to that required with low-LET cobalt gamma rays or orthovoltage X-rays. RBE increases with LET until the phenomenon of overkill occurs. LET and RBE values vary along the path of a proton beam [2,3]. They are initially low and increase to the highest value at the terminal part of the Bragg peak. Modulation of the peak should effectively spread out the region over which the higher RBE is operative, and this is confirmed experimentally, but highest values of RBE are predicted and continue to be found at the end or beyond the plateau region [4,5]. Higher proton energies have a lower average LET and therefore a lower ‘average’ RBE than lower proton energies [3,4]. Thus 60 MV protons will have a higher RBE than 200 MV protons. From a theoretical perspective, RBE is expected to increase with decreasing dose per fraction. This fractionation effect is due to more repair of sub-lethal DNA damage at small doses per fractions with the low-LET reference radiation than with higher LET test radiation [3]. The standard definition for RBE is the ratio of doses for each radiation type at an experimental surviving fraction of 0.1 [3,4]. This is a restrictive definition and probably inappropriate for use over a wide range of dose per fraction, particularly if the RBE is greater than 1.1. The maximum RBE (RBEmax) is defined as the ratio of the initial slopes of the low- and high-LET cell survival
2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved.
Table 1 – Estimates of sample size (n) in each treatment arm to show various outcome differences for a significance level of 5% (0.05) for two study powers Percentage differences in outcomes Power of study 80% 90%
5%
10%
25%
n=1100 n=1200
n=420 n=600
n=60 n=90
S17
are generally larger but equal for late and early normal tissue effects in skin. Significantly higher neutron RBEs in the central nervous system (CNS) are probably caused by enhanced neutron dose due to the increase in hydrogen density of myelin-rich tissue. Such effects are not expected to be significant in proton therapy, where electron density is the main cause of absorption as in the case of X-rays. Inclusion of RBE with the biological effective dose (BED) Concept
Modified from Bentzen [12].
curves: this can be interpreted as the ratio of the radiosensitivity values of the low and high LET radiations. In proton radiotherapy, generic values of proton RBE (usually 1.1) are used to convert absorbed dose in Grays to cobalt Gray equivalent: the X-ray dose is divided by 1.1 to give the equivalent proton dose, regardless of the dose per fraction used. Estimations of proton RBE have been reported in the literature. At Boston, one late reacting tissue and a wide range of acute responding tissues were studied and a relatively uniform RBE of 1.1 was found by Urano et al. [6]. More recently, Paganetti et al. [7], using an intestinal crypt assay, found RBEs of 1.1–1.2 and the variation with depth was found to be larger for lower proton energies. Some interesting inter-relationships have been tested: (1) Monte Carlo techniques suggests that RBE is independent from the tissue / ratio [8]. (2) Lung radiation experiments in mice show that the late reaction RBE is no different from acute reactions although RBE appears to vary with the time period following exposure [9]. (3) Neutron studies provide supporting evidence that values increase in the same ratio for both early and late tissues [10]. More recently, the Boston group [11] have collected the data on in vitro and in vivo experiments and found a less marked inverse relationship between dose per fraction and RBE for doses that range as low as 1.1 Gy per fraction in a variety of tissues. Because of biological variation, it is probably unrealistic to expect that studies of this type will estimate RBE accurately enough to distinguish a 2–5% change in RBE, such as between 1.1 and a 5% increase 1.11.05=1.155. For statistical precision, very large numbers of syngeneic animals would be required, probably between 500 and 1000 per point estimate of the RBE. For clinical trials, because of heterogeneity, the numbers of patients given in Table 1 are required to confirm differences in outcomes. There is a further concern in that there are no reported in vivo data where tumour control and a normal tissue iso-effect are studied simultaneously after proton therapy, that is a true therapeutic ratio (TR) has not been studied. The RBE values are small for the dose schedules used in proton radiotherapy. For neutrons, the RBE values
The BED concept is increasingly useful in clinical radiobiology [13]. RBE effects can be included within BED equations [14,15]. RBEMax is the ratio of the non-repairable () radiosensitivity parameters
at near zero dose, where the
subscripts H and L refer to high and low LET radiations respectively. Consequently, H =L · RBEMax
(1)
It is assumed that the radiosensitivity parameter is relatively unchanged by LET, i.e.H =L. Within the LQ model, radiation effect (E) can be expressed as E=n(d+d2) where n is the number of fractions of dose d such that D, the total dose will equal nd. The BED for low LET radiation (BEDL) may be written as:
The BED for high LET (BEDH) radiation will be obtained by dividing E instead by H and multiplying throughout by RBEM so that,
where (/)L is the late normal tissue fractionation sensitivity for megavoltage photons: the same as that utilized in more common (low-LET) applications of the model. The inclusion of RBEMax ensures that the high LET BED is expressed in the same biological units as the low-LET value. Low-LET / ratios, which are increasingly known for a variety of tissues and tumours, can then be used to derive high-LET BEDs. The RBEMax dominates the bracketed portion of the equation when dose per fraction is low but becomes less important when dose per fraction is high. The low LET / ratio influences the balance between the RBE effect and the dose per fraction effect. Equation 3 also allows estimation of the RBEmax from existing in vivo data for which the low-LET / ratio is known. Results Use of Simple BED Calculations in Proton Therapy
Until now, generic RBE values, such as 1.1, have been used to modify the proton dose. Subsequent estimation
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of BED will use a modified dose per fraction parameter, which will introduce errors mostly in the quadratic term. Alternatively, a more accurate method would be to use the modified BED equations with RBEmax. Simple BED-RBEmax calculations are presented for cases where the protons are initially assumed not to posses normal tissue sparing properties. If we assume that the low-LET normal tissue tolerance is 60 Gy in 30 fractions then (from Equation 4) BED=100 Gy3. Similarly, the tumour BED is determined as being 72 Gy10. This value is to be compared with the calculation results presented below. Using Equation 6, it is found that, for protons with RBEmax of 1.4 (as found for the Clatterbridge 60 MeV proton beam), only 242 Gy fractions are required to obtain the same normal tissue effect for /=3Gy. The associated tumour BED, for /=10Gy, is then found to be 76.8 Gy: 100=2n(1.4+2/3) n=24, proton BEDtum =48(1.4+2/10) =76.8 Gy10 This is larger than the BED of 72 Gy10 for X-rays. A further increase in tumour BED is found on calculating a new smaller proton dose per fraction. The tumour proton BED is 80.7 Gy (c.f. 72 Gy10 for the X-rays at 2 Gy per fraction). The predicted tumour kill is enhanced for protons and the therapeutic ratio (TR) is improved as follows: 100=30d(1.4+d/3) d=1.7 Gy proton BEDtum =301.7(1.4+1.7/10) =80.7 Gy10. Should the RBEmax increase, for example to 1.7 for late effects, a smaller tumour BED is found compared with X-rays, regardless of whether a new dose per fraction is used, or if the number of fractions remains the same. Then we have 100=2n(1.7+2/3) n=21, proton BEDtum =212(1.4+2/10) proton BEDtum =67.2 Gy10 This result is less than 72 Gy10, indicating a decreased TR. For a fixed number of 30 fractions and changing dose per fraction and total dose, we have 100=30d(1.7+d/3) d=1.5 Gy proton BEDtum =301.5(1.4+1.5/10) proton BEDtum =69.75 Gy10 The predicted tumour BED is smaller for protons if the / ratio for the late effect exceeds that of the acute effect. A reduction in the TR is then predicted. These differences in BED will be much smaller for higher energy protons (where RBEmax is smaller), but will be generally improved when we include a specific dose reduction for normal tissues. For example, if the
normal tissue dose is 65% for protons and 75% for X-rays relative to 100% at tumour, for a normal tissue iso-effect we obtain for 1.65 Gy per fraction in the normal tissue 100=n1.65 (1+1.1.65/3) n=39 The tumour BED for X-rays will be 391.651/ 0.8(1+1.65/(0.810))=97 Gy10. This is significantly greater than the original value of 72 Gy10. For protons with RBEmax of 1.2 and for the same dose per fraction, we have 100=n1.65(1.2+1.65/3) and n=34.6 The proton tumour BED will then be =100.4 Gy10. This value is substantially greater than the original 72 Gy10 and also far exceeds that for the X-rays. The TR is likely to further improve. Some recent conclusions of further modelling are as follows: (1) If tumour />late normal tissue /, i.e. the majority of clinical situations, improved outcomes are predicted providing dose per fraction is kept below critical values which may be calculated. If the late-responding tissues have a higher RBEmax there is a more severe upper constraint on the dose per fraction that may be used. (2) If tumour /
Graphical Methods Optimum dose per fraction
The optimum dose per fraction, which provides the maximum tumour cell kill for the same degree of normal tissue effect, can be estimated [15–17]. The effects of normal tissue sparing, which can accrue from the beam geometry, can also be crudely incorporated. This is achieved through use of a fractional sparing parameter (g) such that if the modal tumour dose is 100% and the normal tissue critical volume modal dose is 75% then g is 0.75. The BED formulations given above are used with an RBEmax of 1.4 in these examples. The method does not use the generic RBE values, which if used do not produce the same gains in TR. Initially, if no geometric advantage is assumed (normal tissue dose=tumour dose; g =1) and there is a uniform normal tissue RBEmax in normal tissue and tumour. The values of K refer to the daily dose equivalent of tumour cell repopulation in units of Gy10/day. A value of 0.3 Gy10 per day is used to represent relatively
Fig. 1 – Plot of tumour BED (Gy10) for the same normal tissue iso-effect as 50 Gy in 25 fractions at increasing dose per fraction for X-rays and protons with an RBEmax of 1.4. Here, g=1, which signifies no normal tissue sparing.
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Fig. 3 – Plot of tumour BED (Gy10) for the same normal tissue iso-effect as 50 Gy in 25 fractions at increasing dose per fraction for X-rays and protons with an RBEmax of 1.4. Here, g=0.7, which signifies 70% sparing of dose for protons and 0.8, which signifies 80% sparing for X-rays.
BED is increased from 10 Gy10 to be 23 Gy10. These differences will be smaller for higher energy protons, but will still depend on the RBEmax and the geometrical sparing achieved. RBEmax values
Fig. 2 – Plot of tumour BED (Gy10) for the same normal tissue iso-effect as 50 Gy in 25 fractions at increasing dose per fraction for X-rays and protons with an RBEmax of 1.4. Here, g=0.75, which signifies 75% sparing of dose for protons but sparing for X-rays.
slow tumour repopulation and the normal tissue isoeffect is taken to be 50 Gy in 25 fractions for X-rays, as would be appropriate for the brainstem. The turnover points in Figs 1–3 represent the optimum dose per fraction for each modality and the tumour kill is uniformly better with protons when the same absolute dose per fraction is used for each class of radiation. The difference in BED due to the RBE is over 10 Gy10 at 1 Gy per fraction and around 8 Gy10 at the turnover points, with decreasing differences at higher doses per fraction. When the normal tissue sparing improves (g=0.75) for both modalities the tumour BED increases and the differences between the radiation types are similar to the first case. The increment of tumour
Fig. 4 contains plots of the RBE variation with dose per fraction for three different RBEmax values, 1.4, 1.2 and 1.15. It can be seen that for the cases where RBEmax =1.15–1.2, as would be expected for relatively high-energy protons, say greater than 150 MeV, it would be very difficult to detect such small changes from biological experiments. For example, a value different from a ‘rounded’ 1.1 in the range of fractionation between 1–3 Gy would be unlikely if the biological system used can only provide a 10% level of accuracy. A further example of the difficulty inherent in the assessment of marginal changes in RBE at low doses per fraction is shown in Fig. 5. This shows the relatively wide 95% confidence limits for RBE in a group of 250 individuals (with a mean / of 3 Gy (with standard deviation=0.3 Gy), for a mean RBEmax of 1.2 (standard deviate=0.025). Investigation of the variable / ratios and the resultant RBEs (see Fig. 6), using the BED-Rmax equations given above, provides interesting results. The change in RBE with dose per fraction depends on the tissue or tumour / ratio, with lower ratios for late-reacting tissues having the lower RBEs, although there is a common RBEmax. This suggests that RBE values should differ between tissue and tumour types, while RBEmax remains constant for a particular proton beam. RBE values are predicted to be lower for tissues with small / ratios.
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Fig. 4 – The predicted relationship between dose per fraction and RBE for three different values of RBEmax (1.15, 1.2 and 1.4).
Fig. 5 – Plot of mean RBE (bold line), with 95% confidence limits (feint lines), against dose per fraction for 250 individuals.
Differential normal tissue sparing ratios
The extent of the tumour BED improvement ratio can be impressive but in practical situations the g values will not be extreme and more modest differences will occur. Fig. 7 shows the tumour BED improvement ratio for protons versus X-rays (proton sparing=g1, proton sparing=g2). The ratio of g1/g2 will exceed unity when the proton sparing is superior. It can be seen that when tissue sparing is extremely good, and is equally good for protons and X-rays (g1/g2=1), there is no advantage – a slight detriment is actually seen because of the extreme hypofractionation. However, at most practical values of tissue sparing and where there is a slight advantage for protons, then the potential benefits appear to be considerable. It should be remembered in this context
Fig. 6 – Predicted relationship between RBE and dose per fraction for different / ratios of cells or tissues.
Fig. 7 – Plot of predicted tumour BED ratios for protons and X-rays against the g1 parameter, the treatment being limited by the constraints of a g1 parameter for protons and a g2 parameter for X-rays. A larger tumour BED ratio indicates improved outcomes for protons.
that tumour BED increments of say 20 Gy10 may result in a 20–40% increase in tumour control, depending on the gradients of the dose–response curves and the tumour control probability expected from the X-ray treatment. Correspondingly, should it be possible to deliver the same tumour BED by X-rays or protons, then the normal tissue effects would be reduced for the proton therapy. Implications for high LET radiotherapy
Inclusion of RBEmax values within standard BED equations allows more refinement of high-LET isoeffective calculations, and puts them on an equal footing with
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those for X-ray therapy. The RBEmax represents a ‘latent’ RBE factor that manifests itself subtly as dose per fraction is varied and should be protective with respect to the normal tissues providing that iso-effect calculations are adhered to. For proton beams, the changes in overall RBE may not be large and will therefore be extremely difficult to identify in clinical studies or animal experiments. However, small changes in the RBE of say 2–4% would have significant clinical impact on normal tissues, particularly as their dose– response curves have steeper slopes. If treatment is planned with a constraint in terms of normal tissue dose, as in the optic nerve and brainstem for chordoma treatments, the use of a slightly incorrect generic RBE could produce a significant clinical error. For example, to equate a dose of 55 Gy in 30 fractions, we have
Conclusions
NT BED=55 (1+1.83/2)=105.3 Gy2
+ Appropriate tumour types may be identified for proton therapy from the known low LET parameters that are increasingly available from clinical data sets. + The RBEmax estimates and estimates of improvement based on BEDs will be smaller for higher proton energies. + Modelling may identify areas where more basic research can provide further specific information to identify optimal use of protons, that is safer treatments and substantial potential gains for the selective use of protons. + More studies are required of & values for X-rays and protons in log and plateau growth phases to determine if RBEmax changes with cell cycle time. + More in vivo experiments could test if changes in RBEmax occurs by use of BED equations in tissues where / parameter is known.
For protons using RBE=1.1, we would divide the dose per fraction by 1.1 to give 1.83/1.1=1.66 Gy protons. Now if we use 1.66 Gy per fraction protons and the RBE is actually 1.125, we would obtain (using the standard BED equations without RBEmax: BED=1.66301.125 (1+1.1251.66/2) =108.34 Gy2. This represents a 108/105=nearly 3% increase in the NT BED, which could result in a larger NTCP (normal tissue complication probability) of say 3–10%. Alternatively, the RBEmax BED method could be used. This would be as follows: 105.325=n d (RBEmax +d/(/)) where for the same number of fractions (30), we obtain, for RBEmax =1.2, 105.33=30 d (1.2+d/2) d=1.71 Gy For this dose per fraction we obtain BED=301.71 (1.2+1.71/2)=105.4 Gy2. This result is the same as that for the X-ray BED. This example is a single illustration that the BED-RBEmax method ‘falls safe’ with respect to normal tissue tolerance when compared with the generic RBE method. The use of the RBEmax effectively provides a sliding scale of RBE, which is protective on normal tissues when compared to the generic RBE methodology. RBEmax can itself be derived from in vivo isoeffect data where the low-LET / is known. This will be given by:
or
This exploratory paper has presented a prospectus for further fundamental research with important clinical applications. The modelling predictions are testable within scientific experiments and in developmental clinical trials. The recent recommendations from Boston that the generic RBE method should be preserved is very practical but does miss an opportunity to further improve the results of proton therapy, which has an associated morbidity [18–20]. The future work necessary can be summarized as follows:
Radiobiology
Clinical
+ Future clinical objectives should recognize the potential of modern radiobiological models and seek to integrate these with the treatment planning process. There is no justification for continued use of oversimplistic concepts such as co-equivalent Grays. + Studies of volume effects and changes in RBE as Bragg peak is modulated; translation to equivalent uniform dose (EUD), as defined by Niemierko in Boston [21]. By means of BED dose volume histograms, as advocated by Wheldon et al. in the U.K. [22], EUD may be converted to equivalent uniform BED (EUBED). + Comparisons of the best available X-ray IMRT and proton plans in terms of the physical and likely BED. + Optimize dose per fraction for photon and proton therapies based on the likely tumour radiobiological parameters as obtained from clinical data sets. In these ways scientific principles can be used to decide which tumour type and anatomical sites that are best treated by protons. The further investigation of RBE effects could also have important conclusions in other areas of radiotherapy, e.g. iodine and palladium
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seed implants in prostate cancer etc. The use of optimization techniques for protons in parallel with conventional X-ray therapy may also yield significant benefits. References 1 Fowler JF. What can we expect from dose escalation using proton beams? Clin Oncol 2003;15:S10–S15. 2 Suit H, Urie M. Proton beams in radiation therapy. J Nat Cancer Institute 1992;84:155–164. 3 Hall E. Alternative Radiation Modalities. In Radiobiology for the Radiologist, 5th Edn. Philadelphia: Lippincott, Williams & Wilkins, 2000;432 – 445. 4 Gerweck LE, Kosin SV. Relative biological effectiveness of proton beams in clinical therapy. Radiother Oncol 1999;50:135–142. 5 Paganetti H, Goitein M. Radiobiological significance of beam-line dependent proton energy distribution in a spread out Bragg peak. Med Phys 2000;27:1119–1126. 6 Urano M, Verhey LJ, Goitein M, et al. Relative biological effectiveness of modulated proton beams in various murine tissues. Int J Radiat Oncol Biol Phys 1984;10:509–514. 7 Paganetti H, Olko P, Kobus H, et al. Calculation of relative biological effectiveness for proton beams using biological weighting functions. Int J Radiat Oncol Biol Phys 1997;37:719–729. 8 Paganetti H, Gerweck LE, Goitein M. The general relation between tissue response to x-irradiation (alpha/beta-values) and the relative biological effectiveness (RBE) of protons: prediction by the K track-structure model. Int J Radiat Biol 2000;76:985–998. 9 Guellette J, Bohm L, Slabbert JP, et al. Proton relative biological effectiveness (RBE) for survival in mice after thoracic irradiation with fractionated doses. Int J Rad Oncol Biol Phys 2000;47:1051– 1058. 10 Joiner MC, Bremner JC, Denekamp J, Maughan RL. The interaction between X-rays and 3 MeV neutrons in the skin of the mouse foot. Int J Radiat Biol 1984;46:625–638.
11 Paganetti H, Niemierko A, Ancukiewicz M, et al. Relative biological effectiveness (RBE) values for proton beam therapy. Int J Radiat Oncol Biol Phys 2002;53:407–421. 12 Bentzen S. Towards evidence based radiation oncology: improving the design, analysis, and reporting of clinical outcome studies in radiotherapy. Radiother Oncol 1998;46:5–18. 13 Jones B, Dale RG, Deehan C, Hopkins KI, Morgan DAL. The role of biologically effective dose (BED) in Clinical Oncology. Clin Oncol 2001;13:71–81. 14 Dale RG, Jones B. The assessment of RBE effects using the concept of biologically effective dose. Int J Radiat Oncol Biol Phys 1999;43:639–645. 15 Jones B, Dale RG. Estimation of optimum dose per fraction for high LET radiations: implications for proton radiotherapy. Int J Radiat Oncol Biol Phys 2000;48:1549–1557. 16 Jones B, Tan LT, Dale RG. Derivation of the optimum dose per fraction from the Linear Quadratic model. Br J Radiol 1995;68: 894–902. 17 Jones B, Dale RG. Radiobiologically based assessments of the net costs of fractionated focal radiotherapy. Int J Radiat Oncol Biol Phys 1998;41:1139–1148. 18 Urie MM, Fullerton B, Tatsuzaki H et al. A dose–response analysis of injury to cranial nerves and/or nuclei following proton beam radiation therapy. Int J Radiat Oncol Biol Phys 1992;23:27– 39. 19 Santoni R, Liebsch N, Finkelstein DM, et al. Temporal lobe (TL) damage following surgery and high-dose photon and proton irradiation in 96 patients affected by chordomas and chondrosarcomas of the base of the skull. Int J Radiat Oncol Biol Phys 1998;41:59–68. 20 Jones B, Errington RD. Commentary: proton beam therapy. Br J Radiol 2000;73:802–805. 21 Niemierko A. Reporting and analysing dose distributions: a concept of equivalent uniform dose. Med Phys 1997;24:103–110. 22 Wheldon TE, Deehan C, Wheldon EG, Barrett A. The linear quadratic transformation of dose volume histograms in fractionated radiotherapy. Radiother Oncol 1998;46:285–295.