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First published online November 26, 2007
British Journal of Radiology (2008) 81, 59-68
© 2008 British Institute of Radiology
doi: 10.1259/bjr/59827901
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Full paper

Designing equivalent treatment regimens for prostate radiotherapy based on equivalent uniform dose

X A Li, PhD1, J Z Wang, PhD2, R D Stewart, PhD3, S J Dibiase, MD4, D Wang, MD1 and C A Lawton, MD1

1 Department of Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, 2 Department of Radiation Medicine, Ohio State University, Columbus, OH 43210, 3 School of Health Sciences, Purdue University, West Lafayette, IN 47907-1338, 4 Department of Radiation Oncology, Cooper Health System, One Cooper Plaza, Camden, NJ 08103, USA

Correspondence: Prof X A Li, Department of Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. E-mail: ali{at}radonc.mcw.edu


   Abstract
Top
 Abstract
Introduction
 Methods and materials
 Results
 Discussion and conclusions
 References
 
The purpose of this work was to determine alternative radiotherapy (RT) regimens that are biologically equivalent to clinically proven treatments using different RT modalities or different fractionation schemes. The concept of equivalent uniform dose (EUD) is used with the linear quadratic model to determine equivalent treatment regimens using two representative sets of parameters derived from clinical data: (i) {alpha}/β = 3.1 Gy and {alpha} = 0.15 Gy–1, and (ii) {alpha}/β = 1.5 Gy and {alpha} = 0.04 Gy–1. The EUD values for the critical structure (rectum) are also calculated. Representative dose volume histograms were used to account for dose inhomogeneities for different RT modalities. A series of alternative and equivalent fractionation regimens that can be used with different radiotherapy modalities for localized prostate cancer were determined. For example, the alternative regimens, calculated with the {alpha}/β ratio of 3.1 Gy, that would be biologically equivalent to external beam RT (EBRT) of 76 Gy (38x2.0 Gy) include: EBRT hypofractionation of 21x3.0 Gy; I-125 implant of 156 Gy; Pd-103 implant of 128 Gy; high dose rate (HDR) brachytherapy of 4x10.5 Gy; I-125 implant of 65 Gy combined with EBRT of 23x2.0 Gy; and HDR brachytherapy of 3x5.9 Gy combined with EBRT of 23x2.0 Gy. Similar data for other parameters are also presented. With caution, the data presented may be useful in designing clinical trials to explore new RT strategies, such as image-guided intensity-modulated RT.


   Introduction
Top
 Abstract
 Introduction
Methods and materials
 Results
 Discussion and conclusions
 References
 
Various radiotherapy (RT) modalities, such as external beam radiotherapy (EBRT) (e.g. conventional EBRT, three-dimensional conformal RT (3DCRT) and intensity-modulated RT (IMRT)), low dose rate permanent implant and high dose rate (HDR) brachytherapy, are being used for the radiotherapeutic management of localized prostate cancer. These modalities are used either alone (monotherapy) or in combination. Despite recent advances in treatment planning technology that aim to target tumour and spare normal tissues, the appropriate choice of RT modality, the dose prescription for that modality, and the planning and reporting of different treatment plans appear to be somewhat arbitrary. It is unlikely that these issues will be resolved until further results from current clinical trials are available and additional trials are initiated. Recently, investigators have shown the importance of dose escalation using EBRT, either alone or combined with HDR brachytherapy. For example, Hanks et al [1] reported on a series of 375 patients treated with 3DCRT and noted a dose response with freedom from biochemical failure (FFBF) at 2 years of 72% at doses less than 71 Gy, compared with 85% for patients receiving doses ≥71 Gy. Recent studies by these investigators confirmed that favourable results with dose escalation remain in the long term [2, 3]. The benefit of higher doses may be particularly evident in patients with high-risk disease. In a randomized trial that compared 70 Gy and 78 Gy of EBRT [4], the higher dose was associated with a significant improvement in the 5-year FFBF in men with pre-treatment prostate-specific antigen (PSA) >10 ng ml–1 (75% vs 48%) but not in men with a pre-treatment PSA <10 ng ml–1. Zelefsky et al [5] demonstrated that patients receiving doses ≥75.6 Gy had a 93% chance of achieving a nadir PSA value of ≤1 ng ml–1 in 2 years, compared with 80% for those receiving lower doses. In a more recent study, Zelefsky et al [6] confirmed that 90% of patients receiving 75.6 Gy or 81.0 Gy achieved a PSA nadir of 1.0 ng ml–1 compared with 76% and 56% for those treated with 70.2 Gy and 64.8 Gy, respectively. They reported that the 5-year actuarial FFBF was significantly improved in patients with intermediate and unfavourable prognosis who received a dose ≥75.6 Gy [6]. As for EBRT combined with HDR brachytherapy, Martinez et al [7, 8] conducted a dose escalation clinical trial for unfavourable prostate cancer treated with two schemes: a low dose scheme (46 Gy of EBRT and 15–19.5 Gy of HDR delivered in three fractions) and high dose scheme (46 Gy of EBRT and 16.5–23.0 Gy of HDR delivered in two fractions). They observed that the 5-year biochemical control rate was 52% and 87% for the low and high dose groups, respectively. With the recent emergence of image-guided 3DCRT and IMRT, studies on dose escalation for localized prostate cancer are active and ongoing [9, 10]. Such studies, however, do not exist for other RT modalities that are currently used as either monotherapy or combined therapy. Intuitively, it is desirable to determine alternative regimens that are equivalent to these clinically proven treatments using different RT modalities, as different modalities offer different social and economical advantages and disadvantages.

Recently, it has been postulated that the {alpha}/β ratio for prostate cancer may be much lower (1.2–3.8 Gy) than 10 Gy, the value normally assumed for tumour [11–18]. Brenner et al [11, 12] and Fowler et al [13] derived an {alpha}/β ratio of 1.5 Gy from the compiled clinical data. Unfortunately, such an {alpha}/β ratio was linked with an extremely low radiosentivity ({alpha}{approx}0.04 Gy–1) and extremely low clonogen numbers (in the order of 10–100). Taking into account the effect of tumour proliferation, Wang et al [15, 16] analysed several clinical data sets, and reported an {alpha}/β ratio of 3.1 Gy, with the number of clonogens estimated to be 106–107 depending on the risk level of prostate patient groups. Nahum et al [19] and Valdagni et al [20] contested the low {alpha}/β values, having incorporated the heterogeneity of radiosensitivity and the tumour hypoxia effect into their data analysis. However, their data modelling was based on model parameters obtained from in vitro measurements. Carlone et al [21] have also included tumour heterogeneity of radiosensitivity in modelling prostate cancer, and studied its impact on the estimated {alpha}/β ratio. They pointed out that, owing to the large uncertainty existing in current clinical data, one could not give an {alpha}/β ratio estimate using the heterogeneous model with any statistical significance.

If the {alpha}/β ratio for prostate cancer is really lower than that for the rectum, hypofractionation treatments would be preferable for better tumour control [22, 23]. Indeed, Kupelian et al [24] recently reported a favourable long-term outcome when using hypofractionation dose escalation for localized prostate cancer. In another independent randomized trial, Pollack et al [25] reported that the acute toxicity was acceptable with a hypofractionation dose escalation. When considering the availability of technology, patient convenience and treatment cost, the choice of hypofractionation regimen can vary extensively. Methodology for calculating equivalent regimens will be helpful in the design of clinical trials that aim to test a new hypofractionation regimen.

The purpose of this work was to calculate alternative RT regimens that would be equivalent, in terms of tumour control, to a clinically proven treatment using a different RT modality or different fractionation scheme. The implications of these alternative regimens on the critical structure (e.g. rectum) are also estimated. Calculations are based on radiobiological models using the concept of equivalent uniform dose (EUD) to take into account dose inhomogeneity. The dependence on model parameters is studied to take into consideration the controversy over the {alpha}/β ratio. Caution needs to be exercised in using these model-dependent data for clinical decision-making purposes.


   Methods and materials
Top
 Abstract
 Introduction
 Methods and materials
Results
 Discussion and conclusions
 References
 
The concept of EUD is used as a measure of the biological effectiveness of a RT regimen. The EUD is defined as the biologically equivalent dose that, if given uniformly, would lead to the same biological effect as the actual non-uniform dose distribution [26]. EUD is a convenient quantity to compare EBRT with brachytherapy [26–28]. In this work, EUDs for both the target (prostate) and the critical structure (rectum) are calculated.

Calculations for the prostate
The EUD for prostate cancer was calculated using the linear-quadratic (LQ) formalism extended to consider EBRT, and HDR and permanent brachytherapy [29–31]. The LQ formulae to describe these single or combined modalities are presented in detail in a previous work [27].

To account for dose heterogeneity in both EBRT and brachytherapy, the survival fraction (S) was calculated based on the dose–volume histogram (DVH) using the equation:



Formula 001

where V0 is the tumour volume, and Vi is the sub-volume corresponding to dose bin Di in the DVH. The representative prostate DVHs for EBRT (3DCRT) and brachytherapy, shown in Figure 1Go and based on CT, were used to identify equivalent treatment regimens. Equation (1) implicitly assumes that the density of tumour clonogens and spatial radiosensitivity are uniformly distributed throughout the tumour.


Figure 1
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  		Figure 1. Representative dose–volume histograms of prostate and rectum for external beam radiotherapy (EBRT) and brachythrerapy (BT).

 
The numerical value of the EUD is relative to the value delivered by a standard reference regimen. In this study, EBRT in 2 Gy fractions is selected as the standard reference regimen. As described by Wang and Li [27], the EUD that results in the surviving fraction S can be calculated by:


Formula 002

where {alpha} and β characterize intrinsic radiosensitivity, {gamma} is the effective tumour cell repopulation rate ({gamma} = ln(2)/Td; Td is the tumour cell doubling time) and d is the dose per fraction. All of the reported EUD values in this paper correspond to a daily dose fraction of 2.0 Gy delivered in 5 min to mimic a conventional EBRT.

For the regimen of interest, we first calculated the surviving fraction S using the LQ formalism presented previously [27] and the DVHs (Equation (1)) described above. Subsequently, we obtained the EUD based on Equation (2). Two regimens were considered biologically equivalent if they gave the same EUD.

Two representative sets of the LQ parameters were used in the calculations:

1. {alpha}/β = 1.5 Gy, {alpha} = 0.04 Gy–1, repair half time Tr = 114 min and Td = {infty}, as reported by Brenner and Hall [11], Brenner et al [12] and Fowler et al [13].

2. {alpha}/β = 3.1 Gy, {alpha} = 0.15 Gy–1, Tr = 16 min and Td = 42 days, as reported by Wang et al [15, 16].

The 68% confidence intervals (CIs) derived by Wang et al [15, 16] (e.g. {alpha}: ±0.04 Gy–1, {alpha}/β: ±0.5 Gy and Tr: 5–90 min) were used to estimate the ranges of dose prescriptions for equivalent monotherapy regimens. These CIs were treated independently in the calculation; note that the half time for repair reported by Wang et al [15, 16] is very short (16 min). Because of the existing controversy regarding low {alpha}/β ratios, selected calculations were also performed for the LQ parameters usually suggested for tumour, i.e. {alpha}/β = 10 Gy, {alpha} = 0.3 Gy–1, Tr = 60 min and Td = 42 days.

It is debatable whether it is necessary to consider a lag time Tk (the delay in the onset of tumour repopulation) following the start of RT for prostate cancer [32, 33]. To examine the effect of lag time, we performed selected calculations with Tk = 25 days, the value suggested previously [34]. Unless otherwise specified, the lag time was ignored.

Calculations for the rectum
The rectum is normally the dose-limiting structure for prostate radiotherapy. In this work, rectal EUDs for different regimens were calculated. We define the EUD for the rectum as the biologically equivalent dose that, if given uniformly, will lead to the same normal tissue complication probability (NTCP) as the actual non-uniform dose distribution. The Lyman-Kutcher-Burman model [35, 36] was used to calculate NTCP. For a non-uniform dose distribution, the method of effective volume (Veff) was used [36] as follows:


Formula 003

where V0 is the total volume irradiated and Dmax is the maximum dose in the rectum.

As described previously [28], the rectal EUD can be given by


Formula 004

The calculation of EUD for the rectum involves only one adjustable parameter, denoted by n. It has been reported that the n value for the rectum is 0.12 [37]. A value of n = 0.12 was used for all the data reported in this work.

Non-uniform dose distribution for the rectum was considered by using the representative DVHs for EBRT and brachytherapy, as shown in Figure 1Go. The rectal volume in these DVHs included all rectal contents. During the calculation, we first convert the physical dose D'i in each dose bin of the DVH to the equivalent dose in 2 Gy fractions, Di, by using the formulism derived from the LQ model:


Formula 005

where G is the dose protraction parameters described in detail in previous publications [24, 25]. Then, for a given regimen, we obtained the EUD value as expressed in 2 Gy daily fractions using Equation (4). The following LQ parameters were suggested by Brenner et al [38, 39] for the rectum and they were used in the present calculation: {alpha}/β = 5.4 Gy; Tr = 70 min.


   Results
Top
 Abstract
 Introduction
 Methods and materials
 Results
Discussion and conclusions
 References
 
Equivalent regimens for the prostate
Single radiotherapy modality
The required prescribed doses along with the confidence intervals for a series of desired prostate EUD values are listed in GoGoTables 1, 2 and 3Go for EBRT, permanent brachytherapy and HDR brachytherapy used as monotherapy for prostate cancer, respectively. Results from using two sets of LQ parameters — (1) {alpha}/β = 3.1±0.5 Gy, {alpha} = 0.15±0.04 Gy–1, Tr = 16 min (CI: 5–90 min) and Td = 42 days, and (2) {alpha}/β = 1.5 Gy, {alpha} = 0.04 Gy–1, Tr = 114 min, and Td = {infty} — are tabulated. In Table 1Go, the data for the LQ parameters {alpha}/β = 10 Gy, {alpha} = 0.3 Gy–1, Tr = 60 min and Td = 42 days are also included. All EUD values are expressed as the dose of EBRT in 2 Gy daily fractions.


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  		Table 1. Hypofractionation regimens for external beam radiotherapya.

 

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  		Table 2. Permanent implant as monotherapya

 

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  		Table 3. High dose rate brachytherapy as monotherapya

 
In Table 1Go, the total dose and the number of fractions for different fraction sizes of 2.5 Gy, 3 Gy, 4 Gy and 5 Gy, which yield an EUD of 62 Gy, 68 Gy, 72 Gy, 76 Gy, 82 Gy, 86 Gy or 90 Gy, are tabulated. Only data with treatment durations of longer than 3 weeks are presented. It is seen from Table 1Go that, by comparing the calculations with the two low {alpha}/β ratios ({alpha}/β = 3.1 Gy vs 1.5 Gy), the required prescribed doses for a given EUD differ by approximately 3%, 6%, 10% and 15% for fraction sizes of 2.5 Gy, 3 Gy, 4 Gy and 5.0 Gy, respectively. These differences increase considerably when comparing the calculations with {alpha}/β = 10 Gy vs 1.5 Gy. The calculation with Tk = 25 days indicated that the effect of the lag time was small. For the fractionation schemes presented in Table 1Go, all of the values calculated with and without the consideration of the lag time were consistent to within 2%.

Table 2Go lists the required prescribed doses (the minimum peripheral doses), which are equivalent to a series of EUDs, for I-125 and Pd-103 permanent implants as monotherapy. The required prescribed doses and the fraction sizes for HDR as monotherapy that are equivalent to an EUD of 62 Gy, 68 Gy, 72 Gy, 76 Gy, 82 Gy, 86 Gy or 90 Gy are given in Table 3Go. Data for two, three, four, five and six fractions are included in the table.

Combined modality
EBRT combined with either a permanent implant or HDR brachytherapy is commonly used for unfavourable prostate cancer. Table 4Go presents the required prescribed dose that yields EUD values of 68 Gy, 72 Gy, 80 Gy, 90 Gy, 100 Gy or 110 Gy for an I-125 or a Pd-103 implant combined with EBRT of 46 Gy delivered in 2 Gy daily fractions. Results from using two sets of LQ parameters — (1) {alpha}/β = 3.1 Gy, {alpha} = 0.15 Gy–1, Tr = 16 min and Td = 42 days, and (2) {alpha}/β = 1.5 Gy, {alpha} = 0.04 Gy–1, Tr = 114 min and Td = {infty} — are included.


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  		Table 4. Permanent brachytherapy combined with external beam radiotherapya

 
Theoretically, there is an infinite number of combinations of EBRT and brachytherapy that can generate the same EUD. Figure 2Go presents the required dose for I-125 permanent brachytherapy (y-value) for a given EBRT dose (x-value) in a combined treatment of EBRT and permanent brachytherapy that yields a fixed EUD of 70 Gy or 81 Gy. Only data generated with {alpha}/β = 3.1 Gy, {alpha} = 0.15 Gy–1, Tr = 16 min and Td = 42 days are shown. Note that the two curves do not intercept with the x-axis at 70 Gy and 81 Gy, indicating that an extra dose of 10 Gy for brachytherapy or 5 Gy for EBRT is required to compensate for the tumour proliferation that was considered in deriving the LQ parameters [15]. These extra doses would not result in any net cell killing. The combined scheme in Figure 2Go illustrates that a 2 Gy dose from I-125 implants is roughly equivalent to a 1 Gy dose of EBRT, as pointed out previously [27].


Figure 2
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  		Figure 2. Combinations of external beam radiotherapy(EBRT)and I-125 permanent brachytherapy that yield a fixed EUD of 70 Gy or 81 Gy. The data were generated with {alpha}/β = 3.1 Gy, {alpha} = 0.15 Gy–1, Tr = 16 min and Td = 42 days.

 
Table 5Go presents the required fraction size, as well as the number of daily fractions that yields a prostate EUD of 68 Gy, 72 Gy, 80 Gy, 90 Gy, 100 Gy or 110 Gy, for HDR brachytherapy combined with EBRT of 46 Gy delivered in 2 Gy daily fractions.


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  		Table 5. High dose rate brachytherapy combined with external beam radiotherapya

 
A successful example of using EBRT combined with HDR brachytherapy is reported by Martinez et al [7, 8]. Based on a dose escalation trial conducted at the William Beaumont Hospital (WBH), the authors found that the combination of 46 Gy of EBRT and 16.5–23.0 Gy of HDR delivered in two fractions resulted in a favourable outcome (87% of the 5-year biochemical control rate). Alternatively, different fractionations (other than two fractions) may be advantageous in terms of both morbidity and tumour control. Thus, it is interesting to recognize the alternative fractionations that are biologically equivalent to the successful fractionations used in the trials WBH. Table 6Go presents the equivalent alternative fractionations with fraction numbers of three, four and five. These alternative fractionations yield the same EUD as the fractionation used in the WBH trial [7, 8]. Note that, in Table 6Go, the data for the LQ parameters {alpha}/β = 10 Gy, {alpha} = 0.3 Gy–1, Tr = 60 min and Td = 42 days are also presented. The effect of the lag time was examined for the data presented in Table 6Go; no influence was found. This is because the EBRT of 46 Gy is to be delivered in 23 fractions, which is longer than the Tk of 25 days.


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  		Table 6. Alternative HDR fractionations that are biologically equivalent to the HDR fractionations used in the William Beaumont Hospital(WBH) study [7, 8]a

 
Calculations for the rectum
EUD values for the rectum for a series of regimens are presented in GoGoTables 7, 8 and 9Go for EBRT, permanent brachytherapy and HDR brachytherapy as monotherapy for prostate cancer, respectively. The details of these regimens are shown in GoGoTables 1, 2 and 3Go. All EUD values are expressed as the dose of EBRT in 2 Gy daily fractions. The data in Table 7Go are rectal EUDs for hypofractionation regimens with fraction sizes of 2.5 Gy, 3 Gy, 4 Gy and 5 Gy that yield a prostate EUD of 62 Gy, 68 Gy, 72 Gy, 76 Gy, 82 Gy, 86 Gy or 90 Gy. The rectal EUD is reduced with the increase of fraction size for a given prostate EUD, indicating the advantage of hypofractionation. This advantage is primarily caused by (i) the dosimetric sparing of the rectum, a result of technical advances in 3DCRT, and (ii) the assumption that the {alpha}/β ratio for the rectum is larger than that for prostate cancer. Table 8Go lists the rectal EUDs for a prostate EUD of 62 Gy, 68 Gy, 72 Gy, 76 Gy, 82 Gy, 86 Gy or 90 Gy delivered by I-125 and Pd-103 permanent implants as monotherapy. The rectal EUDs calculated for HDR as monotherapy with two, four or six fractions that deliver a prostate EUD of 62 Gy, 68 Gy, 72 Gy, 76 Gy, 82 Gy, 86 Gy or 90 Gy are given in Table 9Go.


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  		Table 7. Equivalent uniform dose(EUD) values of the rectum for the hypofractionation external beam radiotherapy regimens listed in Table 1Go

 

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  		Table 8. Equivalent uniform dose(EUD) of the rectum for a prostate EUD of 62 Gy, 68 Gy, 72 Gy, 76 Gy, 82 Gy, 86 Gy or 90 Gy delivered by I-125 or Pd-103 implant as monotherapy

 

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  		Table 9. Equivalent uniform dose(EUD) of the rectum for high dose rate brachytherapy monotherapy with two, four or six fractions that yields a prostate EUD of 62 Gy, 68 Gy, 72 Gy, 76 Gy, 82 Gy, 86 Gy or 90 Gy

 

   Discussion and conclusions
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion and conclusions
References
 
Alternative radiotherapy regimens that are expected to be biologically equivalent to clinically proven treatments are developed for prostate cancer using the EUD concept. Practical regimens are reported for monotherapy with conventional and hypo-fractionation EBRT, permanent or HDR brachytherapy, or EBRT combined with brachytherapy. The EUD values for both prostate and rectum are provided. For example, the alternative regimens that would be biologically equivalent (in terms of tumour control, e.g. prostate EUD) to the EBRT of 86 Gy (43x2.0 Gy) include: (1) EBRT hypofractionation monotherapy of 23x3.0 Gy; (2) I-125 implant monotherapy of 177 Gy; (3) Pd-103 implant monotherapy of 147 Gy; (4) HDR implant monotherapy of 4x11.5 Gy; (5) I-125 implant of 84 Gy combined with EBRT of 23x2.0 Gy; and (6) HDR brachytherapy of 3x7.4 Gy combined with EBRT of 23x2.0 Gy. These data were calculated with an {alpha}/β ratio of 3.1 Gy. The corresponding data for an {alpha}/β ratio of 1.5 Gy are shown in GoGoGoGoGoTables 1–6Go. For a given alternative regimen, one could obtain the therapeutic gain by considering the EUD values for both prostate and rectum. The data presented may be useful in designing clinical trials to explore new radiotherapy regimens for prostate cancer.

To examine the implications of alternative treatments on critical structures, the EUD values of the rectum for EBRT and brachytherapy as monotherapy were calculated (GoGoTables 7–9Go). For all of the monotherapy regimens considered, rectal EUDs are less than 63 Gy (<60 Gy for most of the regimens). It has been reported by Emami et al [40] that the TD50/5 (the dose resulting in a 50% probability of complications within 5 years from treatment) and TD5/5 (5% probability within 5 years) for the rectum when the entire organ is irradiated are 80 Gy and 60 Gy, respectively. This indicates that, for most of the monotherapy regimens considered, the 5-year rectal complication rate would be less than 5%.

Fowler et al [23] reported potential EBRT hypofractionation schemes for prostate cancer. They used {alpha}/β = 1.5 Gy in their calculation and studied the sensitivity of parameters by varying the {alpha}/β ratio from 1.0 Gy to 2.0 Gy. In the present work, we have generated data not only on EBRT hypofractionation schemes but also on regimens of brachytherapy and EBRT combined with brachytherapy, using the two representative sets of LQ parameters with low {alpha}/β ratios (3.1 Gy and 1.5 Gy). Another difference from the work by Fowler et al [23] is that we used the EUD concept to incorporate non-uniform dose distributions into tumour control probability calculations.

Although it has been argued that the relative biological effectiveness (RBE) for an I-125 or Pd-103 implant may be higher than 1.0 [41], estimates of radiosensitivity parameters for prostate cancer reported in the literature [11–16] do not explicitly consider these effects. However, we believe that the equivalent treatment regimens reported in this work will be relatively insensitive to the RBE of I-125 or Pd-103 because the prescribed doses are derived from iso-effect calculations; that is, all analyses and calculations are subject to the common constraint of 145 Gy for the I-125 implant, equivalent to 71 Gy for EBRT [13, 15]. An independent study of LQ modelling based on EBRT and HDR clinical data [16], which are subjected less to the RBE effect, provided similar estimates on LQ parameters. This indicates that the RBE effect may be insignificant in modelling prostate cancer.

The results generated in this study, although based on the latest clinical data, may be quantitatively limited by the approximations used in the models. In particular, the reliability of the radiobiological parameters involved in the study is under debate [9–16, 19, 20]. The regimens presented are sensitive to the models and parameters used, e.g. for a given EUD, the required EBRT-prescribed doses for a fraction size of 4.0 Gy differ by approximately 10% between the calculations with the two low {alpha}/β ratios ({alpha}/β = 3.1 vs 1.5 Gy). This difference increases to 25% if an {alpha}/β ratio of 10 Gy is compared with 1.5 Gy. In particular, small uncertainties in the model parameters can lead to large calculation errors if there are cold spots in the tumour and/or hot spots in normal tissue. More clinical data are required to validate these parameters. The hypofractionation regimens with small fraction numbers should be used with great caution because of a lack of information on other factors such as dose delivery accuracy, reoxygenation and normal tissue tolerance. It has been argued that hypofractionation may not offer advantages if the {alpha}/β ratio of the tumour is close to that of normal structures, as considered in this study for the case of {alpha}/β = 3.1. However, one could also argue that, because of recent advances in planning and delivery technology, radiation dose distributions are often highly conformed to the target for both EBRT and brachytherapy. Therefore, the gain in tumour control from hypofractionation may exceed the increase of normal tissue toxicity.

The results of this study offer useful data and tools to clinicians considering alternative treatment approaches to prostate cancers. These data could be used to design Phase I/II clinical trials aiming to test efficacy and/or cost effectiveness of an alternative regimen/modality. With improved treatment planning strategies, patient positioning accuracy and treatment delivery technology, alternative treatment approaches appear more realistic. In particular, hypofractionation with EBRT alone becomes more realistic with the advances in image-guided IMRT.


   Acknowledgments
 
This study was partially supported by the MCW Cancer Center Fotsch Fellowship.

Received for publication July 6, 2006. Revision received January 18, 2007. Accepted for publication February 1, 2007.


   References
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion and conclusions
 References
 

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