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British Journal of Radiology 75 (2002),151-161 © 2002 The British Institute of Radiology

Full paper

Potential improvements in the therapeutic ratio of prostate cancer irradiation: dose escalation of pathologically identified tumour nodules using intensity modulated radiotherapy

C M Nutting, MD, MRCP, FRCR 1 C M Corbishley, FRCPath 3 B Sanchez-Nieto, PhD, MIPEM 2 V P Cosgrove, PhD 2 S Webb, DSc, FInstP, FIPEM 2 and D P Dearnaley, MD, FRCP, FRCR 1

1Department of Radiotherapy and 2Joint Department of Physics, Institute of Cancer Research and Royal Marsden NHS Trust, Sutton, SM2 5PT and 3Department of Histopathology, St Georges' Hospital, Blackshaw Road, Tooting, London, UK

Correspondence: Dr C Nutting, Royal Marsden NHS Trust, Fulham Road, London SW3 6JJ, UK


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 
The potential of intensity modulated radiotherapy (IMRT) to improve the therapeutic ratio in prostate cancer by dose escalation of intraprostatic tumour nodules (IPTNs) was investigated using a simultaneous integrated boost technique. The prostate and organs-at-risk were outlined on CT images from six prostate cancer patients. Positions of IPTNs were transferred onto the CT images from prostate maps derived from sequential large block sections of whole prostatectomy specimens. Inverse planned IMRT dose distributions were created to irradiate the prostate to 70 Gy and all the IPTNs to 90 Gy. A second plan was produced to escalate only the dominant IPTN (DIPTN) to 90 Gy, mimicking current imaging techniques. These plans were compared with homogeneous prostate irradiation to 70 Gy using dose–volume histograms, tumour control probability (TCP) and normal tissue complication probability (NTCP) for the rectum. The mean dose to IPTNs was increased from 69.8 Gy to 89.1 Gy if all the IPTNs were dose escalated (p=0.0003). This corresponded to a mean increase in TCP of 8.7–31.2% depending on the {alpha}/ß ratio of prostate cancer (p<0.001), and a mean increase in rectal NTCP of 3.0% (p<0.001). If only the DIPTN was dose escalated, the TCP was increased by 6.4–27.5% (p<0.003) and the rectal NTCP was increased by 1.8% (p<0.01). In the dose escalated DIPTN IMRT plans, the highest rectal NTCP was seen in patients with IPTNs in the posterior peripheral zone close to the anterior rectal wall, and the lowest NTCP was seen with IPTNs in the lateral peripheral zone. The ratio of increased TCP to NTCP may represent an improvement in the therapeutic ratio, but was dependent on the position of the IPTN relative to the anterior rectal wall. Improvements in prostate imaging and prostate immobilization are required before clinical implementation would be possible. Clinical trials are required to confirm the clinical benefits of these improved dose distributions.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 References
 
Escalation of radiation dose is one of the major strategies currently being explored in an attempt to improve rates of local control and overall survival in prostate cancer. Several Phase II studies have reported increased local control or improvements in surrogate markers of survival, such as prostate specific antigen (PSA) disease-free survival, using dose escalation and conformal methods [1–3]. A number of randomized studies are currently underway in the USA and Europe.

As the dose to the prostate is increased, the risk of side effects, particularly to the rectum and bladder/urethra, increases [4] because these organs lie close to or partly within the planning target volume (PTV). In a randomized control trial, the incidence of proctitis and rectal bleeding have been shown to be reduced by three-dimensional conformal radiotherapy (3DCRT) [5] and, using meticulous methods, dose escalation to greater than 80 Gy has been possible with minimal severe late morbidity [6].

Intensity modulated radiotherapy (IMRT) techniques have been used to deliver doses in excess of 80 Gy to the prostate, with dose constraints on the anterior rectal wall [7, 8]. The results of this approach have recently been reported, with very low rates of rectal bleeding at doses of 81–86 Gy [9]. Data regarding long-term tumour control and normal tissue late side effects are awaited.

Prostate tumours typically arise in the peripheral zone of the prostate gland and are commonly multifocal. Histological examination of radical prostatectomy specimens frequently reveals a single, large, dominant intraprostatic tumour nodule (DIPTN) as well as separate, smaller, secondary (non-dominant) tumour nodules (NDIPTNs) within the prostate [10]. An alternative strategy to irradiation of the whole prostate gland would be to escalate the dose of radiation to these intraprostatic tumour nodules (IPTNs) with the aim of increasing tumour control with less irradiation of surrounding normal tissues.

Improvements in non-invasive prostate imaging modalities such as dynamic MRI [11], magnetic resonance spectroscopy (MRS) [12] and functional imaging [13] hold the promise of improvements in tumour localization. This may allow IPTNs to be visualized and targeted in dose escalation strategies. The gold standard against which all imaging modalities should be compared is histopathological identification of tumour in prostatectomy specimens [14]. Sequential large block sections of the whole prostatectomy specimen can be used to map the position of tumours within the prostate [15, 16]. These data allow identification of areas within the prostate gland that could be specifically targeted to receive higher doses of radiation [17].

IMRT has the potential to deliver high doses of radiation to areas within the prostate most efficiently by delivering a higher dose per fraction. Such concomitant boost techniques have been termed simultaneous modulated accelerated radiotherapy [18] or, alternatively, simultaneous integrated boost (SIB) [19]. IMRT techniques have been described that give a SIB to the DIPTN by production of a purposefully inhomogeneous dose distribution [20].

In this planning study we have modelled the potential of IMRT, using a SIB technique, to increase the dose to IPTNs identified from sequential large block sections of whole prostatectomy specimens (Figure 1Go). We have estimated the effects of various dose distributions on tumour and normal tissues using physical and biological endpoints. Tumour control probability (TCP) and normal tissue complication probability (NTCP) for the rectum were calculated to model the clinical impact of the accuracy of tumour imaging on the TCP.



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  		Figure 1. An algorithm showing the study design. IMRT, intensity modulated radiotherapy; TCP, tumour control probability; NTCP, normal tissue complication probability.

 

   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 References
 
Prostate maps
Prostate maps were produced from six radical prostatectomy specimens from men with clinically staged T1c–T2a prostate cancer. The men had a median age of 62 years, a Gleason score of 4–7 and PSA range of 4–13 ng ml. The whole prostate specimens were weighed, orientated and inked to show margins, then sectioned in their entirety at 5 mm intervals in the axial plane [15]. The large whole-mount sections were then processed and embedded in paraffin wax, sectioned at 5 µm intervals and stained with haematoxylin and eosin. The sections were then viewed microscopically by an experienced histopathologist (CMC) who outlined the areas of tumour on the surface of the coverslip using a fine point permanent marker pen (Figure 2Go). The largest tumour nodule was designated the DIPTN and the smaller nodules as NDIPTNs. These prostate maps were used to model tumour distribution in patients who had been treated with radiotherapy.



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  		Figure 2. Generation of prostate maps. (a) Gross prostatectomy specimen showing a tumour in the peripheral zone. (b, c) Typical prostate maps. The microscopic areas of tumour were marked on the cover slip of each slide using a fine marker pen.

 
Generation of target volumes
Six different patients who had recently been treated with 3DCRT for prostate carcinoma were studied. These patients also had clinical stage T1c–T2a prostate cancer and were therefore similar to the men from whom the prostate maps had been produced. A radiotherapy planning CT scan of the pelvis was taken and the CT datasets were transferred to an inverse treatment planning system (CORVUS version 3.0; Nomos Corporation, Pittsburgh, PA) [20]. The prostate gland and organs-at-risk were outlined on each CT image in accordance with International Commission on Radiological Units and Measurements Report 50 [21]. The PTV was defined as the prostate gland with a margin of 10 mm added in three dimensions. The whole bladder was outlined as well as the rectum from anus to rectosigmoid junction. The prostatic urethra was outlined from prostate apex to base.

The positions of IPTNs were transferred from the prostatectomy maps onto the corresponding CT images. Each prostate map was paired with a CT scan from a patient with similar prostate size and tumour stage. The CT images were in a slightly different plane to the histopathological whole-mount sections, and the radical prostatectomy specimens were on average smaller than the CT-generated prostate volumes. This was partly owing to prostate gland shrinkage due to the histopathological fixation process, but also to the known overestimation of prostate gland volume by CT scanning [22, 23]. During the transfer process these factors were taken into account by delineating the IPTN relative to the apex, base, urethra and lateral prostate gland borders. The size of the IPTN outlined on the CT images was therefore larger than on the histological sections to allow for the shrinkage described, but the proportional relationship of size of the nodule to size of the prostate gland was maintained.

IMRT treatment planning
For the treatment planning exercise, three plans were created. The first plan (PTV alone) was designed to treat the PTV to a dose of 70 Gy±5% in 2 Gy fractions using 6 MV photons. The dose of 70 Gy was chosen as it is a "standard" dose frequently used in North America using conventional radiotherapy methods. The second plan was designated IPTN boost and was designed to treat the PTV to 70 Gy, but escalate the dose to all IPTNs to 90 Gy. This plan represented what would be achievable with tumour localization accuracy close to the gold standard. The third plan was designated DIPTN boost and was designed to escalate the dose to the DIPTN to 90 Gy and to treat the remainder of the PTV including the NDIPTNs to 70 Gy. This plan represented an intermediate scenario where only the DIPTN was localized, assuming that the limit of accuracy of any imaging modality would be 5 mm [24].

For the inverse planning process, doses to the PTV and IPTNs were constrained to ±5%, although for the SIB plans, dose inhomogeneity within the PTV was accepted as inevitable owing to the penumbra of the boost volume. The following normal tissue constraints were used for the whole prostate irradiation: bladder goal dose 60 Gy, maximum dose 73.5 Gy; and rectum goal dose 60 Gy, maximum dose 73.5 Gy. The urethra goal dose was less than 73.5 Gy. For escalated dose plans the constraints were: bladder goal dose 60 Gy, maximum dose 80 Gy; and rectum goal dose 63 Gy, maximum dose 80 Gy. These constraints were based on radiation tolerance of particular organs [25] and our experience of the acceptable dose delivered to each organ using 3DCRT [26]. A nine-field technique was used, with equispaced beams arranged every 40° starting from a direct anterior beam. This beam arrangement has been said to provide the optimal dose distribution for prostate cancer IMRT [27]. No attempt was made to optimize the beam directions. IMRT plans were produced for a 6 MV linear accelerator (Elekta Oncology Systems, Crawley, UK) for delivery with a dynamic multileaf collimation technique.

Plans to treat the PTV alone to 70 Gy were normalized to a dose–volume point such that 50% of the PTV received the prescription dose. The other two types of plan were normalized such that the minimum dose to the PTV was equivalent to the PTV alone plan. This was done because the mean PTV dose was effected to a variable extent by the boost volume in each patient, which made planning comparisons difficult.

Comparison of treatment plans
The minimum PTV dose was defined as the dose received by >=99% of the PTV, and the maximum dose was defined as the dose received by <=1% of the PTV [28–30]. The PTV and IPTN mean dose as well as dose ranges were calculated. Mean doses to the rectum, bladder and prostatic urethra were calculated, and the volumes of these organs treated to 90%, 80%, 50% and 20% of the prescription dose were estimated. Doses to the target volumes and organs-at-risk were compared using a paired Student's t-test. Differences were reported as statistically significant at the p<0.05 level (two-tailed).

Tumour control probability ({Delta}TCP) and normal tissue complication probability (NTCP) were estimated for each treatment plan using Bioplan software [31]. TCP calculations were based on the Poisson model [32–34]. A first set of calculations was made with parameters derived from modelling clinical data on prostate cancer patients with stage B and C tumours [35] ({alpha}=0.29 Gy-1, {sigma}{alpha}=0.07 G-1, {alpha}/ß=10). It was assumed that the clonogenic cell density for the IPTN identified from the prostate maps was 107 cm-3 [36] and that the ratio of clonogenic cells within the tumour nodules and the rest of the prostate was 90/10. Based on these assumptions, the clonogenic cell density for the rest of the prostate gland was calculated as: Go


using mean values of volume of prostate and IPTN. Calculations were also made assuming clonogenic cell ratios of 95/5 and 80/20, but this did not have any significant impact on the results.

The {alpha}/ß ratio for prostate cancer is controversial, and several authors have suggested that lower {alpha}/ß ratio values (<3 Gy) are more appropriate for prostate cancer [37–42]. We therefore also calculated the TCP using {alpha}/ß=1.49 Gy and {alpha}=0.0391 Gy-1 taken from Fowler et al [41]. Using the Poisson model, to get a relatively shallow ({gamma}{approx}2) dose–response curve (as in Figure 1Go of Fowler's paper) with such a low value for {alpha} it is necessary to assume a very low number of clonogens (No{approx}290 clonogens) and {sigma}{alpha}=0. One could argue that this low value for {alpha} is the result of pooling clinical results from many patients and that it is only the most resistant (hypoxic) cells from the heterogeneous population that determine outcome (i.e. that only a minority of radioresistant clonogenic cells determine TCP and that patient heterogeneity has been implicitly taken into account in the clinical data). We made also the assumption, as for the previous set of parameters, that the clonogenic cell number ratio from prostate to lesions is 10/90. Thus, clonogenic cell density was estimated No x 0.9/volume of IPTN and No x 0.9/volume of prostate for the IPTN and prostate, respectively.

For each dose region in the tumour, the {Delta}TCP method [34] was used to estimate the change in overall TCP owing to an increase or decrease in dose deposition (with respect to the prescription dose) inside each of the subvolumes. This method is of relevance here because it quantifies the impact of the desired non-uniform dose distributions on the total TCP. All {Delta}TCP values shown in this paper were calculated with respect to a level of 70 Gy, reflecting the gain over uniform irradiation to that dose.

Rectal NTCPs were calculated using both the Lyman–Kutcher–Burman (LKB) model [43, 44] and the relative seriality model [45]. Parameters for the LKB model for rectal complications (severe proctitis/necrosis/stenosis/fistula) were n=0.12, m=0.15 and TD50=80 Gy from Burman et al [46]. Using the same endpoints, relative seriality model parameters for the rectum were {gamma}=2.56, s=0.75 and TD50=80 Gy [47]. Physical dose–volume histograms (DVHs) as well as biologically effective DVHs (using an {alpha}/ß ratio of 3 Gy) were used for the calculations.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 References
 
Examples of a gross tumour specimen along with prostate maps of two patients are shown in Figure 2Go. The distribution of IPTNs is shown for all six patients in Figure 3Go. Patients 1–5 had multifocal disease in the prostate gland, and patient 6 had a solitary IPTN. The volumes of the prostate, DIPTN and NDIPTNs are shown in Table 1Go. Figure 4Go shows the dose distributions at the level of the isocentre for one patient. Figure 4aGo shows the dose distribution for irradiation of the PTV to 70 Gy. The dose distribution is homogeneous to within ±10%, and the isodose lines exhibit conformal avoidance of the rectum. Figure 4bGo shows the dose distribution through the isocentre for the dose escalation of both IPTNs to 90 Gy, and Figure 4cGo shows a corresponding dose distribution for escalation of the DIPTN only. These dose distributions show the potential of IMRT to deliver localized areas of high dose within the PTV without affecting the conformality of the isodoses around the prostate gland itself. The isodoses maintained avoidance of surrounding organs-at-risk. Figures 5Goa–c shows the DVH for the three plans.



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  		Figure 3. The position of intraprostatic tumour nodules for each of the six patients. The planning target volume is red, the DIPTN is orange and the NDIPTN is blue.

 

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  		Table 1. Volume of prostate gland, DIPTN and NDIPTN, and position of DIPTN in each of the six patients

 


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  		Figure 4. Dose distributions for (a) prostate only, (b)intraprostatic tumour nodule (IPTN) boost and (c) dominant IPTN boost techniques.

 


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  		Figure 5. Dose–volume histograms for (a) prostate only, (b) intraprostatic tumour nodule (IPTN) boost and (c) dominant IPTN boost techniques.

 
Table 2Go shows a comparison of the dose statistics for each treatment plan for the PTV. Table 3Go shows the comparative dose statistics for the rectum, bladder and urethra and the NTCP values for the rectum. These tables show that in these six patients, IMRT was able to generate conformal dose distributions for irradiation of the whole of the PTV with a mean dose of 69.8 Gy (mean dose range 67.6–73.6 Gy). Second, the IPTNs identified from histological sections were dose escalated to a mean dose of 89.1 Gy (mean dose range 86.8–92.7 Gy) (p<0.001). PTV minimum dose was maintained, and the PTV mean dose increased from 69.8 to 76.1 Gy owing to the dose build-up close to the IPTNs. The dose within the PTV became much more inhomogeneous. The average increase in TCP was 8.7% (range 5.3–12.7%), from 87% to 95.7% (p<0.001) for an {alpha}/ß ratio of 10 Gy. When the {alpha}/ß ratio of 1.49 Gy was used, the predicted TCP gain was 31.2% (range 14.6–50.5%), from 64.4% to 95.6% (p<0.001). The maximum dose to the rectum, bladder and urethra was increased in the dose-escalated plans. For the rectum the increase was from 72.9 Gy to 81.8 Gy (p<0.001), for the bladder it was from 72.0 Gy to 74.9 Gy (p=0.002) and for the urethra it was from 71.7 Gy to 85.8 Gy (p<0.001). This was equivalent to an increase in rectal NTCP of 3.0% (range 1.4–3.9%) (p<0.001) and 2.0% (range 0.8–2.5%) for the LKB and relative seriality models, respectively. For the plans that escalated the dose to the DIPTN only, the mean dose to the DIPTN was 89.0 Gy (mean dose range 86.3–92.0 Gy). Doses to the NDIPTNs and to the remainder of the prostate gland were 72.4 Gy and 74.7 Gy, respectively, owing to dose build-up around the DIPTN. The average increase in TCP was 6.4% (range 3.5–11.1%) (p=0.004) for {alpha}/ß ratio=10, and 27.5% (range 11.4–47.9%) (p<0.001) for {alpha}/ß ratio=1.49. These results (i.e. a lower gain in TCP compared with the other boost plans) are consistent with irradiating fewer clonogenic tumour cells to a high dose. There was an increase in the doses delivered to the bladder, rectum and urethra at each dose level. The average increase in rectal NTCP was 1.8% (range 0.7–2.6%) (p=0.02) and 1.1% (range 0.5–1.7%) for the LKB and relative seriality models, respectively.


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  		Table 2. Average dose statistics (in Gy ±SD) for the three intensity modulated radiotherapy techniques: PTV alone (PTV alone prescribed to 70 Gy); IPTN boost (PTV prescribed to 70 Gy and IPTN to 90 Gy); DIPTN boost (PTV prescribed to 70 Gy, DIPTN prescribed to 90 Gy). TCP calculations included in this table have been made for {alpha}/ß 10 Gy

 

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  		Table 3. Average dose statistics (in Gy ±1SD) for each organ-at-risk for the three intensity modulated radiotherapy techniques. PTV alone (PTV alone prescribed to 70 Gy); IPTN boost (PTV prescribed to 70 Gy and IPTN to 90 Gy); DIPTN boost (PTV prescribed to 70 Gy and DIPTN prescribed to 90 Gy). NTCP calculations correspond to the LKB model

 
For both types of boost plan, the dose delivered to the rectum and urethra were dependent on the proximity of the boost region to these structures. For example, patients 2 and 4 had tumour nodules in the lateral part of the peripheral zone of the prostate. In these patients the increase in rectal NTCP in the DIPTN boost plan was low (0.9%). By comparison, patients 1, 3, 5 and 6 had a DIPTN in the posterior part of the peripheral zone of the prostate, close to the rectum. In these patients the equivalent increase in rectal NTCP(LKB) was 2.2%. Similarly, the urethral maximum dose was dependent on the proximity of the DIPTN to the urethra, being particularly high in patients 3 and 6 where tumour was invading the transitional zone. These conclusions were not affected by the choice of NTCP calculation model, as no significant differences were seen between NTCP calculations using the LKB or relative seriality models. {Delta}TCP calculations and a graphical plot are shown in Figure 6Go.



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  		Figure 6. (a) Dose–volume histogram (DVH) for the prostate ({square}) and the intraprostatic tumour nodule (IPTN) () of one patient corresponding to irradiation of the prostate to 70 Gy and dose escalation of the IPTN to 90 Gy. (b) Tumour control probability ({Delta}TCP) histogram corresponding to the DVH above ({alpha}/ß=10 Gy).

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 References
 
In this study the theoretical possibility of dose escalation of IPTNs was explored as a strategy for the treatment of prostate cancer.

Prostate cancer most commonly arises in the peripheral zone that extends around the posterior and lateral aspects of the prostate gland and around the prostate apex. Tumours less commonly occur in the transitional zone, and are rare in the anterior part of the gland. The posterior part of the peripheral zone is adjacent to the anterior rectal wall, such that when irradiating a tumour nodule in this area only limited reduction in dose fall off can be achieved between the nodule and the rectal wall. The risk of rectal complications therefore limit the dose that can safely be delivered to an IPTN in this region, and in most dose escalation studies this region of the peripheral zone is constrained to 70–75 Gy by the use of rectal shielding [8, 48]. Similarly, selective dose escalation of IPTNs that invade the transitional zone of the prostate, close to the urethra, may be associated with high probability of urethral complications. This study predicts increased dose to the urethra in DIPTN boost and IPTN boost plans (mean dose increased from 69.5 Gy to 75 Gy and 76.6 Gy, respectively), but clinical studies have not shown increased late urinary side effects, even when the prostate was irradiated to 81 Gy [9].

This planning study suggests that this technique of prostate cancer dose escalation may be most appropriate for IPTNs in the lateral peripheral zone when there is a distance of several millimetres between the rectal wall and the IPTN. In this situation, there may be sufficient distance to allow significant fall off of dose between the nodule and both the rectal wall and the urethra. It is patients with this disease distribution who potentially have the most gain in therapeutic ratio using this technique.

There are many issues around clinical implementation of such a technique. First, the prostate gland itself would require reproducible and accurate positioning. This could be achieved by immobilization, for example using a rectal balloon catheter [49], or by image guided patient set-up, for example setting up to implanted gold seeds within the prostate [50] or a radio-opaque urethral catheter [51].

Second, advances in multimodality imaging are required to accurately define the position of such IPTNs. Contrast enhanced dynamic MRI [10] and MRS [11] have the potential to produce the required definition. These imaging modalities would need to be fused with CT images to correct distortion, or be transformed to correct geometrical and chemical shift artefacts and allow accurate dose calculation. The data presented here suggests that if the imaging modality was sensitive enough to identify the DIPTN, then the majority of the benefit of increased dose delivery would remain, even if smaller IPTNs were not identified. Clearly this will relate to the size of the IPTNs and their proximity to the DIPTN, but if a 5 mm definition were possible, all DIPTNs in these patients would be detected.

The magnitude of the predicted effect of this IMRT technique on tumour control varied by a factor of three depending on the {alpha}/ß ratio used to calculate the TCP. The uncertainty of the appropriate values for modelling both TCP and NTCP is problematic as there is very little reliable clinical data on which to base such algorithms. Despite these caveats, the TCP and NTCP calculations do give a measure of the likely magnitude of the effects of such dose distributions and offer support to the clinical evaluation of this technique. If the {alpha}/ß ratio for early stage prostate cancer is as low as 1.49 Gy, then the dose per fraction delivered is much more important than previously recognized, and the application of such concomitant boosts using large fraction sizes is more likely to confer significant clinical benefits.

In this study we used a 10 mm margin around the prostate, but if effective immobilization or improved localization were achievable then this would allow a smaller margin of 5 mm to be used. This should be sufficient to account for microscopic tumour spread [52, 53] and would further reduce irradiation of surrounding organs.

The most appropriate dose and fractionation schedule for this technique is not known. There does appear to be a relationship between dose and local control for localized prostate cancer up to and above 80–90 Gy [1]. The use of a SIB technique causes an increased dose per fraction to the IPTN, and this produces a higher biologically effective dose (especially if {alpha}/ß ratio are even lower than 3 Gy). More clinical data are required in this area before any firm conclusions regarding the ideal dose can be made.

Ideally a balance between the increased predicted control and complications should be made using either dose customization to measure uncomplicated tumour control probability or by selecting prostate and DIPTN dose based on fixed NTCP [32, 54]. It has been predicted in modelling studies that dose customization based on a fixed rectal NTCP would allow an increase in TCP of more than 9% in patients' prostate cancer [55–57]. More clinical data correlated with dose–volume information are required before this strategy can be explored in more detail.

These different approaches to dose escalation of prostate cancer will require technical advances in both imaging and treatment delivery, as well as improvements in understanding the mechanisms of normal tissue damage before these approaches are applicable to clinical practice. Careful clinical trial design will be essential to confirm whether the improvements in dose distributions can be translated into clinically relevant endpoints.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
References
 
IMRT can be used to significantly increase the dose to IPTNs. The ratio of increased TCP to NTCP may represent an improvement in the therapeutic ratio but is dependent on the position of the IPTN relative to the normal tissue structures. Improvements in prostate imaging and immobilization are required before clinical implementation would be possible. Clinical trials are required to confirm the clinical benefits of these improved dose distributions.


   Acknowledgments
 
We thank the Nomos Corporation for their collaboration in the evaluation of the CORVUS treatment planning system. This work was generously supported by a Programme grant from The Cancer Research Campaign (CRC) under grant reference SP2312/0201.

Received for publication March 29, 2001. Revision received July 31, 2001. Accepted for publication August 17, 2001.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 

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