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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. STAGING ERRORS
  5. ANATOMICAL MISSES
  6. REQUIRED RADIATION DOSE
  7. THE FUTURE
  8. DISCUSSION
  9. CONFLICT OF INTEREST
  10. REFERENCES

For the delivery of good-quality external beam radiotherapy (EBRT) in localized prostate cancer, under-dosage to the peripheral zone (tumour) is one likely cause of poor results. The quality is improved by daily verification of the position of the prostate, and the use of magnetic resonance imaging (MRI) in delineation. Currently these are demands on quality that should be incorporated in each radiotherapy department. The use of MRI in staging is also expected to improve patient selection for EBRT. Furthermore, an adequate radiation dose should be delivered. In this overview we describe what the urologist should expect from radiation oncologists to obtain the optimum results for the patients.


Abbreviations
(EB)RT

(external beam) radiotherapy

IM

intensity-modulated

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. STAGING ERRORS
  5. ANATOMICAL MISSES
  6. REQUIRED RADIATION DOSE
  7. THE FUTURE
  8. DISCUSSION
  9. CONFLICT OF INTEREST
  10. REFERENCES

The clinical results of external beam radiotherapy (EBRT) alone for localised prostate cancer have been reported extensively. For T1 and T2 tumours the results of EBRT are estimated to be equal to those from radical prostatectomy and brachytherapy. The 10-year survival rates are considered excellent, at 90–94% for well-differentiated tumours and 45–67% for poorly differentiated tumours [1]. However, the outcome of randomized trials is considered more reliable to predict the ‘true’ treatment results. To our knowledge there is only one randomized trial specifically on localized tumours, where 70 Gy radiation alone resulted in a 5-year survival of only ≈78%[2]. Randomized trials have mainly been conducted for locally advanced tumours, questioning hormone therapy [3,4] or dose-escalation [5,6]. These trials reported a 5-year survival of only ≈60% in the RT-alone arm [3].

When assessing more closely the data from the randomized trials, it seems that in most studies the relapse or survival curves start with an overlap of both curves; the curves only begin to separate after a few years [2–5]. In these trials, 20–30% of patients have already had failure in the first few years of follow-up. There was no gain for the experimental arm because of a more substantial failure in the RT-alone arm. Reasons for these failures can be divided into staging errors, where patients in whom the treatment failed already had metastases, or into RT delivery errors, where the prostate was not adequately dosed by the radiation (an ‘anatomical miss’). If both staging errors and anatomical misses are reduced, a significant improvement of clinical outcome can be expected.

In prostate cancer, randomized trials take a long time before producing results. Because of many technical improvements, both staging accuracy and the accuracy of radiation delivery have developed rapidly in recent years. Therefore it is likely that the outcome of current treatments already differs from the outcome reported in these randomized trials. The question arises as to how quality in EBRT for localised prostate cancer influences the clinical outcome, or stated differently; what can urologists currently expect from radiation oncologists to ensure optimum treatment results for their patients. In this review we present an overview of previous reports to try to answer this question. There was no report that specifically addressed this question. As quality is a broad concept, here we chose only to discuss the most relevant topics, i.e. staging errors, anatomical misses and the required radiation dose.

STAGING ERRORS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. STAGING ERRORS
  5. ANATOMICAL MISSES
  6. REQUIRED RADIATION DOSE
  7. THE FUTURE
  8. DISCUSSION
  9. CONFLICT OF INTEREST
  10. REFERENCES

Locally advanced tumours are known to have a poorer outcome than localized tumours. The main cause for this is probably that these patients usually have a higher tumour volume, a higher PSA level and extracapsular tumour extension, which probably causes early dissemination. In patients with metastases the quality of local EBRT will, of course, not directly influence the outcome.

Underlying all studies reporting clinical outcome is the specificity of TRUS and a DRE to differentiate between localized (T1 and T2) and locally advanced (T3) tumours. The specificity of a DRE, together with plain TRUS, is only 41%[7], and this explains why radical prostatectomies are often incomplete [8]. Consequently, the clinical stages in the cited studies, which mainly used TRUS for staging, are less reliable. Some tumours were staged as being localized while they were actually locally advanced, and vice versa. Compared to radical prostatectomy there is no final pathology report after EBRT, and thus the reason for poor results from EBRT cannot be easily addressed.

The staging error in differentiating between localized and locally advanced tumours is especially important for the benefits of adjuvant and neoadjuvant hormonal treatment in T3 tumours [2–4]. Hormonal therapy increases the 5-year overall survival from 62% to 78%[3], and the 10-year survival from 39% to 49%[4].

Another possible reason to explain the outcome of EBRT is extracapsular tumour extension. In (limited) T3 tumours after radical prostatectomy, extracapsular extension is >2 mm in ≈85% and >5 mm in ≈15% of patients [8]. Thus, given the relatively small margins of EBRT around the prostate, anatomical misses are to be expected in larger T3 tumours.

ANATOMICAL MISSES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. STAGING ERRORS
  5. ANATOMICAL MISSES
  6. REQUIRED RADIATION DOSE
  7. THE FUTURE
  8. DISCUSSION
  9. CONFLICT OF INTEREST
  10. REFERENCES

The uncertainties in radiation delivery have been extensively described; the two uncertainties that produce the largest treatment errors are movement of the prostate and delineation errors [9,10]. Both might cause an anatomical miss.

The prostate moves from day to day; at the time the cited randomized studies were conducted there was only limited knowledge about prostate translations and rotations. If there was any verification of target position it was by reference to the bony anatomy, and only in the first treatment fractions. Currently there is strong evidence showing that the position of the prostate does not correlate with the bony anatomy in the anterior-posterior direction [11]. The mean uncorrected systematic radiation error of the prostate position is large, especially a 2.8-mm shift of the prostate dorsally (towards the rectum) occurs with a sd of 4.8 mm. Random errors in this direction are on average 3.5 mm, again towards the rectum [12]. There is also a time trend, where the prostate is situated more ventrally (towards the symphysis) at the start of treatment, and gradually shifts ≈1.5 mm towards the rectum during treatment (Fig. 1) [12]. This means that with no verification of prostate position, the peripheral zone (where most of the tumours are located [13]) shifts out of the radiation field in most treatments, even if large radiation margins are used. The same is true for the apex, which moves caudally during treatment with a sd of 2.9 mm and a random error of 2.3 mm [12]. These are strong reasons for poor results from EBRT. There is published confirmation, where patients with an initially distended rectum are shown to have a greater risk of failure [14]. The main reason for movement of the prostate in the anterior-posterior direction is an altered rectum, filling during therapy by feces or gas [14]. Hence, an empty rectum is very important at the time of treatment planning, and should be ensured during daily treatment delivery, to improve local control in EBRT for prostate cancer [14]. Efforts are made to modify rectal filling, e.g. by diet or medication, although to date the evidence for this approach remains limited. Therefore, the proper verification of position will always be necessary. This stresses the need for image-guided RT, e.g. by fiducial markers or cone-beam CT. The current consensus is that the position of the prostate should be verified in EBRT during the entire treatment period. There are many different ways of verification, e.g. gold fiducial markers, TRUS or cone-beam CT. Using gold-fiducial markers in 452 patients, with daily verification, our systematic positioning error was reduced to 0.2 mm in all directions, with a sd of 0.8 mm [12]. Although there are no long-term clinical results yet, toxicity was limited, with <1% acute and late grade 3 or 4 bladder or rectal toxicity (Lips, submitted).

image

Figure 1. The trend in prostate position in the vertical direction (towards the rectum) during the 35 radiation fractions (452 patients). The left upper corner of the picture shows two MRI scans of the same patient. The left MRI is before the first treatment and the right during treatment. If the planning target volume is the black line, it is apparent that the peripheral zone would shift outside the treatment volume.

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The delineation of the prostate is the basis of the EBRT plan; if the prostate is not correctly delineated, e.g. if a tumour-bearing part of the prostate is missed, the delivery of radiation is less likely to be successful. The commonly used imaging method to delineate the prostate is CT. Unfortunately, the prostate, and particularly the apex, is hardly visible on CT, due to poor soft-tissue contrast. The tumour within the prostate is invisible. Also, the borders between prostate and rectum are not clearly visible, mostly in the caudal parts of the prostate. MRI has excellent soft-tissue contrast and therefore seems preferable for delineation. CT-derived prostate volumes are larger than MRI-derived volumes, especially toward the seminal vesicles and the apex of the prostate [10]. However, it is likely that there are many individual cases where the sole use of CT resulted in an anatomical miss of the tumour itself, or of the apex, where most of the tumour is situated [13]. In the study of Milosevic et al. [15], if only CT had been used, the apex would have been under-dosed in 17% of the patients [15]. Using MRI for delineation reduces the amount of rectal wall irradiated, and probably would decrease rectal and urological complications. MRI can also be used to visualize the tumour within the prostate, and visualize the apex. Furthermore, the specificity for differentiating between T2 and T3 is higher than with TRUS, with a specificity of up to 97% when using dynamic contrast-enhanced MRI [16]. Currently several consensus articles have been published on delineating the prostate and its implications for treatment planning [17]. CT delineation was the starting point in all the clinical trials cited above, and this might partly explain the disappointing results of EBRT.

REQUIRED RADIATION DOSE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. STAGING ERRORS
  5. ANATOMICAL MISSES
  6. REQUIRED RADIATION DOSE
  7. THE FUTURE
  8. DISCUSSION
  9. CONFLICT OF INTEREST
  10. REFERENCES

As recurrence after treatment with conventional RT used to be common, the hypothesis was proposed that prostate cancer needs a higher radiation dose. In several randomized trials, conventional radiation doses of up to 70 Gy were compared to higher doses of ≈80 Gy [5,6,18]. Freedom from biochemical relapse was significantly better in the high-dose arm than in the conventional dose-arm, with increase in the 5-year value from 15–30% to 60–80%[5,6,18]. This gain is very impressive considering that the peripheral zone will have been under-dosed in these trials, which lacked the required daily verification of position, as described above.

THE FUTURE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. STAGING ERRORS
  5. ANATOMICAL MISSES
  6. REQUIRED RADIATION DOSE
  7. THE FUTURE
  8. DISCUSSION
  9. CONFLICT OF INTEREST
  10. REFERENCES

Currently the clinical outcome of EBRT is difficult to interpret; if there is a biochemical recurrence it is not clear whether there is a local relapse (a result of sub-optimal irradiation) or disseminated disease (not related to EBRT). At present there is no easy way to reliably find or exclude a local recurrence; this will be necessary to gain knowledge about the effect of radiation on the tumour, the probability of tumour control.

Currently new MRI techniques are being developed which are expected to identify local recurrences in the future; these new techniques are already used for biological (or functional) imaging. Biological characteristics are considered more important for RT choices than merely anatomical imaging [19], and especially the imaging of hypoxia is expected to be of clinical value [20]. Another important biological characteristic is PSA kinetics. A higher PSA doubling time will probably mean faster cell doubling, a higher risk of metastasis and possibly more radio-resistance.

The technical aspects of delivery have also changed, from conventional and conformal RT to intensity-modulated (IM) RT. With IMRT the radiation beam can be shaped to avoid the organs at risk, e.g. bladder or rectum. This will probably not directly result in a better outcome, only in reducing toxicity. In the future IMRT will be required for a the safety of further dose increases. Another way to enable further dose increases is to combine EBRT with brachytherapy, as with brachytherapy it is possible to deliver a very high local dose. The future of prostate RT will be an individualized dose distribution with a heterogeneous dose based on biological local tumour characteristics, termed image-guided RT, and used to improve the daily anatomical localization of the prostate.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. STAGING ERRORS
  5. ANATOMICAL MISSES
  6. REQUIRED RADIATION DOSE
  7. THE FUTURE
  8. DISCUSSION
  9. CONFLICT OF INTEREST
  10. REFERENCES

What can urologists currently expect from radiation oncologists to optimise the outcome for their patients? For the quality of delivery of EBRT in men with local prostate cancer, severe under-dosage to the peripheral zone (tumour) has partly caused the poor results of EBRT. Quality is improved by daily verification of the position of the prostate and the use of MRI in delineation; these quality demands should be incorporated in each RT department.

For localized prostate cancer (T1,2) recent reports suggest that EBRT might have poorer long-term results than prostatectomy [21], possibly explained by staging errors and anatomical misses. In a large study the outcome of EBRT was shown to be significantly worse when there were inadequate radiation doses (<72 Gy) than for prostatectomy, brachytherapy or high-dose EBRT (>72 Gy) [22].

For optimal results from EBRT of locally advanced tumours, higher doses (≥78 Gy) are needed, and in selected cases the addition of hormonal therapy. However, randomized studies of dose escalation and hormonal therapy were conducted without the required quality of delivery described above. It is not clear whether the clinical improvements from adding hormonal therapy or increasing the dose compensates for the poor delivery of RT. Quality of life and toxicity are valid factors if these trials were repeated using current and optimum RT standards. However, in prostate cancer randomized trials take a long time before producing results, and by that time the results might be outdated.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. STAGING ERRORS
  5. ANATOMICAL MISSES
  6. REQUIRED RADIATION DOSE
  7. THE FUTURE
  8. DISCUSSION
  9. CONFLICT OF INTEREST
  10. REFERENCES
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