British Journal of Radiology (2003) 76, 897-903
© 2003 British Institute of Radiology
doi: 10.1259/bjr/68756213
A retrospective study of bladder morbidity in patients receiving intracavitary brachytherapy as all or part of their treatment for cervix cancer
J M Wilkinson, MSc1,
M A Harris, FRCR2,
S E Davidson, FRCR2,
R S Welch, FRCR2,
R D Hunter, FRCR2 and
R Swindell, MSc3
1 North Western Medical Physics, 2 Department of Clinical Oncology and 3 Statistics Department, Christie Hospital NHS Trust, Manchester M20 4BX, UK
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Abstract
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A retrospective study has been undertaken in an attempt to identify physical parameters that could confidently be used to predict an enhanced risk of bladder morbidity following intracavitary brachytherapy. 366 women received brachytherapy as all, or part, of their treatment for cervical cancer at the Christie Hospital in 1990 and 1991, and of these, 60 patients developed identifiable bladder morbidity (graded on a scale of 1–4 using the Franco-Italian glossary). These were age and stage matched with 60 asymptomatic women who were also treated for cervical cancer by brachytherapy during the same time period. The sizes of applicators used in the two groups were noted and compared. The two groups were also compared with respect to the heights of the applicator set above the symphysis pubis, the degree of anteversion or retroversion of the applicator sets and where possible, the doses at the International Commission on Radiation Units and Measurements (ICRU) bladder reference point. Where CT scans of the applications were available, these were reviewed to see if any differences in the size, shape or location of the bladder were apparent. No significant difference was found between the two groups of patients for any of the parameters investigated. The physical factors investigated in this study cannot be used to reliably predict bladder complications. There was a significant correlation between bladder morbidity and morbidity in other pelvic sites.
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Introduction
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The incidence of serious bladder morbidity after radical radiotherapy for cervical carcinoma treated with a combination of external beam radiotherapy and brachytherapy is reported to be between 1% and 7% [1, 2]. The real figure may be much higher than this as these numbers are often obtained retrospectively from case notes, and when postal questionnaires have been used in long-term survivors the incidence of urinary morbidity reported has been up to 56% [3]. The elapsed time between treatment and assessment will influence the observed incidence rate and although most complications will be seen within 3 years, progression of bladder symptoms has been recorded for periods extending up to 20 years following therapy [4–6]. It is known that the development of urinary morbidity may be affected by inherent patient characteristics, such as pre-existing morbidity from pelvic deliveries and previous surgery which cannot be modified [7], but it is also presumed to be affected by the radiation dose to critical pelvic structures, the radiotherapy treatment techniques and the volumes of individual organs irradiated. A report committee of the International Commission on Radiation Units and Measurements (ICRU) defined a bladder reference point in ICRU Report 38 [8] and recommended its use for recording and reporting a representative bladder dose, with the hope that this might subsequently be correlated with morbidity. The dose at this point is intended to be representative of the dose to the trigone, but is not necessarily the highest dose in the bladder [9, 10]. However, some authors have claimed success in reducing bladder morbidity by controlling dose at this point [2, 11].
This paper describes a retrospective study of physical parameters and includes a comparison of doses at the ICRU bladder reference point in patients who did and who did not develop bladder morbidity.
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Materials and methods
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At the Christie Hospital 366 patients received intracavitary brachytherapy as all or as part of their treatment for carcinoma of the cervix over the 2 year period from 1 January 1990 to 31 December 1991. The age range was from 24 years to 90 years with a mean age of 57 years. In the majority of cases a Selectron-LDR after-loading unit was used to simulate the original Manchester Radium System with a central intrauterine tube and two transverse vaginal ovoids [12]. The intrauterine tube for the after-loading system was designed locally and was such that the source train turned through a 40° angle before passing through the external os and entering the uterus. This implies that, typically, the axis of the uterus is expected to lie at an angle of 40° to the axis of the vagina. Gauze packing was placed behind the ovoids to push back the rectum and to stabilize the applicator position. Doses were prescribed at the Manchester Point A, and over the period in question the Point A dose rate using the Selectron-LDR machine was approximately 1.7 Gy h-1. If the patient had a small vaginal vault then a single line source with a vaginal cylinder designed to mimic ovoids in tandem was used. A minority of patients had either a pre-loaded or manually after-loaded caesium insertion instead, with a Point A dose rate of 0.58 Gy h-1. In all cases the applicators were inserted in theatre under general anaesthetic, and the treating doctor chose what was considered to be the appropriate applicator size and combination at the time of insertion.
The dose to the anterior rectal wall was controlled by dose rate measurements that were made in the rectum at the time of the insertion. If the projected dose at the point where the measured dose rate was highest was more than two thirds of that at Point A then the packing was removed and replaced, or, if this was not sufficient, a different applicator set was substituted or the Point A dose reduced appropriately.
There was no specific control of bladder dose during this period, but concurrent with many, but not all, of the applications a balloon catheter with contrast material was inserted, and in these cases it is possible retrospectively to locate the ICRU bladder reference point and hence to calculate the ICRU bladder reference dose. Anteroposterior and lateral radiographs were taken to check applicator positions after each insertion. Some, but not all, patients were CT scanned following applicator insertion.
During Selectron treatment the positions of protruding applicator parts were examined every 2 h. If applicator movement was suspected then repeat radiographs were taken. Only rarely was significant movement confirmed, and in those cases treatment was terminated and the further clinical management was decided on a case by case basis.
Patients were assessed for morbidity between October 1995 and March 1996, a mean of 5 years post treatment. At this stage 60 patients (16%) were judged to have suffered some degree of bladder morbidity and these were graded according to the Franco-Italian glossary [13]. These patients will be referred to in this paper as the morbidity set. A control set of a further 60 patients was selected by the hospital statistician from the remaining 306 asymptomatic women. Patients in the control set were matched with those in the morbidity set for age and for clinical staging, and where possible, for the treating doctor, but no other selection criteria were applied. The number of patients in the control set was limited to 60 as a consequence of meeting the age and stage matching criteria. The two sets were presented (to JMW) as lists of hospital registration numbers but without any initial indication of which was the morbidity set and which were the controls, i.e. all retrospective measurements and calculations, and the film and CT scan reviews were carried out without prior knowledge of the morbidity status.
Patients from the two sets were divided into four groups based on the treatment technique used, which in turn reflected disease bulk and clinical staging. The numbers in these divisions are summarized in Table 1
. Within each group treatments have been categorized as standard or non-standard. All those categorized as standard were treated on the Selectron and to a standard prescription. All patients who had all or part of their intracavitary treatment by the pre-loaded or manually after-loaded technique were categorized as non-standard as these applications may result in a different radiobiological response due to the lower dose rate. Dose fractions prescribed at the lower dose rate were approximately 10% higher than those for the corresponding standard category. The non-standard categories also include patients whose prescribed dose was reduced, either because of high rectal readings or in acknowledgment of their general medical condition, and a small number of patients who, for a variety of reasons, did not complete the treatment as originally intended.
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Table 1. Patient numbers in the different treatment groups with different X-ray therapy (XRT) and intracavitary therapy (ICT) components to their treatment
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Patients in Group 1 had small bulk, early stage disease (stages 1 and 2a), and were treated radically with intracavitary brachytherapy alone. Those listed as standard were all treated by two equal fractions 7 to 10 days apart, and had a total Point A dose of 67.5 Gy.
Patients in Group 2 had medium volume disease with parametrial involvement, mainly stage 2b. The external beam technique was an anteroposterior parallel pair using 4 MV X-rays that incorporated a specially designed filter that reduced the dose in a central 40 mm strip to approximately 50% of that in the parametria. The dose prescribed to the parametria was 32.5 Gy in 16 fractions over 21 days. This was followed by two intracavitary applications, 7 to 10 days apart and the standard prescription was 27.5 Gy to Point A at each fraction, totalling 55 Gy.
Patients in Group 3 had bulky central disease, but no evidence of significant adenopathy on pre-treatment CT scanning. These patients were treated with a four-field megavoltage X-ray technique, followed by a single intracavitary application. There were two standard prescriptions within this group; 40 Gy in 20 fractions followed by 32.5 Gy to Point A or 45 Gy in 20 fractions followed by 22.5 Gy to Point A. Patients from both prescription regimens appeared in each set.
Group 4 was a small subgroup where positive lymph nodes were demonstrated on imaging. They were treated with a four field megavoltage technique covering the whole pelvis and its lymph node drainage areas and extending from the pelvic floor to the top of the fifth vertebra. This was followed by a single intracavitary application. The standard prescription was 40 Gy in 20 fractions and 33.75 Gy at Point A.
The morbidity and control sets were assessed and compared to see if any differences between them could be identified in any of the following areas:
- Choice of applicators. The intrauterine tubes that were used ranged in length from 35 mm to 80 mm, and the vaginal sources were contained in small, medium or large ovoids, or in vaginal cylinders. The two patient sets were reviewed across all treatment groups to see if one set showed a preference, relative to the other, for a particular applicator choice. With the Manchester System the volume of tissue irradiated, for any given prescribed dose, increases with applicator size and hence if larger applicators were more commonly used in the morbidity set this could indicate a possible dose–volume relationship.
- Height and anteversion/retroversion of the applicator set. Both the height of the applicator set within the pelvis, and the degree of anteversion or retroversion of the applicator set, varied widely, and conceivably these parameters could influence bladder dose. We have noted that overzealous posterior packing can prevent anterior vaginal packing, and the applicators may then be pushed forward causing the bladder to saddle the applicators. This not only leads to an adverse dose–volume relationship but may also increase morbidity risk due to mechanical trauma. The height of the applicators was characterized by the distance from the top of the symphysis pubis to the external os, as shown in Figure 1, and this was measured for all applications. The convention for quantifying anteversion or retroversion is shown in Figure 2. This angle was measured, to the nearest 5°, for all insertions where after-loading applicators were used.
- The ICRU bladder dose. The dose at the ICRU bladder reference point was calculated for all treatments in groups 1 and 2 who were treated on the Selectron, i.e. at the higher dose rate, and met the standard treatment criteria. It was also necessary for the bladder balloon to be present and visible on the check films at each insertion. This limited the number of cases available for comparison with 11 in the control set and 12 in the morbidity set in group 1, and five in the control set and six in the morbidity set in group 2. Subsequently, for patients in the morbidity set, the variation of the ICRU reference dose with morbidity grade was reviewed. No attempt was made to compare ICRU reference doses in groups 3 and 4 as patient numbers in the standard categories were small and the intracavitary component of the treatment was less dominant.
- Size shape and location of the bladder on the CT scans. A selection of insertions that had CT scans were reviewed to see if the size, shape and location of the bladder as it appeared on the CT scans were noticeably different between the two sets.
- Morbidity in other sites. If a patient's bladder morbidity was consequent on that patient's individual susceptibility to radiation damage then concurrent damage in other sites may be expected. To investigate this possibility the incidence of vaginal, small bowel and sigmoid, and rectal morbidity was compared in the two sets.
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Figure 1. Anteroposterior radiograph showing the convention for assessing the height of the applicator within the pelvis.
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Statistics
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Due to the small numbers in some groups a normal distribution could not be assumed and so non-parametric tests were used for the assessments. However, for the measurement of the height of the applicator in the pelvis and the total dose to the ICRU 38 bladder dose point more data was available and a two-tailed t-test was performed as well to ensure that a weak association was not missed. The parametric statistics are quoted in the text for these so as to avoid confusion. The non-parametric tests used were either a Mann-Whitney U-test or a chi squared test.
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Results
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A comparison of applicator selection in each of the two sets is shown in Figure 3. Although the number of patients was the same for each of the two sets the total number of insertions differed slightly, and hence the numbers have been normalized and presented as percentages. Nearly 90% of all the applications used central tube lengths that were either 40–45 mm or 60–65 mm where the pellet loading patterns simulated the loadings of the so-called medium and long central tubes of the historical Manchester radium system. Vaginal applicators were most commonly small ovoids, with a very small increase in the proportion of medium and large ovoids in the morbidity set. Statistical testing confirmed that there was no significant difference (for chi squared test on ovoid size p=0.97, and for intrauterine length p=0.63).
The mean height of the applicators in the pelvis was 38 mm in the control set and 35 mm in the morbidity set and in each case the standard deviation was 16 mm. Again formal testing confirmed that the difference was not statistically significant (p=0.2).
The distribution of the degree of anteversion or retroversion is shown in Figure 4. The superposed normal distribution curve is a least squares fit to the combined data from the two sets, and corresponds to a mean anteversion angle, relative to the 40° applicator, of 4.3° with a standard deviation of 9.8°. Formal testing again confirmed no statistically significant difference between the two sets (p=0.8).
The results of the dose calculations at the ICRU bladder reference point are illustrated by the scatter lines in Figure 5, where the crosses correspond to the total dose from the intracavitary component, summed over the two insertions, for individual patients. For patients in treatment group 2 the reference point received an additional dose of approximately 16.5 Gy in 16 fractions from the external beam component. Intuitively from these results one would not expect there to be a statistically significant difference between the two groups on the basis of the ICRU bladder reference doses and this is confirmed by formal statistical analysis (p=0.86 for treatment group 1 and p=0.38 for treatment group 2). The results of the review of ICRU bladder reference dose with morbidity grade in treatment groups 1 and 2 are shown in Figure 6.
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Figure 5. Ranges of dose calculated at the International Commission on Radiation Units and Measurements (ICRU) bladder reference point for patients in the control and morbidity sets in treatment groups 1 and 2.
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Figure 6. Ranges of dose at the International Commission on Radiation Units and Measurements (ICRU) bladder reference point for the different morbidity grades.
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The review of the CT data showed some cases where the bladder extended several centimetres above the external os, and others where the upper limit was at the same level or below the vaginal sources. In some cases bladder was visible lateral to the vagina, and in others it was not. Examples of these observations could be found in both sets. The numbers within any treatment group were small and there was no obvious quantifiable parameter that would be suitable for statistical evaluation.
Table 2 shows the distribution of morbidity grades between the four treatment groups. There were no grade 4 complications, and only 7 at grade 3, which is less than 2% of the treated population. Most morbidity was grade 2 (approximately 10% of the treated population). There is no evidence to suggest that the morbidity grade distribution is related to any of the treatment techniques employed.
Concurrent morbidity in other sites is shown in Table 3. 60% of patients in the bladder morbidity set also suffered vaginal morbidity compared with 27% of the control set, and this difference is shown to be highly significant when subjected to a chi squared test (p=0.0005). For morbidity in the small bowel and sigmoid the corresponding figures were 33% and 10%, and for the rectum they were 30% and 7%. These differences are also statistically significant (p=0.004 and p=0.002, respectively).
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Discussion
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On the basis of this study none of the parameters investigated, including the dose to the ICRU bladder reference point, can be used to predict an enhanced risk of bladder morbidity. Studies elsewhere have shown a relationship between bladder dose and morbidity, although it has never been possible objectively to derive a practical bladder dose limit. A consensus recommendation of a panel of experts, representing the American Brachytherapy Society (ABS) [14], was that every effort should be made to keep the intracavitary bladder dose to less than 90% of Point A dose and the total bladder dose below 80 Gy, but this recommendation was made on the basis of suggestive evidence and non-published clinical experience, rather than on published studies. Although not specifically stated in the text of their article, it is implied that the ABS recommendations apply to classical low dose rates of between 0.5 Gy h-1 and 0.65 Gy h-1 at Point A.
Tan et al [15] reported on the outcome of cervix treatments at the Clatterbridge Centre for Oncology (Merseyside, UK) where the dose rate at a second control point, located 25 mm superior to the ICRU bladder reference point and on a line parallel to the intrauterine applicator, was taken into account, as well as that at the ICRU point itself. They used a single line intracavitary applicator with a unique method for determining the source loading pattern [16], and several brachytherapy planning requirements had to be met before the treatment was allowed to proceed. Requirements pertinent to bladder dose control were that the dose rate at Point A had to be 1 Gy h-1 (±5%), the dose rate at one of the two bladder control points had to be less than 80% of that at Point A, and at the other had to be less than 120%. If these constraints were not met then the source distribution was changed or the prescribed dose was adjusted. In the Clatterbridge protocols, treatments were dominated by the external beam component with doses mainly in the range 40 Gy to 50 Gy. The intracavitary component, when given, was prescribed at Point A with the majority of patients (60.6%) being given 20 Gy in a single fraction. In 10 cases (4.4%) there was no intracavitary component. The median follow-up time was 42 months, and they reported acceptable control rates, with 54.7% actuarial incidence of grade 1 urinary complications, but only 2.7% for grade 2 and 0.6% for grade 3. They were not able to show significant correlation between the severity of the urinary complications and the dose to the reference points, although it was implied that their low incidence of serious bladder morbidity was a result of their bladder dose control strategy. In our study we focused on the dose at the ICRU reference point, as this is the only point cited in international recommendations.
Comparing results between studies is problematic owing to the different treatment regimens, which may have different prescription conventions, different relative dose contributions from the external beam and intracavitary components, different external beam doses per fraction and different intracavitary dose rates. It is well established that the brachytherapy dose rate is an important parameter in modifying the risk of normal tissue injury [17–20]. There may also be differences with concurrent chemotherapy regimens, and further difficulties in comparison arise as a result of different morbidity grading schemes.
In our study the dose rate was approximately three times that used historically in low dose rate intracavitary therapy. The group 1 treatments were by intracavitary irradiation alone, and the group 2 treatments were heavily biased towards the intracavitary component. For those patients with morbidity in treatment group 1, and for whom the ICRU bladder reference dose could be calculated, the mean was 42.1 Gy (62% of the prescribed Point A dose) with a standard deviation of 13.3 Gy. For the corresponding patients in group 2 the mean was 32.3 Gy (59% of the prescribed Point A dose) with a standard deviation of 13.8 Gy, but group 2 patients received an additional 16.5 Gy at the bladder reference point from external beam therapy. For only three patients did we calculate bladder reference doses that were greater than 90% of the prescribed Point A dose; all were in treatment group 1 and two suffered grade 2 morbidity and one was in the control set. In absolute terms the doses at the ICRU bladder reference point in our study were low. They were much lower than the 80 Gy recommended by the ABS [14] and much lower, for example, than the mean doses in the study reported by Pourquier et al [2], which, for the bladder morbidity cases, ranged from 71 Gy to 82 Gy depending on the size of the external beam component. This apparently large discrepancy in dose will be a result of the different intracavitary dose rates and the different contributions from the intracavitary and external beam components. In the French study [2] the major contribution, in all cases, was from the external beam therapy, and the cumulative bladder dose for morbidity (external beam plus brachytherapy) apparently decreased as the external beam component was reduced. For the same external beam dose these authors observed a higher mean dose to the bladder reference point from the intracavitary therapy in patients with morbidity relative to those without morbidity, but even so there was a huge overlap, and many patients who did not experience morbidity received higher doses at the reference point than many who did. In our study there was also a huge overlap and we could detect no statistically significant difference between the control and morbidity set. Lee et al [20] concluded that clinically significant injury may develop from relatively small regions of high dose, which throws some doubt on the value of the ICRU bladder reference point as this is an unreliable indicator of the maximum dose to the bladder mucosa [9, 10], but it is unlikely that this alone would explain the magnitude of the overlap.
Pourquier et al [2] also reported an increase in the severity of the complication with increasing mean bladder reference dose, and a similar trend was observed by Montana and Fowler [21] who, using a different grading system, reported a mean bladder dose of 66 Gy for patients with grade I cystitis and 68.56 Gy for patients with grade III cystitis. In our study, using the Franco-Italian system, there were no cases of grade 4 complications, i.e. no deaths, and only two cases of grade 3 in the subset for which retrospective ICRU bladder reference dose calculations were possible. The numbers, therefore, are too small to draw any statistically valid conclusions about trends. However, of the 23 patients in treatment group 1 for whom bladder reference doses could be calculated, it should be noted that there were, relative to the two patients with grade 3 morbidity, 3 patients with higher calculated bladder doses who developed lower grade morbidity, and 4 patients with higher doses who experienced no morbidity.
The most striking features of our results are the wide ranges of calculated bladder reference dose (27.3 Gy to 70.9 Gy in treatment group 1, and 15 Gy to 48.8 Gy plus external beam radiotherapy in treatment group 2) that cover the incidence of grade 2 morbidity, and the fact that there are also many patients in the control set who had higher calculated bladder reference doses than a large proportion of the patients in the morbidity set. This suggests that there may be other factors instead of, or in addition to, dose that cause, or strongly contribute to, the observed complications.
It will be essential in future to ensure that pre-existing conditions that may lead to morbidity are considered [7] and that they are accurately recorded. Hypertension, diabetes, diverticulitis and pelvic inflammatory disease [22] have been implicated in the development of morbidity, as has previous pelvic surgery [23]. Furthermore some basic patient characteristics including race, body habitus and in particular, heavy smoking have also been correlated with bladder complications following cervix radiotherapy [24]. Pelvic floor laxity due to age or multiparity is known to increase the incidence of urinary problems [25, 26], and mechanical trauma from the insertion itself could conceivably contribute to increased risk.
Another very important finding from our study was the significant correlation between morbidity in the bladder and morbidity in other pelvic sites. It cannot be assumed that this is an all round high dose effect given the tissues involved and their different relationships to each other in three-dimensional geometry. Higher than average doses in some parts of the irradiated volume will frequently be associated with lower than average doses in others. Again it remains possible that some patients have enhanced radiation sensitivity, either due to intrinsic factors or to one or more of the pre-disposing factors discussed above.
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Conclusion
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The physical factors investigated in this study cannot be used reliably to predict bladder complications. Restricting the bladder reference dose to 90% of the Point A dose, as recommended by the ABS, will not prevent bladder morbidity, but serious bladder morbidity will also not necessarily follow if bladder reference doses are above this (at least up to 100% of the Point A dose). Radiation oncologists, therefore, should be wary about reducing prescribed doses on the basis of physical parameters, and thereby risking loss of disease control. The effects of individual patient characteristics and pre-existing clinical factors, perhaps in conjunction with dose information, need to be prospectively and systematically investigated.
Received for publication October 28, 2002.
Revision received July 3, 2003.
Accepted for publication July 29, 2003.
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References
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Abstract
Introduction
) and (b) retroversion (-
