Acute and Late Toxicity in Radical Radiotherapy for Bladder Cancer

Clinical Oncology (2009) 21: 598e609 doi:10.1016/j.clon.2009.04.008

Original Article

Acute and Late Toxicity in Radical Radiotherapy for Bladder Cancer W. Majewski, R. Tarnawski Department of Radiotherapy, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Poland

ABSTRACT: Aims: To evaluate the incidence, severity and kinetics of acute and late toxicity from bladder and bowels in patients with bladder cancer treated with radical radiotherapy. Materials and methods: The retrospective analysis was based on 487 patients with T2, T3 bladder cancer, treated with radiotherapy between 1975 and 1995. The pelvis was irradiated electively in 303 patients; in the remaining patients, the bladder alone was treated. The mean total radiation dose to the bladder was 65.5 Gy. Various schedules of protracted, conventional and accelerated radiotherapy were used. The influence of selected factors on maximum acute toxicity and late toxicity was assessed. The kinetics of acute toxicity was also evaluated. The median follow-up was 76 months. Results: Seven patients did not complete treatment due to excessive acute toxicity. The incidence of grade R 3 acute bladder and bowel toxicity was 5 and 3%, respectively. The actuarial, 5-year incidence of grade R 3 late bladder and bowel toxicity was 12 and 3%, respectively. The most important factors influencing acute toxicity were: T-stage (P [ 0.004) for the bladder and pelvic irradiation (P [ 0.044) and dose intensity (P [ 0.000) for the bowels. The latency of both early bladder and bowel toxicity was correlated with dose intensity. The most important factor influencing late bladder toxicity was acute toxicity score (P [ 0.000). Late bowel toxicity was also influenced by acute bowel toxicity (P [ 0.04). Conclusions: The severity of acute bowel toxicity is related to pelvic irradiation and dose intensity. The severity of acute bladder toxicity depends on T-stage. The increase in dose intensity is associated with shorter latency to maximum acute bladder and bowel toxicity. The severity of acute bladder and bowel toxicity influences the risk of late effects from those organs. Majewski, W., Tarnawski, R. (2009). Clinical Oncology 21, 598—609 ª 2009 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Acute toxicity, bladder cancer, late toxicity, radiotherapy

Introduction Radiotherapy, as a single modality or in combination with chemotherapy, is a commonly used organ-sparing approach for patients with invasive bladder cancer, in institutions preferring conservative treatment or in case of contraindications for cystectomy [1e12]. However, the results of bladder-sparing treatment are still unsatisfactory; therefore, much effort is aimed at improving the treatment outcome. It seems that such improvement might come from the appropriate combination of chemoand radiotherapy schemes, unconventional fractionation or dose-escalation scheduling [1,2,7,8,10e12]. More intensified treatment modalities may potentially improve local control and survival rates, but on the other hand, they can be associated with increased risk of adverse effects [10,13,14]. Because radiotherapy is the integral part of bladder-sparing treatment methods, the detailed evaluation of radiation toxicity, with emphasis on the role of radiotherapy parameters, is of particular interest. 0936-6555/09/210598þ12 $36.00/0

The present analysis on adverse effects is the continuation of a previous study from our institution on the doseetimeecure relationship in bladder cancer [7]. The aim of the study was to evaluate the incidence, severity and kinetics of acute and late toxicity from bladder and bowels in patients with bladder cancer treated with radiotherapy using various fractionation schemes.

Materials and Methods Materials This retrospective study was based on 662 consecutive patients with bladder cancer treated with radical radiotherapy alone at the M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch between 1975 and 1995. The inclusion criteria were as follows: patients with histologically proven transitional cell carcinoma, clinical stage T2 or T3, age %75 years, at least one functional kidney, bladder capacity R 120 ml, no previous surgery for bladder cancer except transurethral resection/electrocoagulation, no

ª 2009 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

TOXICITY IN RADIOTHERAPY FOR BLADDER CANCER

previous chemotherapy/installations, total radiation dose O59 Gy, no previous or synchronous malignancies. The application of total radiation doses below 59 Gy in 33 patients was due to: planned total dose !59 Gy, patients’ refusal for further treatment, co-morbidities and excessive acute toxicity. Radiotherapy was prematurely finished in seven patients, due to acute toxicity. Those patients were included in the analysis of acute toxicity, but they were excluded from the analysis of late effects. All other patients with total doses below 59 Gy were not included in the study group according to the inclusion criteria. In total, 487 patients fulfilled the inclusion criteria. Detailed information on the patients’ characteristics, treatment parameters and results have been published elsewhere [7]. Before 1985, patient data consisted of a clinical examination, chest X-rays, intravenous pyelography, and laboratory blood tests. After 1985, some patients had computed tomography and pelvic ultrasound examinations. The classification of T-stage was based on cystoscopy and transurethral resection/electrocoagulation findings and bimanual examination (UICC, 1978). The patients’ characteristics are presented in Table 1.

Radiotherapy Between 1975 and 1985, 169 patients (35%) were irradiated with 60Co photons, and after 9e23 MV photons were used in 318 patients (65%).

Table 1 e Patients’ characteristics Parameter Gender Male Female Age

Patients

439 48

(%)

90 10

Mean 59 years; range 32e74 years

T-stage T2 T3

168 319

35 65

Ureteral obstruction No Yes Not specified

337 87 63

69 18 13

Bladder capacity before radiotherapy !200 ml 63 200e300 ml 189 R300 ml 176 Adequate (without 59 given absolute values)

13 39 36 12

Bladder capacity before radiotherapy

Mean 270 ml; range 120e700 ml

599

Pelvic irradiation was not used in the earlier period of our study until 1987; this was due to our previous policy for bladder cancer. From that period it has been routine in our centre to irradiate the pelvis at the first stage of radiotherapy. Radiotherapy was carried out using a partially rotational  (300 ), three- or four-field technique with the planning target volume enclosing the bladder with a 2.0 cm margin. From 1987, patients were irradiated using the 2 þ 1 technique (using high-energy X photons). The 2 þ 1 technique consisted of pelvic irradiation with two opposed AP þ PA fields to a total dose of 40e44 Gy and a subsequent  partially rotational boost field (270 or 240 ) enclosing the bladder with a 2.0 cm margin. The total radiation dose was specified to the isocentre. The total dose to the bladder ranged from 59.2 to 72 Gy, with a mean of 65.5 Gy (median 66 Gy). The overall treatment time ranged from 30 to 91 days, with a mean of 51 days. The reasons for prolonged treatment time were: fractionation scheme (split-course or protracted fractionation) and unplanned gaps due to toxicity, public holidays or machine breakdown. Various fractionation schedules were used. Most of the unconventional fractionation schedules were smaller, pilot studies carried out on consecutive years to assess their efficacy. In the earlier period of the study (1975e1983), a comparison study was conducted to evaluate the results of split-course vs continuous-course radiotherapy. Most of the patients were treated with conventional fractionation. Detailed characteristics of treatment-related parameters are shown in Table 2. In the accelerated hyperfractionated boost group the pelvis was initially irradiated once a day and then a boost was given twice a day with a minimum gap of 6 h between fractions. In the accelerated hyperfractionation group the pelvis was initially irradiated twice a day and subsequently twice a day a boost was given. The minimum gap between daily fractions was 6 h. The protracted fractionation scheme was prolonged pelvic irradiation with a dose per fraction of 1.6e1.7 Gy. Because the dose intensity for the protracted and splitcourse fractionation groups were similar, these patient groups were analysed together.

Follow-up Patients had scheduled follow-up appointments every month during the first year after the completion of radiotherapy, every 2 months during the second year, and every 4e6 months thereafter; in long-term survivors, follow-up appointments were annual. The first cystoscopic examination was carried out 3e4 months after the completion of radiotherapy. During the first 3 years after irradiation they were carried out at least two times a year and thereafter at least annually. In cases of patient complaints indicating late bowel morbidity, a rectoscopy or colonoscopy was carried out, when necessary. The median follow-up was 75.5 months and ranged from 6 to 187 months. Only 54 (11%) and 15 (3%) patients were lost from follow-up before 5 and 2 years, respectively, after irradiation.

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Table 2 e Treatment-related parameters Parameter Technique of irradiation Rotational Three- or four-field 2þ1 Fractionation schedule (1) Split-course (SCF)/protracted fractionation (PF)* Small fields, once a day, 1.8e2.5 Gy/fraction If treated: pelvis, once a day, 1.6e1.7 Gy (PF)/2.0 Gy/fraction (SCF) (2) Conventional fractionation (CF) Pelvis and boost once a day, 1.8e2.5 Gy/fraction (3) Accelerated hyperfractionated boost (AHB) Pelvis once a day, 2.0 Gy/fraction Boost twice a days, 1.3e1.4 Gy/fraction (4) Accelerated hyperfractionation (AHF) Pelvis and subsequent boost twice a day, 1.2e1.5 Gy/fraction Mean total dose/mean overall treatment time by fractionation schedule

Dose per fraction: pelvis Dose per fraction: boost Total radiation dose 59.2e!64 Gyy 64e!68 Gy 68e72 Gy Total radiation dose Overall treatment time 30e!40 days 40e!50 days 50e!60 days 60e!70 days R70 days Overall treatment time Dose intensity Dose intensity !9 Gy/week 9e10 Gy/week 10e12 Gy/week O12 Gy/week

Patients

(%)

134 50 303

28 10 62

171

35

193

40

38

8

85

17

SCF/PF 66 Gy/60 days CF 65.4 Gy/53 days AHB 66 Gy/45 days AHF 65.6 Gy/41 days Median 2.0 Gy (1.2e2.5 Gy) Median 2.0 Gy (1.2e2.5 Gy) 91 309 87 Mean 65.5 Gy, Median 66 Gy (59.2e72 Gy)

19 63 18

68 167 156 71 25 Mean 51 days, Median 50 days (30e91 days) Mean 9.3 Gy/week, Median 9.1 Gy/week (5e15 Gy/week)

14 34 32 15 5

87 157 144 99

18 32 30 20

*In SCF, the split was introduced after pelvic irradiation and lasted between 1 and 2 weeks. ySeven patients did not finish planned RT and received doses lower than 59 Gy due to pronounced toxicity.

End Points and Statistics Overall survival and local control rates were calculated from the start of radiotherapy using an actuarial method. The data on both acute and late toxicity were retrospectively collected from patients’ charts and then scored according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) classification (Appendix). The analysis was based on the evaluation of the maximum toxicity score throughout treatment for each patient. The crude toxicity rates were compared between fractionation schedules using the chi-squared test. The probability of acute treatment toxicity in relation to selected clinical and treatment-related factors was estimated using ordinal multinomial logistic regression. In general, the

same factors that were analysed in the univariate model were also included in the multivariate analysis irrespective of the significance level. However, we used dose intensity instead of the normalised dose and overall treatment time because seven patients had treatment terminated prematurely, due to early toxicity, and many patients had treatment gaps, which could have influenced the results of the analysis. The total radiation dose was converted into EQD2 and was calculated using the incomplete repair model according to equation (1) [15]: EQD2 ¼ Dd  ð1 þ HmÞ þ ða=bÞ=2þða=bÞ

ð1Þ

where D ¼ total dose, d ¼ dose per fraction, Hm ¼ incomplete repair factor. We assumed a/b ¼ 10 and

TOXICITY IN RADIOTHERAPY FOR BLADDER CANCER

601

Table 3 e Acute bladder toxicity by analysed factors (uni- and multivariate ordinal multinomial logistic regression) Acute bladder toxicity rate

Multinomial logistic regression Univariate coefficient

G0

G1

G2

G3þ

T-stage T2 T3 Ureteral obstruction

52% 37%

27% 39%

19% 17%

2% 7%

0.47

0.01

0.640

0.004

42% 37%

36% 40%

17% 18%

5% 5%

0.14

0.53

0.016

0.95

Bladder capacity !200 ml 200e300 ml O300 ml

35% 38% 47%

30% 40% 32%

25% 16% 16%

10% 6% 5%

0.002

0.02

0.001

0.24

Age !50 years 50e60 years 60e70 years O70 years

43% 41% 43% 41%

35% 36% 35% 33%

19% 16% 18% 20%

3% 6% 4% 6%

0.001

0.89

0.019

0.11

Beam energy 60 Co X 9e20 MV

41% 42%

33% 36%

21% 17%

5% 5%

0.113

0.52

0.589

0.14

Pelvic irradiation No Yes

42% 42%

33% 36%

20% 17%

5% 5%

0.096

0.58

0.184

0.63

EQD2 !64 Gy 64e66 Gy 66e68 Gy R68 Gy

40% 40% 47% 41%

33% 37% 35% 36%

17% 18% 17% 19%

10% 5% 1% 4%

0.037

0.10





Overall treatment time 30e!40 days 47% 40e!50 days 45% 50e!60 days 37% 60e!70 days 49% R70 days 16%

35% 37% 37% 31% 28%

15% 14% 22% 14% 32%

3% 4% 4% 6% 24%

0.029

0.00





Dose intensity !9 Gy 9e10 Gy 10e12 Gy O12 Gy

30% 36% 42% 33%

16% 20% 18% 19%

7% 3% 5% 2%

0.020

0.63

0.032

0.49

No Yes

47% 41% 35% 46%

P-value

Multivariate coefficient

Factors

P-value

All continuous-scale factors were analysed in the logistic model as continuous variables.

a repair half-time of 1 h for acute bladder and intestine toxicities. Dose intensity was presented as a dose accumulated during 1 week. It was calculated as a dose accumulated to the time point of maximum acute toxicity score and divided by latency in weeks. In case of no toxicity or toxicity occurring after the completion of radiotherapy, as well as for late effects, dose intensity was simply calculated as the ratio of total radiation dose and overall treatment time. A comparison of acute toxicity kinetics between selected groups of patients was carried out using the non-parametric KruskalleWallis test.

Late toxicities were evaluated using both the crude and actuarial methods, based on the maximum late toxicity score after treatment. The late toxicity scoring was based on the RTOG/EORTC scale (Appendix). Latency was calculated from the end of radiotherapy. Symptoms were regarded as late toxicity if they occurred or persisted after the third month from the end of radiotherapy. If no toxicity occurred, patients were censored at last follow-up. The risk of late radiation toxicity with respect of selected factors was estimated using the Cox proportional hazard model [16]. The same factors that were analysed in the univariate model were also included in the multivariate analysis, irrespective of significance level.

602

CLINICAL ONCOLOGY

Table 4 e Acute bowel toxicity by analysed factors (uni- and multivariate ordinal multinomial logistic regression) Acute bowel toxicity rate

Multinomial logistic regression

Factors

G0

G1

G2

G3þ

Univariate coefficient

P-value

Multivariate coefficient

P-value

Age !50 years 50e60 years 60e70 years O70 years

57% 65% 59% 65%

22% 24% 20% 24%

19% 7% 17% 6%

2% 4% 4% 5%

0.002

0.88

0.009

0.44

Beam energy 60 Co X 9e20 MV

76% 54%

17% 24%

4% 17%

3% 5%

1.010

0.00

0.042

0.92

Pelvic irradiation No Yes

76% 53%

17% 24%

4% 18%

3% 5%

1.130

0.00

0.870

0.05

EQD2 !64 Gy 64e66 Gy 66e68 Gy R68 Gy

56% 63% 54% 86%

19% 22% 31% 10%

16% 13% 12% 4%

9% 2% 3% 0%

0.068

0.004





Overall treatment time 30e!40 days 43% 40e!50 days 54% 50e!60 days 65% 60e!70 days 84% R70 days 72%

28% 26% 22% 10% 12%

22% 16% 10% 4% 8%

7% 4% 3% 2% 8%

0.044

0.00





Dose intensity !9 Gy 9e10 Gy 10e12 Gy O12 Gy

13% 32% 24% 24%

6% 11% 18% 28%

1% 2% 4% 16%

0.430

0.00

0.405

0.00

80% 55% 54% 32%

All continuous-scale factors were analysed in the logistic model as continuous variables.

Normalised doses (EQD2 Gy) for late toxicity were calculated using equation (1), assuming a/b ¼ 6 for bladder and a/b ¼ 3 for bowel and a repair half-time of 2.5 h.

Results Actuarial 5- and 10-year local control rates were 47 and 41%, respectively, and actuarial 5- and 10-year overall survival rates were 40 and 28%, respectively.

Acute Radiation Toxicity Radiotherapy was well tolerated. Only 5 and 3% of patients had severe (grade R 3) acute bladder and bowel toxicities, respectively. Seven patients (1.5%) did not complete RT due to excessive toxicity. Tables 3 and 4 show the results of ordinal multinomial logistic regression. Acute bladder toxicity was mainly influenced by T-stage. Dose intensity was not correlated with early bladder reactions. The most important factors influencing the probability of acute bowel toxicity were: pelvic irradiation and dose intensity.

The acute bowel toxicity, but not bladder early radiation toxicity, was significantly associated with the fractionation schedule (Tables 5 and 6). The mean latency period to the maximum acute bladder toxicity was not different (40e42 days) between all types of fractionation. However, a shortening of latency to maximum bladder toxicity with acceleration of treatment was observed when a dose intensity parameter was used instead of the fractionation schedule. Also, the latency to acute bowel toxicity was correlated with dose intensity (Figs. 1 and 2). This implies that accumulated dose is important for both acute bladder and bowel toxicity.

Late Toxicity The 5-year actuarial risk of moderate (grade R 2) and severe (grade R 3) late toxicities was 35 and 12%, respectively, for bladder and 7 and 3%, respectively, for bowels. Tables 7 and 8 present the results of the Cox proportional hazard regression (all factors were verified for proportionality assumptions). The most important risk indicator of the late bladder toxicity was the acute bladder

TOXICITY IN RADIOTHERAPY FOR BLADDER CANCER 160

Acute bladder toxicity grade

SCF/PF (n ¼ 171) CF (n ¼ 193) AHB (n ¼ 38) AHF (n ¼ 85) Overall (n ¼ 487) Chi-squared test P-value

0

1

67 (39%) 81 (42%) 16 (42%) 41 (48%) 205 (42%) 2.82 0.97

62 66 14 29 171

2

(36%) (34%) (37%) (34%) (35%)

33 36 6 11 86

3

(19%) (19%) (16%) (13%) (18%)

9 10 2 4 25

(5%) (5%) (5%) (5%) (5%)

Latency period (days)

Table 5 e Acute bladder toxicity by fractionation schedule

Fractionation schedule

toxicity score. The severity of acute bowel toxicity also had a significant effect on late bowel toxicity. Figures 3 and 4 show the actuarial freedom from grade R 2 late bladder or bowel toxicity in relation to various acute toxicity grades. In patients with urethral obstruction, the risk of late bladder toxicity was, unexpectedly, significantly lower than in patients without urethral obstruction. Interestingly, younger patients had significantly higher risk of late bowel effects than older patients. Although the multivariate analysis did not reveal a significant role of pelvic irradiation for the risk of late bowel toxicity, the late bowel effects occurred in four patients (2%) not irradiated to pelvic volume and in 34 patients (11%) irradiated to the pelvis. On univariate analysis, pelvic irradiation had a significant effect on late bowel toxicity (P ¼ 0.01). Tables 9 and 10 summarise late toxicity scores in relation to the fractionation schedule. The fractionation schedule was not a significant factor in relation to late bladder toxicity, but it was of prognostic importance for

100 80 60 40

1 32 49 9 20 110

(19%) (25%) (24%) (23%) (23%)

2 6 21 6 28 61

(3.5%) (11%) (16%) (33%) (12%)

3 1 4 0 11 16

4

6

8

10

12

14

16

18

Dose Intensity (Gy/week) Fig. 1 e Correlation between dose intensity and latency to the development of the maximum acute bladder toxicity. Spearman R ¼ 0.75, P ¼ 0.000.

late bowel toxicity. However, the relationship between fractionation schedule and late bowel toxicity did not strictly follow the increase in dose intensity because the most pronounced late bowel toxicity was observed in partially accelerated treatment (accelerated hyperfractionated boost). No significant differences in latency to late toxicity in relation to fractionation schedule were observed.

Discussion Acute Toxicity The relationship between the probability of acute bowel toxicity and treatment-related parameters was more predictable by radiobiological principles than for acute bladder toxicity. In the current analysis, dose intensity was significantly related to the probability and severity of acute bowel toxicity, which is a typical observation for hierarchical, early-reacting tissues [17,18]. This is caused

(0.5%)* (2%)* (0%) (13%) (3%)

SCF, split-course fractionation; PF, protracted fractionation; CF, conventional fractionation; AHB, accelerated hyperfractionated boost; AHF, accelerated hyperfractionation. *One patient in SCF and CF group with grade 4 toxicity.

Latency period (days)

0

2

140

Acute bowel toxicity grade

132 (77%) 119 (62%) 23 (60%) 26 (31%) 300 (62%) 92 0.00

120

20

Table 6 e Acute bowel toxicity by fractionation schedule

SCF/PF (n ¼ 171) CF (n ¼ 193) AHB (n ¼ 38) AHF (n ¼ 85) Overall (n ¼ 487) Chi-squared test P-value

140

0

SCF, split-course fractionation; PF, protracted fractionation; CF, conventional fractionation; AHB, accelerated hyperfractionated boost; AHF, accelerated hyperfractionation.

Fractionation schedule

603

120 100 80 60 40 20 0

4

6

8

10

12

14

16

18

20

Dose Intensity (Gy/week) Fig. 2 e Correlation between dose intensity and latency to the development of the maximum acute bowel toxicity. Spearman R ¼ 0.53, P ¼ 0.000.

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CLINICAL ONCOLOGY

Table 7 e The influence of the selected factors on the actuarial risk of late bladder toxicity (uni- and multivariate Cox proportional hazard analysis)

Parameter

Median time to bladder toxicity (months)

Grade R2 late bladder toxicity

Grade R2 late bladder toxicity

Univariate analysis

Multivariate analysis

Coeff. B

expB (RR)

P-value

Coeff. B

expB (RR)

P-value

T-stage T2 T3

13 12

0.25

1.29

0.17

0.11

1.11

0.67

Ureteral obstruction No Yes

12 12

0.45

1.56

0.13

0.78

2.18

0.02

Bladder capacity !200 ml 200e300 ml O300 ml

11 12 12

0.001

0.99

0.53

0.001

1.0

0.54

Age !50 years 50e60 years 60e70 years O70 years

14 15 12 9.5

0.008

1.01

0.42

0.012

1.01

0.36

Beam energy 60 Co X 9e20 MV

15 12

0.35

1.42

0.08

0.47

1.60

0.36

Pelvic irradiation No Yes

14 12

0.23

1.26

0.24

0.068

0.93

0.88

EQD2 !64 Gy 64e66 Gy 66e68 Gy O68 Gy

12 11.5 12 17

0.05

0.95

0.12

0.015

0.99

0.74

Dose intensity !9 Gy/week 9e10 Gy/week 10e12 Gy/week O12 Gy/week

12 11.5 13.5 15

0.036

0.96

0.46

0.105

1.11

0.50

Treatment time 30e!40 days 40e!50 days 50e!60 days 60e!70 days R70 days

11 12 11 14 19

0.009

1.01

0.29

0.011

1.01

0.70

Acute toxicity Grade 0 Grade 1 Grade 2 Grade 3þ

19 12 9 11

0.49

1.64

0.00

0.560

1.75

0.00

All continuous-scale factors were analysed in the Cox proportional hazard model as continuous variables.

by depopulation of the epithelium, which overcomes its regenerative capacity. In some studies, the excessive shortening of the overall treatment time, associated with too high dose intensity, has even resulted in high,

unacceptable acute bowel toxicity [13,14]. On the other hand, such a relationship was not observed in the present study for the bladder. The lack of clear influence of dose intensity on acute bladder toxicity may be explained by

TOXICITY IN RADIOTHERAPY FOR BLADDER CANCER

605

Table 8 e The influence of the selected factors on the actuarial risk of late bowel toxicity (uni- and multivariate Cox proportional hazard analysis) Grade R 2 late bladder toxicity

Grade R 2 late bladder toxicity

Univariate analysis

Multivariate analysis

Median time to bowel toxicity (months)

Coeff. B

expB (RR)

P-value

Coeff. B

expB (RR)

P-value

Age !50 years 50e60 years 60e70 years O70 years

18.5 14 11 6

0.05

0.94

0.01

0.056

0.95

0.01

Beam energy 60 Co X 9e20 MV

12 13

2.38

10.84

0.02

1.610

5.00

0.32

Pelvic irradiation No Yes

12 13.5

2.45

11.7

0.01

1.102

2.98

0.50

EQD2 !64 Gy 64e66 Gy 66e68 Gy R68 Gy

11 13 31 

0.066

0.94

0.27

0.090

1.10

0.29

Dose intensity !9 Gy/week 9e10 Gy/week 10e12 Gy/week O12 Gy/week

13 15 13 12

0.12

1.13

0.24

0.300

0.74

0.41

Treatment time 30e!40 days 40e!50 days 50e!60 days 60e!70 days R70 days

12 14 12 16 

0.03

0.97

0.24

0.080

0.93

0.34

Acute toxicity Grade 0 Grade 1 Grade 2 Grade 3þ

43 12 10 10

0.59

1.8

0.004

0.490

1.63

0.04

Parameter

All continuous-scale factors were analysed in the Cox proportional hazard model as continuous variables.

a slow bladder epithelium turnover [19,20] or by the fact that bladder toxicity results mainly from functional disturbances of bladder walls [21], which appear early after the start of radiotherapy and may not be so dependent on dose intensity. With the increase in dose intensity we also observed a significant shortening of the latency to maximum acute bladder and bowel toxicity. In the case of bowels, it is not surprising, but in the case of the bladder it needs explanation. The correlation between latency to bladder toxicity and dose intensity may be in large part caused by the inflammatory and functional nature of the response to radiation injury [22]. However, other factors may also have some influence, such as a relatively accelerated

cellular turnover in bladder irritated by multiple transurethral resections, concomitant infections etc., which makes bladder reaction latency similar to those in bowels. EQD2 has not influenced acute bladder toxicity significantly, and caused an inverse correlation with acute bowel toxicity in the current univariate analysis. This was caused by the seven cases who terminated treatment with lower total doses due to excessive toxicity. Therefore, EQD2 was not included in the final multivariate model. However, when the model was calculated after the exclusion of the seven cases with excessive toxicity (results not shown), EQD2 was not statistically significant for acute bladder and bowel toxicity.

Actuarial freedom from Grade >=2 Late Bladder Toxicity (%)

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CLINICAL ONCOLOGY

to have a poorer response to radiotherapy. These factors, together with bladder irritation during radiotherapy, could probably lead to more intensified symptoms in patients with a higher T-stage.

100 90 80 GRADE-0

70 GRADE-1

60 50

Late Toxicity

GRADE-2

40 30 20 GRADE-3

10 0

0

20

40

60

80

100

120

140

160

180

200

220

Months

Fig. 3 e Influence of the acute bladder toxicity score on the actuarial freedom from grade R2 late bladder toxicity.

Actuarial freedom from Grade>=2 Late Bowel Toxicity (%)

It is obvious that with the increase in total dose up to high levels, toxicity should increase, but the lack of a clear doseeeffect relationship for acute toxicity in the present study might be caused by the narrow range of total doses (mean 65.5 Gy, standard deviation 2.65 Gy) and treatment modifications in case of progressive toxicity (gaps, dose restrictions, etc.). Also, it is possible that the retrospective and inhomogeneous nature of our material could have had a role. However, in some studies there has also not been a clear doseeresponse relationship between dose and acute bladder [22e24] and bowel [24e26] toxicity within a given range of total doses. The influence of pelvic irradiation on acute bowel toxicity is justifiable, because it is a result of the larger volume of the bowels within the planning target volume. On the basis of our study, it seems that the important factor for acute bladder toxicity is T-stage, which is similar to the observation of Tonoli et al. [12]. More extensive tumours (higher T-stage) are probably associated with more pronounced pre-treatment symptoms. Moreover, they tend

100 GRADE-2

90 GRADE-3

80

GRADE-0 GRADE-1

70 60 50 40 30 20 10 0

0

20

40

60

80

100

120

140

160

180

200

220

Months

Fig. 4 e Influence of the acute bowel toxicity score on the actuarial freedom from grade R2 late bowel toxicity.

The severity of late bladder and bowel toxicity was significantly and strongly correlated with acute toxicity. Other investigators have also recorded a significant association between acute and late toxicity from both bladder and bowels [27,28]. However, a low number of patients with late grade R 2 late bowel toxicity (21 patients) in our study make the interpretation of the results on late bowel toxicity cautious, as opposed to the results on late bladder toxicity. Despite an earlier concept of the differentiation between the mechanism and target cells for acute and late effects [29], a concept of comprehensive relationships at the cellular and molecular level, explaining the mechanisms of acute and late radiation toxicity and their association, is now more common [18,30]. In case of the relationship between acute and late bladder toxicity, there is probably another mechanism. The slow bladder epithelium turnover leads to the development of persisting and delayed adverse radiation effects, which are morphologically characteristic for acute toxicity [20], but according to the latency criteria they are considered as a late toxicity. A relatively high a/b  6 for late bladder toxicity estimated by some investigators [31] indicates that a potential advantage of accelerated hyperfractionation may be considerably diminished by late toxicity, especially with high dose intensity scheduling. It was reported by clinical investigations [14,32], and may be caused by incomplete repair of sublethal damage between daily fractions, due to the slow component of repair [33]. However, several other studies suggest moderate and acceptable late bladder and bowel toxicity in accelerated treatments [13,34e36]. Our results showed no significant relationship between dose intensity and late bladder and bowel toxicity, which suggests that moderate treatment acceleration may not be associated with increased late effects. Experimental as well as clinical studies have revealed a doseeresponse relationship of late bladder [20,21,27,28] and bowel morbidity [27,28,37]. We did not observe a significant association between EQD2 and late bladder and bowel toxicity. Perhaps the range of total doses between 60 and 70 Gy is within the area of slight to moderate risk of late bladder toxicity [38,39] and severity of late bladder effects might potentially increase steeply above some dose threshold (for instance O70 Gy) [8]. With respect to both bowel and bladder toxicity, treatment modifications by dose limitation in case of pronounced acute toxicity could also be responsible for a diminishing late doseeeffect relationship. Moreover, a relatively low number of analysed events and the retrospective character of our study influenced the possibility to detect potential relationships.

TOXICITY IN RADIOTHERAPY FOR BLADDER CANCER

607

Table 9 e Late bladder toxicity and its kinetics by fractionation schedule Late bladder toxicity grade Fractionation schedule SCF/PF (n ¼ 171) CF (n ¼ 187) AHB (n ¼ 38) AHF (n ¼ 84) Overall (n ¼ 480) Test P-value

0 115 125 23 51 314

(67%) (67%) (61%) (61%) (65%)

1 13 22 3 7 45

2

(8%) (12%) (8%) (8%) (9%)

3

24 (14%) 31 (17%) 9 (24%) 15 (18%) 79 (16%) 16.9* 0.15

15 9 3 11 38

(9%) (5%) (8%) (13%) (8%)

4 4 (2%) 0 (0%) 0 (0%) 0 (0%) 4 (1%) 1.11y 0.77

Mean latency period (months) 16 19 15 19 18

SCF, split-course fractionation; PF, protracted fractionation; CF, conventional fractionation; AHB, accelerated hyperfractionated boost; AHF, accelerated hyperfractionation. *Chi-squared test. yKruskall-Wallis test.

Table 10 e Late bowel toxicity and its kinetics by fractionation schedule Late bowel toxicity grade Fractionation schedule SCF/PF (n ¼ 171) CF (n ¼ 187) AHB (n ¼ 38) AHF (n ¼ 84) Overall (n ¼ 480) Test P-value

0 164 174 32 71 441

(96%) (93%) (84%) (85%) (92%)

1 4 6 0 8 18

(2%) (3%) (0%) (10%) (4%)

2

3

0 (0%) 1 (0.5%) 2 (5%) 2 (2%) 5 (1%) 35.5* 0.000

3 4 1 1 9

(2%) (2%) (2%) (1%) (2%)

4 0 (0%) 2 (1%) 3 (8%) 2 (2%) 7 (1%) 4.72y 0.19

Mean latency period (months) 31 18 17 10 18

SCF, split-course fractionation; PF, protracted fractionation; CF, conventional fractionation; AHB, accelerated hyperfractionated boost; AHF, accelerated hyperfractionation. *Chi-squared test. yKruskall-Wallis test.

More pronounced bladder toxicity in patients without ureteral obstruction and higher risk of bowel late toxicity in younger patients may be partially explicable by the fact that those patients are at higher risk of developing late toxicity due to better prognosis and longer survival. The rates of late bladder and bowel toxicity in our study were quite acceptable and comparable with other published series [8,12,40]. On the other hand, most investigators have reported higher acute toxicity rates than in the present study, especially in accelerated treatment regimens [3,6,14,25,34e36]. We assume that some underestimation of adverse effects is conceivable in our retrospective study comprising clinical material from a 20-year period. However, in our opinion it may be the cause for slight effects, as those that were strenuous were commonly reported by patients during radiotherapy and follow-up. Quality of life analyses have indicated good quality of life and patient satisfaction, with appropriate bladder function in 74e84% of patients [41,42]. This corresponds with the rate of patients without or experiencing only minor bladder morbidity (grade 0e1) observed in the current study. However, the analysis of post-irradiation bowel function showed conflicting results, because late bowel complaints were reported by 29e32% of patients in some studies

[41,42], and in another analysis only 3% of patients complained of rectal bleeding and 3% of diarrhoea [43]. Nevertheless, the results of those investigations suggest that in retrospective studies of radiotherapy for bladder cancer, late bowel toxicity may be underestimated. The retrospective nature of our study was associated with other constraints: it was not possible to estimate precisely the kinetics of recovery from acute toxicity as well as reliably and accurately estimate radiobiological parameters of acute radiation toxicity, such as a/b or repopulation (Dprolif). This was caused, among others, by treatment modification in patients with more pronounced acute toxicity (i.e. gaps, prolonging treatment, dose limitations).

Conclusions The retrospective analysis of our material revealed that the risk factors of acute bowel toxicity were: pelvic irradiation and dose intensity. The risk factor of acute bladder toxicity was T-stage. An increase in dose intensity was associated with a significantly shorter latency period to the development of the maximum acute bladder and bowel toxicity. The severity of acute bladder and bowel toxicity significantly influenced the risk of late effects from those organs.

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Appendix Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scoring system for acute and late bladder and bowel reactions Grade

Bladder

Bowels

Acute radiation toxicity 1 Frequency of urination/nocturia twice pre-treatment habit, dysuria, urgency not requiring medication 2

3

4

Increased frequency or change in quality of bowel habits not requiring medication/rectal discomfort not requiring analgesics Diarrhoea requiring parasympathologic drugs/mucous discharge not necessitating sanitary pads/rectal or abdominal pain requiring analgesics Diarrhoea requiring parenteral support/severe mucous or blood discharge necessitating sanitary pads/abdominal distention (flat plate radiograph shows distended bowel loops) Acute or subacute obstruction, fistula or perforation. Gastrointestinal bleeding requiring transfusion, abdominal pain tenesmus requiring tube decompression or bowel diversion

Frequency of urination or nocturia that is less than every hour. Dysuria, urgency bladder spasm requiring local anaesthetic Frequency with urgency and nocturia hourly or more frequently/dysuria, pelvis pain or bladder spasm requiring frequent narcotic/gross haematuria with/without clot passage Haematuria requiring transfusion not secondary to clot passage, ulceration or necrosis

Late radiation toxicity 1 Slight epithelial atrophy. Minor teleangictasia (microscopic haematuria) 2 Moderate frequency-generalised teleangiectasia. Intermittent macroscopic haematuria 3

4

Mild diarrhoea. Mild cramping. Bowel movement less than five times daily. Slight rectal discharge or bleeding Moderate diarrhoea and colic bowel movement more than five times daily. Excessive rectal or mucous or intermittent bleeding Obstruction or bleeding requiring surgery

Severe frequency and dysuria. Severe generalised teleangiectasia (often with petechiae). Frequent haematuria. Reduction in bladder capacity (!150 ml) Necrosis. Contracted bladder (capacity !100 ml), severe hemorrhagic cystitis

Author for correspondence: W. Majewski, Department of Radiotherapy, Maria Sklodowska-Curie Cancer Center and Institute of Oncology, Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-100 Gliwice, Poland. Tel/Fax: þ4832-278-80-01; E-mail: wmajewski1@ poczta.onet.pl Received 14 October 2007; received in revised form 26 February 2009; accepted 28 April 2009

Necrosis. Perforation. Fistula

6

7

8

References 1 Cerevek J, Cufer T, Krageli B, Zakotnik B, Stanonik M. Sequential transurethral surgery, multiple drug chemotherapy, and radiation for invasive bladder carcinoma: initial report. Int J Radiat Oncol Biol Phys 1993;25:777e782. 2 Coppin CML, Gospodarowicz MK, James K, et al. Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. J Clin Oncol 1996;14: 2901e2907. 3 Cowan RA, McBain CA, Ryder WDJ, et al. Radiotherapy for muscle-invasive carcinoma of the bladder: results of a randomized trial comparing conventional whole bladder with doseescalated partial bladder radiotherapy. Int J Radiat Oncol Biol Phys 2004;59:197e207. 4 Davidson SE, Symonds RP, Snee MP, Upadhyay S, Habeshaw T, Robertson AG. Assessment of factors influencing the outcome of radiotherapy for bladder cancer. Br J Urol 1990;66:288e293. 5 Duncan W, Quilty PM. The results of a series of 963 patients with transitional cell carcinoma of the urinary bladder primarily

9 10

11

12

13

treated by radical megavoltage X-ray therapy. Radiother Oncol 1986;7:299e310. Horwich A, Dearnaley D, Huddart R, et al. A randomised trial of accelerated radiotherapy for localized invasive bladder cancer. Radiother Oncol 2005;75:34e43. Majewski W, Maciejewski B, Majewski S, Suwinski R, Miszczyk L, Tarnawski R. Clinical radiobiology of stage T2eT3 bladder cancer. Int J Radiat Oncol Biol Phys 2004;60:60e70. Pollack A, Zagars GK, Swanson DA. Muscle-invasive bladder cancer treated with external beam radiotherapy: prognostic factors. Int J Radiat Oncol Biol Phys 1994;30:267e277. Salminen E. External beam radiation treatment of urinary bladder carcinoma. Acta Oncol 1990;29:909e914. Shipley WU, Winter KA, Kaufman DS, et al. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol 1998;16: 3576e3583. Tester W, Caplan R, Heaney J, et al. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol 1996;14:119e126. Tonoli S, Bertoni F, de Stefani A, et al. Radical radiotherapy for bladder cancer: retrospective analysis of a series of 459 patients treated in an Italian institution. Clin Oncol (R Coll Radiol) 2006;18:52e59. Cole DJ, Durrant KR, Roberts JT, Dawes JTK, Yosef H, Hopewell W. A pilot study of accelerated fractionation in the

TOXICITY IN RADIOTHERAPY FOR BLADDER CANCER

14

15

16 17

18 19 20

21

22

23

24 25

26

27

28

29

radiotherapy of invasive carcinoma of the bladder. Br J Radiol 1992;65:792e798. Moonen L, van der Voet H, Horenblas S, Bartelink H. A feasibility study of accelerated fractionation in radiotherapy of carcinoma of the urinary bladder. Int J Radiat Oncol Biol Phys 1997;37: 537e542. Joiner MC, Bentzen SM. Timeedose relationships: the linearquadratic approach. In: Steel GG, editor. Basic clinical radiobiology. London: Arnold; 2002. Cox DR. Regression models and life-tables. J R Stat Soc B 1972; 34:187e220. Bentzen SM, Saunders MI, Dische S, Bond SJ. Radiotherapyrelated early morbidity in head and neck cancer: quantitative clinical radiobiology as deduced from the CHART trial. Radiother Oncol 2001;60:123e135. Denham JW, Hauer-Jensen M. The radiotherapeutic injuryea complex wound. Radiother Oncol 2002;63:129e145. Hainau B, Dombernowsky P. Histology and cell proliferation in human bladder tumors. Cancer 1974;33:115e126. Stewart FA. Mechanism of bladder damage and repair after treatment with radiation and cytostatic drugs. Br J Cancer 1986;53:280e291. Dorr W, Eckhardt M, Ehme A, Koi S. Pathogenesis of acute radiation effects in the urinary bladder. Strahlenther Oncol 1998;174(Suppl III):93e95. Denham JW, Hauer-Jensen M, Kron T, Langberg CW. Treatmenttime-dependence models of early and delayed radiation injury in rat small intestine. Int J Radiat Oncol Biol Phys 2000;48:871e887. Cox JD, Guse C, Asbell S, Rubin P, Sause WT. Tolerance of pelvic normal tissues to hyperfractionated radiation therapy: results of protocol 83-08 of the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1988;15:1331e1336. Morrison R. The results of treatment of cancer of the bladder e a clinical contribution to radiobiology. Clin Radiol 1975;26:67e75. Quilty PM, Duncan W, Kerr GR. Results of a randomised study to evaluate influence of dose on morbidity in radiotherapy for bladder cancer. Clin Radiol 1985;36:615e618. Vijayakumar S, Awan A, Karrison T, et al. Acute toxicity during external-beam radiotherapy for localized prostate cancer: comparison of different techniques. Int J Radiat Oncol Biol Phys 1993;25:359e371. Zelefsky MJ, Cowen D, Fuks Z, et al. Long term tolerance of high dose three-dimensional conformal radiotherapy in patients with localized prostate carcinoma. Cancer 1999;85:2460e2468. Schultheiss TE, Lee WR, Hunt MA, Hanlon AR, Peter RS, Hanks GE. Late GI and GU complications in the treatment of prostate cancer. Int J Radiat Oncol Biol Phys 1997;37:3e11. Michalowski A. On radiation damage to normal tissues and its treatment. I Growth factors. Acta Oncol 1990;29:1017e1023.

609

30 Williams J, Chen Y, Rubin P, Finkelstein J, Okunieff P. The biological basis of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003; 13:182e188. 31 Bentzen SM, Lundbeck F, Christensen LL, Overgaard J. Fractionation sensitivity and latency of late radiation injury to the mouse urinary bladder. Radiother Oncol 1992;25:301e307. 32 Lievens Y, Vanuytsel L, Rijnders A, van Poppel H, van der Schueren E. The time course of development of late side effects after irradiation of the prostate with multiple fractions per day. Radiother Oncol 1996;40:147e152. 33 van der Aardweg GJMJ, Hopewell JW. The kinetics of repair for sublethal radiation-induced damage in the pig epidermis: an interpretation based on a fast and slow component of repair. Radiother Oncol 1992;23:94e104. 34 Plataniotis G, Michalopoulos E, Kouvaris J, Vlahos L, Papavasiliou C. A feasibility study of partially accelerated radiotherapy for invasive bladder cancer. Radiother Oncol 1994; 33:84e87. 35 Pos FJ, van Tienhoven G, Hulshof MCCM, Koedooder K, Gonzales DG. Concomitant boost radiotherapy for muscleinvasive bladder cancer. Radiother Oncol 2003;68:75e80. 36 Yavuz AA, Yavuz MN, Ozgur GK, et al. Accelerated superfractionated radiotherapy with concomitant boost for invasive bladder cancer. Int J Radiat Oncol Biol Phys 2003;56:734e745. 37 Pilepich MV, Krall JM, Sause WT, et al. Correlation of radiotherapeutic parameters and treatment related morbidity in carcinoma of the prostate e analysis of RTOG study 75-06. Int J Radiat Oncol Biol Phys 1987;13:351e357. 38 Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21: 109e122. 39 Rubin P, Casarett G. A direction for clinical radiation pathology. The tolerance dose. Front Radiat Ther Oncol 1972;6:1e16. 40 Chahal R, Sundaram SK, Iddenden R, Forman DF, Weston PMT, Harrison SCW. A study of the morbidity, mortality and long-term survival following radical cystectomy and radical radiotherapy in the treatment of invasive bladder cancer in Yorkshire. Eur Urol 2003;43:246e257. 41 Fokdal L, Hoyer M, Meldgaard P, von der Maase H. Long-term bladder, colorectal and sexual functions after radical radiotherapy for urinary bladder cancer. Radiother Oncol 2004;72: 139e145. 42 Henningsohn L, Wijkstrom H, Dickman PW, Bergmark K, Steineck G. Distressful symptoms after radical radiotherapy for urinary bladder cancer. Radiother Oncol 2002;62:215e225. 43 Caffo O, Fellin G, Graffer U, Luciani L. Assessment of quality of life after cystectomy or conservative therapy for patients with infiltrating bladder carcinoma. Cancer 1996;78:1089e1097.