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Acute morbidity related to treatment volume during 3D-conformal radiation therapy for prostate cancer
Radiotherapy and Oncology 71 (2004) 43–53 www.elsevier.com/locate/radonline
Acute morbidity related to treatment volume during 3D-conformal radiation therapy for prostate cancer ´ sa Karlsdo´ttira,*, Dag C. Johannessena, Ludvig Paul Murena, Tore Wentzel-Larsenb, Olav Dahla A a
Section of Oncology, Institute of Medicine, Haukeland University Hospital, University of Bergen, N-5021 Bergen, Norway b Centre for Clinical Research, Haukeland University Hospital, University of Bergen, N-5021 Bergen, Norway Received 22 July 2003; received in revised form 18 December 2003; accepted 13 January 2004
Abstract Purpose: To investigate the relation between acute toxicity and irradiated volume in the organs at risk during three-dimensional conformal radiation therapy for prostate cancer. Methods and materials: From January to December 2001, we treated 132 prostate cancer patients to a prescribed target dose of 70 Gy. Twenty-six patients (20%) received irradiation to the prostate only (Group P), 86 patients (65%) had field arrangements encompassing the prostate and seminal vesicles (Group PSV) while 20 (15%) received modified pelvic fields (Group MPF). A four-field conformal box technique was used. Acute toxicity according to the RTOG scoring system was prospectively recorded throughout the course of treatment. Results: Overall, radiation was well tolerated with 11%, 16% and 35% Grade 2 gastro-intestinal (GI) toxicity and 19%, 34% and 35% Grade 2 or higher genito-urinary (GU) toxicity in Groups P, PSV and MPF, respectively. In univariate and multivariate analyses treatment group was a significant predictor for Grade 2 or higher acute morbidity. In multivariate logistic regression, the rectum dose – volume histogram parameters were correlated to the incidence of acute Grade 2 GI toxicity, with the fractional volumes receiving more than 37 – 40 Gy and above 70 Gy showing the statistically strongest correlation. The fractional bladder volume receiving more than 14 – 27 Gy showed the statistically strongest correlation with acute GU toxicity. Conclusions: 3D-CRT radiation therapy to 70 Gy for prostate cancer was well tolerated. Only two of the 132 patients in the cohort experienced acute bladder toxicity Grade 3, none had Grade 3 rectal toxicity. Uni- and multivariate analyses indicated that the volume treated was a significant factor for the incidence of Grade 2 or higher acute morbidity. q 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Prostate cancer; Radiotherapy; Acute toxicity; Volume effects
1. Introduction Conformal radiotherapy (CRT) where fields are shaped to the tumour to spare normal tissues has been used since 1995 at our institution for prostate cancer [7]. Previous studies have shown that a decrease in the irradiated normal tissue volumes reduces the acute toxicity [39,42]. In our series, the treated volume around the prostate varied according to the defined stage and risk factors (TNM, PSA and Gleason score), from prostate only, to prostate and seminal vesicules, and in the most unfavorable cases, pelvic irradiation. These three groups appeared suitable for an assessment of the influence of irradiated volume on observed acute effects. We have therefore prospectively * Corresponding author. 0167-8140/$ - see front matter q 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2004.01.014
recorded the side effects in a cohort of consecutive prostate cancer patients treated at our institution, and we here report the acute toxicity recorded during the course of radiotherapy (RT) to a tumour dose of 70 Gy. We also assessed the influence of volume and dose – volume histogram (DVH) parameters for the organs at risk (ORs) on the frequency of side effects.
2. Materials and methods 2.1. Patient material Throughout the year 2001, 132 consecutive patients with prostate cancer were treated with curative intent with CRT at Haukeland University Hospital. The primary tumour was
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clinically staged according to the 1997 TNM classification for prostate cancer [15]. Histopatologic specimens were routinely graded according to the Gleason pattern score [29]. Patients with distant metastases were excluded if positive findings occurred in the routine bone scan. Six of the included patients (5%) had previously undergone a transurethral resection of the prostate (TURP), which may increase the side effects [35]. Patient and tumour characteristics are summarized in Table 1. Patients presenting with more advanced tumours in the prostate (stage $ T2a, PSA . 10 or Gleason score $ 7 [4 þ 3 but not 3 þ 4]) were candidates for a 6-months course of luteinizing hormone-releasing hormone analogue and antiandrogen (Maximal Androgen Blockade, MAB). Due to different practise among the referring urologists and patients demand, as many as 113 of all patients (86%) received endocrine treatment (Table 1). The endocrine treatments started 3 – 4 months before CRT and were administered to reduce the prostate volume and thereby reduce the dose of radiation delivered to the rectum and bladder. Androgen deprivation gives a decrease in the prostate volume by approximately 30– 50% [10,17,26,27, 38,43,47,48]. The hormone therapy continued during and one month after the start of RT, to exploit the possible synergy between hormone therapy and radiation [1]. The study complied with the national Norwegian Ethics regulations.
2.2. Treatment technique 2.2.1. Prescription dose All patients were prescribed a total dose of 70 Gy (mean dose in the planning target volume, PTV). Patients were treated with one 2 Gy fraction per day, 5 days a week over 7 weeks. A dose of 50 Gy was given during a five-week period to a large volume, while an additional 20 Gy was given over the last two weeks to a smaller target volume (the boost volume), see below. One patient discontinued treatment at 60 Gy, because of symptomatic intermittent claudication assumed to increase the risk of late side effects. 2.2.2. Treatment planning All patients were planned and treated supine. A spiral CT scan was performed with the patients supine on a flat CT couch, acquiring slices from the L3/L4 vertebrae level down to the level of the perineum. Slices 5-mm thick with 5-mm interval (5/5 slices) were acquired through the target volume, while 10/10 slices were acquired in the regions above and below. The responsible oncologist contoured the prostate and seminal vesicles, the ORs, the rectum (using the first slice below the recto-sigmoid flexure as the superior limit and the first slice above the anal verge as the inferior limit) and the bladder (from apex to dome). Both the rectum and bladder volumes were defined as the volume within the outer wall contour in the organs, including the contents of these hollow organs.
Table 1 Clinical characteristics of the patients Group P
Group PSV
Group MPF
No. of patients
26
86
20
Median age (years) Age range (years)
64 53.7–77.3
66.9 51.9–77.1
67.2 47.3–71.4
0.22
Concurrent cardiovascular disease
8 (31%)
29 (34%)
9 (45%)
0.36
DM (Diabetes mellitus)
2 (8%)
0
0
Urinary symptoms before treatment
13 (50%)
37 (43%)
10 (50%)
Clinical stage T1 T2 T3 T4
26 (100%) 0 0 0
43 (50%) 42 (49%) 0 1 (1%)
0 0 20 (100%) 0
Gleason sum #6 $7 Unknown
19 (73%) 7 (27%)
52 (60%) 34 (40%)
8 (40%) 11 (55%) 1 (5%)
PSA (ng/l) #4 4.1– 10 10.1–20 .20
1 (4%) 23 (88%) 2 (8%)
1 (1%) 22 (26%) 52 (60%) 11 (13%)
4 (20%) 8 (40%) 8 (40%)
Endocrine treatment
13 (50%)
81 (94%)
19 (95%)
Group P: prostate only, Group PSV: prostate and seminal vesicle and Group MPF: modified pelvic field.
P-value
1.0
,0.001
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Patients were stratified into three treatment groups according to T-stage, PSA and Gleason score: Group P. In patients with clinically organ-confined disease of stage T1c, PSA # 10 and Gleason score # 7 (3 þ 4 but not 4 þ 3), the clinical target volume (CTV) encompassed the prostate only with 5 mm margin. Two PTVs were constructed using an automated 3D expansion of the CTV. The PTV prescribed 50 Gy was constructed by adding 15 mm to the CTV in all directions apart from the rectum where a 10 mm margin was used. For the boost PTV that was prescribed 70 Gy a margin of 10 mm was added to the CTV, except towards the rectum where 5 mm was used. If necessary, the posterior margin was further adjusted to not include more than one-third of the rectal circumference. Group PSV. Patients with clinically organ-confined disease of stage T1c with PSA . 10 but # 30 or Gleason score $ 7 (4 þ 3 but not 3 þ 4) as well as all patients with T2 disease received radiation to the prostate and seminal vesicles to 50 Gy, followed by a 20 Gy boost to the prostate only. Again the PTVs were constructed from CTVs using the 3D expansion procedure. The PTV prescribed 50 Gy was constructed by adding first 5 mm to the prostate and seminal vesicles to define the CTV, then an additional 15 mm on to the CTV, except towards the rectum where a 10 mm margin was used. The boost PTV prescribed 70 Gy was defined by adding first a margin of 5 mm to the prostate only to define the CTV, then an additional 10 mm on to the CTV, except towards the rectum where 5 mm was used. Again, the posterior margin was restrained to not include more than one-third of the rectal circumference. Group MPF. In patients with stage T3 or N þ a larger volume was treated with modified pelvic fields to 50 Gy, followed by a reduced volume, which encompassed the prostate and seminal vesicle [3]. In the craniocaudal direction the upper limit of the modified pelvic fields was the L5-S1 interspace, the lower limit was the ischial tuberosity, and the lateral borders were 1 cm beyond the maximal width of the true pelvis. The posterior border was restrained not to include more than half of the rectal circumference or 10 mm margin to prostate and seminal vesicle. The boost PTV prescribed 70 Gy was defined by adding a margin of 5 mm to the prostate and seminal vesicle to define the CTV, then an additional 10 mm was added to the CTV except towards the rectum where 5 mm was used. Again, the posterior margin was restrained to not include more than one-third of the rectal circumference. Photon beams with 10 – 15 MV beam quality were used for all patients. All patients except one were treated with a four-field conformal box technique, consisting of anterior, posterior and two lateral beams (one patient was treated with a 6-field technique; anterior, posterior and four lateral oblique fields). Multileaf collimators (MLCs) were used to shape the fields. Patients were instructed to refrain from micturition 1 –2 h before treatment to exclude the bladder as far as possible from the high dose volume.
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2.2.3. Dose– volume histograms DVHs were calculated for the total treatment plan (to 70 Gy) for both ORs, e.g. the bladder and rectum, to investigate a possible correlation with observed toxicity. Since both the rectum and bladder were defined as solid organs, the DVHs contained the dose to the whole of this volume (i.e. including contents). From the DVHs of each patient, the mean dose and the volume fraction above dose levels from 0 to 75 Gy in steps of 1 Gy were derived. DVHs were available for 127 of the 132 patients (artefacts due to hip prothesis in two patients, technical problems with data transfer in three patients). A dose calculation matrix of approximately 5 £ 5 £ 5 mm3 were used in all patients. 2.3. Acute toxicity The Radiation Therapy Oncology Group (RTOG) acute toxicity scoring system was used to grade gastro-intestinal (GI) and genito-urinary (GU) morbidity during the course of treatment [6] Anal symptoms were scored according to the modified scoring system of Koper et al. [24] (Table 2). In general, GI or GU symptoms that needed medical prescriptions were scored at least as Grade 2 toxicity (Table 2). Patients were seen before and at least two times during treatment (week two and six), and more frequently if required. The patient’s oncologist performed the recordings and grading of acute symptoms as part of the routine clinical follow up, and the scoring was controlled and confirmed by ´ K). another oncologist (A 2.4. Statistical analysis The statistical analyses were performed with the SPSS statistics package (v 11.0.1, SPSS Inc , Chicago, USA), StatXact 5 (Cytel Software, Cambridge, MA, USA) and R [19]. To evaluate differences between treatments groups, testing the effect of comorbidity on toxicity and effect of volume on acute toxicity the Jonckheere – Terpstra test was used. To evaluate the difference between groups for median DVH, one-way ANOVA with Scheffe post hoc analysis was used (the nonparametic version were seen to give the same results). A permutation test (StatXact 5) was performed to evaluate the difference in relative DVH parameters between patients with Grade 0 þ 1 vs. Grade 2 or higher morbidity. The effect of various treatment and background variables on acute toxicity was tested by logistic regression. In the DVH analyses, the significance of differences between the groups was tested by ANOVA and the Kruskal – Wallis-test. The effects of including each DVH variable in our logistic regression models were evaluated using the crude correlation measure of predictive power introduced by Zheng and Agresti [50] and their P-values based on the likelihood ratio test [21]. Two-sided tests were used throughout, and P-values of less than 0.05 were considered statistically significant.
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Table 2 The modified RTOG acute scoring system used in this study Grade
Lower GI including rectum
Genitourinary
Anala
0 1
No change Increased frequency or change in quality of bowel habits not requring medication/rectal discomfort not requiring analgesics. Diarrhea requiring parasympatholytic drugs/mucoous discharge not necessitating sanitary pads/rectal or abdominal pain requiring analgesics. Diarrhea requiring parental support/serve mucous or blood discharge necessitating sanitary pads/abdominal distention
No change Frequency of urination or nocturia twice pretreatment habit/dysuria, urgency not requiring medication Frequency of urination or nocturia that is less frequent than every hour. Dysuria, urgency, bladder spasm requiring local anesthetic
No change Discomfort or pain not requiring analgesics
Frequency with urgency and nocturia hourly or more frequently/dysuria, pelvis pain or bladder spasm requiring regular, frequent narcotic/gross hematuria Hematuria requiring transfusion/acute bladder obstruction not secondary to clot passage, ulceration or necrosis
Discomfort or pain requiring narcotics
2
3
4
Acute or subacute obstruction, fistula or perforation; GI bleeding requiring transfusion; abdominal pain or tenesmus requiring tube decompression or bowel diversion a
Discomfort or pain requiring analgesics
ad modum Koper et al. (19) and RTOG (18).
3. Results Of the 132 patients, 130 (98.5%) completed treatment without interruption. In one patient, a 3-day treatment break was required because of heart disease, and one discontinued treatment after 60 Gy. Acute GI symptoms generally consisted of increased frequency of bowel movement, change in stool consistency, rectal discomfort, tenesmus and urgency. The overall GI morbidity was low in all three groups ðP ¼ 0:06Þ; as 3 of 26 (11%) in Group P, 14 of 86 (16%) in Group PSV and 7 of 20 (35%) in Group MPF required medication for relief of Grade 2 GI symptoms. There was no Grade 3 or 4 acute GI toxicity (Table 3). Acute GU symptoms generally consisted of increased urinary frequency, urgency, dysuria and nocturia. Also the overall GU morbidity was relatively low and not significantly different in the three groups, with 5 of 26 (19%), 27 of 86 (32%) and 7 of 20 (35%), in Groups P, PSV and MPF, respectively, required medication for relief of GU symptoms (Grade 2). Only 2 patients (2%), both in the PSV Group, developed acute Grade 3 toxicity with acute urinary retention that required catheterization for a short period. Both were able to complete the course of treatment without further side effects or delay (Table 3). Patients presenting with symptoms of prostatism before RT, had significantly more acute Grade $ 2 GU symptoms ðP ¼ 0:02Þ during therapy. Acute anal symptoms generally consisted of anal irritation or pain. The anal morbidity was uniformly low in all groups; 4% P, 3% PSV and none Grade 2 anal discomfort in MPF, Table 3. There was a significant correlation ðP ¼ 0:02Þ; between the three treatment groups and the incidence of any toxicity $ Grade 2. The patients in Group P, PSV, and MPF
developed any Grade 2 or higher acute side effects in 23.1, 44.2 and 60%, respectively. The difference between Group P and Group MPF were significant ðP ¼ 0:01Þ; but reached only a trend between Group P and Group PSV ðP ¼ 0:06Þ; whereas there was no significant difference between Group PSV and Group MPF ðP ¼ 0:21Þ: Table 1 shows that 31%, 34% and 45% of the patients in Groups P, PSV and MPF had a history of cardiovascular disease before radiation therapy. There was a significant Table 3 The fraction (and number) of patients with the different RTOG acute GI, GU and anal side effect scores in the different treatment groups
GI Grade 0 Grade 1 Grade 2
Group P ðn ¼ 26Þ
Group PSV ðn ¼ 86Þ
Group MPF ðn ¼ 20Þ
35% (9) 54% (14) 11% (3)
28% (24) 56% (48) 16% (14)
30% (6) 35% (7) 35% (7)
26% (4) 66% (17) 19% (5) 0
9% (8) 57% (49) 32% (27) 2% (2)
15% (3) 50% (10) 35% (7) 0
65% (17) 31% (8) 4% (1)
58% (50) 39% (33) 3% (3)
60% (12) 40% (8) 0
P ¼ 0.06 GU Grade Grade Grade Grade
0 1 2 3
P ¼ 0.2 Anal Grade 0 Grade 1 Grade 2 P ¼ 0.7 Group P: prostate only, Group PSV: prostate and seminal vesicle and Group MPF: modified pelvic field.
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correlation between cardiovascular disease and any Grade 2 toxicity in Group P ðP ¼ 0:05Þ; but not in the other groups. Analysing the different organs separately, the GI toxicity in Group P correlated highly significantly with cardiovascular diseases ðP ¼ 0:002Þ: 3.1. Analysis of DVH parameters and toxicity in the treatment groups The rectum DVHs between the three groups were significantly different ðP , 0:001Þ (Fig. 1a), e.g. on average 50% of the rectum received a dose of 43 Gy for Group P, 49 Gy for Group PSV and 62 Gy for Group MPF. All pairwise comparisons between the three groups (i.e. Group P vs. Group PSV; Group P vs. Group MPF; Group PSV vs. Group MPF) at various dose levels (20, 40, 60, 65 and 70 Gy) showed significant differences, except for 60 and 65 Gy between Group P and Group PSV, and for 20 Gy between Group PSV and Group MPF (Fig. 1a). Comparing each group separately the DVH analyses for the rectum failed to reveal a statistically significant correlation between acute GI toxicity and rectal volume ðP . 0:05Þ: However, analysing all patients there was a significant difference at 40 Gy ðP ¼ 0:03Þ and a trend at 60, 65 and 70 Gy ðP ¼ 0:06 – 0:09Þ between the fractional rectum volume and the incidence of acute GI toxicity (Table 4). As for the rectum there was a highly significant difference in the bladder DVHs between the three groups ðP , 0:001Þ (Fig. 1b), e.g. on an average 50% of the bladder received a dose of 54 Gy for Group P, 62 Gy for Group PSV and 70 Gy for Group MPF. Pairwise comparison between the three groups for various dose levels (20, 40, 60, 65 and 70 Gy) were all significant, except at 20 Gy between Group PSV and Group MPF. Similar irradiated fractional bladder volumes per dose level were found within the three groups for patients with RTOG Grade 0 and 1 compared to patients with RTOG Grade 2 and 3 ðP . 0:05Þ: However, when all patients were taken together there was a significant difference above 20 Gy ðP ¼ 0:05Þ; Table 4. 3.2. Multivariate analysis of volume effects The variables acute toxicity, treatment group, cardiovascular disease, T-staging, PSA, Gleason score, hormone treatment, TUR-P and age were initially included in a multivariate logistic regression. Of these, treatment group ðP ¼ 0:04Þ was the only independent predictor for the incidence of any acute Grade $ 2 morbidity. Multivariate logistic regression with the variables absolute volume, maximum dose, treatment group, cardiovascular disease and age was subsequently used to examine the relationship between the DVH variables (fractional volumes receiving in excess of the different dose levels) and toxicity. For the rectum, the regression analysis was
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repeated substituting at each stage the fractional rectum volumes receiving more than dose levels in the range of 0 –75 Gy. The fractional rectum volumes were initially used alone, and then together with the maximum rectum dose and subsequently also the absolute volume of the rectum. The analysis documented that the rectum DVH parameters were correlated to the incidence of acute Grade 2 GI toxicity (Fig. 2a and b). When including the DVH parameters only, fractional rectum volumes in the range of 37 –40 Gy and above 70 Gy showed the strongest statistically significant correlation (Fig. 2a and b). When the maximum rectum dose was also included in the model, only a marginal statistical significance remained for the fractional volumes above 70 Gy. At the highest level of correlation, seen at doses above 70 Gy, both with and without the maximum dose in the model, a crude correlation coefficient of approximately 0.30 was observed. The factors included in the model at this stage thus explained roughly 9% of the variation in the clinically observed incidence of acute Grade 2 GI morbidity. A similar analysis of the bladder acute GU toxicity documented that the bladder DVH parameters were correlated with the incidence of acute Grade 2– 3 GU toxicity (Fig. 3a and b). When including the DVH parameters only, fractional bladder volumes in the range of 14– 27 Gy showed a statistically significant correlation (Fig. 3a and b). When age was also included in the model, only a marginal statistically significance remained for the fractional volumes between 21– 224 Gy. At the highest level of correlation, seen at doses of 22 –23 Gy, a crude correlation coefficient of approximately 0.28 was observed, i.e. the factors (age and DVH parameters) included in the model at this stage explained roughly 8% of the variation in the clinically observed incidence of acute Grade 2 –3 GU morbidity.
4. Discussion In this report, we have presented acute radiation toxicity data after CRT for prostate carcinoma, treating different volumes according to the tumour stage and documented risk factors. Overall, the patients exhibited a relative low incidence of severe toxicity, indicating a good short-term tolerance to radiation of a dose of 70 Gy when delivered by our CRT technique. The fundament of CRT is that there is a dose response relationship for tumour control and that there are dose/ volume response relationships for the involved normal tissues. The dose and volume response of normal tissue in general is such that irradiating a smaller volume to a higher dose is possible within generally accepted limits of complications [14,25]. Both univariate and multivariate analysis indicated that volume treated was an independent and significant factor for the incidence of acute morbidity of Grade 2 or higher in our study.
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Fig. 1. The mean DVH for (a) rectum and (b) bladder for Group P, PSV and MPF. The differences between the DVHs were statistically significant ðP , 0:001Þ:
It has been shown that a history of diabetes was significantly associated with the development of Grade 2 or higher acute GI and GU complications [37]. In our material only two patients had known diabetes, neither of these experienced Grade 2 or higher toxicity. Cardiovascular disease on the other hand correlated significantly with Grade 2 GI toxicity in Group P, but not in the other groups. The dose-limiting ORs in RT of prostate cancer are the rectum and the bladder. With regard to reliable DVH data, these organs present special problems because they are both hollow and tend to have temporal variations in size, shape and position due to difference in filling [16,20,30]. The
rectum and bladder DVHs based on the planning scan only may therefore not be representative for all of the daily treatment sessions, confounding the correlation between DVH parameters and toxicity. Still, it seems reasonable to assume that DVHs of the organ with content are less sensitive to organ motion than DVHs of the wall or surface only [30 –32]. Currently, we are investigating whether inclusion of rectum motion improves the correlation between the DVH parameters and toxicity. In particular the GI toxicity remained very favorable for Groups P and PSV, with 11% and 16% Grade 2 toxicity, respectively, but there was only a trend towards higher Grade 2 toxicity (35%) observed in Group MPF ðP ¼ 0:06Þ:
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Table 4 Median rectum/bladder dose and fractional rectum/bladder volume above various dose levels for patients with Grade 0 þ 1 vs. Grade 2 þ 3 acute rectum /bladder effects Group P ðn ¼ 25Þ
Group PSV ðn ¼ 82Þ
Group MPF ðn ¼ 20Þ
GIa Toxicity (Grade) Median dose (Gy) $20 Gy (%) $40 Gy (%) $60 Gy (%) $65 Gy (%) $70 Gy (%)
0þ1 44 88 55 26 21 10
2 43 96 65 26 22 12
0þ1 49 100 68 29 18 6
0þ1 61 100 95 52 43 28
2 63 100 98 58 46 31
0þ1 50 97 68 31 22 10
2 53 99 77 37 27 15
0.29 0.03 0.08 0.09 0.06
GUb Toxicity (Grade) Median dose (Gy) $20 Gy (%) $40 Gy (%) $60 Gy (%) $65 Gy (%) $70 Gy (%)
0þ1 53 89 69 49 39 16
2 59 97 79 51 43 23
0þ1 63 99 85 62 54 10
0þ1 70 100 100 91 77 58
2 69 100 100 88 77 57
0þ1 62 97 83 63 54 18
2 63 100 86 62 52 20
0.05 0.44 0.85 0.69 0.72
a b
2 49 99 67 28 17 6 2þ3 62 100 83 57 47 9
All patients ðn ¼ 127Þ
P-value
GI; gastrointestinal. GU; genito-urinary.
No patients experienced Grade 3 or higher toxicity. The rectum dose in the three groups were clearly different, e.g. the median dose was 43 and 49 Gy in Group P and PSV vs. 62 Gy in MPF, being a likely explanation for the difference in toxicity. However, it should be mentioned that the RTOG acute GI toxicity scoring system does not strictly discriminate between small bowel and rectal toxicity. According to Koper et al. [24], anal morbidity also contribute to the GI toxicity. The low anal toxicity being reported indicates a low anal radiation dose with our treatment technique. Jackson et al. [21] found that late rectal bleeding correlates with the volume receiving doses above 70 Gy, but reported also a correlation between bleeding and the volume exposed to intermediate doses (40 –50 Gy). This possibly indicates that when high-dose region are surrounded by extensive volumes receiving intermediate doses, the ability of this surrounding tissue to aid in the repair of a central injury may be inhibited. The present study confirms these findings, with a similar correlation between Grade 2 GI morbidity and the relative rectal volume receiving high (above 70 Gy) and intermediate doses (37 – 44 Gy) (Fig. 2b). It has been suggested that urethral mucositis and oedema within the prostate cause most of the urinary symptoms. This assumption is supported by the nature of the symptoms (frequency, urgency) as well as the particularly low incidence of acute GU toxicity in patients treated with 3D-CRT after radical prostatectomy [44]. The finding that the use of Intensity-Modulated RT (IMRT) for prostate cancer reduces rectum toxicity but not bladder toxicity despite reduced dose to the bladder [40] further supports the notion that most of the acute GU toxicity is caused by RT effects on the urethra within the prostate rather than in the bladder. According to this view, it seems unlikely that GU
symptoms can be avoided when irradiating the whole prostate and thus a segment of the urethra. In agreement with this, the differences in GU toxicity between the treatment groups in this series were less pronounced than the differences in GI toxicity, despite considerable consistent differences in the DVH and the DVH parameters also for the bladder. The correlation between bladder DVH parameters and bladder toxicity (Grade 0 þ 1 vs. Grade 2 þ 3) found for doses in the range 14– 27 Gy and the difference found for fractional bladder volumes receiving more than 20 Gy were in general also slightly weaker than the corresponding correlations found for the rectum. Still, this sensitivity to low doses (equivalent to 0.4 – 0.8 Gy per treatment fraction) was statistically significant, and warrants further investigation. Its biological explanation is uncertain, but it probably reflects a RT side effect linked to the whole (or most) of the bladder, e.g. reduced elasticity. It is also interesting to note that it coincides with the daily dose range for the so-called radiation hypersensitivity effect that recently has gained immense interest in experimental radiobiology [23]. Further follow-up will reveal whether this low dose sensitivity remains in the persisting late toxicity. Bladder doses with our technique were relatively high, but there was still only 2% Grade 3 GU toxicity rate in our material, in accordance with previous 3D-CRT series for prostate cancer, showing a 0 – 3% incidence of acute grade 3 and 4 GU toxicity [5,24,36,49]. We found statistically significant differences between patients with Grade 0 – 1 vs. Grade 2 – 3 acute GU effects for low doses only, but Valicenti et al. [41] found that the fraction of the bladder (# 30% vs. . 30%) receiving more than the prescription dose (68.4 Gy to 79.2 Gy)
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Fig. 2. (a) The crude correlation coefficient of the parameters included in the multivariate analysis of the rectum DVH data. At each dose level, the corresponding fractional rectum volume fraction is included in the model, either alone (‘DVH alone’) or together with the maximum rectum dose (‘Dmax’). (b) The significance levels from the multivariate analysis of each of the fractional rectum volumes when these were included one at each stage in the model, with only DVH variables (DVH-alone) or with DVH parameters and the maximum rectum dose included in the model (Dmax). The P-values are based on the likelihood ratio test.
were a significant predictor for acute GU effects. They also showed that men with poor baseline urinary function who were given HT had a significantly increased risk of acute GU side effects. Zelefsky et al. [45] and Schultheiss et al. [37] found in their studies that the presence of acute symptoms during
3D-CRT correlated with a higher incidence of Grade 2 or more late GI and GU toxicity. Still the association of acute and late injuries was not sufficiently strong to predict which patients would develop late complications. O’Brien et al. have also suggested an association between acute and late rectal toxicity [34]. Despite these reports, the relationship
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Fig. 3. (a) The crude correlation coefficient of the parameters included in the multivariate analysis of the bladder DVH data. At each dose level, the corresponding fractional bladder volume fraction is included in the model, either alone (DVH alone) or together with age. (b) The significance levels from the multivariate analysis of each of the fractional bladder volumes when these were included one at each stage in the model, with only DVH variables (DVH-alone) or with DVH parameters and age included in the model. The P-values are based on the likelihood ratio test.
between acute and late morbidity is still not understood [8,37,45]. Hanks et al. [14] observed that with 3D-CRT, Grade 2 acute toxicity were more volume than dose dependent. Also Nuyttens et al. [33] reported a dose – volume relations for acute Grade 2 rectal symptoms, but not for late side effects. Emami et al. [9] and Burman et al. [4] assumed that the volume effects for severe late reaction in the rectum were low. In contrast, Mameghan et al. [28], described a volume dependency for severe late bowel complication as also found by others [18,22].
It is widely accepted that increasing the dose to the tumour using conformal treatment can increase the tumour control; the challenge remains to achieve this while maintaining acceptable levels of complications. Since 2002, we have escalated the tumour dose for T1c, T2 and T3 tumours up to 78 Gy, with the BeamCathw system [2]. With this system, we can visualize the prostatic urethra with electronic portal imaging and thereby accurately localize the prostate prior to treatment. Late chronic side effects still limit the dose that can safely be given, and are probably
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linked to the volume of normal tissues irradiated. Studies of this new positioning technique have documented that it is possible to increase the total dose to 76 Gy without increasing acute or late side effects compared to standard CRT to 71 Gy [11 –13]. Dose escalation without increased toxicity in prostate RT has also been achieved with IMRT [46]. In conclusion, this study showed that 3D-CRT for prostate cancer to 70 Gy was well tolerated. Only two of the 132 patients in the cohort experienced acute bladder toxicity Grade 3, none had Grade 3 rectal toxicity. Uni- and multivariate analyses indicated that the volume treated was a significant factor for the incidence of Grade 2 or higher acute morbidity. A decrease in acute toxicity may result in a decrease in late complications, as late effects may be consequential acute effects. Therefore, the importance of acute toxicity should not be underestimated.
[12]
[13]
[14]
[15]
[16]
[17]
Acknowledgements [18]
This study was supported by generous grants from the Norwegian Cancer Society. The authors would like to thank Yngve Kvinnsland for assistance with assessment of DVHs.
[19] [20]
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Acute morbidity related to treatment volume during 3D-conformal radiation therapy for prostate cancer ´ sa Karlsdo´ttira,*, Dag C. Johannessena, Ludvig Paul Murena, Tore Wentzel-Larsenb, Olav Dahla A a
Section of Oncology, Institute of Medicine, Haukeland University Hospital, University of Bergen, N-5021 Bergen, Norway b Centre for Clinical Research, Haukeland University Hospital, University of Bergen, N-5021 Bergen, Norway Received 22 July 2003; received in revised form 18 December 2003; accepted 13 January 2004
Abstract Purpose: To investigate the relation between acute toxicity and irradiated volume in the organs at risk during three-dimensional conformal radiation therapy for prostate cancer. Methods and materials: From January to December 2001, we treated 132 prostate cancer patients to a prescribed target dose of 70 Gy. Twenty-six patients (20%) received irradiation to the prostate only (Group P), 86 patients (65%) had field arrangements encompassing the prostate and seminal vesicles (Group PSV) while 20 (15%) received modified pelvic fields (Group MPF). A four-field conformal box technique was used. Acute toxicity according to the RTOG scoring system was prospectively recorded throughout the course of treatment. Results: Overall, radiation was well tolerated with 11%, 16% and 35% Grade 2 gastro-intestinal (GI) toxicity and 19%, 34% and 35% Grade 2 or higher genito-urinary (GU) toxicity in Groups P, PSV and MPF, respectively. In univariate and multivariate analyses treatment group was a significant predictor for Grade 2 or higher acute morbidity. In multivariate logistic regression, the rectum dose – volume histogram parameters were correlated to the incidence of acute Grade 2 GI toxicity, with the fractional volumes receiving more than 37 – 40 Gy and above 70 Gy showing the statistically strongest correlation. The fractional bladder volume receiving more than 14 – 27 Gy showed the statistically strongest correlation with acute GU toxicity. Conclusions: 3D-CRT radiation therapy to 70 Gy for prostate cancer was well tolerated. Only two of the 132 patients in the cohort experienced acute bladder toxicity Grade 3, none had Grade 3 rectal toxicity. Uni- and multivariate analyses indicated that the volume treated was a significant factor for the incidence of Grade 2 or higher acute morbidity. q 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Prostate cancer; Radiotherapy; Acute toxicity; Volume effects
1. Introduction Conformal radiotherapy (CRT) where fields are shaped to the tumour to spare normal tissues has been used since 1995 at our institution for prostate cancer [7]. Previous studies have shown that a decrease in the irradiated normal tissue volumes reduces the acute toxicity [39,42]. In our series, the treated volume around the prostate varied according to the defined stage and risk factors (TNM, PSA and Gleason score), from prostate only, to prostate and seminal vesicules, and in the most unfavorable cases, pelvic irradiation. These three groups appeared suitable for an assessment of the influence of irradiated volume on observed acute effects. We have therefore prospectively * Corresponding author. 0167-8140/$ - see front matter q 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2004.01.014
recorded the side effects in a cohort of consecutive prostate cancer patients treated at our institution, and we here report the acute toxicity recorded during the course of radiotherapy (RT) to a tumour dose of 70 Gy. We also assessed the influence of volume and dose – volume histogram (DVH) parameters for the organs at risk (ORs) on the frequency of side effects.
2. Materials and methods 2.1. Patient material Throughout the year 2001, 132 consecutive patients with prostate cancer were treated with curative intent with CRT at Haukeland University Hospital. The primary tumour was
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clinically staged according to the 1997 TNM classification for prostate cancer [15]. Histopatologic specimens were routinely graded according to the Gleason pattern score [29]. Patients with distant metastases were excluded if positive findings occurred in the routine bone scan. Six of the included patients (5%) had previously undergone a transurethral resection of the prostate (TURP), which may increase the side effects [35]. Patient and tumour characteristics are summarized in Table 1. Patients presenting with more advanced tumours in the prostate (stage $ T2a, PSA . 10 or Gleason score $ 7 [4 þ 3 but not 3 þ 4]) were candidates for a 6-months course of luteinizing hormone-releasing hormone analogue and antiandrogen (Maximal Androgen Blockade, MAB). Due to different practise among the referring urologists and patients demand, as many as 113 of all patients (86%) received endocrine treatment (Table 1). The endocrine treatments started 3 – 4 months before CRT and were administered to reduce the prostate volume and thereby reduce the dose of radiation delivered to the rectum and bladder. Androgen deprivation gives a decrease in the prostate volume by approximately 30– 50% [10,17,26,27, 38,43,47,48]. The hormone therapy continued during and one month after the start of RT, to exploit the possible synergy between hormone therapy and radiation [1]. The study complied with the national Norwegian Ethics regulations.
2.2. Treatment technique 2.2.1. Prescription dose All patients were prescribed a total dose of 70 Gy (mean dose in the planning target volume, PTV). Patients were treated with one 2 Gy fraction per day, 5 days a week over 7 weeks. A dose of 50 Gy was given during a five-week period to a large volume, while an additional 20 Gy was given over the last two weeks to a smaller target volume (the boost volume), see below. One patient discontinued treatment at 60 Gy, because of symptomatic intermittent claudication assumed to increase the risk of late side effects. 2.2.2. Treatment planning All patients were planned and treated supine. A spiral CT scan was performed with the patients supine on a flat CT couch, acquiring slices from the L3/L4 vertebrae level down to the level of the perineum. Slices 5-mm thick with 5-mm interval (5/5 slices) were acquired through the target volume, while 10/10 slices were acquired in the regions above and below. The responsible oncologist contoured the prostate and seminal vesicles, the ORs, the rectum (using the first slice below the recto-sigmoid flexure as the superior limit and the first slice above the anal verge as the inferior limit) and the bladder (from apex to dome). Both the rectum and bladder volumes were defined as the volume within the outer wall contour in the organs, including the contents of these hollow organs.
Table 1 Clinical characteristics of the patients Group P
Group PSV
Group MPF
No. of patients
26
86
20
Median age (years) Age range (years)
64 53.7–77.3
66.9 51.9–77.1
67.2 47.3–71.4
0.22
Concurrent cardiovascular disease
8 (31%)
29 (34%)
9 (45%)
0.36
DM (Diabetes mellitus)
2 (8%)
0
0
Urinary symptoms before treatment
13 (50%)
37 (43%)
10 (50%)
Clinical stage T1 T2 T3 T4
26 (100%) 0 0 0
43 (50%) 42 (49%) 0 1 (1%)
0 0 20 (100%) 0
Gleason sum #6 $7 Unknown
19 (73%) 7 (27%)
52 (60%) 34 (40%)
8 (40%) 11 (55%) 1 (5%)
PSA (ng/l) #4 4.1– 10 10.1–20 .20
1 (4%) 23 (88%) 2 (8%)
1 (1%) 22 (26%) 52 (60%) 11 (13%)
4 (20%) 8 (40%) 8 (40%)
Endocrine treatment
13 (50%)
81 (94%)
19 (95%)
Group P: prostate only, Group PSV: prostate and seminal vesicle and Group MPF: modified pelvic field.
P-value
1.0
,0.001
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Patients were stratified into three treatment groups according to T-stage, PSA and Gleason score: Group P. In patients with clinically organ-confined disease of stage T1c, PSA # 10 and Gleason score # 7 (3 þ 4 but not 4 þ 3), the clinical target volume (CTV) encompassed the prostate only with 5 mm margin. Two PTVs were constructed using an automated 3D expansion of the CTV. The PTV prescribed 50 Gy was constructed by adding 15 mm to the CTV in all directions apart from the rectum where a 10 mm margin was used. For the boost PTV that was prescribed 70 Gy a margin of 10 mm was added to the CTV, except towards the rectum where 5 mm was used. If necessary, the posterior margin was further adjusted to not include more than one-third of the rectal circumference. Group PSV. Patients with clinically organ-confined disease of stage T1c with PSA . 10 but # 30 or Gleason score $ 7 (4 þ 3 but not 3 þ 4) as well as all patients with T2 disease received radiation to the prostate and seminal vesicles to 50 Gy, followed by a 20 Gy boost to the prostate only. Again the PTVs were constructed from CTVs using the 3D expansion procedure. The PTV prescribed 50 Gy was constructed by adding first 5 mm to the prostate and seminal vesicles to define the CTV, then an additional 15 mm on to the CTV, except towards the rectum where a 10 mm margin was used. The boost PTV prescribed 70 Gy was defined by adding first a margin of 5 mm to the prostate only to define the CTV, then an additional 10 mm on to the CTV, except towards the rectum where 5 mm was used. Again, the posterior margin was restrained to not include more than one-third of the rectal circumference. Group MPF. In patients with stage T3 or N þ a larger volume was treated with modified pelvic fields to 50 Gy, followed by a reduced volume, which encompassed the prostate and seminal vesicle [3]. In the craniocaudal direction the upper limit of the modified pelvic fields was the L5-S1 interspace, the lower limit was the ischial tuberosity, and the lateral borders were 1 cm beyond the maximal width of the true pelvis. The posterior border was restrained not to include more than half of the rectal circumference or 10 mm margin to prostate and seminal vesicle. The boost PTV prescribed 70 Gy was defined by adding a margin of 5 mm to the prostate and seminal vesicle to define the CTV, then an additional 10 mm was added to the CTV except towards the rectum where 5 mm was used. Again, the posterior margin was restrained to not include more than one-third of the rectal circumference. Photon beams with 10 – 15 MV beam quality were used for all patients. All patients except one were treated with a four-field conformal box technique, consisting of anterior, posterior and two lateral beams (one patient was treated with a 6-field technique; anterior, posterior and four lateral oblique fields). Multileaf collimators (MLCs) were used to shape the fields. Patients were instructed to refrain from micturition 1 –2 h before treatment to exclude the bladder as far as possible from the high dose volume.
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2.2.3. Dose– volume histograms DVHs were calculated for the total treatment plan (to 70 Gy) for both ORs, e.g. the bladder and rectum, to investigate a possible correlation with observed toxicity. Since both the rectum and bladder were defined as solid organs, the DVHs contained the dose to the whole of this volume (i.e. including contents). From the DVHs of each patient, the mean dose and the volume fraction above dose levels from 0 to 75 Gy in steps of 1 Gy were derived. DVHs were available for 127 of the 132 patients (artefacts due to hip prothesis in two patients, technical problems with data transfer in three patients). A dose calculation matrix of approximately 5 £ 5 £ 5 mm3 were used in all patients. 2.3. Acute toxicity The Radiation Therapy Oncology Group (RTOG) acute toxicity scoring system was used to grade gastro-intestinal (GI) and genito-urinary (GU) morbidity during the course of treatment [6] Anal symptoms were scored according to the modified scoring system of Koper et al. [24] (Table 2). In general, GI or GU symptoms that needed medical prescriptions were scored at least as Grade 2 toxicity (Table 2). Patients were seen before and at least two times during treatment (week two and six), and more frequently if required. The patient’s oncologist performed the recordings and grading of acute symptoms as part of the routine clinical follow up, and the scoring was controlled and confirmed by ´ K). another oncologist (A 2.4. Statistical analysis The statistical analyses were performed with the SPSS statistics package (v 11.0.1, SPSS Inc , Chicago, USA), StatXact 5 (Cytel Software, Cambridge, MA, USA) and R [19]. To evaluate differences between treatments groups, testing the effect of comorbidity on toxicity and effect of volume on acute toxicity the Jonckheere – Terpstra test was used. To evaluate the difference between groups for median DVH, one-way ANOVA with Scheffe post hoc analysis was used (the nonparametic version were seen to give the same results). A permutation test (StatXact 5) was performed to evaluate the difference in relative DVH parameters between patients with Grade 0 þ 1 vs. Grade 2 or higher morbidity. The effect of various treatment and background variables on acute toxicity was tested by logistic regression. In the DVH analyses, the significance of differences between the groups was tested by ANOVA and the Kruskal – Wallis-test. The effects of including each DVH variable in our logistic regression models were evaluated using the crude correlation measure of predictive power introduced by Zheng and Agresti [50] and their P-values based on the likelihood ratio test [21]. Two-sided tests were used throughout, and P-values of less than 0.05 were considered statistically significant.
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Table 2 The modified RTOG acute scoring system used in this study Grade
Lower GI including rectum
Genitourinary
Anala
0 1
No change Increased frequency or change in quality of bowel habits not requring medication/rectal discomfort not requiring analgesics. Diarrhea requiring parasympatholytic drugs/mucoous discharge not necessitating sanitary pads/rectal or abdominal pain requiring analgesics. Diarrhea requiring parental support/serve mucous or blood discharge necessitating sanitary pads/abdominal distention
No change Frequency of urination or nocturia twice pretreatment habit/dysuria, urgency not requiring medication Frequency of urination or nocturia that is less frequent than every hour. Dysuria, urgency, bladder spasm requiring local anesthetic
No change Discomfort or pain not requiring analgesics
Frequency with urgency and nocturia hourly or more frequently/dysuria, pelvis pain or bladder spasm requiring regular, frequent narcotic/gross hematuria Hematuria requiring transfusion/acute bladder obstruction not secondary to clot passage, ulceration or necrosis
Discomfort or pain requiring narcotics
2
3
4
Acute or subacute obstruction, fistula or perforation; GI bleeding requiring transfusion; abdominal pain or tenesmus requiring tube decompression or bowel diversion a
Discomfort or pain requiring analgesics
ad modum Koper et al. (19) and RTOG (18).
3. Results Of the 132 patients, 130 (98.5%) completed treatment without interruption. In one patient, a 3-day treatment break was required because of heart disease, and one discontinued treatment after 60 Gy. Acute GI symptoms generally consisted of increased frequency of bowel movement, change in stool consistency, rectal discomfort, tenesmus and urgency. The overall GI morbidity was low in all three groups ðP ¼ 0:06Þ; as 3 of 26 (11%) in Group P, 14 of 86 (16%) in Group PSV and 7 of 20 (35%) in Group MPF required medication for relief of Grade 2 GI symptoms. There was no Grade 3 or 4 acute GI toxicity (Table 3). Acute GU symptoms generally consisted of increased urinary frequency, urgency, dysuria and nocturia. Also the overall GU morbidity was relatively low and not significantly different in the three groups, with 5 of 26 (19%), 27 of 86 (32%) and 7 of 20 (35%), in Groups P, PSV and MPF, respectively, required medication for relief of GU symptoms (Grade 2). Only 2 patients (2%), both in the PSV Group, developed acute Grade 3 toxicity with acute urinary retention that required catheterization for a short period. Both were able to complete the course of treatment without further side effects or delay (Table 3). Patients presenting with symptoms of prostatism before RT, had significantly more acute Grade $ 2 GU symptoms ðP ¼ 0:02Þ during therapy. Acute anal symptoms generally consisted of anal irritation or pain. The anal morbidity was uniformly low in all groups; 4% P, 3% PSV and none Grade 2 anal discomfort in MPF, Table 3. There was a significant correlation ðP ¼ 0:02Þ; between the three treatment groups and the incidence of any toxicity $ Grade 2. The patients in Group P, PSV, and MPF
developed any Grade 2 or higher acute side effects in 23.1, 44.2 and 60%, respectively. The difference between Group P and Group MPF were significant ðP ¼ 0:01Þ; but reached only a trend between Group P and Group PSV ðP ¼ 0:06Þ; whereas there was no significant difference between Group PSV and Group MPF ðP ¼ 0:21Þ: Table 1 shows that 31%, 34% and 45% of the patients in Groups P, PSV and MPF had a history of cardiovascular disease before radiation therapy. There was a significant Table 3 The fraction (and number) of patients with the different RTOG acute GI, GU and anal side effect scores in the different treatment groups
GI Grade 0 Grade 1 Grade 2
Group P ðn ¼ 26Þ
Group PSV ðn ¼ 86Þ
Group MPF ðn ¼ 20Þ
35% (9) 54% (14) 11% (3)
28% (24) 56% (48) 16% (14)
30% (6) 35% (7) 35% (7)
26% (4) 66% (17) 19% (5) 0
9% (8) 57% (49) 32% (27) 2% (2)
15% (3) 50% (10) 35% (7) 0
65% (17) 31% (8) 4% (1)
58% (50) 39% (33) 3% (3)
60% (12) 40% (8) 0
P ¼ 0.06 GU Grade Grade Grade Grade
0 1 2 3
P ¼ 0.2 Anal Grade 0 Grade 1 Grade 2 P ¼ 0.7 Group P: prostate only, Group PSV: prostate and seminal vesicle and Group MPF: modified pelvic field.
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correlation between cardiovascular disease and any Grade 2 toxicity in Group P ðP ¼ 0:05Þ; but not in the other groups. Analysing the different organs separately, the GI toxicity in Group P correlated highly significantly with cardiovascular diseases ðP ¼ 0:002Þ: 3.1. Analysis of DVH parameters and toxicity in the treatment groups The rectum DVHs between the three groups were significantly different ðP , 0:001Þ (Fig. 1a), e.g. on average 50% of the rectum received a dose of 43 Gy for Group P, 49 Gy for Group PSV and 62 Gy for Group MPF. All pairwise comparisons between the three groups (i.e. Group P vs. Group PSV; Group P vs. Group MPF; Group PSV vs. Group MPF) at various dose levels (20, 40, 60, 65 and 70 Gy) showed significant differences, except for 60 and 65 Gy between Group P and Group PSV, and for 20 Gy between Group PSV and Group MPF (Fig. 1a). Comparing each group separately the DVH analyses for the rectum failed to reveal a statistically significant correlation between acute GI toxicity and rectal volume ðP . 0:05Þ: However, analysing all patients there was a significant difference at 40 Gy ðP ¼ 0:03Þ and a trend at 60, 65 and 70 Gy ðP ¼ 0:06 – 0:09Þ between the fractional rectum volume and the incidence of acute GI toxicity (Table 4). As for the rectum there was a highly significant difference in the bladder DVHs between the three groups ðP , 0:001Þ (Fig. 1b), e.g. on an average 50% of the bladder received a dose of 54 Gy for Group P, 62 Gy for Group PSV and 70 Gy for Group MPF. Pairwise comparison between the three groups for various dose levels (20, 40, 60, 65 and 70 Gy) were all significant, except at 20 Gy between Group PSV and Group MPF. Similar irradiated fractional bladder volumes per dose level were found within the three groups for patients with RTOG Grade 0 and 1 compared to patients with RTOG Grade 2 and 3 ðP . 0:05Þ: However, when all patients were taken together there was a significant difference above 20 Gy ðP ¼ 0:05Þ; Table 4. 3.2. Multivariate analysis of volume effects The variables acute toxicity, treatment group, cardiovascular disease, T-staging, PSA, Gleason score, hormone treatment, TUR-P and age were initially included in a multivariate logistic regression. Of these, treatment group ðP ¼ 0:04Þ was the only independent predictor for the incidence of any acute Grade $ 2 morbidity. Multivariate logistic regression with the variables absolute volume, maximum dose, treatment group, cardiovascular disease and age was subsequently used to examine the relationship between the DVH variables (fractional volumes receiving in excess of the different dose levels) and toxicity. For the rectum, the regression analysis was
47
repeated substituting at each stage the fractional rectum volumes receiving more than dose levels in the range of 0 –75 Gy. The fractional rectum volumes were initially used alone, and then together with the maximum rectum dose and subsequently also the absolute volume of the rectum. The analysis documented that the rectum DVH parameters were correlated to the incidence of acute Grade 2 GI toxicity (Fig. 2a and b). When including the DVH parameters only, fractional rectum volumes in the range of 37 –40 Gy and above 70 Gy showed the strongest statistically significant correlation (Fig. 2a and b). When the maximum rectum dose was also included in the model, only a marginal statistical significance remained for the fractional volumes above 70 Gy. At the highest level of correlation, seen at doses above 70 Gy, both with and without the maximum dose in the model, a crude correlation coefficient of approximately 0.30 was observed. The factors included in the model at this stage thus explained roughly 9% of the variation in the clinically observed incidence of acute Grade 2 GI morbidity. A similar analysis of the bladder acute GU toxicity documented that the bladder DVH parameters were correlated with the incidence of acute Grade 2– 3 GU toxicity (Fig. 3a and b). When including the DVH parameters only, fractional bladder volumes in the range of 14– 27 Gy showed a statistically significant correlation (Fig. 3a and b). When age was also included in the model, only a marginal statistically significance remained for the fractional volumes between 21– 224 Gy. At the highest level of correlation, seen at doses of 22 –23 Gy, a crude correlation coefficient of approximately 0.28 was observed, i.e. the factors (age and DVH parameters) included in the model at this stage explained roughly 8% of the variation in the clinically observed incidence of acute Grade 2 –3 GU morbidity.
4. Discussion In this report, we have presented acute radiation toxicity data after CRT for prostate carcinoma, treating different volumes according to the tumour stage and documented risk factors. Overall, the patients exhibited a relative low incidence of severe toxicity, indicating a good short-term tolerance to radiation of a dose of 70 Gy when delivered by our CRT technique. The fundament of CRT is that there is a dose response relationship for tumour control and that there are dose/ volume response relationships for the involved normal tissues. The dose and volume response of normal tissue in general is such that irradiating a smaller volume to a higher dose is possible within generally accepted limits of complications [14,25]. Both univariate and multivariate analysis indicated that volume treated was an independent and significant factor for the incidence of acute morbidity of Grade 2 or higher in our study.
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Fig. 1. The mean DVH for (a) rectum and (b) bladder for Group P, PSV and MPF. The differences between the DVHs were statistically significant ðP , 0:001Þ:
It has been shown that a history of diabetes was significantly associated with the development of Grade 2 or higher acute GI and GU complications [37]. In our material only two patients had known diabetes, neither of these experienced Grade 2 or higher toxicity. Cardiovascular disease on the other hand correlated significantly with Grade 2 GI toxicity in Group P, but not in the other groups. The dose-limiting ORs in RT of prostate cancer are the rectum and the bladder. With regard to reliable DVH data, these organs present special problems because they are both hollow and tend to have temporal variations in size, shape and position due to difference in filling [16,20,30]. The
rectum and bladder DVHs based on the planning scan only may therefore not be representative for all of the daily treatment sessions, confounding the correlation between DVH parameters and toxicity. Still, it seems reasonable to assume that DVHs of the organ with content are less sensitive to organ motion than DVHs of the wall or surface only [30 –32]. Currently, we are investigating whether inclusion of rectum motion improves the correlation between the DVH parameters and toxicity. In particular the GI toxicity remained very favorable for Groups P and PSV, with 11% and 16% Grade 2 toxicity, respectively, but there was only a trend towards higher Grade 2 toxicity (35%) observed in Group MPF ðP ¼ 0:06Þ:
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Table 4 Median rectum/bladder dose and fractional rectum/bladder volume above various dose levels for patients with Grade 0 þ 1 vs. Grade 2 þ 3 acute rectum /bladder effects Group P ðn ¼ 25Þ
Group PSV ðn ¼ 82Þ
Group MPF ðn ¼ 20Þ
GIa Toxicity (Grade) Median dose (Gy) $20 Gy (%) $40 Gy (%) $60 Gy (%) $65 Gy (%) $70 Gy (%)
0þ1 44 88 55 26 21 10
2 43 96 65 26 22 12
0þ1 49 100 68 29 18 6
0þ1 61 100 95 52 43 28
2 63 100 98 58 46 31
0þ1 50 97 68 31 22 10
2 53 99 77 37 27 15
0.29 0.03 0.08 0.09 0.06
GUb Toxicity (Grade) Median dose (Gy) $20 Gy (%) $40 Gy (%) $60 Gy (%) $65 Gy (%) $70 Gy (%)
0þ1 53 89 69 49 39 16
2 59 97 79 51 43 23
0þ1 63 99 85 62 54 10
0þ1 70 100 100 91 77 58
2 69 100 100 88 77 57
0þ1 62 97 83 63 54 18
2 63 100 86 62 52 20
0.05 0.44 0.85 0.69 0.72
a b
2 49 99 67 28 17 6 2þ3 62 100 83 57 47 9
All patients ðn ¼ 127Þ
P-value
GI; gastrointestinal. GU; genito-urinary.
No patients experienced Grade 3 or higher toxicity. The rectum dose in the three groups were clearly different, e.g. the median dose was 43 and 49 Gy in Group P and PSV vs. 62 Gy in MPF, being a likely explanation for the difference in toxicity. However, it should be mentioned that the RTOG acute GI toxicity scoring system does not strictly discriminate between small bowel and rectal toxicity. According to Koper et al. [24], anal morbidity also contribute to the GI toxicity. The low anal toxicity being reported indicates a low anal radiation dose with our treatment technique. Jackson et al. [21] found that late rectal bleeding correlates with the volume receiving doses above 70 Gy, but reported also a correlation between bleeding and the volume exposed to intermediate doses (40 –50 Gy). This possibly indicates that when high-dose region are surrounded by extensive volumes receiving intermediate doses, the ability of this surrounding tissue to aid in the repair of a central injury may be inhibited. The present study confirms these findings, with a similar correlation between Grade 2 GI morbidity and the relative rectal volume receiving high (above 70 Gy) and intermediate doses (37 – 44 Gy) (Fig. 2b). It has been suggested that urethral mucositis and oedema within the prostate cause most of the urinary symptoms. This assumption is supported by the nature of the symptoms (frequency, urgency) as well as the particularly low incidence of acute GU toxicity in patients treated with 3D-CRT after radical prostatectomy [44]. The finding that the use of Intensity-Modulated RT (IMRT) for prostate cancer reduces rectum toxicity but not bladder toxicity despite reduced dose to the bladder [40] further supports the notion that most of the acute GU toxicity is caused by RT effects on the urethra within the prostate rather than in the bladder. According to this view, it seems unlikely that GU
symptoms can be avoided when irradiating the whole prostate and thus a segment of the urethra. In agreement with this, the differences in GU toxicity between the treatment groups in this series were less pronounced than the differences in GI toxicity, despite considerable consistent differences in the DVH and the DVH parameters also for the bladder. The correlation between bladder DVH parameters and bladder toxicity (Grade 0 þ 1 vs. Grade 2 þ 3) found for doses in the range 14– 27 Gy and the difference found for fractional bladder volumes receiving more than 20 Gy were in general also slightly weaker than the corresponding correlations found for the rectum. Still, this sensitivity to low doses (equivalent to 0.4 – 0.8 Gy per treatment fraction) was statistically significant, and warrants further investigation. Its biological explanation is uncertain, but it probably reflects a RT side effect linked to the whole (or most) of the bladder, e.g. reduced elasticity. It is also interesting to note that it coincides with the daily dose range for the so-called radiation hypersensitivity effect that recently has gained immense interest in experimental radiobiology [23]. Further follow-up will reveal whether this low dose sensitivity remains in the persisting late toxicity. Bladder doses with our technique were relatively high, but there was still only 2% Grade 3 GU toxicity rate in our material, in accordance with previous 3D-CRT series for prostate cancer, showing a 0 – 3% incidence of acute grade 3 and 4 GU toxicity [5,24,36,49]. We found statistically significant differences between patients with Grade 0 – 1 vs. Grade 2 – 3 acute GU effects for low doses only, but Valicenti et al. [41] found that the fraction of the bladder (# 30% vs. . 30%) receiving more than the prescription dose (68.4 Gy to 79.2 Gy)
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Fig. 2. (a) The crude correlation coefficient of the parameters included in the multivariate analysis of the rectum DVH data. At each dose level, the corresponding fractional rectum volume fraction is included in the model, either alone (‘DVH alone’) or together with the maximum rectum dose (‘Dmax’). (b) The significance levels from the multivariate analysis of each of the fractional rectum volumes when these were included one at each stage in the model, with only DVH variables (DVH-alone) or with DVH parameters and the maximum rectum dose included in the model (Dmax). The P-values are based on the likelihood ratio test.
were a significant predictor for acute GU effects. They also showed that men with poor baseline urinary function who were given HT had a significantly increased risk of acute GU side effects. Zelefsky et al. [45] and Schultheiss et al. [37] found in their studies that the presence of acute symptoms during
3D-CRT correlated with a higher incidence of Grade 2 or more late GI and GU toxicity. Still the association of acute and late injuries was not sufficiently strong to predict which patients would develop late complications. O’Brien et al. have also suggested an association between acute and late rectal toxicity [34]. Despite these reports, the relationship
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Fig. 3. (a) The crude correlation coefficient of the parameters included in the multivariate analysis of the bladder DVH data. At each dose level, the corresponding fractional bladder volume fraction is included in the model, either alone (DVH alone) or together with age. (b) The significance levels from the multivariate analysis of each of the fractional bladder volumes when these were included one at each stage in the model, with only DVH variables (DVH-alone) or with DVH parameters and age included in the model. The P-values are based on the likelihood ratio test.
between acute and late morbidity is still not understood [8,37,45]. Hanks et al. [14] observed that with 3D-CRT, Grade 2 acute toxicity were more volume than dose dependent. Also Nuyttens et al. [33] reported a dose – volume relations for acute Grade 2 rectal symptoms, but not for late side effects. Emami et al. [9] and Burman et al. [4] assumed that the volume effects for severe late reaction in the rectum were low. In contrast, Mameghan et al. [28], described a volume dependency for severe late bowel complication as also found by others [18,22].
It is widely accepted that increasing the dose to the tumour using conformal treatment can increase the tumour control; the challenge remains to achieve this while maintaining acceptable levels of complications. Since 2002, we have escalated the tumour dose for T1c, T2 and T3 tumours up to 78 Gy, with the BeamCathw system [2]. With this system, we can visualize the prostatic urethra with electronic portal imaging and thereby accurately localize the prostate prior to treatment. Late chronic side effects still limit the dose that can safely be given, and are probably
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linked to the volume of normal tissues irradiated. Studies of this new positioning technique have documented that it is possible to increase the total dose to 76 Gy without increasing acute or late side effects compared to standard CRT to 71 Gy [11 –13]. Dose escalation without increased toxicity in prostate RT has also been achieved with IMRT [46]. In conclusion, this study showed that 3D-CRT for prostate cancer to 70 Gy was well tolerated. Only two of the 132 patients in the cohort experienced acute bladder toxicity Grade 3, none had Grade 3 rectal toxicity. Uni- and multivariate analyses indicated that the volume treated was a significant factor for the incidence of Grade 2 or higher acute morbidity. A decrease in acute toxicity may result in a decrease in late complications, as late effects may be consequential acute effects. Therefore, the importance of acute toxicity should not be underestimated.
[12]
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[14]
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[16]
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Acknowledgements [18]
This study was supported by generous grants from the Norwegian Cancer Society. The authors would like to thank Yngve Kvinnsland for assistance with assessment of DVHs.
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