Risk factors of late rectal bleeding after carbon ion therapy for prostate cancer

Int. J. Radiation Oncology Biol. Phys., Vol. 66, No. 4, pp. 1084 –1091, 2006 Copyright © 2006 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/06/$–see front matter

doi:10.1016/j.ijrobp.2006.06.056

CLINICAL INVESTIGATION

Prostate

RISK FACTORS OF LATE RECTAL BLEEDING AFTER CARBON ION THERAPY FOR PROSTATE CANCER HITOSHI ISHIKAWA, M.D., PH.D.,* HIROSHI TSUJI, M.D., PH.D.,* TADASHI KAMADA, M.D., PH.D.,* NAOKI HIRASAWA, M.D.,* TAKESHI YANAGI, M.D., PH.D.,* JUN-ETSU MIZOE, M.D., PH.D.,* KOICHIRO AKAKURA, M.D., PH.D.,† HIROYOSHI SUZUKI, M.D., PH.D.,† JUN SHIMAZAKI, M.D., PH.D.,† AND HIROHIKO TSUJII, M.D., PH.D.* *Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan; †Department of Urology, Graduate School of Medicine, Chiba University, Chiba, Japan Purpose: The aim of this study was to determine the risk factors for late gastrointestinal (GI) morbidity after hypofractionated carbon ion radiotherapy (C-ion RT) for prostate cancer. Methods and Materials: Between April 2000 and November 2003, a Phase II clinical trial of C-ion RT with a total dose of 66 GyE in 20 fractions was performed on 175 patients with prostate cancer, and the correlations of clinical and dosimetric parameters with the incidence of late GI toxicity in 172 patients who survived for more than 18 months were investigated. Results: Although no Grade 3– 4 late morbidities of the rectum were observed, Grade 1 and 2 morbidities developed in 23 (13%) and 4 (2%) patients, respectively. Dose–volume histogram analysis revealed that the percentage of rectal volume receiving 50% of the prescribed dose (V50) was significantly higher in patients with rectal toxicity than without toxicity (13.2 ⴞ 5.6% with toxicity; 11.4 ⴞ 4.0% without toxicity, p ⴝ 0.046). Multivariate analysis demonstrated that the use of anticoagulation therapy ( p ⴝ 0.010) and rectal V50 ( p ⴝ 0.012) were significant risk factors for the occurrence of Grade 1–2 late GI toxicity. Conclusions: Although C-ion RT with hypofractionation yielded favorable results regarding late GI complication, dosimetric parameter was a very important factor in the occurrence of rectal bleeding after C-ion RT as well as photon beam RT. Our results provide useful information for physicians applying charged particle RT in the treatment of prostate cancer. © 2006 Elsevier Inc. Prostate cancer, Carbon ion therapy, Rectal bleeding, DVH, Hypofractionation.

and C-ion radiation therapy (C-ion RT) has been performed for prostate cancer patients at our institute since 1995 (14, 15). In the first dose escalation studies, 35 patients with advanced disease (T2b-T3b) received C-ion RT (16). The total dose was increased from 54 Gray equivalents (GyE) up to 72 GyE in 20 fractions over 5 weeks in 10% increments. Although local control was achieved in all patients except 1 who had received a total dose of 54 GyE, Grade 3 late morbidities of the rectum or bladder/urethra developed in 5 (36%) of 14 patients who received 72 GyE. The results of that trial were used to determine the maximum dose tolerated by the rectum in C-ion RT. A second Phase I–II study was initiated in January 1998 using a shrinking field technique. While a total dose of 60 to 66 GyE in 20 fractions

INTRODUCTION Hypofractionated radiation therapy (RT) has recently attracted much attention as a treatment for localized prostate cancer because of the relatively low ␣/␤ ratio of prostate cancer cells (1–3). The potential benefit of hypofractionated RT is therefore anticipated as an alternative dose escalation method for prostate cancer (3– 6). Indeed, high-dose-rate (HDR) brachytherapy and three-dimensional conformal RT (3D-CRT) with intensity-modulated radiation therapy with hypofractionation have yielded desirable results for prostate cancer with comparable morbidity rates to high-dose 3DCRT with conventional fractionation (7–10). It is thought that carbon ion (C-ion) beams offer unique biologic and physical properties that benefit RT (11–13),

Acknowledgment—We thank Kazutoshi Kono and Norikazu Tanabe for preparation and assessment of the data of dosimetric parameters in this study. Received June 6, 2006, and in revised form June 26, 2006. Accepted for publication June 27, 2006.

Reprint requests to: Hiroshi Tsuji, M.D., Ph.D., Research Center for Charged Particle Therapy, National Institute of Radiological Sciences (NIRS), 4-9-1 Anagawa, Inage-ku, Chiba-city, 263-8555 Japan. Tel: (⫹81) 43-251-2111; Fax: (⫹81) 43-256-6506; E-mail: [email protected] Supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. 1084

Risk factors of rectal bleeding after carbon ion RT

Table 1. Characteristics of patients treated with carbon-ion radiotherapy

Age (years) Median (range) ⱕ70 ⱖ71 T stage T1 T2a T2b T3 Gleason sum 4–5 6 7 8–9 Prostate-specific antigen (ng/mL) ⱕ19.9 20.0–49.9 ⱖ50.0

Low risk (n ⫽ 33)

High risk (n ⫽ 139)

All (n ⫽ 172)

71 (60–80) 16 (48%) 17 (52%)

70 (53–83) 74 (53%) 65 (47%)

70 (53–83) 90 (52%) 82 (48%)

22 (67%) 11 (33%) 0 (0%) 0 (0%)

34 (25%) 13 (9%) 29 (21%) 63 (45%)

56 (33%) 24 (14%) 29 (17%) 63 (36%)

14 (42%) 19 (58%) 0 (0%) 0 (0%)

5 (4%) 16 (11%) 77 (56%) 41 (29%)

19 (11%) 35 (20%) 77 (45%) 41 (24%)

33 (100%) 0 (0%) 0 (0%)

65 (47%) 46 (33%) 28 (20%)

98 (57%) 46 (27%) 28 (16%)

was delivered to patients with T1b-T2a diseases, fixed doses of 66 GyE in 20 fractions of C-ion RT combined with androgen deprivation therapy (ADT) was given to patients with T2b-T3b diseases (16). After successful completion of the study, no Grade 3 or worse late complications have been observed to present. Therefore, based on the results of the previous two Phase I-II dose escalation studies (17), we designed a Phase II trial with a hypofractionation schedule that delivered a fixed total dose of 66 GyE with a daily fraction dose of 3.3 GyE to further confirm the efficacy and feasibility of C-ion RT for localized prostate cancer. Although many investigators have showed the risk factors for late morbidities after RT for prostate cancer (5, 18 –22), to our knowledge, no report has examined risk factors for morbidity after charged-particle RT under a hypofractionated regimen. Therefore, based on update data of the Phase II study that used a 66 GyE fixed dose, we investigated correlations of clinical and dosimetric parameters with incidence of gastrointestinal (GI) morbidities after C-ion RT. METHODS AND MATERIALS Patients For the Phase II trial, 175 patients received C-ion RT between April 2000 and November 2003. Patient eligibility was the same as that for a recently reported study (17), such that patients were eligible if they had previously untreated T1-T3 primary adenocarcinoma of the prostate. Three patients, who had died of intercurrent disease (1 patient) or prostate cancer (2 patients) within 18 months after C-ion RT (6, 13, and 17 months, respectively), were excluded from this study, although none of these patients had exhibited late complications. Thus the present study evaluated data of 172 patients. Patient characteristics are shown in Table 1. The median age of the patients was 70 years (range, 53– 83 years) and

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a median value of prostate-specific antigen (PSA) of 17.5 ng/mL before the start of treatment, with values ranging from 3.4 to 200.0 ng/mL. Clinical stage according to the 1997 American Joint Committee on Cancer staging system (23) at presentation was 56 patients with T1, 24 with T2a, 29 with T2b, and 63 with T3. Gleason scores (GS) of all tumors based on review by a single pathologist before C-ion RT were 19 patients with GS 4/5, 35 with GS 6, 78 with GS 7, and 40 with GS 8/9.

Protocol The protocol of the Phase II trial has been described elsewhere (17). Patients were divided into two groups according to the three major risk factors: T stage, initial PSA value, and GS. Patients with T1/T2aN0M0, initial PSA value ⬍20 ng/mL, and GS ⬍7 were stratified into the low-risk group, whereas patients with T2b/T3 tumors, initial PSA ⱖ20 ng/mL, or GS ⱖ7 were assigned to the high-risk group. C-ion RT without ADT was performed for 33 of 172 patients with low-risk tumors, whereas C-ion RT combined with ADT was performed for the remaining 139 patients in the high-risk group.

C-ion therapy and hormonal therapy The technique of C-ion RT for prostate cancer has also been described previously (16, 17). C-ion RT was performed only on the prostate and seminal vesicle without pelvic irradiation, irrespective of patient risk factors. Briefly, the head and feet of the patients were positioned in a customized cradle (Moldcare; Alcare, Tokyo, Japan) and the pelvis was immobilized with a low-temperature thermoplastic sheet (Shellfitter; Keraray, Co., Ltd., Osaka, Japan) in the supine position. The bladder was filled with 100 mL sterilized water from the anterior direction at CT planning and at each session. The rectum was emptied as much as possible by the patient’s own effort before each treatment session, and a laxative or enema was used, if necessary. Based on 5-mm thick computed tomography (CT) images, 3D treatment planning was carried out using our original HIPLAN software (National Institute of Radiological Sciences, Chiba, Japan). The clinical target volume (CTV) included the prostate and the seminal vesicles after reference to both CT and magnetic resonance imaging data. The initial planning target volume (PTV1) was created by adding a 10-mm anterior and lateral margins and a 5-mm posterior margin to the CTV. After the first 10 fractions, boost therapy was performed using the second PTV (PTV2), in which the posterior edge was set in front of the anterior wall of the rectum to reduce the rectal dose, whereas the anterior and lateral margins remained the same as for PTV1. C-ion RT was performed once per day, four fractions per week (Tuesday–Friday). One port was used for each session, with five irregular shaped ports, including one anteroposterior port and a pair of lateral ports for PTV1 and another pair of lateral ports for PTV2. PTV2 was exposed to more than 90% of the prescribed dose. The dose–volume histogram (DVH) of the rectum was checked for each patient so that dose constraints determined by the prior studies were satisfied. A representative dose distribution is shown in Fig. 1. The irradiated dose was fixed at 66 GyE in 20 fractions over 5 weeks with a fraction dose of 3.3 GyE, which was determined according to the results of the previous two Phase I-II trials. Radiation fields were verified by digital orthogonal fluoroscopy at each session, and the treatment couch was adjusted using a computer-aided online positioning system. Treatments were performed immediately after confirming that the maximum deviation of all

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Statistics Survival times were evaluated according to the Kaplan-Meier method (25). Cumulative toxicity rates of late toxicity were compared by the log–rank test as a univariate analysis among the different subgroups. Clinical and dosimetric parameters affecting the occurrence of late GI toxicity were analyzed by multivariate analysis using Cox’s proportional hazard model. Differences were considered significant if the p value fell below 0.05.

RESULTS

Fig. 1. Representative dose distribution of carbon ion radiotherapy.

measured points was less than 2 mm by comparing reference images with actual images. Before C-ion RT, neoadjuvant ADT was performed on high-risk patients for 2– 6 months and consisted of medical or surgical castration with or without antiandrogen. Adjuvant ADT was administered for 12 months or longer, with the median duration of total neoadjuvant and adjuvant ADT administration in the current study being 26 months. In contrast, low-risk patients received C-ion RT only.

DVH evaluation Because all patients received an enema to empty the rectum before the acquisition of CT scans, the rectum was delineated by identifying its external contours on CT images from just above the anal verge to the point at which it turned into the sigmoid colon. Based on DVH data obtained from the HIPLAN software, percentages of rectal volume receiving 30 –90% of the prescribed doses in 10% increments were expressed as DVH parameters V30 –V90. As mentioned previously, the irradiated volume of the rectum was constrained to be lower than average for patients without Grade 2 or higher rectal bleeding in prior studies; that is, V50, V70, and V90 did not exceed 6%, 12%, and 24%, respectively.

Follow-up Patients were followed by both the referred urologist and a radiation oncologist at three monthly intervals for the first 3 years after C-ion RT and at three to six monthly intervals thereafter. Acute and late toxicities from C-ion RT were scored both during the C-ion RT treatment period and the follow-up period according to the toxicity criteria of the Radiation Therapy Oncology Group and the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (24).

Survival and recurrence Follow-up examination was carried out periodically for all patients, with a median follow-up period of 46 months (range, 27–71 months) or until death. At the last follow-up, 2 patients had died of recurrent prostate cancer and 6 patients had died of intercurrent diseases with no evidence of recurrence. Although biochemical relapses were observed in 18 (10.5%) of 172 patients, local tumor control was achieved in all but 1 patient. Incidence of late GI toxicity Incidences of the acute and late GI morbidities are summarized in Table 2. Grade 1 acute GI toxicities were observed in only 2 (1%) of 172 patients. With regard to late toxicity, Grade 1 and Grade 2 rectal bleeding developed in 23 (13%) and 4 (2%) patients, respectively, but no Grade 3 or worse morbidities of the rectum were observed. Twentytwo (81%) of the 27 Grade 1 and 2 late toxicities occurred within 2 years after C-ion RT. The 5-year actuarial rates of developing Grade 1-2 and Grade 2 GI complications were 16.0% (95% confidence intervals [CI], 10.2–21.8%) and 2.7 (95% CI, 0.1–5.3%), respectively (Fig. 2). However, these complications resolved naturally or immediately after medication during follow-up examination in approximately half of the affected patients. Only 13 (8%) and 2 (1%) of patients had Grade 1 and 2 GI toxicities, respectively, at last follow-up (Table 2). Correlation of DVH parameters and late toxicity Figure 3 shows the average normalized rectal volume at each dose level according to occurrence of Grade 1-2 rectal bleeding, and Table 3 summarizes the mean percentages of DVH parameters from V30 to V90. V30 –V90 percentages in patients who experienced rectal bleeding were higher than for patients in the nontoxicity group. In particular, the mean V50 of patients with bleeding was 13.2 ⫾ 5.6%,

Table 2. Incidence of acute and late toxicities at the rectum after carbon ion radiotherapy Acute

Late

Grade

0

1

2

3

0

1

2

3

Maximum (%) Last follow-up (%)

170 (99)

2 (1)

0 (0)

0 (0)

145 (85) 157 (91)

23 (13) 13 (8)

4 (2) 2 (1)

0 (0) 0 (0)

Risk factors of rectal bleeding after carbon ion RT

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Grade 1-2 Grade 2

25

0 0

12

24

36

48

60

Times after carbon ion therapy (months) Fig. 2. Cumulative incidence curves of late Grade 1-2 and Grade 2 gastrointestinal complications after carbon ion radiotherapy.

which was significantly higher than the V50 of 11.4 ⫾ 4.0% observed in patients without the bleeding ( p ⫽ 0.046). Risk factors of incidence of rectal bleeding To identify significant risk factors for rectal bleeding after C-ion RT, univariate and multivariate analyses were

25

Grade 1-2 gastrointestinal toxicity

(⫹)

(⫺)

p value

Rectum (mean ⫾ SD, %) V30 V40 V50 V60 V70 V80 V90

22.6 ⫾ 6.9 16.9 ⫾ 5.4 13.2 ⫾ 5.6 8.8 ⫾ 3.6 6.7 ⫾ 3.7 4.8 ⫾ 2.5 2.3 ⫾ 2.0

19.8 ⫾ 6.3 15.2 ⫾ 5.4 11.4 ⫾ 4.0 7.7 ⫾ 3.4 5.9 ⫾ 2.9 4.0 ⫾ 2.3 1.9 ⫾ 1.4

0.052 0.165 0.046 0.148 0.194 0.114 0.237

performed using an end point of cumulative incidence of toxicity. Univariate analysis demonstrated that the p values of the DVH parameter V50 and the patient characteristics anticoagulation therapy fell below 0.10 (Table 4). For V50, the 5-year cumulative rate of rectal bleeding was 12.3% (95% CI, 6.0 –18.6%) for 111 patients with V50 ⱕ13%, but 22.2% (95% CI, 11.5–32.9%) for 61 patients with V50 ⬎ 13% ( p ⫽ 0.07). Anticoagulation therapy was associated Table 4. Analysis for risk factors of Grade 1–2 morbidity

Characteristics Univariate analysis DVH parameters PTV (mL)

Rectal bleeding

V30

Yes (n=27)

V50

No (n=145) Irradiated volume at the rectum (%)

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Table 3. Correlation between dose-volume histogram parameters and Grade 1-2 rectal bleeding

50

Complication rates (%)

●

20

V70 V90

15

Mean: 㼳2SE

* p=0.046

Patient characteristics Age T-stage ADT

10

DM HT 5

Anticoagulation

0 20

30

40

50

60

70

80

90

100

Percentages of prescribed dose

Fig. 3. Average of normalized rectal volumes receiving 30% of the prescribed dose (V30) to V90 according to occurrence of rectal bleeding.

Multivariate analysis V50 Anticoagulation

Subgroup

Number of patients

5-year rate (%)

p value

ⱕ150 ⬎150 ⱕ22% ⬎22% ⱕ13% ⬎13% ⱕ6.5% ⬎6.5% ⱕ2.5% ⬎2.5%

93 79 108 64 111 61 95 77 113 59

13.6 18.7 12.1 21.6 12.3 22.2 15.7 16.2 14.7 17.9

0.37

ⱕ70 ⬎70 T1b-T2a T2b-T3b No Yes No Yes No Yes No Yes

90 82 80 92 33 139 152 20 112 60 152 20

14.7 17.6 14.4 17.5 12.1 17.0 16.9 10.6 15.8 16.7 13.3 35.4

0.43

0.14 0.07 0.91 0.57

0.84 0.86 0.45 0.72 0.002

Hazard ratio

95% CI

p value

2.48 2.57

1.14–5.44 1.08–6.14

0.02 0.03

Abbreviations: DVH ⫽ dose-volume histogram; PTV ⫽ planning target volume; ADT ⫽ androgen deprivation therapy; DM ⫽ diabetes mellitus; HT ⫽ hypertension.

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50 Anticoagulation: Yes (n=20)

Complication rates (%)

Anticoagulation: No (n=152)

25

p=0.002

0 0

12

24

36

48

60

Times after carbon ion therapy (months)

Fig. 4. Cumulative late Grade 1-2 gastrointestinal complication rates according to use of anticoagulation treatment. The 5-year complication rate of patients treated with anticoagulation therapy was 35.4%, compared with 13.3% for nontreated patients ( p ⫽ 0.002).

with a 2.7-fold risk of late GI toxicity. The 5-year late GI toxicity rates were 35.4% (95% CI, 14.4 – 46.4%) for patients receiving the therapy and 13.3% (95% CI, 7.7–18.9%) for the nontreatment group ( p ⫽ 0.002, Fig. 4). Further investigation revealed that V50 was a significant risk factor in the 152 patients who did not undergo anticoagulation therapy. The 5-year GI toxicity rate of V50 ⬎13% patients was 20.6% ⫾ 11.1%, compared with 9.5% ⫾ 6.0% for the V50 ⱕ13% patient group ( p ⫽ 0.048, Fig. 5). Thus results of the multivariate analysis showed that anticoagulation treatment and V50 percentage acted as independent risk factors for occurrence of late GI toxicity after C-ion RT for prostate cancer (Table 4).

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related to late rectal bleeding after RT, and the rectal dose and irradiated volume were particularly thought to be key factors in the occurrence of bleeding (5, 18 –20, 29 –31). In the present study, because of the relatively small number of patients who developed Grade 2 toxicity (4 patients), the risk factors for Grade 1 or higher GI toxicity were investigated. Our results indicated that DVH parameters such as V50 were important predictors of the GI toxicity after C-ion RT as well as photon therapy, although charged particle therapy gives a better dose distribution concentrated to the target area and can avoid irradiation of the organ at risk. The V50 percentage in the group of patients with bleeding at the rectum was significantly higher than for the group of patients without the bleeding ( p ⫽ 0.046), and multivariate analysis showed that V50 was an independent risk factor of late rectal toxicity in addition to treatment with anticoagulation therapy ( p ⫽ 0.02), even though the rectal dose was reduced by the shrinking technique and given according to the dose constraints obtained in the previous studies. For patients who did not receive the anticoagulation therapy, the 5-year late GI complication rate for the V50 ⱕ13% patient group was 20.6% compared with 9.5% for the V50 ⬎ 13% patient group. The reason why V50 was a better predictor of late rectal bleeding after C-ion RT rather than other irradiated volumes percentages at high dose levels such as V70 and V90 is unclear. Although a number of studies have showed an association between larger irradiated rectal volumes at the high dose levels and high incidence of bleeding after RT (5, 18 –20, 29 –33), intermediate doses at around 30 –50 Gy have been also associated with the development of late toxicity in several of these studies (18, 20, 32, 33). The

50

Late rectal bleeding is a well-known dose-limiting factor in RT for prostate cancer (18 –20, 26 –28). In 1995, the first Phase I-II dose escalation study using C-ion RT for locally advanced (T2b-T3) prostate cancer was started at our institution (11). Since then, results from our two Phase I-II dose escalation studies have indicated that approximately 11% of patients (10 of 95) who received C-ion RT experienced Grade 2-3 late GI morbidities (16). Based on these results, a total dose of 66 GyE in 20 fractions over 5 weeks with a fraction dose of 3.3 GyE was determined to be the optimal dose, with a shrinking technique used to reduce the rectal dose (17). Using this regimen, the present study observed Grade 2 late rectal bleeding in only 4 (2%) of 172 patients and no patient with Grade 3 toxicity. Therefore, our fractionation schedule and PTV settings appear to be useful for C-ion RT for prostate cancer. Several studies have investigated various risk factors

Complication rates (%)

V50 >13% (n=102)

DISCUSSION

V50 䍯13% (n=50)

25

p=0.048

0 0

12

24

36

48

60

Times after carbon ion therapy (months)

Fig. 5. Cumulative late Grade 1-2 gastrointestinal complication rates according to receiving 50% of the prescribed dose (V50) of the rectum in patients who did not receive anticoagulation therapy (n ⫽ 152). The 5-year complication rate of patients with V50 ⬎13% was 20.6%, compared with 9.5% for patients with V50 ⱕ13% ( p ⬍ 0.05).

Risk factors of rectal bleeding after carbon ion RT

reduced impact of irradiated volumes at higher dose levels observed in our study might be due to the very small volumes involved during the latter half of the C-ion RT treatment course based on PTV2. Indeed, V90 was only about 2% of the whole rectal volume, which corresponded to about 1.7 mL on average when converted into actual volume. Thus, based on DVH data collected before treatment, it may be useful to examine V50 of the rectum in determining PTV1 when optimizing of the C-ion RT treatment plan. Although dose fractionation remains a controversial issue regarding rectal toxicity after RT for prostate cancer, few reports have examined late GI toxicity after the delivery of hypofractionated RT at higher equivalent doses than received by standard fractionation. Kuperian et al. (7) recently reported the long-term outcomes of hypofractionated intensity-modulated radiation therapy with a total dose of 70 Gy in 28 fractions (2.5 Gy per fraction) that was at least equivalent to the 81 Gy dose given in 45 fractions as reported by Zelefsky et al. (27) using the linear-quadratic model. In that study, Grade 2 or higher late rectal toxicity rate was observed in only 5% of patients at the last followup. Therefore, the results of that study indicated that use of a well-localized dose distribution could minimize rectal toxicity even if a hypofractionated regimen was applied. In high linear energy transfer radiotherapies, such as C-ion RT, the relative biologic effectiveness (RBE) of the beams can make dose fractionation more complicated. Distributions of physical doses and linear energy transfer in actual multiportal C-ion RT are too complex to allow investigation into the influences of such factors on rectal toxicity. Therefore, the estimation of RBE in clinical applications requires a series of assumptions. For C-ion RT at the National Institute of Radiological Sciences, RBE was defined as the distal part of the spreadout Bragg peak equal to 3.0 irrespective of other factors, such as the tissue of interest and dose fractionation (11, 13, 15, 34). Despite the application of this roughly determined RBE, actual incidences of late rectal toxicity in our study were comparable to or slightly lower than incidences reported in various studies of high-dose RT for prostate cancer (7, 20, 27, 29, 30, 35). If the predetermined RBE values were correct and the linear-quadratic model can be applied to C-ion RT, then the dose fractionation of 66.0 GyE as 20 fractions as used in the present study can be regarded as equal to a 83.2 GyE dose in the standard fractionation of 2 Gy per fraction with a 3 Gy ␣/␤ value. The significant risk factor of V50 that we identified in this study therefore corresponded to the rectal volume irradiated by more than 41.6 GyE, which is consistent with the findings of other reports that showed a significant correlation between rectal toxicity and rectal volumes irradiated at intermediate doses (30 –50 Gy) (18, 20, 32, 33). From this point of view, the assumptions used to determine the RBE for C-ion RT seem to be reasonable, at least for late rectal complications. It is thought that diabetes mellitus (DM) is a major risk

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factor for developing radiation-induced injuries in normal tissues. For prostate cancer, some investigators have proposed that DM is also a highly significant predictor of late GI toxicity after external beam RT by conventional fractionation (35, 36). Furthermore, Akimoto et al. (5) recently reported that DM played a key role in the incidence of rectal toxicity after hypofractionated external beam RT for prostate cancer. Taking these findings into consideration, it is possible that DM might inhibit the repair of radiationinduced damages to the rectal mucosa and surrounding connective tissues because of disturbance of the blood vessels (36, 37). Although we observed that Grade 2-3 rectal bleeding was associated with a history of DM in our first dose-escalation study of C-ion RT for prostate cancer (16), no such relationship between DM and the Grade 1-2 rectal bleeding was apparent in the current study. This seemingly contradictory result may be caused by the low incidence of GI toxicity from the considerable reduction of irradiated rectal volume using our shrinking technique for C-ion RT in this Phase II study (14). Studies have also examined whether ADT is involved in late GI toxicity in RT for prostate cancer, and some have indicated that ADT was an unfavorable factor in terms of toxicity (29, 38 – 40), although the exact mechanism remained unclear. Fiorino et al. (30) reported that Grade 2 GI morbidity appeared in 12.8% of patients who received a combination therapy of RT and adjuvant ADT, whereas only 6.8% of patients were affected after treatment with RT alone. Recently, Liu et al. (41) showed that a short course (⬍2 months) of neoadjuvant ADT was significantly related to incidence of late Grade 2 GI morbidity, because the volume of the prostate changed during RT. However, in our study, no relationship between ADT treatment and late toxicity was observed. One explanation for this is that changes in prostate volume during C-ion RT were limited, because C-ion RT was performed at least 2 months after the commencement of neoadjuvant ADT. Furthermore, the relatively small PTV in the high-risk group may have reduced the influence of ADT on late toxicity. The average PTVs for the high-risk and low-risk groups in this study were 149.4 ⫾ 39.0 mL and 184.5 ⫾ 26.0 mL, respectively ( p ⬍ 0.001). In conclusion, the usefulness of hypofractionated C-ion RT for prostate cancer has been further confirmed with regard to the incidence of late rectal complications. These promising results were achieved through improved dose distribution of the C-ion beams and the accurate adjustment techniques. Our multivariate analysis revealed that the rectal V50 percentage and use of anticoagulation therapy were significant risk factors for occurrence of late GI toxicity. To achieve favorable results for late rectal bleeding, it appears to be important to reduce the rectal volume exposed to irradiation by C-ion RT through the setting of PTV1. Although further investigations are needed, our results provide useful information on the application of charged particle RT, including C-ion RT, for prostate cancer.

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Physics

Volume 66, Number 4, 2006

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