Correlation Between Dosimetric Parameters and Late Rectal and Urinary Toxicities in Patients Treated With High-Dose-Rate Brachytherapy Used as Monotherapy for Prostate Cancer

Int. J. Radiation Oncology Biol. Phys., Vol. 75, No. 4, pp. 1003–1007, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter

doi:10.1016/j.ijrobp.2008.12.051

CLINICAL INVESTIGATION

Prostate

CORRELATION BETWEEN DOSIMETRIC PARAMETERS AND LATE RECTAL AND URINARY TOXICITIES IN PATIENTS TREATED WITH HIGH-DOSE-RATE BRACHYTHERAPY USED AS MONOTHERAPY FOR PROSTATE CANCER KOJI KONISHI, M.D., YASUO YOSHIOKA, M.D., FUMIAKI ISOHASHI, M.D., IORI SUMIDA, PH.D., YOSHIFUMI KAWAGUCHI, M.D., TADAYUKI KOTSUMA, M.D., KANA ADACHI, M.D., MASAHIRO MORIMOTO, M.D., SHOICHI FUKUDA, M.D., AND TAKEHIRO INOUE, M.D. Department of Radiation Oncology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan Purpose: To evaluate the correlation between dosimetric parameters and late rectal and urinary toxicities in highdose-rate brachytherapy (HDR-BT) used as monotherapy for prostate cancer. Methods and Materials: The data of 83 patients treated with HDR-BT alone for prostate cancer from 2001 through 2005 at Osaka University Hospital were analyzed. Median follow-up time was 36 months (range, 18–70). The total prescribed dose was 54 Gy in nine fractions over 5 days. Correlation between dosimetric parameters and late toxicities was examined. Results: The means of V30, V40, V50, V60, V70, D1cc, D2cc, D5cc, and D10cc of the rectum were significantly higher in 18 patients who presented with late rectal toxicity (Grades 1–3 rectal bleeding) than in the other 65 patients who did not. A significant difference was observed for D1cc–10cc but not for D5–90. The statistically most significant difference was observed for V40 and D5cc. Late rectal toxicity rate was significantly higher for patients with rectal V40 $ 8 cc than those with the rectal V40 < 8 cc (42% vs. 8%; p < 0.001), as well as for patients with rectal D5cc $ 27 Gy compared with those with rectal D5cc < 27 Gy (50% vs. 11%; p < 0.001). Dosimetric parameters of the urethra of 15 patients with late urinary toxicity were not significantly different from the 68 patients without toxicity. Conclusion: Rectal V40 < 8 cc and D5cc < 27 Gy may be dose–volume constraints in HDR-BT used as monotherapy for prostate cancer. Ó 2009 Elsevier Inc. Prostate cancer, High-dose-rate brachytherapy, Late toxicity, Dose–volume constraint, Monotherapy.

INTRODUCTION

Recently, it has become possible for us to use DVH analysis by upgrading the treatment planning computer, which enabled us to begin evaluating retrospectively the correlation between dosimetric parameters and late rectal and urinary toxicities in patients treated with HDR-BT alone for prostate cancer, as reported in this study. Some investigations using DVH analysis of HDR-BT combined with EBI have been published (14, 15), but this is the first report of the correlation between late rectal and urinary toxicities and the pure dosimetric parameters of HDR-BT (i.e., not affected by EBI) for prostate cancer.

High-dose-rate brachytherapy (HDR-BT) is one of the most efficient and effective modalities for radiation dose enhancement because of its excellent conformity and rapid dose falloff outside the target volume. HDR-BT is most commonly used in combination with external beam irradiation (EBI) for locally advanced prostate cancer. Many investigations of HDR-BT in combination with EBI have been published (1–8). However, we initiated HDR-BT as monotherapy on the basis of the concept that the use of HDR-BT alone is the most efficient way to enhance the radiation dose to the prostate. We reported the results for the first time in 2000 (9). Other groups introduced HDR-BT alone afterward (10, 11). Subsequently, we reported a low incidence of late toxicity after the use of HDR-BT alone in 2003 and 2006 (12, 13). However, the dose–volume histogram (DVH) could not be fully analyzed in these studies because of problems with the planning computer system.

METHODS AND MATERIALS Patient characteristics and selection Between 1995 and 2006, 133 patients were treated with HDR-BT as monotherapy for prostate cancer at Osaka University Hospital, Japan. DVH analysis became available in 2001, and in 2005, we

Reprint requests to: Yasuo Yoshioka, M.D., Department of Radiation Oncology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel: (+81) 6-6879-3482; Fax: (+81) 6-6879-3489; E-mail: yoshioka@radonc. med.osaka-u.ac.jp Presented at the 5th Japan–U.S. Cancer Therapy Symposium and

the 5th S. Takahashi Memorial International Joint Symposium in Sendai, Japan, September 7, 2007. Conflict of interest: none. Received April 7, 2008, and in revised form Dec 8, 2008. Accepted for publication Dec 14, 2008. 1003

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Table 1. Characteristics of patients Number of patients Age Median Range TNM classification T1cN0M0 T2aN0M0 T2bN0M0 T2cN0M0 T3aN0M0 T3bN0M0 T4N0M0 GS Median Range Pretreatment PSA (ng/mL) Median Range Risk group Low (T1c–2b, GS # 6, PSA < 10 ng/mL) Intermediate High (T3–4 or GS $ 8 or PSA $ 20 ng/mL) Hormonal therapy Yes No Follow-up (months) Median Range

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Implant technique 83 68 47–78 20 15 10 1 25 10 2 7 2-10 14.9 3.8-171.0 14 20 49 67 16 36 18–70

Abbreviations: GS = Gleason score; PSA = prostate-specific antigen.

changed the treatment protocol from 54 Gy in nine fractions over 5 days to 45.5 Gy in seven fractions over 4 days. For this study, therefore, the data for only the 83 patients treated with a total dose of 54 Gy in nine fractions from 2001 through 2005 were analyzed. The median age at diagnosis was 68 years (range, 47–78). All patients had biopsy-proven adenocarcinoma of the prostate. According to the 2002 TNM classification by the International Union Against Cancer, 20 patients had T1c, 15 had T2a, 10 had T2b, 1 had T2c, 25 had T3a, 10 had T3b, and 2 had T4 (only bladder neck invasion). None of the patients had nodal or distant metastases radiographically. The initial PSA (iPSA) level range was 3.8–171.0 ng/mL (median, 14.9), and the Gleason Score (GS) range was 2–10 (median, 7). We defined low-risk patients as those with iPSA < 10.0 ng/mL, GS # 6, and T1c–T2b; intermediate risk patients as those who were neither low- nor high-risk; and high risk as those with iPSA $ 20.0 ng/ mL, GS $ 8, or T3–T4. According to this definition, 14 patients were classified as low risk, 20 as intermediate risk, and 49 as high risk (Table 1).

Hormonal therapy The treatment protocol for hormonal therapy was as follows. Patients with a large prostate volume (more than 40 mL), intermediate-risk patients, and high-risk patients received 6–12 months of neoadjuvant hormonal therapy, and high-risk patients received 3-year or lifetime adjuvant hormonal therapy consisting of luteinizing hormone releasing hormone agonist and antiandrogens. Final decisions concerning hormonal therapy were made by urologists. Neoadjuvant therapy, adjuvant hormonal therapy, or both were administered to 67 patients.

The implant technique has been described in detail in a previous report (9). In brief, it involves continuous epidural anesthesia, realtime transrectal ultrasonography (TRUS) guidance, use of metallic applicators and applicator stoppers (Trocar Point Needles and Needle Stoppers; Nucletron, Veenendaal, The Netherlands), and an original template and its cover plate (Taisei Medical, Osaka, Japan). Under real-time TRUS monitoring of the largest cross-section of the prostate, the applicators were placed on the line encompassing the prostate (with extracapsular invasion, if any) and within the prostate, but sparing the urethra, at 1.0- to 1.5-cm intervals. For the posterior (rectal) side, the applicators were placed 0–3 mm inside the prostate capsule. The top 2 cm of the catheters was placed within the bladder pouch. When a seminal vesicle was included in the target, placement of some applicators involved piercing the medial half of the seminal vesicle.

Treatment planning and irradiation The clinical target volume (CTV) comprised the whole prostate gland plus 5 mm in all directions except for the posterior (rectal) margin. The posterior margin varied from 2 to 5 mm depending on the distance to the rectal wall. If extracapsular invasion was observed or strongly suspected, the area with the margin was included in the CTV. If seminal vesicle invasion was observed or strongly suspected, the medial half of the seminal vesicle with the margin was also included in the CTV. Forty-nine patients were treated with these extra margins. The planning target volume (PTV) was equal to the CTV except in the cranial direction, where it was greater. The top 2 cm of the applicators was placed within the bladder pouch, so that the PTV included a 1-cm margin in the cranial direction from the CTV. This margin was established not only to prevent creation of a cold area at the base of the prostate but also as insurance against the possibility of the applicators coming out. One hour before administration of each irradiation fraction, a urinary balloon catheter was clipped in place to keep the urine within the bladder pouch so that the opposite side of the bladder wall and the bowels were kept away from the irradiation field. Treatment planning was done with the aid of a computer-assisted planning system (PLATO; Nucletron) using geometric optimization and one prescription dose point (5 mm distant from one source in the central plane). The source dwell positions were located on the prostate surface and inside the prostate (except in the cranial direction, where it was located 1 cm outside the prostate). The prescribed dose was 6 Gy. Patients remained in bed under epidural anesthesia for 5 days from Monday to Friday and underwent irradiation twice daily with an interval of at least 6 hours. The treatment consisted of nine fractions of 6 Gy each (total 54 Gy). The isoeffective dose corresponded to approximately 116 Gy administered at 2 Gy per fraction according to the linear-quadratic model and on the assumption of an a/b ratio of 1.5 Gy for prostate cancer, or otherwise to 97 Gy on the assumption of an a/b ratio of 3 Gy. Prophylactic antibiotics were administered twice daily from the day of implant through Day 7.

Dosimetric analysis The rectum was delineated from 1 cm cranially to the seminal vesicles to 1 cm caudally to the prostatic apex as solid organs (not as rectal wall) on the CT images, and the urethra within the PTV was delineated by identifying the urinary catheter. The volumes of the rectum receiving 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, and 100% of the prescribed dose (V10, V20,

DVH parameters and late toxicities after prostate HDR-BT monotherapy d K. KONISHI et al.

Table 2. Late toxicities in 83 patients treated with HDR-BT alone CTCAE v3.0 Grade

Rectal toxicities Urinary toxicities Total*

0

1

2

3

4

5

Total

65 68 53

13 9 20

4 5 9

1 1 1

0 0 0

0 0 0

83 83 83

Abbreviations: CTCAE v3.0 = Common Terminology Criteria for Adverse Events, Version 3.0; HDR-BT = high-dose-rate brachytherapy. * Some patients showed both rectal and urinary events. V30, V40, V50, V60, V70, V80, V90, V100, respectively) and the volumes of the urethra receiving 100%, 110%, 120%, 130%, 140%, and 150% of the prescribed dose (V100, V110, V120, V130, V140, V150, respectively) were calculated. The respective radiation doses covering 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, and 90% (D5, D10, D20, D30, D40, D50, D60, D70, D80, D90, respectively) of the rectum and the urethra were also calculated. In addition, the minimal radiation doses for the most irradiated rectal volumes of 1 cm3, 2 cm3, 5 cm3, and 10 cm3 (D1cc, D2cc, D5cc, D10cc, respectively) were calculated.

Follow-up and toxicity analysis Radiation oncologists and urologists performed the follow-up evaluations at least every 3 months, and these comprised digital examinations, PSA study, and questioning about urinary and bowel symptoms. Late toxicity was scored according to the Common Terminology Criteria for Adverse Events, Version 3.0 (CTCAE v3.0) by the National Cancer Institute. Late toxicity was defined as symptoms that persisted or presented beyond 6 months after treatment completion. Urinary and bowel symptoms should be evaluated not only through physician interview but also patient administration of the quality of life instruments. However, in the early period of this study, we were not aware of this. We are now evaluating the urinary and bowel symptoms through both means. The median followup time for this study was 36 months (range, 18–70).

Statistical analysis Unpaired two-tailed t test and Fisher’s exact test were used for comparisons between dosimetric parameters and late rectal and urinary toxicities. Values of p < 0.05 were considered significant.

RESULTS Late toxicity Grade 4 or 5 late toxicity was not detected in any patients, and Grade 3 was detected in only one patient, who developed urethrorectal fistula 46 months after HDR-BT. Nine patients showed Grade 2 late toxicities, consisting of four cases of rectal bleeding, two cases of dysuria, two cases of urinary frequency, and one case of hematuria. Twenty patients showed Grade 1 late toxicities, consisting of 13 cases of rectal bleeding, five cases of urinary frequency, and four cases of hematuria. The remaining 53 patients showed no late toxicity. Some patients showed both rectal and urinary events (Table 2).

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Table 3. Comparison of mean values of rectal dosimetric parameters Parameters

Grade 0 (n = 65)*

Grade 1–3 (n = 18)*

V10 (cc) V20 (cc) V30 (cc) V40 (cc) V50 (cc) V60 (cc) V70 (cc) V80 (cc) V90 (cc) V100 (cc) D5 (Gy) D10 (Gy) D20 (Gy) D30 (Gy) D40 (Gy) D50 (Gy) D60 (Gy) D70 (Gy) D80 (Gy) D90 (Gy) D1cc (Gy) D2cc (Gy) D5cc (Gy) D10cc (Gy)

29.9  10.4 21.1  6.0 12.7  3.4 6.9  2.2 3.5  1.5 1.6  1.0 0.67  0.59 0.24  0.31 0.07  0.13 0.07  0.14 32.7  5.3 28.1  4.9 22.8  4.3 19.4  4.1 16.8  3.9 14.6  3.7 12.8  3.4 11.0  3.2 9.3  3.0 7.5  2.7 34.9  4.6 30.8  4.1 24.0  3.2 18.3  2.6

33.0  8.4 22.7  3.2 15.2  2.5 9.1  2.1 5.1  1.6 2.6  1.1 1.20  0.78 0.46  0.50 0.15  0.26 0.04  0.10 35.2  5.9 30.2  5.6 24.3  5.1 20.4  5.0 17.5  4.8 14.9  4.6 12.6  4.4 10.7  4.1 8.9  3.8 7.2  3.2 38.5  4.4 34.3  3.7 27.2  2.8 20.7  2.3

p 0.210 0.153 0.001 < 0.001 0.001 0.002 0.014 0.088 0.227 0.322 0.109 0.161 0.258 0.411 0.601 0.773 0.929 0.783 0.757 0.737 0.005 0.002 < 0.001 0.001

D5–D90 and D1cc–D10cc are against the total prescribed dose (54 Gy). * Mean  SD.

Correlation between dosimetric parameters and late rectal toxicities Comparison of mean values of rectal dosimetric parameters between the 18 patients who presented with late rectal toxicities and the 65 patients who did not is shown in Table 3. The patients with late rectal toxicities had significantly higher means of V30, V40, V50, V60, V70, D1cc, D2cc, D5cc, and D10cc of the rectum. The most significant statistical difference was observed for V40 and D5cc (both p’s < 0.001). We sought for a threshold value, and the late rectal toxicity rate was significantly higher for patients with rectal V40 $ 8 cc than for those with rectal V40 < 8 cc (42% vs. 8%, p < 0.001; Table 4). Moreover, the late rectal toxicity rate was significantly higher for patients with rectal D5cc $ 27 Gy than for those with rectal D5cc < 27 Gy (50% vs. 11%, p < 0.001; Table 5). Correlation between dosimetric parameters and late urinary toxicities The comparison of mean values of urinary dosimetric parameters between the 15 patients who presented with late urinary toxicities and the 68 patients who did not is shown in Table 6. There were no significant differences between the two groups. DISCUSSION In 2003 and 2006, we reported enhanced tumor control and a low incidence of late toxicity after HDR-BT alone for

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Table 4. Comparison of the late rectal toxicity rate (V40 < 8 cc vs. $ 8 cc)

V40 < 8 cc V40 $ 8 cc Total

Grade 0

Grade 1–3

Total

46 19 65

4 14 18

50 33 83

p < 0.001.

locally advanced prostate cancer (12, 13). In the study presented here, the incidence and severity of late rectal and urinary toxicity were also thought to be within acceptable limits, with crude rates of Grade 2 or worse late rectal and urinary toxicity of 6.0% and 7.2%, respectively. Sanguineti et al. reported that the 2-year estimates of Grade 2–4 late rectal toxicity for patients receiving or not adjuvant androgen deprivation therapy (ADT) were 30.3  5.2% and 14.1  3.8% (16). In this study, among 67 patients who had received ADT, 14 patients presented with late rectal toxicity and 53 did not; among 16 patients who had not received ADT, 4 patients presented with late rectal toxicity and 12 did not. There was no significant difference between the two groups (p = 0.731). As mentioned earlier, the isoeffective dose used in this study corresponded to approximately 116 Gy administered at 2 Gy per fraction according to the linear-quadratic model and assuming an a/b ratio of 1.5 Gy for prostate cancer or otherwise to 97 Gy on the assumption of an a/b ratio of 3 Gy. Despite this high isoeffective dose, the incidence of late toxicity was deemed to be low. This low incidence may be attributable to the excellent conformity of HDR-BT and the rapid dose falloff outside the target. Because of this low incidence, no significant correlation was observed between dosimetric parameters and Grade 2 or worse late toxicity in this study (data not shown). However, a significant correlation was established between dosimetric parameters and the incidence rate of Grade 1 or worse late rectal toxicity. The means of V30, V40, V50, V60, V70, D1cc, D2cc, D5cc, and D10cc of the rectum were significantly higher in the 18 patients with any degree of late rectal toxicity than in the 65 patients without such toxicity. Akimoto et al. (15) reported that the differences in the percentages of the entire rectal volume receiving 10%, 30%, and 50% of the prescribed radiation dose between the patients with and without rectal bleeding were statistically significant in HDR-BT combined with EBI. In the prostate low-dose-rate brachytherapy (LDR-BT) literature, the rectal V100 has been found to be predictive of rectal bleeding (17). In this study, rectal V100 did not predict for toxicity. One possible reason for this was that rectal V100 was small (mean values, 0.07 cc vs. 0.04 cc) in this study (Table 3), and it may be attributable to the excellent conformity of HDR-BT and the rapid dose falloff outside the target. One of the most interesting and significant results in this study was that a significant difference was observed for D1cc–10cc but not for D5-90. One possible reason for this was that the rectal volumes of the 83 patients varied so widely

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Table 5. Comparison of the late rectal toxicity rate (V5cc < 27 Gy vs. $ 27 Gy)

D5cc < 27 Gy D5cc $ 27 Gy Total

Grade 0

Grade 1–3

Total

54 11 65

7 11 18

61 22 83

p < 0.001.

(13.1–76.6 cc) that the variation in rectal volume percentages was reflected in differences in absolute volume. However, DXcc (the minimal radiation doses for the most irradiated rectal volumes of X cm3) is not likely to be affected by differences in rectal volume and would therefore reflect the highest dose to a given small volume. In relation to this, the European Group of Curietherapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) working group for gynecological brachytherapy recommended D0.1cc, D1cc, D2cc, D5cc, and D10cc of organs at risk, not D5 and D10 (18). The most statistically significant difference in these rectal parameters was identified for V40 and D5cc (both p’s < 0.001), and we also determined the threshold values for each of the parameters. The late rectal toxicity rate was significantly higher for patients with rectal V40 $ 8 cc than for those with rectal V40 < 8 cc (42% vs. 8%, p < 0.001). Also, the late rectal toxicity rate was significantly higher for patients with rectal D5cc $ 27 Gy than for those with rectal D5cc < 27 Gy (50% vs. 11%, p < 0.001). There was no significant correlation between dosimetric parameters and the incidence of Grade 1 or worse late urinary toxicity, but our study covered only dosimetric parameters of the urethra. Some other dosimetric parameters—for example, of the bladder neck or penile bulb—may warrant a similar investigation, but this is beyond the scope of this study. Table 6. Comparison of mean values of urinary dosimetric parameters Parameters

Grade 0 (n = 68)*

Grade 1–3 (n = 15)*

p

V100 (cc) V110 (cc) V120 (cc) V130 (cc) V140 (cc) V150 (cc) D5 (Gy) D10 (Gy) D20 (Gy) D30 (Gy) D40 (Gy) D50 (Gy) D60 (Gy) D70 (Gy) D80 (Gy) D90 (Gy)

0.57  0.17 0.47  0.19 0.28  0.19 0.099  0.12 0.021  0.055 0.0044  0.015 70.7  5.8 69.3  5.4 67.7  5.0 66.5  5.0 65.4  4.8 64.4  4.8 63.0  4.9 61.2  5.0 58.4  5.7 53.4  7.0

0.55  0.18 0.44  0.19 0.22  0.16 0.069  0.12 0.026  0.067 0.0073  0.028 70.7  5.9 69.5  5.8 68.0  5.7 67.0  5.7 66.0  5.7 64.8  5.9 63.5  6.0 61.7  6.4 58.7  6.8 54.4  6.9

0.664 0.609 0.283 0.407 0.791 0.704 0.963 0.912 0.840 0.789 0.764 0.788 0.785 0.802 0.903 0.617

D5–D90 are against the total prescribed dose (54 Gy). * Mean  SD.

DVH parameters and late toxicities after prostate HDR-BT monotherapy d K. KONISHI et al.

Furthermore, with a median follow-up of only 36 months (range, 18–70), additional urinary toxicity will probably become manifest. With recent developments in remote afterloading HDR-BT devices and computer planning systems, various optimization programs are now available (19–22). It is possible to minimize rectal dose but maintain adequate prostate coverage by using these techniques. It is therefore possible to reduce the late rectal toxicity rate after HDR-BT alone by implementing such optimization programs with the appropriate dose–volume constraints—for example, rectal V40 < 8cc or rectal D5cc < 27 Gy.

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Furthermore, we consider our treatment regimen of 54 Gy in nine fractions to be a good model for hypofractionated stereotactic external beam radiotherapy, and our results may function as useful guidelines for this treatment setting. However, it is to be noted that extrapolation of our results to hypofractionated external beam radiotherapy should be done with great caution because it is difficult to achieve such a rapid dose falloff outside the target volume with this modality compared with HDR-BT. This is an issue for future study. Additionally, DVH analysis including interfraction organ motion in external beam radiotherapy and applicator displacement in HDR-BT remains to be conducted.

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