Late Rectal Toxicity from Image-guided Intensity Modulated Radiotherapy for Prostate Cancer

Patients and Methods

Patient population. We retrospectively analyzed 47 men treated in the Nagoya University Hospital between May 2008 and December 2009 who received IG-IMRT with in-room CT imaging for prostate cancer. This study was approved by the Institutional Review Board of the Nagoya University Hospital, and all patients provided written informed consent.

The median age of patients was 68 years (range=55-80 years). Patients' characteristics are shown in Table I. All men had a biopsy-confirmed adenocarcinoma of the prostate, that was proven pathologically in our hospital. The median initial PSA level was 11.6 ng/ml (range=4.2–363.0 ng/ml). Men were classified into low-, intermediate-, and high-risk groups based on the National Comprehensive Cancer Network (NCCN) risk group classification. Five men (10.6%) had low-risk disease, 18 men (38.3%) had intermediate risk disease, and 24 men (51.1%) had high-risk disease. The 24 men in the high-risk group included 4 men with lymph node metastases at diagnosis and 1 with a distant metastasis to the para-aortic lymph nodes.

Androgen deprivation therapy (ADT). Forty-three men (91.5%) received hormonal therapy. Most men had high- or intermediate-risk disease. As per our hospital protocol, hormonal therapy was not administered to patients with low-risk disease in principle, and courses were usually short (<6 months) for those with intermediate-risk disease and longer (>24 months) for those with high-risk disease. With long-term hormonal therapy, PSA values were very low, and lymph node metastases were remarkably reduced or had disappeared on diagnostic imaging by CT/MRI. Therefore, radiation therapy to a prostate region was judged to provide significant clinical benefit, and IMRT was performed.

Concomitant disease. Nine men (19.1%) were being treated for diabetes and 6 (12.8%) were being treated with anticoagulant therapy or antiplatelet therapy (AC therapy) before, during, and after RT for cardiovascular or cerebrovascular disease.

Pre-treatment procedure. The most important normal organs near the prostate target are the rectum and bladder. Each organ exhibits significant day-to-day shape variations if uncontrolled during routine treatment (11). Therefore, we implemented the following measures. Simethicone was prescribed to reduce gas and feces in the rectum, beginning 1 week before the patients underwent CT scans. In the absence of daily defecation, hydrated magnesium sulfate was used as a laxative, and a purgative medication was added on a case-by-case basis. No patient was implanted with gold fiducial markers in the prostate gland before the treatment-planning CT scan was acquired. All men were instructed to empty their rectums using the medication described above and fill their bladders by drinking 250–500 ml of water 30 min to 1 h before the treatment-planning CT. Planning CT images were obtained at 2-mm slice thickness continuously for 3 days, and the best images obtained are shown in Figure 1, from patients with full bladders and rectums empty of gas and contents, were transferred to the treatment-planning system. Treatment planning and verification lasted 7 to 10 days.

Radiation therapy. Of the 47 men, 5 began treatment in the prone position, and the other 42 in the supine position. All men underwent CT scans using the in-room CT system (GE HiSpeed NX/i, General Electric Medical Systems, Waukesha, WI, USA) that was installed in the treatment room. Prostate position was assessed before administration of each fraction through in-room CT image guidance. Men were positioned first using lasers and skin marks. Then, an in-room CT was acquired. To quantify setup error, we first performed a pelvic bone match using the in-room CT. Then, matching was manually adjusted by a radiation therapist to overlap the prostate on the planning CT and in-room CT scans. Feces and gas in the rectum, change in bladder volume, and deviation of adjacent intestines (large and small intestines) from the planning CT images were checked. When feces and gas and were noted in the rectum, we encouraged defecation or passage of gas. However, if the situation did not improve, deaeration was performed by inserting a catheter into the rectum through the anus. In addition, patients were encouraged to drink water when they had insufficient bladder volumes. CT images were acquired once again after some time. After there was enough geometric verification, irradiation was performed.

Target volume definitions and organs at risk. The clinical target volume (CTV) included the prostate and the base of the seminal vesicles in low-risk men, but the CTV included the prostate and proximal two-thirds of seminal vesicles for intermediate- and high-risk men. The planning target volume (PTV) was obtained using automatic expansions of the CTV, adding 9 mm in the left, right, and anterior directions, 6 mm in the posterior direction, 10 mm in the superior direction, and 9 mm in the inferior direction.

Dose volume histograms (DVHs) are widely used in conformal radiotherapy to evaluate normal tissue complication probabilities (NTCPs). The DVH is an effective tool to evaluate 3D dose distributions of the rectum wall and to estimate the complication probability of the rectum in high-dose conformal radiotherapy (12). The rectum was defined as a cylindrical structure around the outer rectal wall. The thickness of the rectal wall was defined with a 4-mm internal wall extraction, and to determine PTV, 10 mm was added to the superior and inferior directions of the rectal wall craniocaudal length. In a similar way, the bladder was entirely contoured, and a 4-mm inner wall defined the bladder wall volume (Figure 1).

To plan treatment and delivery, an isocentric five-field technique was used. The beam angles used were posterior (0°), right posterior oblique (75°), right anterior oblique (135°), left anterior oblique (225°), and left posterior oblique field (285°) in the prone position. Meanwhile, in the supine position, the beam angles were 35°, 105°, 180°, 225°, and 325°, respectively. Treatments were planned using an inverse optimization algorithm. All men were treated to a prescribed dose of 74 Gy in 37 daily fractions of 2.0 Gy using 10-MV photons.

We present the dose distribution information of a typical case treated with IMRT. The isodose distributions, superimposed on the PTV, rectum, and bladder are shown in Figure 1 in the transverse and sagittal planes. The DVH parameters evaluated included the volume of normal tissue receiving: 70 Gy (V70); 65 Gy (V65); 60 Gy (V60); 50 Gy (V50); 45 Gy (V45); and 30 Gy (V30) expressed as absolute percentages in the rectal wall volume and the overall volume of the rectum. Dose-volume constraints for surrounding normal tissues were as follows: V40 ≤65% (ideal constraint (IC): ≤60%),V60 ≤35% (IC: ≤30%), V70 ≤25% (IC: ≤20%), and V78 <1% for the rectal wall; V40 ≤65% (IC: ≤60%) and V70 ≤35% for the bladder wall; V65 ≤1.0 mL (IC: ≤0.5 mL) for the colon; and V60 ≤1.0 mL (IC: ≤0.3 mL) for the small intestine. Meanwhile, dose-volume constrains for PTV were as follows: D90 ≥90% (IC: ≥95%), V90 ≥96% (IC: ≥98%), max ≤110%, and mean ≥99% and ≤103% (Table II).

Follow-up. Follow-up evaluations after treatment were performed at intervals of 3-6 months for 5 years. The median follow-up time was 33 months (range=24-46 months). During the follow-up study, we performed a physical interview, physical examination, and serum PSA measurement. Additionally, on an as-needed basis, residual urine measurements were performed. When PSA relapse was suspected because of increased PSA levels, we performed bone scintigraphy and whole body CT.

Late toxicity. Late toxicity was scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (13). In brief, grade 1 toxicity is mild, and intervention is not required. Grade 2 toxicity indicates that there are moderate symptoms, and medical intervention or minor cauterization should be performed for the indicated symptoms. Grade 3 toxicity indicates severe or medically significant, but not immediately life-threatening, symptoms. Transfusions or radiologic, endoscopic, or elective operative interventions are indicated. Grade 4 indicates life-threatening consequences, and urgent intervention is required.

Statistical analysis. The rate of grade 2 LRT was calculated using the Kaplan-Meier method. In this study, the following were analyzed as possible risk factors for LRT: hormone use, hemorrhoid diagnosis, diabetes, AC therapy, age, and DVH parameters of the rectal wall and rectum (V30, V45, V50, V60, V65, and V70). Categorical and continuous variables were analyzed using Fisher's exact tests and unpaired t-tests, respectively, for univariate analysis, and all variables were evaluated using logistic regression for multivariate analysis. A two-sided probability value of less than 0.05 was considered to indicate statistical significance.