Factors influencing late rectal toxicity after radical radiotherapy of localized and locally advanced prostate cancer Research Article

Transcription

1 Cancer Therapy Vol 5, page 253 Cancer Therapy Vol 5, , 2007 Factors influencing late rectal toxicity after radical radiotherapy of localized and locally advanced prostate cancer Research Article Gerald Lim 1,#, Harold Lau 1,#, *, Penny Brasher 2 1 Department of Radiation Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada 2 Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada *Correspondence: Harold Lau, Department of Radiation Oncology, Tom Baker Cancer Centre, St NW, Calgary, AB, T2N 4N2, Canada; Tel: ; Fax: ; haroldl@cancerboard.ab.ca Key words: hormones, prostate cancer, radiotherapy, rectal bleeds, rectal toxicity Abbreviations: body mass index, (BMI); Tom Baker Cancer Centre, (TBCC) #presented in part at the American Society of Clinical Oncology 2005 Prostate Cancer Symposium, February 18, 2005, Orlando, FL This study received institutional funding from the Tom Baker Cancer Centre for data entry support. We have no financial interest or otherwise with respect to the information submitted in this article. Received: 18 May 2007; Accepted: 29 June 2007; electronically published: August 2007 Summary Radiation injury to the rectum is a common sequelae of radiotherapy to the prostate. We reviewed our institutional experience to identify factors influencing late rectal toxicity after external beam radiotherapy for localized and locally advanced prostate cancer. 418 patients with localized prostate cancer treated with external beam radiotherapy from September 2000 to March 2003 were reviewed. The endpoints of interest included grades 2-4 late ano-rectal toxicity and rectal bleeding. Patient and treatment factors were analyzed. The median ICRU prostate dose delivered was 73.7 Gy (in fractions over 8 weeks). Median follow-up was 30 months. Cumulative incidence of grade 2-3 late ano-rectal toxicity and rectal bleeding at 30 months was 15.2% and 12.5% respectively. Adjuvant hormonal therapy was significantly associated with grade 2-3 rectal bleeding while total prostate dose, and % rectum receiving > 60 Gy and 70 Gy showed a trend to increasing grades 2-3 bleeding. Diabetes and % rectum receiving > 60 Gy were significant in increasing the hazard ratio of grades 2-3 ano-rectal symptoms. Hormonal therapy, diabetes, and % rectum receiving > 60 Gy appeared to be associated with significant late rectal toxicity in this single institutional experience. Such factors require further validation in ongoing radiotherapy doseescalation trials for prostate cancer. I. Introduction External beam irradiation has been a mainstay of prostate cancer treatment. However, due to its anatomic proximity to the rectum, radiation injury to the rectum is a common sequelae of radiotherapy to the prostate. Acutely, up to 85% of patients experience some bowel and bladder morbidity including dysuria, perianal discomfort, and frequency (Franklin, 1996). Long term complications can include: rectal bleeding, fistulas, fecal incontinence, and generalized rectal discomfort. In rare cases, colostomy is required. Late rectal toxicity can have a significant impact on patients quality of life (Potosky et al, 2004). Up to 9% of patients report moderate to severe impairment in quality of life (Lilleby et al, 1999) and up to 55% report some type of bowel dysfunction (Hanlon et al, 2001). Clinicians need the ability to estimate the risk of rectal injury prior to treatment and determine factors which may be modified to minimize complications. We reviewed the experience at this institution to identify factors influencing late rectal toxicity after radiotherapy for localized prostate cancer. 253

2 Lim et al: Rectal bleeding after RT for prostate cancer II. Methods and Materials A. Study population The cohort consisted of 418 consecutive patients with nonmetastatic prostate cancer who were started radical radiotherapy between September 2000 and December 2002 at the Tom Baker Cancer Centre (TBCC). The TBCC is the only radiation oncology facility servicing patients from the entire region of Southern Alberta (population approximately 1.4 million in 2001). Data from a cohort of patients receiving curative radiotherapy for prostate cancer were entered into a database during this period. Baseline, treatment, and follow-up information was abstracted from patient charts. The study was approved by the Conjoint Health Research Ethics Board of the University of Calgary. For purposes of defining treatment, patients were stratified into one of three risk categories per Canadian Consensus (Lukka, 2002): low risk T1 to T2a and Gleason 6 or less with PSA 10 or less; intermediate risk T2b-, or Gleason 7, or PSA 10 to 20; or high risk T3 or higher, or Gleason 8-10, or PSA greater than 20 In high risk patients, additional staging included bone scans and CT abdomen and pelvis. Patients with radiographic evidence of metastases were not included in this analysis. B. Treatment protocols General treatment guidelines for the 3 groups of patients during this period were as follows: 1) High risk patients were treated with pelvic irradiation to 46.8 Gy in 26 fractions followed by prostate boost to Gy in 13 fractions; neoadjuvant hormones were given for 3-6 months followed by adjuvant hormones for another 1-2 years, for a total of 2-3 years of hormones. 2) Intermediate risk patients were treated with prostate and seminal vesicle irradiation to 56.7 Gy in 27 fractions followed by a prostate boost to 16.8 Gy in 8 fractions. Neoadjuvant and concurrent hormones were given for 3-6 months at the discretion of the radiation oncologist. Some patients were treated with neoadjuvant and concurrent hormones on the RTOG randomized trial. 3) Low risk patients were generally treated with prostate only irradiation to 73.5 Gy in 35 fractions. Hormonal therapy was not routinely given in this group. C. Treatment planning All patients were simulated supine on a CT simulator (AcQSim, Picker International, St. David, PA) with a full bladder. Patients were positioned using an ankle rest without individualized immobilization. Urethrograms were performed if requested by the radiation oncologist. Since January 2002, all prostate patients were planned with 3D treatment planning at TBCC. Treatment verification was based on bone anatomy using off-line EPID. D. 2!D Treatment planning From Sep 2000 to Dec 2001, 160 (38% of cohort) patients were treated using a 2 1/2 D planning technique ie. blocking with multi-leaf collimators was shaped based on volume contours of the prostate +/- seminal vesicles (GTV/CTV) and adding 1cm to form a PTV with a further 1 cm margin added to the PTV to determine the block (MLC) placement. Dose-calculation was based on the one central slice through the isocenter. For elective pelvic nodal radiotherapy, field borders were defined superiorly at S1/S2; inferiorly at 2.0 cm below the prostatic apex, anteriorly at the anterior symphysis pubis; posteriorly at the S3/S4 interspace; and laterally 2.0 cm lateral to the pelvic brim. Care was taken to ensure adequate coverage of the internal and external iliac lymph nodes and seminal vesicles in the pelvic field. All treatment was carried out on Varian Linear Accelerators with either 15 or 18 MV photon energies. The majority of patients were treated with a 4-field beam arrangement. A few cases were treated with a 3-field technique. E. 3D Treatment planning From Jan 2002 to Dec 2002, 258 (62% of cohort) patients underwent 3D treatment planning on ADAC Pinnacle (Philips Medical systems, MA) software. The prostate was contoured in its entirety. Seminal vesicles, if included in the treatment plan, were contoured up to 1.0 to 1.5 cm proximal to the prostate. Pelvic nodes were contoured by outlining the internal and external iliac vessels. A CTV to PTV expansion/margin of 1.0 to 1.5 cm was used. The rectal margin was cm. For normal organ contouring, the rectum was contoured as a solid organ from the anal verge to the recto-sigmoid junction for a total length of approximately 10-12cm. The bladder was contoured in its entirety. For planning purposes, the rectal dose constraints were as follows: no more than 15% of the rectal volume exceeding 75Gy, 25% excedding 70Gy, 35% exceeding 65Gy, and 50% exceeding 60Gy. Bladder dose constraints were as follows: no more than 25% exceeding 80Gy, 25% exceeding 75Gy, 35% exceeding 70Gy, and 50% exceeding 65Gy. F. Follow-up During treatment, patients were assessed weekly for acute toxicity. Standard practice at the centre was to reassess patients 6-8 weeks after treatment, then every 6 months for the first 5 years. The inclusion dates (Sept 2000 to December 2002) were chosen such that there would be a minimum of 6 months followup after completion of the radiation at the time of chart review (Fall, 2003). Some patients did not adhere to the follow-up schedule due to inter-current illness, or distance from the cancer centre. Approximately 10% of patients did not have follow-up data beyond 6 months. At each follow-up visit, physical examination including a digital rectal exam was performed and information on sexual function, urinary, and ano-rectal morbidity according to the RTOG/CTC criteria was collected by the examining physician. Late rectal morbidity using CTC v2.0 grade and late rectal bleeding using a modified CTC/RTOG grade were recorded at each follow-up (Tables 1 and 2). Table 1. CTC v2.0 Late Ano-rectal Toxicity Grading Grade 1 Grade 2 Grade 3 Grade 4 Increased stool frequency, occasional blood-streaked stools or rectal discomfort (including hemorrhoids) not requiring medication. Increased stool frequency, bleeding, mucus discharge, or rectal discomfort requiring medication; anal fissure. Increased stool frequency/diarrhea requiring parenteral support; rectal bleeding requiring transfusion; or persistent mucus discharge, necessitating pads. Perforation, bleeding or necrosis or other life-threatening complication requiring surgical intervention (eg. Colostomy). 254

3 Cancer Therapy Vol 5, page 255 Table 2. Combined RTOG / CTC Rectal Bleeding Criteria Grade 1 Grade 2 Grade 3 Grade 4 Slight rectal bleeding, blood-streaked stools, no treatment required [CTC, RTOG] Rectal bleeding requiring medical treatment [CTC]; intermittent bleeding [RTOG] Bleeding requiring transfusion [CTC]; Significant rectal bleeding requiring surgery or cautery [RTOG]; or hyperbaric oxygen Require Surgical Intervention Colostomy [CTC]; Necrosis / perforation / fistula [RTOG] G. Outcomes of interest and statistics The primary outcome of interest was time to late ano-rectal toxicity grades 2 4 and time to rectal bleeds grades 2-4. The secondary endpoint was time to any rectal bleeding. Late anorectal toxicity was determined according to the CTC v 2.0 late ano-rectal toxicity scale (Table 1). Rectal bleeding was classified according to a combined RTOG / CTC rectal bleeding criteria (Table 2). Patient and treatment factors were analyzed for their correlation with late rectal morbidity. These include cardiovascular disease, diabetes, hypertension, age at diagnosis, body mass index (BMI) (>25 kg/m 2 vs.! 25) at initial visit, pelvic lymph node treatment, seminal vesicle treatment, treatment plan (3D vs. 2 " D), % rectum # 60 Gy, % rectum # 70 Gy, prostate volume, total prostate dose, use of neoadjuvant hormones, and adjuvant hormones after radiotherapy. Data were entered into an EPI-6 database. Statistical analyses were carried out according to the procedures of STATA (StataCorp Stata Statistical Software: Release 8.2 College Station, TX: Stata Corporation) and R (R Development Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria. Cumulative actuarial incidence of late toxicity was determined as one minus the Kaplan Meier toxicity-free estimate (Kaplan and Meier, 1958). Differences were assessed using the Cox proportional hazards model (Cox, 1972). Since all patients were alive at last follow-up, no adjustment for the competing risk of death was necessary in this study (Satagopan et al, 2004). Due to missing data, only 10% of the patients had the complete set of data on patient/treatment variables. Therefore, multivariable modeling was not performed. III. Results The patient and treatment characteristics are listed in Tables 3 and 4. The median age at diagnosis was 70.3 years (range 47 to 89 years). The median PSA was 9.4 ng/l (range 0.8 to 188). The median ICRU prostate dose was 73.7 Gy (range 50 and 82 Gy). 97% of all patients received a dose between Gy. Pelvic lymph node irradiation was given to 63 patients (15.1%). Neoadjuvant hormones were given in 336 patients (80.4%). For 3Dplanned patients, the percent rectum volume receiving greater than or equal to 60 Gy was a median of 38% (range 0 to 65%); and the percent rectum volume receiving greater than or equal to 70 Gy was a median of 20% (range 0 and 35%). There was no incidence of late grade 4 toxicity (Table 5). The 30-month cumulative incidence of late anorectal toxicity grades 2-3 was 15.2% (CI: 11.2% -19.0%) (Figure 1). The rate of late rectal bleeding grade 2-3 at 30 months was 12.6 % (CI: %) (Figure 2). Of the 48 cases with grade 2 or higher rectal bleeding, 42 were sent for further gastroenterology assessment. The cause of bleeding was deemed to be radiation proctitis in all evaluated patients. 3 patients also had coexisting hemorrhoids. No other causes of bleeding were recorded. Table 3. Patient Characteristics, n=418 Variable Patients Age Median 70.3 Range Clinical T stage (1992 AJCC) T1 162 (38.8%) T2a,b 127 (30.4%) T2c 70 (16.7%) T3 47 (11.2%) T4 1 (0.2%) Tx 11 (2.6%) PSA (ng/ml) Median 9.4 Range Biopsy gleason score (34.7%) (49.5%) (15.8%) Comorbidities Cardiovascular disease 101 (24.2%) Diabetes 46 (11.0%) Hypertension 171 (40.9%) 255

4 Lim et al: Rectal bleeding after RT for prostate cancer Table 4. Treatment Characteristics Variable Patients Hormonal treatment Neoadjuvant hormones 336 (80.4%) Hormones during RT 322 (77.0%) Hormones after RT 94 (22.5%) 3D treatment planning 258 (61.7%) Prostate dose, Gy Median Range Field Treated Prostate only 222 (53.1%) Pelvic Lymph nodes included 63 (15.0%) Seminal vesicles included (but not pelvic nodes) 133 (31.8%) % rectum volume! 60 Gy n = 256 Median 38 Range 0-65 % rectum volume! 70 Gy n = 245 Median 20 Range 0-35 Table 5. Number of patients and grades of severity of ano-rectal toxicity and rectal bleeding Outcome Grade Late ano-rectal toxicity Late rectal bleed Figure 1. Cumulative risk of late ano-rectal toxicity grades 2-4 for entire cohort 256

5 Cancer Therapy Vol 5, page 257 Figure 2. Cumulative risk of late rectal bleeds grades 2-4 for entire cohort In the univariable regression analyses only the presence of diabetes (p=0.04) and percentage of rectum receiving >60 Gy (p=0.04) were correlated with an increased risk of late ano-rectal toxicity (Table 5). Patients receiving adjuvant hormones after radiation had an increased risk of late rectal bleeding (p=0.05) (Table 7 and Figure 3). Total dose (p=0.08), percent rectum >60 Gy (p=0.07), and 70 Gy (p=0.06) showed a trend to increasing grades 2-3 rectal bleeding. Table 7. Hazard Ratios for Late Rectal Bleeds! Grade 2* Variable n Hazard Ratio Logrank Test (95% CI) P value Binary predictors, Yes vs No Cardiovascular disease ( ) 0.27 Diabetes ( ) 0.51 Hypertension ( ) 0.88 Neoadjuvant hormones ( ) 0.55 Hormones during RT ( ) 0.20 Hormones after RT ( ) 0.05 Nodes included in field ( ) 0.33 Seminal vesicles included in field ( ) D treatment planning ( ) 0.27 Acute toxicity ( ) 0.38 Continuous predictors % of rectum receiving > 60 Gy ( ) 0.07 % of rectum receiving > 70 Gy ( ) 0.06 Total dose to prostate (Gy) ( ) 0.08 BMI** ( ) 0.50 Prostate volume ( ) 0.70 * Univariable Cox model. No adjustment has been made for multiple testing. **BMI data was only collected on 124 patients. 257

6 Lim et al: Rectal bleeding after RT for prostate cancer Figure 3. Cumulative incidence of late rectal bleeds grade 2-3 with (Y=Yes) or without (N=No) adjuvant hormones after therapy. IV. Conclusions In our institutional experience, the 30 month Kaplan- Meier rates of grade 2-3 late rectal bleeding and ano-rectal toxicity was 12.6% and 15.2%. There was no incidence of grade 4 rectal bleeding. Patient factors including age, cardiovascular disease, diabetes, hypertension, and body mass index did not show any influence on rates of late rectal bleeding. Total prostate dose and use of adjuvant hormones were found to correlate with increased rates of grade 2-3 rectal bleeding while diabetes and the percent of rectum receiving greater than 60 Gy were found to correlate with increased rates of late ano-rectal toxicity. V. Discussion The incidences of late rectal morbidity described in our cohort is consistent with those reported in the literature. Our rates of grade 2 or higher ano-rectal toxicity and rectal bleeding at 30 months are 15.2% and 12.6% respectively which fall into the range reported in the literature thus far (Table 8). There are some differences in the definitions of grading of rectal bleeding which may influence reported results. Electrocautery or argon plasma coagulation is often used to treat radiation proctitis. In our criteria, if cautery or coagulation was used to treat rectal bleeding, it was considered grade 3. This is consistent with the Memorial Sloan-Kettering definition (Jackson et al, 2001). However, the Fox Chase and MD Anderson criteria require more than two such procedures to be designated as a grade 3 complication (Schultheiss et al, 1997; Huang et al, 2002). In the original SOMA classification, coagulation was not mentioned in the rectal toxicity grading (Coia et al, 1995). Proposed rectal dose volume constraints have been widely published in the literature. These single institutional analyses have shown increased rectal bleeding when the volume receiving >50Gy was greater than or equal to 66% and when the volume receiving >70Gy was greater than or equal to 30% (Fiorino et al, 2003). Rectal complications were also found to be higher when the volume receiving >70Gy was greater than 26% (Huang et al, 2002). In addition, Koper et al showed a strong volume-effect relation at 60Gy (Koper et al, 2004). At our institution, we employ similar rectal dose volume constraints as set out in the RTOG P0126 study. Correspondingly, only a few of 3D planned patients had > 50% of rectal volume exceeding 60 Gy (12.5% pts); or >25% rectum receiving > 70 Gy (22.5% pts). This may account for our relatively low rate of serious rectal toxicity. Patient variables such as age (Skwarchuk et al, 2000), diabetes (Herold et al, 2000) and bowel disease (Liux et al, 2004) can increase the risk of late rectal toxicity. Our study also found diabetes to be related to late ano-rectal toxicity. The amount of follow-up time can also influence the observed rates of late rectal toxicity. Fox Chase Cancer Centre reported that the median time to late rectal toxicity was 18 months (Teshima et al, 1997). Our minimum follow-up was 3 months and our median followup for those patients who did not experience an ano-rectal toxicity was 29.3 months. 258

7 Cancer Therapy Vol 5, page 259 Table 8. Summary of rectal toxicity studies. Author N Followup (Median) Michalski et al, 2005 Huang et al, months Jackson et al, 2001 Dose Incidence of grade 2 and higher late rectal toxicity or bleeding yrs 78 Gy 21% (bowel toxicity) None Peeters et al, Minimu m 30 months 31 months Gy 70.2 Gy 75.6 Gy 68 Gy 78 Gy 25% (6 yr rate, rectal toxicity) 5% (rectal bleed) 12% (rectal bleed) 23.2% (GI toxicity) 26.5% (GI toxicity) Factors associated with increased rectal bleeding or toxicity Hemorrhoids, dose to rectum and volume irradiated (in particular V70>26.2%) Group 1 V71>15%, Group 2 V77>14% History of abdominal surgery, pretreatment GI symptoms, dose Teshima et al, Gy 13.3% (rectal bleed) Dose > 74Gy 1997 Fiorino et al, yrs % (rectal bleed) Acute bleeding, dose, Gy V50>66%, V70>30% TBCC months 74 Gy 14.5% (rectal toxicity) Diabetes and V60 for anoretal toxicity, adjuvant hormones for rectal bleeding Adjuvant hormone use is now considered standard of care for high risk prostate cancer (Bolla et al, 1997, 2002). In our cohort use of adjuvant hormones was associated with an increased risk of late rectal bleeding grade # 2 (HR = 1.80, P=0.05). This effect has been seen in several other studies. Sanguineti et al. found adjuvant androgen deprivation increases rectal toxicity on multivariate analysis which included other factors such as total dose, acute symptoms, diabetes, and treating physician. They found adjuvant androgen deprivation to impact late rectal toxicity increasing the risk by 2.23 times and suggested that adjuvant hormomal therapy may slow the reparative process of the irradiated rectal tissue (Sanguineti et al, 2002). Feigenberg and colleagues found in 2005 androgen deprivation to increase late GI morbidity as well. The 5 year risk for grade 2 or 3 GI morbidity was 17% for no androgen deprivation vs 19% for short term androgen deprivation (! 6 months), and 25% for long term androgen deprivation (>6 months) (Feigenberg et al, 2005). Liu et al. showed only neoadjuvant short term androgen deprivation and not neoadjuvant long term androgen deprivation to increase the risk of late grade 3 GI toxicity (Liu et al, 2004). Our study did not show any correlation between neoadjuvant androgen deprivation and rates of late rectal bleeding and toxicity. Acknowledgements The authors thank Sony Brar, Drs Alex Balogh, Steve Angyalfi, and Jackson Wu for their contributions to the prostate cancer database. References Bolla M, Collette L, Blank L, Warde P, Dubois J B, Mirimanoff RO, Storme G, Bernier J, Kuten A, Sternberg C, Mattelaer J, Lopez TJ, Pfeffer JR, Lino CC, Zurlo A, Pierart M (2002) Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 360, Bolla M, Gonzalez D, Warde P, Dubois JB, Mirimanoff R, Storme G, Bernier J, Kuten A, Sternberg C, Gil T, Collette L, Pierart M (1997) Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 337, Coia LR, Myerson RJ, Tepper JE (1995) Late effects of radiation therapy on the gastrointestinal tract. Int J Radiat Oncol Biol Phys 31, Cox DR (1972) Regression models and life tables. J R Stat Soc Ser B 34, Feigenberg SJ, Hanlon AL, Horwitz EM, Uzzo RG, Eisenberg D, Pollack A (2005) Long-term androgen deprivation increases Grade 2 and higher late morbidity in prostate cancer patients treated with three-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys 62, Fiorino C, Sanguineti G, Cozzarini C, Fellin G, Foppiano F, Menegotti L, Piazzolla A, Vavassori V, Valdagni R (2003) Rectal dose-volume constraints in high-dose radiotherapy of localized prostate cancer. Int J Radiat Oncol Biol Phys 57, Franklin CI (1996) Acute morbidity of radiation therapy for prostate carcinoma. Australasian Radiology 40, Hanlon AL, Watkins BD, Peter R, Hanks GE (2001) Quality of life study in prostate cancer patients treated with threedimensional conformal radiation therapy: comparing late bowel and bladder quality of life symptoms to that of the normal population. Int J Radiat Oncol Biol Phys 49,

8 Lim et al: Rectal bleeding after RT for prostate cancer Herold D, Hanlon AL, Hanks GE (2000) Diabetes mellitus: a predictor for late radiation morbidity. Int J Radiat Oncol Biol Phys 43, Huang EH, Pollack A, Levy L, Starkschall G, Dong L, Rosen I, Kuban DA (2002) Late rectal toxicity: dose-volume effects of conformal radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 54, Jackson A, Skwarchuk MW, Zelefsky MJ, Cowen DM, Venkatraman ES, Levegrun S, Burman CM, Kutcher GJ, Fuks Z, Liebel SA, Ling CC (2001) Late rectal bleeding after conformal radiotherapy of prostate cancer. II. Volume effects and dose-volume histograms. Int J Radiat Oncol Biol Phys 49, Kaplan EL and Meier P (1958) Nonparametric estimation of incomplete observations. J Am Stat Assoc 53, Koper PC, Heemsbergen WD, Hoogeman MS, Jansen PP, Hart GA, Wijnmaalen A J, van OM, Boersma LJ, Lebesque JV, Levendag P (2004) Impact of volume and location of irradiated rectum wall on rectal blood loss after radiotherapy of prostate cancer. Int J Radiat Oncol Biol Phys 58, Lilleby W, Fossa S, Waehre H, Olsen D (1999) Long-term morbidity and quality of life in patients with localized prostate cancer undergoing definitive radiotherapy or radical prostatectomy. Int J Radiat Oncol Biol Phys 43, Liu M, Pickles T, Agranovich A, Berthelet E, Duncan G, Keyes M, Kwan W, McKenzie M, Morris J, Pai H, Tyldesley S, Wu J (2004) Impact of neoadjuvant androgen ablation and other factors on late toxicity after external beam prostate radiotherapy. Int J Radiat Oncol Biol Phys 58, Lukka H (2002) Prostate cancer: risk categories and role of hormones and radiotherapy. Can J Urol 9(Suppl 1), Michalski JM, Winter K, Purdy JA, Parliament M, Wong H, Perez CA, Roach M, Bosch W, Cox JD (2005) Toxicity after three-dimensional radiotherapy for prostate cancer on RTOG 9406 dose Level V. Int J Radiat Oncol Biol Phys 62, Peeters ST, Heemsbergen WD, van Putten WL, Slot A, Tabak H, Mens JW, Lebesque JV, Koper PC (2005) Acute and late complications after radiotherapy for prostate cancer: results of a multicenter randomized trial comparing 68 Gy to 78 Gy. Int J Radiat Oncol Biol Phys 61, Potosky AL, Davis WW, Hoffman RM, Stanford JL, Stephenson RA, Penson DF, Harlan L C (2004) Five-year outcomes after prostatectomy or radiotherapy for prostate cancer: the prostate cancer outcomes study. J Natl Cancer Inst 96, Sanguineti G, Agostinelli S, Foppiano F, Franzone P, Garelli S, Marcenaro M, Orsatti M, Vitale V (2002) Adjuvant androgen deprivation impacts late rectal toxicity after conformal radiotherapy of prostate carcinoma. Br J Cancer 86, Satagopan JM, Ben-Porat L, Berwick M, Robson M, Kutler D, Auerbach AD (2004) A note on competing risks in survival data analysis. Br J Cancer 91, Schultheiss TE, Lee WR, Hunt MA, Hanlon AL, Peter RS, Hanks GE (1997) Late GI and GU complications in the treatment of prostate cancer. Int J Radiat Oncol Biol Phys 37, Skwarchuk MW, Jackson A, Zelefsky MJ, Venkatraman ES, Cowen DM, Levegrun S, Burman CM, Fuks Z, Leibel SA, Ling CC (2000) Late rectal toxicity after conformal radiotherapy of prostate cancer (I): multivariate analysis and dose-response. Int J Radiat Oncol Biol Phys 47, Teshima T, Hanks GE, Hanlon AL, Peter RS, Schultheiss TE (1997) Rectal bleeding after conformal 3D treatment of prostate cancer: time to occurrence, response to treatment and duration of morbidity. Int J Radiat Oncol Biol Phys 39,