Time course of late rectal toxicity after radiation therapy for prostate cancer

(2010) 13, 138 143 & 2010 Nature Publishing Group All rights reserved 1365-7852/10 ORIGINAL ARTICLE www.nature.com/pcan Time course of late rectal toxicity after radiation therapy for prostate cancer K Odrazka 1,2,3, M Dolezel 1,3, J Vanasek 1, M Vaculikova 4, M Zouhar 5, J Sefrova 5, P Paluska 5, M Vosmik 5, T Kohlova 6, I Kolarova 1, Z Macingova 5, P Navratil 7, M Brodak 7 and P Prosvic 8 1 Department of Radiation Oncology, Multiscan and Pardubice Regional Hospital, Pardubice, Czech Republic; 2 First and Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic; 3 Institute for Postgraduate Medical Education, Prague, Czech Republic; 4 Department of Clinical Oncology, Nachod Regional Hospital, Nachod, Czech Republic; 5 Department of Oncology and Radiotherapy, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic; 6 Department of Nuclear Medicine, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic; 7 Department of Urology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic and 8 Department of Urology, Nachod Regional Hospital, Nachod, Czech Republic Rectum and bladder are the crucial organs at risk for curative radiation therapy of localized prostate cancer. We analyzed the incidence, profile and time course of late rectal radiation toxicity. A total of 320 patients with T1 3 prostate cancer were treated with three-dimensional conformal radiation therapy (3D-CRT). The prescription dose was 70 Gy for T1 and T2 patients (n ¼ 230) and 74 Gy for patients with locally advanced T3 tumors (n ¼ 90). Late rectal toxicity was graded according to the Fox Chase modification of the Radiation Therapy Oncology Group (RTOG) and Late Effects Normal Tissue Task Force (LENT) criteria. The median follow-up time was 6.2 years (range 0.2 10.7 years). At 5 years, the risk for the development of grade 2 and 3 rectal toxicities was 15.6 and 7.0%, respectively. All new cases of grade 2 and 3 rectal toxicities were observed within 5 years after treatment. Prevalence of grade 2 and 3 rectal symptoms showed fluctuation with maximum at 1.5 years and the minor peak at 4.5 years. Toxicity profile changed significantly over time. The proportion of rectal bleeding within grade 2 and 3 toxicity decreased from 85% at 1.5 years to 46% at 4.5 years. Conversely, the proportion of fecal incontinence among grade 2 and 3 rectal symptoms gradually increased (0% at 1.5 years vs 27% at 4.5 years). Late rectal radiation toxicity represents a dynamic process. Rectal bleeding decreases and fecal incontinence increases over time. (2010) 13, 138 143; doi:10.1038/pcan.2009.56; published online 29 December 2009 Keywords: rectal toxicity; late toxicity; radiation therapy Introduction External beam radiation therapy has long been recognized as highly efficient treatment modality for patients with localized prostate cancer. Rectum and urinary bladder are the limiting organs at risk. Even with advanced radiotherapy techniques, it is not feasible to completely spare these organs because of microscopic disease extension, physiological prostate movement and set-up uncertainties. As a result of partial rectum irradiation, late rectal toxicity develops in a significant proportion of patients. In recent reports, grade 2 (requiring medication) and grade 3 (requiring major Correspondence: Dr K Odrazka, Department of Radiation Oncology, Multiscan and Pardubice Regional Hospital, Kyjevska 44, Pardubice 532 03, Czech Republic. E-mail: odrazka@seznam.cz Received 20 September 2009; revised 1 November 2009; accepted 15 November 2009; published online 29 December 2009 intervention) rectal toxicity rates ranged from 6 to 24% and from 1 to 10%, respectively. 1 5 Rectal bleeding, increased stool frequency, tenesmus/ pain and fecal incontinence are the representative symptoms of late radiation proctopathy. Although the radiation-induced late damage of the rectal wall is persistent in nature, symptoms of radiation proctopathy are not stable over time. Rectal bleeding, in particular, can be successfully treated. Consequently, resolution of symptoms has been shown in a significant proportion of patients. 6 8 Data regarding the time course of rectal toxicity are limited and heterogeneous. The median time to development of late rectal toxicity is 12 30 months. 7 10 Prevalence rates of rectal symptoms have been reported with peak values ranging from 12 to 48 months. 6,11,12 Therefore, we primarily focused on the time course of late rectal toxicity in patients treated with the three-dimensional conformal radiation therapy (3D-CRT) for localized prostate cancer. The secondary objective of our retrospective study was the rectal toxicity profile and its behavior over time.

Patients and methods Patient characteristics Between December 1997 and December 2003, a total of 331 patients with localized prostate cancer were primarily treated with 3D-CRT at the Department of Oncology and Radiotherapy, Charles University Hospital in Hradec Kralove. Patients with following characteristics were considered for radiation therapy: localized prostatic disease, no clinical or surgical signs of nodal involvement and no clinical evidence of distant metastases 1997 and 2002 American Joint Committee on Cancer stage T1 3 N0 (pn0) M0. All patients provided written consent before treatment. In all, 11 patients were excluded from the analysis because of staging uncertainty (6 patients), incomplete therapy (4 patients) and inadequate follow-up (1 patient). Thus, 320 patients were evaluable for late toxicity. The disease and treatment characteristics are summarized in Table 1. Treatment An extended description of the 3D-CRT treatment planning and delivery has been previously published. 13 Patients were positioned and treated in a supine position, with a vacuum cushion or knee and feet support (Vac-Lok/Dual Leg Positioner Cushion, MED- TEC, Orange City, IA, USA) to immobilize the legs and pelvis. A 3D treatment planning system (Cadplan 2.7.9., Varian, Palo Alto, CA, USA) was used for all treatment plans. The planning target volume included prostate and the base of seminal vesicles with a margin of 10 mm (anterior, posterior and laterals) and 15 mm (cranial and caudal). The planning target volume should compensate for the set-up errors and pelvic organs movement during radiation therapy. Table 1 Patient characteristics n ¼ 320 Age median (range) 70 (48 81) T stage T1 50 (15.6) T2 174 (54.4) T3 96 (30.0) Risk groups Low risk 59 (18.4) Intermediate risk 110 (34.4) High risk 151 (47.2) Prostate surgery TURP 75 (23.4) TVRP 23 (7.2) PLNS 97 (30.3) Hormonal therapy 129 (40.3) Dose 70 Gy 230 (71.9) 74 Gy 90 (28.1) Abbreviations: PLNS, pelvic lymph node sampling; TURP, transurethral resection of prostate; TVRP, transvesical resection of prostate. Data expressed as number (percentage) unless otherwise stated. Patients were treated with four coplanar wedged fields (two lateral fields, 901 and 2701, and two anterior oblique fields, 301 and 3301). Particular beams were shaped with a multileaf collimator in conformity with the 3D planning target volume projections to exclude as much of the rectum and bladder as possible. The prescribed dose was specified to the isocenter (approximate center of the prostate). Dose inhomogeneity in the range of 92 107% in the planning target volume was considered acceptable, although the recommended 95 107% variation was fulfilled in the majority of patients. A 6 MV linear accelerator (Clinac 600 C, Varian) has been used to deliver radiation. The prescribed dose was 70 Gy in patients with T1 and T2 tumors and 74 Gy in patients with T3 tumors, delivered in daily fractions of 2 Gy, 5 days a week. Hormonal therapy had been given to 129 patients with T3 and/or bulky tumors. All patients with hormonal therapy received neoadjuvant androgen suppression. Luteinizing hormone-releasing hormone analog and antiandrogen were initiated 3 to 4 months before 3D- CRT and continued during the treatment course. Moreover, 27/129 (20.9%) patients with poorly differentiated tumors (Gleason score 8 10) were subsequently treated with adjuvant androgen suppression luteinizing hormone-releasing hormone analog at least 3 years or bilateral orchiectomy. Toxicity evaluation All patients were scheduled to be examined every 3 months for the first 2 years, every 6 months for the next 3 years and once a year thereafter. Late gastrointestinal (GI) and genitourinary symptoms were recorded at each visit, using the Fox Chase modification of the Radiation Therapy Oncology Group (RTOG) and Late Effects Normal Tissue Task Force (LENT) toxicity criteria (Table 2). 2,14 In comparison with the commonly used RTOG criteria, this composite toxicity scale enables more accurate assessment of diarrhea/increased stool frequency, rectal bleeding and fecal incontinence. The overall grading of the late toxicity corresponded to the worst symptom/intervention recorded at any time after 3D-CRT. To assess the time behavior of GI symptoms, toxicity grades were also registered at 6-month intervals for 5 years after treatment. These fractional toxicity grades resulted from the worst symptom/intervention observed within each of the 6-month periods of follow-up. Toxicity management Patients with mild bowel/rectal discomfort were instructed about the nature of their symptoms and about proper modification of dietary habits. If more imperative symptoms occurred, diphenoxylate was administered to alleviate diarrhea and codeine was prescribed against increased frequency/tenesmus. Patients with persistent rectal pain were treated with common analgesics (ibuprofen and codeine). When painful anal symptoms were more pronounced, cinchocaine containing suppository was temporarily given. Colonoscopy was always recommended whenever patients reported rectal bleeding to distinguish hemorrhagic radiation proctopathy from other colon disorders. 139

140 Table 2 RTOG/FC-LENT late GI toxicity criteria Grade 1 Grade 2 Grade 3 Grade 4 Diarrhea/increased frequency/ tenesmus not requiring medication; rectal bleeding not more than once a week Diarrhea requiring medication more than twice weekly; rectal bleeding at least twice a week or requiring 1 to 2 coagulations; intermittent use of incontinence pads; regular analgesics for pain Diarrhea requiring medication more than twice daily; rectal bleeding requiring transfusion or more than two coagulations; persistent use of incontinence pads; regular narcotic for pain Dysfunction requiring surgery (necrosis, perforation, obstruction) Abbreviations: GI, gastrointestinal; RTOG/FC-LENT, Fox Chase modification of the Radiation Therapy Oncology Group and Late Effects Normal Tissue Task Force late toxicity criteria. The most serious pathologic changes that could be revealed by colonoscopy are second cancers, including radiation-induced rectal cancer. Minor bleeding (less than once a week) has been generally left untreated. Major bleeding (at least once a week and/or significant blood loss) usually required drug therapy or argon plasma coagulation. It was the decision of the gastroenterologist who performed endoscopy of what type of treatment would be preferable. In general, argon plasma coagulation was carried out in patients with significant bleeding who had endoscopic finding of multiple/ confluent teleangiectases in rectal mucosa. Patients with less extensive proctopathy (sporadic/zonal teleangiectases) were treated using anti-inflammatory agents (mesalazine suppository) and/or vasoprotectants (tribenoside and diosmine). % of patients 50 40 30 20 10 0 Figure 1 48.8 31.2 13.8 6.2 0.0 0 1 2 3 4 Grade Cumulative incidence of late rectal toxicity. Statistics Kaplan Meier product-limit method was used for estimating the cumulative risk of the late GI toxicity. Results The entire cohort of evaluable patients included 320 men, with a median follow-up time of 6.2 years (range 0.2 10.7 years). For living patients (n ¼ 228), the median followup time was 7.0 years (range 3.5 10.7 years) and 90.4% of them were followed up for at least 5 years. In the total patient population, neither fatal nor grade 4 GI toxicities have been observed. The majority of patients 256/320 (80.0%) experienced no (grade 0) or only mild (grade 1) GI toxicity. A total of 64 patients (20.0%) required appropriate treatment for the GI symptoms grade 2 or 3 (Figure 1). Rectal bleeding was the dominant symptom in patients with grade 2 and 3 toxicities (Figure 2). At 2 years, the risk of grade 2 and 3 GI toxicities was 10.0 and 3.9%, respectively. Actuarial 5-year estimate for the development of grade 2 and 3 GI toxicities was 15.6 and 7.0%, respectively (Figure 3). The median time to development of grade 2 and 3 GI toxicities was 17 and 22 months, respectively. Among patients with grade 2 toxicity, the prevalence of GI symptoms showed two peaks at 1.5 years and 4.5 years. Similarly, the time flow of grade 3 GI symptoms presented with the first peak at 2 years and the second peak at 5 years (Figure 4). Analysis of grade 2 and 3 toxicity profile over time showed significant differences between the two peaks. The proportion of rectal bleeding among symptoms of GI toxicity gradually decreased 2 (5%) 1 (2%) 7 (16%) 4 (9%) 2 (10%) Grade 2 (n=44) 30 (68%) Grade 3 (n=20) 18 (90%) Bleeding Diarrhea Incontinence Pain >1 symptom Bleeding Incontinence Figure 2 Symptoms of grade 2/grade 3 late rectal toxicity. Diarrhea includes also increased stool frequency. (85% at 1.5 years vs 46% at 4.5 years). On the contrary, the proportion of fecal incontinence within grade 2 and 3 GI toxicity increased from 0% at 1.5 years to 27% at 4.5 years (Figure 5).

Discussion In patients with localized prostate cancer, the target volume for radiation therapy includes prostate and seminal vesicles (mostly the base, less often entire seminal vesicles). The area of clinically relevant dose always covers a portion of rectum and it may/may not cover a segment of sigmoid bowel. 15 Consequently, the GI toxicity in patients irradiated for localized prostate cancer corresponds mainly to rectal toxicity, that is, radiation proctopathy. Toxicity risk Toxicity risk 1.00 0.75 0.50 0.25 0.00 0 2 4 6 8 10 12 1.00 0.75 0.50 0.25 0.00 Figure 3 Grade 2 Grade 3 0 2 4 6 8 10 12 Actuarial risk of grade 2/grade 3 late rectal toxicity. Both the curative effect of radiation therapy on prostate cancer and the development of rectal toxicity are dose dependent. Modern methods of radiation therapy are able to precisely conform the dose distribution to the 3D tumor shape. Therefore, it is possible to safely deliver doses in the range of 75 80 Gy, provided that the dose constraints for rectum and bladder are not exceeded. 3,4,7,9,16 In view of these data, the incidence of late rectal toxicity in our patients seems comparable. We have not observed any new cases of rectal toxicity beyond 5 years from the end of radiation therapy. This is in agreement with other researchers, who reported plateau on the toxicity risk curve starting between 2 and 5 years after treatment. 7 9 Toxicity profile showed quite high rate of rectal bleeding among rectal symptoms 68 and 90% in our patients with grade 2 and 3 toxicity, respectively. Zelefsky et al. 7 from the Memorial Sloan-Kettering Cancer Center published the long-term data on late toxicity in patients treated with doses ranging from 66 to 81 Gy. They reported the manifestation of GI toxicity by means of rectal bleeding in 490% of affected patients. It is noteworthy that the incidence of grade 3 fecal incontinence was very low in our group of patients persistent use of incontinence pads was necessary in only two men out of 320 (0.6%). Analysis of the time course of late rectal toxicity showed evidence of the dynamic process. Researchers from the University of Chicago 6 analyzed a group of patients who received a dose of 60 74 Gy for prostate cancer. The numbers of patients with grade 2 and 3 GI toxicity were highest at 3 to 4 years from the end of radiotherapy (2.9%) and dropped to 1.5% at 5 years after treatment. Quite low absolute values of grade 2 and 3 toxicity are associated with the RTOG toxicity criteria, which had been used during this study. Karlsdottir et al. 8 recently reported the prevalence data in 247 patients with prostate cancer who were treated with conformal radiation therapy to a dose of 70 Gy. Grade 2 or higher rectal toxicities affected 4 5% of patients at 12 24 months after treatment and only 1.4% of patients at 5 years. Interestingly, we found slightly different time course of late rectal toxicity in our group of patients. In agreement with the results mentioned earlier, 6,8 the prevalence of rectal symptoms declined over time from 7.1% at 1.5 years to 2.5% at 5 years for grade 2 symptoms and from 1.9% at 2 years to 1.3% at 5 years for grade 3 symptoms. On the other hand, the prevalence curve clearly showed two peaks for both grade 2 and 3 toxicities. The first peak can be found at approximately 1.5 2 years and the 141 10 Grade 2 Grade 3 % of patients 5 0 7.1 6.6 5.8 4.7 3.8 3.6 3.9 3.3 1.9 2.4 2.5 1.7 0.9 1.0 1.3 0.7 0.7 0.7 0.8 0.0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Figure 4 Prevalence of grade 2/grade 3 late rectal toxicity. Each column denotes the proportion of patients with grade 2/grade 3 late rectal toxicity symptoms during the last 6 months.

142 10 0.3 1.0 % of patients 5 0.8 Pain 7.4 1.6 Incontinence 0.8 Diarrhea Bleeding 2.7 0 05 1 1.5 2 2.5 3 3.5 4 4.5 5 Figure 5 Prevalence and profile of grade X2 late rectal toxicity. Each composite column denotes the proportion of patients with grade X2 late rectal toxicity symptoms during the last 6 months. Only columns with prevalence peaks (1.5 and 4.5 years) include data labels of particular toxicity symptoms. Diarrhea includes also increased stool frequency. second lower peak at 4.5 5 years after treatment. Minimum prevalence was situated between these two peaks, at approximately 3 years from the end of radiotherapy. Probable explanation for the late increase of prevalence at 4 5 years after treatment comes with the analysis of grade 2 and 3 toxicity profile. Rectal bleeding and fecal incontinence are the determinants for prevalence fluctuation. Rectal bleeding culminated at 1.5 2 years and subsequently declined. Conversely, fecal incontinence gradually increased up to 1.6% at 4.5 years, which corresponds to the proportion of 27% among symptoms of grade 2 and 3 rectal toxicity. Capp et al. 17 analyzed data from self-assessment questionnaires collected from patients who were treated within the randomized trial of neoadjuvant hormonal therapy and radiation therapy for prostate cancer. They observed a minor prevalence peak of moderate or severe symptoms at 4 5 years after radiotherapy. Unfortunately, it is not possible to directly compare the rates of incontinence because of differences between RTOG/Fox Chase-LENT toxicity criteria and self-assessment questionnaire. Nevertheless, the researchers reported gradual increase of urgency over time with almost 15% of patients affected at 4 5 years. A certain percentage of patients with urgency will undoubtedly suffer from incontinence. At least two factors are related to the decreasing prevalence of hemorrhagic radiation proctopathy after a maximum at 1 2 years. First, spontaneous regression of radiation mucosal changes, including multiple teleangiectases, has been observed during repeated sigmoidoscopy. 18 Second, local treatment of rectal bleeding is quite successful, especially with argon plasma coagulation. 19 Prevalence of fecal incontinence after radiation therapy showed evidence of progressive worsening of the anorectal function. Yeoh et al. 20 found a decline in rectal compliance and thickening of the external anal sphincter in patients after radiotherapy. Altered morphology of the sphincter may be associated with radiation-induced swelling and fibrosis of the surrounding connective tissue. The risk of fecal incontinence is connected with the radiation dose. It has been shown that patients with severe incontinence had higher minimum dose to the anal canal compared with continent patients or those with slight incontinence. 21 Our observation was consistent because all incontinent patients were treated with higher dose (74 Gy). In conclusion, rectal radiation toxicity is undoubtedly a dynamic process. Rectal bleeding is fairly manageable and the rate of fecal incontinence is low. During radiotherapy planning, maximal effort should be made to keep the doses to rectum and anal canal within tolerance limits. Hopefully, advanced radiotherapy techniques (intensity-modulated radiation therapy and image-guided radiation therapy) will significantly contribute to further reduction of rectal toxicity. Conflict of interest The authors declare no conflict of interest. References 1 Zelefsky MJ, Cowen D, Fuks Z, Shike M, Burman C, Jackson A et al. 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