# Radiation Oncology/Toxicity/Rectum

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Rectum Toxicity

## Scoring

* Christie Hospital; 2002 PMID 12443807 -- "Scoring of treatment-related late effects in prostate cancer." (Livsey JE, Radiother Oncol. 2002 Nov;65(2):109-21.)
** Comparison of LENT/SOMA, UCLA Prostate Cancer Index, and RAND Health survey (SF-36)
** Conclusion: LENT/SOMA more wide-ranging and more informative than UCLA
* Vienna; 2000 PMID 10719695 -- "Endoscopic scoring of late rectal mucosal damage after conformal radiotherapy for prostatic carcinoma." (Wachter S, Radiother Oncol. 2000 Jan;54(1):11-9.)
** Prospective. 44 patients, treated with 3D-CRT 66/33 for prostate CA. Flexible rectosigmoidoscopy. Developed 6-scale score

## RT Tolerance (Prostate CA)
### 2D RT vs 3D-CRT

* Rotterdam, Netherlands (1994-1996) -- conformal RT vs conventional RT
** Randomized. 266 patients, prostate cancer Stage T1-4N0. RT 66/33. Arm 1) conventional RT (rectangular, open fields) vs. Arm 2) conformal RT (conformally shaped fields with MLC). PTV = GTV + 1.5 cm
** 1999 PMID 10098427 -- "Acute morbidity reduction using 3DCRT for prostate carcinoma: a randomized study." (Koper PC, Int J Radiat Oncol Biol Phys. 1999 Mar 1;43(4):727-34.)
*** Outcome: Acute GI Grade 2 conventional 32% vs. conformal 19% (SS); Acute GU Grade 2 in 17% vs. 18% (NS). Further GI analysis: rectal symptoms 18% vs. 14% (NS) but anal symptoms 16% vs. 8% (SS)
*** Conclusion: Significant reduction in GI toxicity, driven by anal symptoms. No difference between rectum/sigmoid and bladder toxicity
* Royal Marsden (1988-1995) -- conformal RT vs conventional RT
** Randomized, extension of original pelvic randomized trial. 225 men with prostate CA, T1-T4N0. NACHT in 68%. RT 64/32. Arm 1) conformal RT vs. Arm 2) conventional RT
** 1999 PMID 9929018 -- "Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomised trial." (Dearnaley DP, Lancet. 1999 Jan 23;353(9149):267-72.) Median F/U 3.6 years
*** Outcome: Radiation-induced proctitis G1+ conformal RT 37% vs. conventional RT 56% (SS), G2+ 5% vs. 15% (SS). No difference in bladder toxicity. No difference in bPFS (78% vs 83%, NS)
*** Conclusion: Conformal RT significantly reduced risk of later proctitis
** 1997 (1988-1993) PMID 9106921 -- "Acute toxicity in pelvic radiotherapy; a randomised trial of conformal versus conventional treatment." (Tait DM, Radiother Oncol. 1997 Feb;42(2):121-36.)
*** Initial randomized study of pelvic RT. 266 patients (prostate 52%, bladder 41%, rectum/other 7%). Most common dose 64/32, but some bladder CA patients 30-36/5-6 fractions
*** Outcome: No statistically significant difference between acute symptoms or medications prescribed
*** Conclusion: Late effects must be collected/analyzed

### 3D-CRT vs IMRT

* Dutch CKVO96-10 PMID 18718725 -- "Role of intensity-modulated radiotherapy in reducing toxicity in dose escalation for localized prostate cancer." (Al-Mamgani A, Int J Radiat Oncol Biol Phys. 2009 Mar 1;73(3):685-91. Epub 2008 Aug 19.)
** Unplanned subset analysis. Dutch randomized dose-escalation trial, subset treated at same institution to 78 Gy using 2 techniques: 3D-CRT sequential boost 78/39 (68/34 + 10/5) or IMRT simultaneous integrated boost 78/39 (PTV1 68/39 and PTV2 78/39). Median F/U 3DCRT 6.3 years, IMRT 4.7 years
** Outcome: 5-year bPFS IMRT 70% vs 3DCRT 61% (NS)
** Acute toxicity: GI G2+ IMRT 20% vs. 3DCRT 61% (SS); GI G3+ 0% vs 13% (SS); acute GU toxicity 53% vs. 69% (NS)
** Late toxicity: GI G2+ IMRT 21% vs. 3DCRT 37% (NS); GI G3+ 0% vs 7% (NS); late GU toxicity 43% vs. 45% (NS)
** Conclusion: IMRT reduced toxicity without compromising outcomes
* Memorial Sloan Kettering; 2001 (1988-1998) PMID 11490237 -- "High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localized prostate cancer." (Zelefsky MJ, J Urol. 2001 Sep;166(3):876-81.)
** Retrospective. 1100 patients with cT1c-T3N0, treated with 3D-CRT or IMRT.
** Outcome: 5-year bPFS favorable risk 85%, intermediate risk 58%, unfavorable risk 38% (SS)
** Late rectal toxicity (81 Gy group): 3D-CRT 14% vs IMRT 2% (SS); no impact of IMRT on GU toxicity
** Conclusion: IMRT associated with minimal rectal toxicity, represents most favorable risk-to-benefit ratio

### DVH Models

* QUANTEC; 2010 PMID 20171506 -- "Radiation dose-volume effects in radiation-induced rectal injury." (Michalski JM, Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3 Suppl):S123-9.)
** Rectum segmentation recommendation: Above anal verge to turn into sigmoid
** Models: LKB parameters n=0.09, m=0.13, TD50=76.9
** DVH constraint recommendations: V50 <50%, V60 <35%, V65 <25%, V70 <20%, V75 <15%. Hypofractionated schedules should be adjusted using conservative rectum a/b = 3
* MRC RT01; 2010 PMID 19540054 -- "Dose-volume constraints to reduce rectal side effects from prostate radiotherapy: evidence from MRC RT01 Trial ISRCTN 47772397." (Gulliford SL, Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3):747-54. Epub 2009 Jun 18.)
** Retrospective. DVH analysis from randomized dose-escalation trial. 7 clinically relevant rectal toxicity endpoints
** Outcome: DVH constraints: V30 <= 80%, V40 <= 65%, V50 <= 55%, V60 <= 40%, V65 <= 30%, V70 <= 15%, and V75 <= 3%
** Conclusion: Entire DVH distribution should be considered to reduce rectal toxicity
* Tubingen, Germany; 2007 PMID 17707277 -- "Principal component analysis-based pattern analysis of dose-volume histograms and influence on rectal toxicity." (Sohn M, Int J Radiat Oncol Biol Phys. 2007 Sep 1;69(1):230-9.)
** Principal component analysis. 262 patients, 4-F 3D-CRT. Correlation of first 3 PCs (96% of DVH shape variability) to Grade 2+ rectal bleeding
** Outcome: PC1 correlated with mean dose, PC2 volume in field overlap, PC3 maximal dose. Only PC2 correlated with toxicity
** Conclusion: CPA can provide information about DVH shape and its relationship to toxicity
* Princess Margaret; 2007 (1997-2003) PMID 17379434 -- "Patient-assessed late toxicity rates and principal component analysis after image-guided radiation therapy for prostate cancer." (Skala M, Int J Radiat Oncol Biol Phys. 2007 Jul 1;68(3):690-8. Epub 2007 Mar 26.)
** Retrospective. 690 men treated for PCA with RT 75.6-79.8 Gy using 3D-CRT of IMRT. Questionnaires sent, received from 63%. Median F/U 2 years
** Late toxicity: GI G1 25%, G2 2.5%, G3 0.7%; GU 16%, 9%, 0.9%. Erectile function sufficient for intercourse in 68%
** Dosimetric models: No dosimetric parameter, including principal component analysis, correlated with late toxicity
** Conclusion: Incidence of toxicity low, with lack of correlation to dosimetric parameters
* William Beaumont, 2007 PMID 17258870 -- "Incidence of late rectal bleeding in high-dose conformal radiotherapy of prostate cancer using equivalent uniform dose-based and dose-volume-based normal tissue complication probability models." (Sohn M, Int J Radiat Oncol Biol Phys. 2007 Jan 25; [Epub ahead of print])
** Retrospective. 319 patients. Models using EUD and DVH NTCP to predict chronic Grade 2+ rectal bleeding. Median F/U 2.8 years (0.1-6.4)
** Toxicity: Grade 2+ bleeding in 16%
** Lyman model: TD50 = 78.4 Gy, n=0.08, m=0.108
** Conclusion: clear confirmation of volume effect, and no correlation with mean dose
* MD Anderson
** 2006 PMID 16504763 -- "Cluster model analysis of late rectal bleeding after IMRT of prostate cancer: a case-control study." (Tucker SL, Int J Radiat Oncol Biol Phys. 2006 Mar 15;64(4):1255-64.)
*** Paired case-control study, 9 patients with Grade 2+ late rectal toxicity compared with similar DVH patients without toxicity.
*** Outcome: Patients with rectal toxicity had significantly larger mean maximum damaged cluster size. Highest prediction of difference at doses ~30 Gy
*** Conclusion: Cluster model incorporates spatial information beyond DVH
** 2004 PMID 15590191 -- "Comparison of rectal dose-wall histogram versus dose-volume histogram for modeling the incidence of late rectal bleeding after radiotherapy." (Tucker SL, Int J Radiat Oncol Biol Phys. 2004 Dec 1;60(5):1589-601.)
*** Planning comparison. Dose-volume histograms (DVH) vs dose-wall histograms (DWH) in 128 patients treated with 3D-CRT. Fit to 4 models (Lyman, mean-dose, parallel-architecture, cutoff-dose). Minimum 2 year F/U
*** Slightly better performance for DWH model. Intermediate dose cut-off predicted as V32 >80%
*** Conclusion: NTCP models fit slightly better with DWH as opposed to DVH
** 2004 (1992-1999) PMID 15050331 -- "Characterization of rectal normal tissue complication probability after high-dose external beam radiotherapy for prostate cancer." (Cheung R, Int J Radiat Oncol Biol Phys. 2004 Apr 1;58(5):1513-9.)
*** Retrospective. 128 patients treated with 3D-CRT to 78 Gy. Endpoint Grade 2+ rectal bleeding. Minimal F/U 2 years
*** Toxicity: Grade 2+ bleeding 23%
*** Lyman model: TD50 = 53.6 Gy, n = 3.91, m = 0.156. Different with/without hemorrhoids
*** Conclusion: Possibly large volume effect; LKB model should be used with caution
** 2002 (1993-1998) PMID 12128107 -- "Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial." (Pollack A, Int J Radiat Oncol Biol Phys. 2002 Aug 1;53(5):1097-105.). Median F/U 5 years
*** Dosimetric analysis of randomized trial. 301 T1-T3 patients, stratified by PSA <10 (65%), 10-20 (35%), >20 (few). Arm 1) 70 Gy vs. Arm 2) 78 Gy. Technique 4F 46/23, Arm 1) 4F RF 24/12, Arm 2) 3D-CRT 6 fields 32/16. CTV = prostate/SV, margin 1.5 cm anterior/inferior, 1.0 cm posterior/superior. No hormones
*** Toxicity: Grade 2+ rectal toxicity 12% vs. 26% (p=0.001); Grade 2+ bladder toxicity NS. Less GI toxicity, if V70 <25% (16% G2) vs if V70 >25% (46% G2)
*** Conclusion: Highly significant FFF improvement for intermediate-to-high risk patients, no benefit if PSA <10. Increased rectal toxicity
* Netherlands Cancer Institute; 1998 PMID 9588921 -- "Estimation of the incidence of late bladder and rectum complications after high-dose (70-78 GY) conformal radiotherapy for prostate cancer, using dose-volume histograms." (Boersma LJ, Int J Radiat Oncol Biol Phys. 1998 Apr 1;41(1):83-92.)
** Retrospective. 130 patients, localized prostate cancer on dose escalating protocol 70 -> 78 Gy. Median F/U 2 years
** Outcome: Severe rectal bleeding if rectal wall V65> 40%, V70 >30%, or V75 >5%
** Conclusion: Dose escalation is feasible, but incidence of severe late rectal bleeding is increased above certain DVH constraints

### Gene Profiling

* Milan, Italy; 2009 PMID 19211196 -- "To bleed or not to bleed. A prediction based on individual gene profiling combined with dose-volume histogram shapes in prostate cancer patients undergoing three-dimensional conformal radiation therapy." (Valdagni R, Int J Radiat Oncol Biol Phys. 2009 Aug 1;74(5):1431-40. Epub 2009 Feb 11.)
** Retrospective. 30 patients, 3D-CRT to >70 Gy. Low-risk bleeding group (V70 <20% and V50 <55%) and bleeding; high-risk group (V70 >25% and V50 >60%) and bleeding, and high-risk group and no bleeding. PCR on lymphoblastoid RNA from peripheral mononucleated cells
** Outcome: nine genes downregulated in low-risk bleeder group; four genes upregulated in high-risk non-bleeder group
** Conclusion: Predictive value of gene panels promising

### Rectal Balloons

* Nijmegen, The Netherlands (2002) -- 3D-CRT +/- endorectal balloon
** Randomized. 48 patients, treated with 3D-CRT to 67.5/30. Arm 1) No endorectal balloon (ERB-) vs. Arm 2) with endorectal balloon (ERB+). PTV = prostate + SV + 9 mm margin. Rectosigmoidoscopy at 3 months, 6 months, 1 year, 2 years. 146 endoscopies and 2,336 mucosal areas analyzed
** 2007 PMID 17161552 -- "Reduced late rectal mucosal changes after prostate three-dimensional conformal radiotherapy with endorectal balloon as observed in repeated endoscopy." (van Lin EN, Int J Radiat Oncol Biol Phys. 2007 Mar 1;67(3):799-811. Epub 2006 Dec 8.) Median F/U 2.5 years
*** Outcome: ERB group significantly lower rectal wall volume exposed to high doses. Late rectal toxicity G1: ERB- 58% vs. ERB+ 21%; G2 4% vs. 0%; G3 4% vs. 0%. Overall G1+ rectal toxicity 67% vs. 21% (SS)
*** Endoscopy: Telangiectasia ERB- vs ERB+ @ 6 months 16% vs. 24%; 1 year 45% vs. 28%; 2 years 39% vs. 24% (SS). High grade telangiectasia @ 1 years 20% vs. 10%; 2 years 19% vs. 9% (SS). Significantly less high grade telangiectasia at lateral and posterior part of Rwall
*** Conclusion: ERB reduced rectal wall volume exposed to >40 Gy, resulting in reduction of late mucosal changes and reduced late rectal toxicity
* Nijmegen, The Netherlands
** 2009 PMID 19523704 -- "Anal wall sparing effect of an endorectal balloon in 3D conformal and intensity-modulated prostate radiotherapy." (Smeenk RJ, Radiother Oncol. 2009 Jun 10.)
*** Treatment planning. 24 patients, 2 planning CTs (ERB-, ERB+), 3D-CRT and IMRT plans generated, dose 78 Gy. Anal wall contoured
*** Outcome: ERB+ significantly reduced D(mean), D(max), and V30-V70 for both 3D-CRT and IMRT plans.
*** Conclusion: ERB showed significant anal wall sparing effect
** 2005 PMID 16168848 -- "Rectal wall sparing effect of three different endorectal balloons in 3D conformal and IMRT prostate radiotherapy." (van Lin EN, Int J Radiat Oncol Biol Phys. 2005 Oct 1;63(2):565-76.)
*** Prospective. 20 patients, 4 planning CTs, with comparison of 3 endorectal balloons: no ERB, ERB1, ERB2, and ERB3 inserted. 3D-CRT and IMRT planned to 78 Gy
*** Outcome: ERBs tolerated well. ERBs resulted in reduction of Rwall exposed to intermediate and high doses
*** Conclusion: ERB showed significant rectal wall sparing effect
* Harvard
** 2006 PMID 16584760 -- "A prospective evaluation of rectal bleeding after dose-escalated three-dimensional conformal radiation therapy using an intrarectal balloon for prostate gland localization and immobilization." (D'Amico AV, Urology. 2006 Apr;67(4):780-4. Epub 2006 Apr 11.)
*** Phase II. 57 men, at least one high-risk feature (PSA >10, GS 7+, T3). 3D-CRT to 75.6 Gy, rectal balloon for first 15 treatments. ADT. Median F/U 1.8 years
*** Outcome: V70 3.7 cm3
*** Toxicity: 2-year G3 rectal bleeding 10%; if anticoagulants 100% vs no anticoagulants 0% (SS). Controlled with APC
*** Conclusion: Dose-escalation with rectal balloon no measurable G3 rectal bleeding, unless patient on anticoagulants
** 2004 PMID 15271308 -- "Impact on rectal dose from the use of a prostate immobilization and rectal localization device for patients receiving dose escalated 3D conformal radiation therapy." (Sanghani MV, Urol Oncol. 2004 May-Jun;22(3):165-8.)
*** Treatment planning. 28 patients. 3 plans: no balloon, boost (15 fractions), or entire course (40 fractions). RT 75.6 Gy
*** Outcome: V70 25% vs. 7% vs 4% (SS)
*** Conclusion: Rectal toxicity could be minimized through use of rectal balloon
* Baylor; 2005 PMID 15749008 -- "Rectal wall sparing by dosimetric effect of rectal balloon used during intensity-modulated radiation therapy (IMRT) for prostate cancer." (Teh BS, Med Dosim. 2005 Spring;30(1):25-30.)
** Retrospective. 116 patients, IMRT 76/35 @ 2.17 Gy/fx. Rectal balloon 100 cc air. Film phantom to simulate 4cm air cavity created by rectal balloon. Median F/U 2.6 years
** Dosimetry: Dose reduction by 15% at distal air-tissue interface, 8% at 1 mm, and 5% at 2 mm. Coverage of posterior prostate wall comparable
** Clinical: Late GI toxicity G1 10%, G2 7%, and G3 2%, no G4. DVH analysis average V70 13%, all <25%
** Conclusion: Rectal balloon reduced anterior, posterior, and lateral rectal wall sparing. Late rectal toxicity low

### Perirectal fat injection

* Oviedo, Spain
** 2009 (2005-2006) PMID 19213607 -- "Transperineal injection of hyaluronic acid in the anterior perirectal fat to decrease rectal toxicity from radiation delivered with low-dose-rate brachytherapy for prostate cancer patients." (Prada PJ, Brachytherapy. 2009 Apr-Jun;8(2):210-7. Epub 2009 Feb 12.)
*** Randomized. 69 patients with low/intermediate PCA, treated with I-125 brachytherapy to 145 Gy. Median prostate volume 35 cc. Arm 1) control vs Arm 2) transperineal perirectal fat injection. Endoscopic follow up. Median F/U 1.5 years
*** Outcome: Endoscopic mucosal damage control 36% vs. HA injection 5% (SS), rectal bleeding 12% vs 0% (SS)
*** Conclusion: Increased distance resulted in smaller rectal dose, less mucosal damage, and no rectal bleeding
** 2007 PMID 17707267 -- "Transperineal injection of hyaluronic acid in anterior perirectal fat to decrease rectal toxicity from radiation delivered with intensity modulated brachytherapy or EBRT for prostate cancer patients." (Prada PJ, Int J Radiat Oncol Biol Phys. 2007 Sep 1;69(1):95-102.)
*** Retrospective. 27 patients treated with IMRT + HDR boost. Transrectal hyaluronic acid injection to perirectal fat under U/S guidance to create 1.5 cm space between rectal wall and prostate. Urethral and rectal TLDs placed during HDR
*** Outcome: No toxicity from HA injection, no change or migration at 1 year. Mean distance between rectum and prostate 2.0cm along entire length of prostate. Median rectal TLD dose decreased from 47% of urethral dose to 39% (SS), and from 7.1 Gy to 5.1 Gy during 11.5 Gy HDR boost
*** Conclusion: Increased rectum-prostate distance significantly decreased rectal dose during HDR brachytherapy

## Management

* Please see the diarrhea page
* Please see the proctitis page