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Partial irradiation of the rectum
Partial Irradiation of the Rectum Andrew Jackson Data gathered from dose escalation protocols for the treatment of prostate cancers conducted in the past 10 years have shown that rectal toxicity can be controlled by the use of careful conformal techniques. The most severe complications of rectal irradiation (obstruction and fistula requiring colostomy) have been essentially eliminated. The most frequent gastrointestinal complications of conformal radiotherapy of prostate cancer are now rectal bleeding associated with telangiectatic changes to the vasculature of the submucosa, and in severe cases, ulceration requiring cautery procedures and or transfusion. The benefits of 3-dimensional conformal radiotherapy (3D-CRT) are strongly technique dependent, with a strong dose response for single techniques for prescription doses over 70 Gy. Studies of rectal motion show that the anterior wall can move
--1 cm during treatment, so portions of the anterior rectal wall will regularly receive the full prescription dose if posterior margin sizes --> 1 cm are used in designing the planning target volume (PTV). There is strong evidence that increased rectal shielding and posterior PTV margin sizes - 0.6 cm reduce rectal complication rates. Despite uncertainties due to rectal motion, studies of dose-volume histograms (DVHs) show that rectal toxicity is strongly influenced by the percent volumes of rectal wall exposed to doses - 70 Gy and higher. Recent data suggests that percent volumes of rectal wall exposed doses between 40 to 50 Gy, and the existence of a reserve of unexposed tissue may also play a role in determining rectal bleeding rates. Copyright 9 2001 by W.B. Saunders Company
n the past 15 years, careful attention to the role of volume effects in rectal toxicity 1~ has greatly reduced the incidence of severe gastrointestinal complications of external beam radiotherapy of prostate cancer. With proper conformal techniques, obstruction and fistula requiring colostomy, once clear obstacles to attempts to prescribe doses over 70 Gy,4 have become extremely rare events that may be associated with prior history of bowel disease or surgery. 4,5 Results from dose escalation protocols conducted in the past 10 years 1&6-1~have shown that, with proper attention to margins used at the prostate/rectal interface, the incidence of proctitis, ulceration, and rectal bleeding can also be controlled and to a large extent eliminated. 11 This has enabled a major increase in prescription doses. At some institutions it is now common practice to deliver over 80 Gy to the prostate, with initial rates of local control showing significant improvements at higher doses. 12,13
diation of the rectal wall, which is dircctly adjacent to these structures posteriorly. Severe late effects include radiation proctitis (including excessive mucosal discharge and rectal bleeding), ulceration, stricture, and fistula. By far the most common of these is rectal bleeding. Time to onset of bleeding varies widely and can occur at any time up to - 3 1/2 years and has a mcdian time to onset of - 1 2 months. 8 After onset, low-grade bleeding is responsive to t r e a t m e n t with steroids and usually resolves within a few months, but higher grade bleeding may require transfusions and/or coagulation procedures and may continue for up to 2 to 3 years. 14 The 2 major grading schemes, Radiation Therapy Oncology Group (RTOG)15 and Late Effects Normal Tissue Task Force (SOMA/LENT), 16 differ in their classifications of grades 2 and 3 rectal bleeding, and various institutions have made their own modifications to these grading schemes. 7,a,17 The major differences between these schemes concern the number of transfusions and or coagulation procedures necessary to define grade 3 rectal bleeding. Table 1 shows the differences in grading schemes of various institutions with respect to transfusion and coagulation procedures. With these variations in mind, careful attention should be paid to the specific symptoms and procedures reported when comparing results ti-om different institutions.
I
Late Rectal Toxicity Radiation treatments of cancers of the prostate and cervix have traditionally been limited by complications arising from the concomitant irra-
t'~rom the Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Andrew Jackson, PhD, Memorial SloanKettering Cancer Center, 1275 York Ave, New York, N Y 10021. Copyright 9 2001 by W..B. Saunders Company 1053-4296/01/1103-0005535.00/0 doi:10.1053/srao.2001.23 481
Findings From Pathology and Endoscopy Coia et al la have reviewed the chronic pathologic changes occurring in the intestine after radio-
Seminars in Radiation Oncology, Vol 11, No 3 (.]-uly), 2001: pp 215-223
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Table 1. Grading Systems
Institution
Grade 2
1. Memorial SloanKettering Cancer Center (Modified RTOG)
Moderate diarrhea and colic; bowel movement -> 5 times daily; excessive rectal mucus or intermittent rectal bleeding
Obstruction or bleeding requiring surgery, coagulation procedure or tramfi~sion
Necrosis, perforation, fistula
2. Fox Chase Cancer Center (Modified RTOG
Moderate diarrhea and colic; bowel movement -> 5 times daily; rectal bleeding with <--2 coagulation procedures; pain requiring nonnarcotic medication
Dysfunction requiring nonsurgical hospitalization; rectal bleeding requiring ->3 coagulation procedures; pain requiring narcotics
Dysfunction requiring surgical intervention; necrosis, perforation, fistula; life threatening bleeding
3. University of Michigan Medical Center (RTOG)
Bleeding simple therapy
Minor outpatient surgery
Major surgery or prolonged hospitalization
4. Massachusetts General Hospital (RTOG)
Symptoms responding to simple outpatient managcment, life style (performance status) not affected
Distressing symptoms altering a patient's lifestyle (performance status) and/or hospital for diagnosis or minor surgical intervention
Major surgical intcrvention or prolonged hospitalization
5. Netherlands Cancer Institute ("Severe") 6. M.D. Anderson Cancer Center (modified RTOG, SOMA/LENT)
Grade 3
Grade 4
Any laser treatment or transfusion ->2 Antidiarrheals per week. Rectal bleeding with <-2 coagulation procedures. OccasionaI steroids for ulceration. Occasional dilatation. Intermittent use of incontinence pads. Regular non-narcotic or occasional narcotic for pain.
->2 Antidiarrheals per day. Rectal bleeding requiring >-3 coagulation procedures or a ~ transfusion; Prolonged steroids per enema. Hyperbaric oxygen for bleeding/ ulceration. Regular dilatation. Persistent use of incontinence pads. Regular narcotic for pain.
Dysfunction requiring surgery intervention. Perforation. L/~threatening bleeding
Grading systems (grade 2 and higher) adopted by the institutions reporting late rectal complications. Where explicitly stated by the reporting authors, the numbers of coagulation procedures or transfusions are shown in italics. Netherlands Cancer Institute reported results using 3 different grading schemes. Correlations of rectal bleeding with dose volume cutoffs were seen with the "Severe" scheme given here. therapy. These include fibrosis and vascular insufficiency, with possible focal areas of stenosis and ulceration. The mucosa appears pale and teangiectatic. Microscopically, the most m a r k e d changes are found in the submucosa, where atypical fibroblasts, collagen proliferation, thickening of walls of small arteries and telangiectatic vessels m a y be found. Endoscopic examinations of the rectal walls of patients treated after prostate t h e r a p y show that grade 2 (or 3) rectal bleeding is usually accompanied by telangiectasia (and ul-
ceration) of the nmcosa of the anterior rectal wall. 19 W a c h t e r et al 2~ performed endoscopy on 44 patients who had received 3-dimensional conformal radiotherapy (3D-CRT) for prostate cancer with isocenter doses of 66 Gy in 2 Gy fi'actions, of whom 9 patients had grade 2 rectal bleeding. All patients were treated with opposed anterior/posterior and lateral beams. Findings included single, multiple, and confluent multiple talengiectatic lesions; congested mucosa, consisting of edema (combined with either focal diffuse
Partial Irradiation of the Rectum
or confluent diffuse reddening); and microulceration. Observations were classified into 3 circumferential regions (anterior, left and right lateral and posterior) in each of 4 superior-inferior regions (0-4, 4-8, 8-12, >12 cm above the anus) in each patient. Attempts were made to correlate endoscopic findings with dose distributions as calculated from each patient's t r e a t m e n t plan. Multiple confluent telangiectatic lesions were found only in the anterior region between 4 to 8 cm above the anus, which was calculated to receive doses greater than 60 Gy in all patients. No telangiectatic lesions were found greater than 12 cm above the anus, which was outside the radiation field. Below this level, single and multiple (but not confluent) telangiectatic lesions could be seen around the circumference of the rectum. Regions calculated to receive less than 30 Gy were either free of telangiectasia or had only single telangiectatic lesions. It should be noted, however, that endoscopic findings did not correlate perfectly with clinical rectal bleeding. While 7 of the 9 patients with grade 2 rectal bleeding showed multiple telangiectatic lesions and/or congested mucosa (edema with confluent diffuse reddening) and microulceration, 7 of the 35 patients without grade 2 bleeding showed similar changes.
Geometry and Motion of the Rectal Wall Doses delivered t o normal organs are conventionally assessed using dose distributions calculated from a single computed tomography (CT) scan taken prior to t r e a t m e n t (the planning scan). Morbidity arising from t r e a t m e n t is usually reported in terms of dose-volume histograms and/or a number of summary statistics of the dose distribution calculated from the planning scan, such as prescription dose, dose to 95% of the organ volume, mean dose, and normal tissue complication probabilities (NTCPs). The geometry of the rectum raises several questions concerning the accuracy and relevancy of these techniques, none of which can be fully addressed at present. The rectum is a flexible tube about 15 to 20 cm long, running from the sigmoid colon through the floor of the pelvis to the anal canal, and constitutes the end of the digestive tract. 2t The upper third of the rectum (the rectal ampulla) is highly
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extensible and may expand greatly as the rectum fills prior to defecation. The rectal wall consists of 2 muscle layers (1 longitudinal muscle layer surrounding a circumferential one) and a mucosal inner lining that reaches into the upper part of the anal canal. Since the mucosa and subnmcosa is the site of rectal bleeding, the dose on the inner surface of the rectal wall would appear to be the quantity of interest. This geometry has led several groups to develop novel ways of describing the dose distributions in the rectal wall. The dose-surface histogram (DSH) 22 quantifies the area of the surface of the rectal wall exposed to a given dose level. The normalized dose-surface histogram (NDSH) 23,24 attempts to account for the stretching of the rectal wall. The dose-circumference histogram (DCH) 25 quantifies the percent circumference of the rectal wall exposed to a given dose as a function of the length along the wall. The spatial dose-volume histogram (zDVH) 26 quantifies the volume of rectal wall on a given C T slice exposed to a particular dose. At present, these novel tools have not been used to analyze bleeding rates in any substantial series of patients. A simple problem (which potentially undermines all the sophisticated methods above) arises from the common practice of partially contouring the length of the rectum. 8,27 In m a n y institutions, for prostate cancer patients, rectal contours are only drawn in slices near to the target volume and DVHs reported in terms of percent volume. Thus, the normalization of each patient's histogram is determined by the length of the target volume, rather than by the total volume of the rectal wall. Additionally, because it is a thin tube, it is difficult to contour the rectal wall in a way that consistently reflects its thickness at any point. 2~ Perhaps the most important limitation of all current methods of analyzing doses to the rectum lies in the fact that the rectal wall moves during the course of treatment, both by distorting (eg, by expanding or contracting), and by moving bodily (eg, in the anterior-posterior direction). Studies of patients with multiple CT scans taken during t r e a t m e n t for prostate cancer 28-34 show that (chiefly as a result of rectal filling) the anterior rectal wall can move - 1 cm in the anteriorposterior direction with respect to the bony anatonly. While the dosimetric consequences of this movement depend on t r e a t m e n t technique, s3-35 it
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should be noted that use of posterior margins of 1 cm or more to define the PTV in prostate treatment will mean that portions of the anterior rectal wall will regularly receive the full prescription dose. These studies show that it may bc impossible to use the planning scan to assess the total dose distribution delivered to the mucosa over the course of treatment. Assuming that variables of the delivered dose distribution do correlate with rectal bleeding, any dosimetric variables from the planning scan that correlate with rectal bleeding must be regarded as surrogates for them. The relationship between such variables from the delivered dose distributions and their surrogates from the planning scans cannot be known until the effects of the motion of the rectal wall are thoroughly understood. It should be noted that differences in treatment technique (such as treating patients prone or supine) are likely to have a large influence on this question, making it presently very difficult to compare predictors of rectal bleeding from institutions using different treatment techniques. With these important caveats, we now turn to the available data on the dose/volume dependence of rectal bleeding.
Dose Distributions and Complication Probabilities Prior to 3D-CRT, quantitative evidence for volume effects in rectal toxicity was essentially nonexistent. Emami et al, 3~ in their widely quoted article on organ tolerance doses, assumed that there was no volume effect for severe late effects in the rectum, but stated that published articles contained little or no information on this subject. Nevertheless, studies of prostate cancer patients treated prior to the advent of 3D-CRT established that late rectal complications increased with prescription doses at or above 70 Gy. Pilepich et a137 reported treatment-related morbidity from RTOG study 77-06, a phase III randomized trial comparing prostate irradiation alone with pelvic irradiation followed by a prostatic boost. For 224 patients whose treatment included pelvic irradiation, the prescription dose to the prostate was found to be significantly correlated with rectal bleeding. A similar, but less dramatic, trend could be seen in rectal bleeding rates for 228 patients who received prostatic irradiation alone, but this was not significant. Smit et al 4
studied the high incidence of radiation proctitis in 154 patients treated between 1983 and 1985. CT scans were taken of all patients and the target (defined as prostate, seminal vesicles and the periprostatic tissue) and rectum were outlined on each slice. Patients were treated supine using a 3-field technique (left and right posterior oblique fields and 1 anterior field) to deliver 70 Gy in 2 Gy fractions to an isodose level encompassing the target. Anterior, posterior, and average rectal doses were estimated by forming the union of the rectal contours when projected vertically onto the isocenter slice. Doses at the points along an anterior-posterior line through the isocenter that fell at the anterior and posterior of this union were used to define the anterior and posterior doses for each patient. Average doses for each patient were calculated as the average within the union on the isocenter slice. Rectal complications were defined as mild, moderate, and severe. Proctitis was called moderate if it required medical treatment such as retention enemas and blood transfusions and severe if it required major surgical procedures such as colostomy. Thc number of mild, moderate, and severe cases of proctitis were 33, 24, and 6, respectively. All 6 severe cases required colostomy. Multivariate analysis revealed that prior bowel disease or pelvic surgery, anterior dose, and mean dose were significantly associated with the incidence of moderate and severe proctitis. Actuarial rates of all grades of proctitis at 30 months were --30%, - 5 0 % , and - 7 5 % for patients with anterior doses of--<70 Gy, 70 to 75 Gy, and greater than 75 Gy, respectively. Despite the lack of evidence for volume effects in rectal complications, with the advent of 3DCRT, several dose escalation trials were established for the treatment of prostate cancer, assuming that the tolerance doses of the rectum would increase as the irradiated volume of the rectum decreased. 5,7,19,13,38-4~ Initial results revealed that the ability of conformal techniques to reduce rectal complications depended on the techniques used. Sandler et al 3~ studied 721 patients treated at University of Michigan Medical Center and Providence Hospital between 1987 to 1992 with prescription doses increasing from 59.4 to 80.4 Gy. A total of 462 of these (generally patients with high T-stage or Gleason score) were treated with pelvic fields to 45 Gy; 60 of them were postprostatectomy patients. The target initially included prostate and seminal vesicles with
Partial Irradiation oJthe Rectum
a 0.5 cm margin in all directions to account for setup error and organ motion. After 1989, the seminal vesicles of patients with T1 to T2 stage disease were treated to 55 Gy. Blocks were custom designed to ensure target coverage by the 95% prescription isodose line. Initially patients were treated supine with a 4-field box technique, but this evolved into a 6-field axial, and then a 4 field nonaxial oblique technique. Rectal toxicity was graded using the R T O G scheme (grade 1, rectal bleeding not requiring therapy; grade 2, bleeding requiring simple therapy; grade 3, requiring minor outpatient surgery; grade 4, major surgery or prolonged hospitalization), and confirmed by endoscopy. Rectal complications were observed in 96 patients, including 12 with grade 3 and 2 with grade 4 complications. The overall actuarial rate of ->grade 3 rectal complication at 3 years was 3%. On univariate analysis, prescription dose was found to be significantly associated with risk of grade 3 or 4 complications. Both grade 4 patients were treated to doses -> 69 Gy. When analyzed by dose, the actuarial rate of ->grade 3 complications at 3 years rose to ~ 8 % for patients treated to greater than 69 Gy. For patients treated to doses of 69 to 71 Gy, a comparison between the 3 t r e a t m e n t techniques could be made. Patients treated with 4 field nonaxial oblique fields had an actuarial complication rate for any rectal toxicity at 2 years of less than 10%, whereas the 6-field and 4-field box axial techniques had rates o f - 2 0 % . Schultheiss et al 6,41 studied late gastrointestinal (GI) toxicity in 712 patients treated supine with 10 to 18 MV photons to prescription doses ranging from 65 to 75 Gy between 1986 and 1994 at Fox Chase Cancer Center. A total of 581 patients received more than 70 Gy. No postprostatectomy patients were included in the study. A total of 562 patients were treated with conformal techniques, and 377 patients (assessed to have high risk of nodal disease) were treated with pelvic fields. T r e a t m e n t plans for patients treated with hormones were generally done on the prostate volume before hormone therapy was begun. Patients treated with pelvic fields received 45 Gy in 1.8 Gy fractions with fields extending from the middle of $1 to 1 cm below the urethrogram cone with the posterior half of the rectum blocked. The clinical target volume (CTV) was the prostate and 1 or both seminal vesicles for patients with stage T2c disease and higher, the
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PTV included a 1-cm margin for most patients. The target volume was treated with a 4-field technique (opposed AP-PA and lateral fields), with doses usually prescribed to the 95% isodose surface (which usually approximated the PTV) and delivered in 2 Gy fractions. A total of 88 patients were treated to 70 to 71 Gy with an additional 0.5 cm blocking of the rectum posteriorly for the last 10 Gy of treatment. 3 Rectal complications were analyzed using a modified R T O G scheme. 17 These modifications were: grade 2, rectal bleeding with 2 or fewer coagulation procedures or pain requiring nonnarcotic medication; grade 3, dysfunction requiring nonsurgical hospitalization or rectal bleeding requiring transfusion or 3 or more coagulation procedures or pain requiring narcotics; grade 4, dysfunction requiring surgical intervention or life-threatening bleeding. It should be noted that in this modified scheme, patients with grades 2 and 3 complications may suffer more severe effects than those classified according to Sandler (given above) or the modified R T O G scheme used at Memorial Sloan Kettering Cancer Center (MSKCC), a which treat a single cautery procedure as a grade 3 complication. A total of 115 patients suffered grade 2 or higher GI complications, 15 of these had grade 3 or higher complications. Multivariate analysis revealed that central axis dose was the strongest correlate with late rectal grade 2 morbidity. O t h e r significant factors were androgen deprivation therapy, lack of increased rectal shielding, acute GI toxicity, and history of diabetes (borderline). T r e a t m e n t with pelvic fields, or seminal vesicle doses greater than 57 Gy, were not significant. Among patients treated without the additional rectal shielding, central axis dose was found to be strongly correlated with grade 2 rectal morbidity, with actuarial rates rising from - 6 % to 7% at 60 months for central axis doses less than 68 Gy, to greater than 40% at 36 months fbr central axis doses of ->77 Gy. Grade 3 rectal morbidity also showed a significant dose response, with actuarial rates of rectal bleeding rising from 0% at 60 months for central axis doses of less than 68 Gy to ~12% at 36 months for central axis doses of ->77 Gy. While follow-up for patients with additional rectal shielding was less than 2 years, treatment with additional rectal shielding reduced the actuarial bleeding rate at 18 months. Kaplan Meyer analysis showed that patients treated without ad-
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ditional rectal blocking to central axis doses both from 71 to 74 Gy and from 74 to 77 Gy had rates of >--grade 2 rectal morbidity at 18 months of - 2 0 % . This was reduced to - 1 2 % among patients treated with additional rectal blocking (all of which were treated to doses between 73 to 76 Gy central axis dose). T r e a t m e n t without additional rectal blocking was associated with a relative risk of 2.0 for late grade 2 rectal morbidity. Neither Sandier et al nor Schultheiss et al used DVHs in their analysis, so they could not give definite evidence of volume effects in their data. Schulthiess et al observed that the dependence of rectal toxicity on hormone therapy may have been due to the fact that, since planning was performed before hormone therapy, the prostate volume was likely to have shrunk, and more normal tissue would have been included in the highdose volume. They also noted that although one explanation for the decrease in toxicity from increased rectal shielding might be a volume effect, it could also be explained as a dose effect. Benk et aP reported data from cumulative DVHs of 41 patients treated at the Massachusetts General Hospital (MGH) after 1982. Patients were treated supine with 10 to 25 MV photon whole pelvis and 160 MeV perineal proton boost fields to prescription doses of 75.6 cobalt gray equivalent (CGE). Whole pelvis doses of 50.4 Gy were delivered in 1.8 Gy fractions with a 4-field box technique. Prostate boost doses of 25.2 CGE were delivered in 2.1 CGE fractions with the rectal wall localized by a lucite probe. The proton beam was designed with a 0.5 cm margin between the target volume and the 90% isodose line, as outlined on a CT scan taken in the treatment position with the lucite probe in place. A schematic representation of the dose distribution indicates that the m i n i m u m dose to the rectal wall on the isocenter slice from both courses of therapy was between 35 and 45 Gy and the m a x i m u m dose in excess of 75 Gy. Contour.s for the anterior rectal wall were defined on the CT scan from the superior limit of the anus to 2 cm superior to the target volume and extended laterally and posteriorly to a midcoronal plane dividing the anterior and posterior rectum. Rectal complications (consisting of rectal bleeding) were defined using the R T O G criteria, x5 A total of 14 cases of rectal bleeding (6 grade 1, and 8 grade 2) were observed, and the presence of telangiectasia was confirmed by endoscopy. Percent volume of ante-
rior rectal wall exposed to 75 CGE was calculated, and Kaplan-Meyer analysis showed that actuarial bleeding rates at 4 years were reduced from greater than 70% to - 2 0 % for patients with ->40% and less than 40% anterior rectal wall exposed to 75 CGE, respectively (P < .005). Hartford et a142 extended this analysis and found that a range of dose-volume cutoffs at lower doses Gy (down to ->70% of the anterior wall receiving 60 Gy) also produced significant correlation with bleeding, as did a model of NTCP. Boersma et al 7 studied DVHs from 130 patients treated for prostate cancer at Netherlands Cancer Institute (NKI). Patients were treated to isocenter doses between 70 to 78 Gy in 2 Gy fractions with 3-field 3D-CRT (opposed wedged laterals and 1 anterior field). Prescription doses were 70, 74 to 76, and 78 Gy for 78, 11, and 41 patients, respectively. Seminal vesicles were included in the C T V for patients with stage --> T3, and for stage T2 patients if the estimated risk of nodal involvement was greater than 15%. 43 The PTV was defined on CT scans using a 1-cm margin around the CTV. Doses above 70 Gy were delivered to a coned down PTV (CTV + 0.5 cm margin) to provide additional rectal shielding. Pelvic nodes were treated to 64% prescription dose ( - 4 5 Gy) at 1.28 Gy per fraction using a simultaneous boost technique delivered with partial transmission shielding. Rectal wall volumes were defined from the sigmoid colon (usually at the sacroilliac joint) to 15 m m below the apex of the prostate. Late rectal toxicity was assessed both by a modified R T O G scheme and by a modified SOMA/LENT scale (similar to the one used by Schultheiss et al) and also by a scheme that classified toxicity as severe if any transfusion or laser cauterization procedures were used to treat rectal bleeding. Grade 2 or higher rectal bleeding (RTOG) was observed in 18 patients; 4 of these cases were called severe because they required 1 or more laser treatments and blood transfusions. No significant correlation with dose-volume parameters was seen for -->grade 2 rectal bleeding. However, actuarial incidence of severe rectal bleeding was significantly correlated with percent volumes of rectal wall receiving doses greater than 65 Gy (volumes greater than 40%, 30%, and 5% for doses greater than 65, 70, and 75 Gy, respectively). All 4 severe cases occurred in patients treated to prescription doses greater than 74 Gy, but this was not statistically significant.
Partial Irradiation of the Rectum
Recently, Storey et al 9 analyzed morbidity in 189 patients with -->2 years follow-up who were treated supine at M.D. Anderson Cancer Center as part of a randomized study begun in 1993.4~ A total of 91 patients in this group were treated with conformal therapy and received total prescription doses of 78 Gy delivered with 28 MV photons. A total of 46 Gy was delivered in 2 Gy fractions by a 4-field technique (AP-PA and opposed lateral fields). The lateral field blocks split the rectum posteriorly, followed the curvature of the rectum and included the seminal vesicles in the field. Cone down boost fields delivered an additional 38 Gy in 2 Gy fractions to the isocenter using a 6-field technique (opposed laterals and 2 pairs of opposed oblique beams, offset 30 ~ from lateral, with 37% of the boost dose coming from the laterals). The CTV was defined as prostate and seminal vesicles, as defined on CT scan. The PTV volume included a 0.75-cm margin posteriorly around the CTV. Rectal contours were defined within the superior and inferior borders of the initial APPA fields (typically - 1 1 cm in length, with the inferior border at the ischial tuberosities) and used to generate DVHs for the rectum. Rectal morbidity was classified using modified R T O G and FCLENT schemes. 17 Storey et al found that the actuarial incidence of->grade 2 rectal toxicity was significantly correlated with percent volume of rectum receiving greater than 70 Gy. Actuarial incidence of ->grade 2 rectal toxicity at 4 years was less than 15% or greater than 35% for patients with --<25% or >25% of rectum exposed to greater than 70 Gy, respectively. The analyses of DVH data from MGH, NKI, and M.D. Anderson discussed above all found correlations between complication rates and rectal volumes exposed to doses at 2arger than 65 Gy. All of these institutions treated large volumes of the rectal wall with large fields delivering between 40 to 50 Gy, which may have saturated any effects of volumes exposed to relatively low doses such as 40 to 50 Gy (although we do not know if the authors looked for such effects). In contrast, Skwarchuk et al 8 and Jackson et al 1~ analyzed factors correlating with rectal bleeding in 171 prostate cancer patients, all of whom were treated prone with a standard 6-field conformal beam arrangement. These patients were selected from 743 patients treated between 1988 and 1995 at MSKCC. ~2,46The CTV was defined as prostate plus seminal vesicles as defined on CT scan, and
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the PTV defined as CTV plus a 1 cm margin, except at the prostate, rectum interface, where a 0.6 cm margin was used to decrease the risk of rectal toxicity. ~2,46 Prescription doses were delivered in 1.8 Gy fractions to the surrounding isodose line on 3 orthogonal planes through the isocenter using 15 to 25 MV photons. One pair of opposed laterals and 2 pairs of opposed oblique (at 45 ~ fi'om lateral) axial fields were used, with the lateral fields delivering - 5 0 % prescription dose. No more than 30% of the rectal wall volume (defined at the time of planning to extend 1 C T slice either side of the PTV) was allowed to receive doses greater than 75.6 Gy. 2 Rectal bleeding was graded according to a modified R T O G scale: grade 2, intermittent bleeding; grade 3, bleeding requiring surgery, coagulation procedure, or transfusion. Eligibility criteria for inclusion in the DVH and dosimetric study were: prescription doses of 70.2 or 75.6 Gy, without rectal bleeding at ->30 months (designated as without bleeding) or diagnosis of rectal bleeding before 30 months (designated as bleeding). T r e a t m e n t plans from all bleeding patients were restored from archive if possible (13 and 36 of 13 and 38 eligible patients treated at 70.2 and 75.6 Gy, respectively), together with a random subset from patients without bleeding (39 and 83 of 208 and 192 eligible patients treated at 70.2 and 75.6 Gy, respectively). The rectal walls of all restored patients were recontoured to correspond to a consistent anatomic definition of the rectum extending from just above the anal verge to just below the sigmoid flexure. Rectal wall DVHs and other dosimetric and geometric summaries of the dose distribution were calculated. Multivariate analysis indicated that models based on either total rectal wall volume, the m a x i m u m rectal wall dose, and enclosure of the rectal wall by the 50% isodose line on the central C T slice, or total rectal wall volume, percent rectal wall volume exposed to 77 Gy, and percent rectal wall volume exposed to 47 Gy were roughly equally good at predicting incidence of rectal bleeding in patients treated to 75.6 Gy. The values of the percent volumes of rectal wall volume exposed to 77 Gy and 47 Gy were determined by the location of the lateral and oblique beam boundaries, respectively. Preliminary analysis shows that the total volume of rectal wall may be replaced by the absolute volume of rectal wall unexposed to doses of 40 to 50 Gy in these models, indicating the
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possible importance of a reserve of unexposed tissue. 47 Similar results were found for patients treated to 70.2 Gy. Skwarchuk et al 8 also examined the actuarial rates of grades 2 and 3 late rectal toxicity in the full set of 743 patients and found a significant dose response for the 6-field t r e a t m e n t plan. Five-year actuarial rates of -->grade 2 toxicity increased from less than 5% at prescription doses less than 65 Gy to - 1 6 % at 75.6 Gy. Model fits of the dose response in the data for the standard 6-field plan indicated an expected grade 2 rectal toxicity rate of - 2 8 % at 81 Gy. However, in response to the increasing rates of rectal bleeding, the 6-field t r e a t m e n t plan was modified for the first patients treated to 81 Gy. The last 9 Gy was delivered with a separate boost plan consisting of wedged posterior oblique beams with the rectum fully blocked. This was successful in keeping rates of 5-year actuarial grade 2 rectal toxicity at 17% for these patients. Preliminary data on patients treated later with intensity modulated radiation therapy (IMRT) to 81 Gy ll indicates that rectal toxicity may be drastically reduced with this t r e a t m e n t modality. DVH data from 4 institutions clearly indicate that the percent volume of rectal wall exposed to doses above 70 Gy 1,7-1~ plays a crucial role in determining the rectal morbidity of prostate treatment. The decrease in rectal toxicity associated with treatment with increased rectal shielding seen at Fox Chase Cancer Center 3,6 supports this hypothesis. Data from Memorial Sloan-Kettering Cancer Center suggest that percent volumes of rectal wall exposed to doses between 40 to 50 Gy and the existence of a reserve of unexposed tissue may also play a role in determining rectal bleeding rates. The quantitative relationship between volumes exposed to given doses and rectal complication rates may be expected to differ between institutions because of differences in t r e a t m e n t technique and consequent differences in organ motion.
References 1. Benk VA, Adams JA, Shipley WU, et al: Late rectal bleeding following combined X-ray and proton high dose irradiation for patients with stages T3-T4 prostate carcinoma. I n t J Radiat Oncol Biol Phys 26:551-557, 1993 2. Kutcher GJ, Leibel SA, Ling CC, et al: New wine in an old bottle? Dose escalation under dose-volume constraints: A
model of conformal therapy of the prostate [editorial; comment]. I n t J Radiat Oncol Biol Phys 35:415-416, 1996 3. Lee WR, Itanks GE, Hanlon AL, et al: Lateral rectal shielding reduces late rectal morbidity tbllowing high dose three-dimensional conformal radiation therapy for clinically localized prostate cancer: Further evidence for a significant dose effect. Int J Radiat Oncol Biol Phys 35: 251-257, 1996 4. Smit WG, Helle PA, van Putten WL, et al: Late radiation damage in prostate cancer patients treated by high dose external radiotherapy in relation to rectal dose. Int J Radiat Oncol Biol Phys 18:23-29, 1990 5. Zelef~ky MJ, Cowen DM, Fuks Z, et al: Long term tolerance of high dose three-dimensional conformal radiotherapy in the treatment of localized prostate cancer. Cancer 85:2460-2468, 1999 6. Schultheiss TE, Lee WR, Hunt MA, et al: Late GI and GU complications in the treatment of prostate cancer. Int J Radiat Oncol Biol Phys 37:3-11, 1997 7. Boersma LJ, van den Brink M, Bruce AM, et ah Estimation of the incidence of late bladder and rectum complications aller high-dose (70-78 GY) conformal radiotherapy for prostate cancer, using dose-volume histograms. I n t J Radiat Oncol Biol Phys 41:83-92, 1998 8. Skwarchuk M, ,Jackson A, Zelefsky M, et al: Late rectal toxicity after 3D-conformal radiation therapy of prostate cancer: Multivariate analysis and dose-response. Int J Radiat Oncol Biol Phys 47:103-113, 2000 9. Storey MR, Pollack A, Zagars G, et al: Complications from radiotherapy dose escalation in prostate cancer: Preliminary results of a randomized trial. Int J Radiat Oncol Biol Phys 48:635-642, 2000 10..Jackson A, Skwarchuk M, Zelefsky M, et al: Late rectal bleeding after 3D-conformal radiation therapy of prostate cancer (II): Volume effects and dose volume histograms. Int J Radiat Oncol Biol Phys 49:685-698, 2001 1i. Zelefsky M, Fuks Z, Happersett L, et al: Clinical experience with intensity modulated radiation therapy (IMRT) in prostate cancer. Radiother Oncol 55:241-249, 2000 12. Zelefsky MJ, Leibel SA, Gaudin PB, et al: Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. IntJ Radiat Oncol Bioi Phys 41:491-500, 1998 13. Hanks GE, Hanlon AL, Schultheiss TE, et al: Dose escalation with 3D conformal treatment: Five year outcomes, treatment optimization, and future directions. Int J Radiat Oncol Biol Phys 41:50t-510, 1998 14. Teshima T, Hanks GE, Hanlon AL, et al: 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 39:77-83, 1997 15. Lawton CA, Won M, Pilepich MV, et al: Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: Analysis of RTOG studies 7506 and 7706. Int J Radiat Oncol Biol Phys 21:935939, 1991 16. Pavy JJ, Dcnekamp J, Letschert J, et al: EORTC Late Effects Working Group. Late Effects toxicity scoring: The SOMA scale. I n t J Radiat Oncol Biol Phys 31:1043-1047, 1995 17. Hanlon AL, Schultheiss TE, Hunt MA, et al: Chronic rectal bleeding after high-dose conformal treatment of
Partial Irradiation of the Rectum
18.
19. 20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
prostate cancer warrants modification of existing morbidity scales. Int J Radiat Oncol BioI Phys 38:59-63, 1997 Cola LR, Myerson RJ, TepperJE: Late effects of radiation therapy on the gastrointestinal tract. Int J Radiat Oncol Biol Phys 31:1213-1236, 1995 Zelefsky MJ: Personal communication, January, 2000 Wachter S, Gerstner N, Goldner G, et al: Endoscopic scoring of late rectal nmcosaI damage after conformat radiotherapy for prostate carcinoma. Radiother Oncol 54:11-19, 2000 Kahle W, Leonhardt H, Platzer W: Digestive System-Rectum, in Color Atlas/Text of Human Anatomy, vol 2. New York, NY, Thieme, 1993, pp 232-233 Li S, Boyer A, Lu Y, et al: Analysis of the dose-surface histogram and dose-wall histogram for the rectum and bladder. Med Phys 24:1107-1116, 1997 Meijer GJ, van den Brink M, Hoogeman MS, et ah Dosewall histograms and normalized dose-surface histograms fbr the rectum: A new method to analyze the dose distribution over the rectum in conformal radiotherapy. Int J Radiat Oncol Biol Phys 45:1073-1080, 1999 MacKay RI, HendryJH, Moore CJ, et ah Predicting late rectal complications tbllowing prostate conformai radiotherapy using biologically effective doses and normalized dose-surface histograms. B r J Radiol 70:517-526, 1997 Zhou SM, Marks LB, Tracton GS, et al: A new threedimensional dose distribution reduction scheme for tubular organs. Med Phys 27:1727-1731, 2000 Cheng CW, Das IJ: Treatment plan evaluation using dose-volume histogram (DVtt) and spatial dose-volume histogram (zDVH). IntJ Radiat Oncol Biol Phys 43:1 I431150, I999 Skwarchuk MaN,Jackson A, Zelefsky M, et al: Correlation of DVH and treatment planning variables with late rectal bleeding after 3D-CRT of prostate cancer: What is the "best" way to defiue the rectal length and volume? Int J Radiat Oncol Biol Phys 45:26I, 1999 (abstr) Melian E, Mageras GS, Fuks Z, et ah Variation in prostate position quantitation and implications lbr threedimensional conformal treatment planning. Int J Radiat Oncol Biol Phys 38:73-81, 1997 Balter JM, Sandler HM, Lam K, et ah Measurement of prostate movement over the course of routine radiotherapy using implanted markers. Int J Radiat Oncol Biol Phys 31:113-118, 1995 Mageras GS, Kutcher GJ, Leibel SA, et ah A method of incorporating organ motion uncertainties into threedimensional conformal treatment plans. IntJ Radiat Oncol Biol Phys 35:333-342, 1996 Roeske JC, Forman JD, Mesina CF, et al: Evaluation of changes in the size and location of the prostate, seminal vesicles, bladder, and rectum dm'ing a course of external beam radiation therapy. Int J Radiat Oncol Biol Phys 33:1321-1329, 1995 van Herk M, Bruce A, Kroes AP, et ah Quantification of organ motion during conformal radiotherapy of the prostate by three dimensional image registration. IntJ Radiat Oncol Biol Phys 33:1311-1320, 1995 Lebesque JV, Bruce AM, Kroes AP, et al: Variation in volumes, dose-volume histograms, and estimated normal tissue complication probabilities of rectum and bladder
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during contormal radiotherapy of T3 prostate cancer. Int J Radiat Oncol Biol Phys 33:1109-1119, 1995 34. Zelefsky MJ, IIappersett L, Leibel SA, et al: The effect of treatment positioning on normal tissue dose in patients with prostate cancer treated with three-dimensional conformal radiotherapy. Int J Radiat Oncol BioI Phys 37:I319, 1997 35. Yah D, Jaffray DA, Wong JW: A model to accumulate fractionatcd dose in a deforming organ. Int J Radiat Oncol Biol Phys .44:665-675, 1999 36. Emami B, LymanJ, Brown A, et al: Tolerance of normal tissue to therapeutic irradiation. I n t J Radiat Oncol Biol Phys 21:109-122, 1991 37. Pilepich M'V, Asbcll SO, Krall JM, et ah Correlation of radiotherapeutic parameters and treatment related morbidity-analysis of RTOG Study 77-06. IntJ Radiat Oncol Biol Phys 13:1007-1012, 1987 38. Sandler HM, McLaughlin PW, Ten ttaken RK, et al: Three dimensional conformal radiotherapy for the treatment of prostate cancer: Low risk of chronic rectal morbidity observed in a large series of patients. Int J Radiat Oncol Biol Phys 33:797-801, 1995 39. Michalski JM, Purdy JA, Winter K, et ah Preliminary report of toxicity following 3D radiation therapy for prostate cancer on 3DOG/RTOG 9406. Int J Radiat Oncol Biol Phys 46:391-402, 2000 40. Perez CA, Michalski JM, Purdy JA, et al: Three dimensional conformal therapy or standard irradiation in localized carcinoma of prostate: Preliminary results of a nonrandomized comparison. Int J Radiat Oncol Biol Phys 47:629-637, 2000 41. Schultheiss TE, Hanks GE, Hunt MA, et ah Incidence of and factors related to late complications in conformal and conventional radiation treatment of cancer of the prostate. Int J Radiat Oncoi Biol Phys 32:643-649, I995 42. Hartford AC, Niemierko A, Adams JA, et ai: Conformal irradiation of the prostate: Estimating long-term rectal bleeding risk using dose-volume histograms. Int J Radiat Oncol Biol Phys 36:721-730, 1996 43. Roach MI: Re: The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J UroI 150:19231924, 1993 44. Pollack A, Zagars GK, Starkschall G, et ah Conventional vs. conformal radiotherapy for prostate cancer: Preliminary results of dosimetry and acute toxicity. Int J Radiat OncoI Biol Phys 34:555-564, 1996 45. Jackson A, Zelefsky M, Cowen D, et al: Rectal bleeding after conformal radiotherapy of prostate cancer and dose volume histograms. Int J Radiat Oncol Biol Phys 42:217, 1998 (abstr) 46. Leibel SA, Zelet~ky MJ, Kutcher GJ, et ah The biological basis and clinical application of three-dimensional conformal external beam radiation therapy in carcinoma of the prostate. Semin Oncol 21:580-597, t994 47. Jackson A, Skwarchuk M, Levegrun S: Volume effects in external beam treatments of prostate cancer. 5th International Symposium on 3D Contbrmal Radiation Therapy and Brachytherapy, New York, NY, 197-199, June 1-3, 2000
--1 cm during treatment, so portions of the anterior rectal wall will regularly receive the full prescription dose if posterior margin sizes --> 1 cm are used in designing the planning target volume (PTV). There is strong evidence that increased rectal shielding and posterior PTV margin sizes - 0.6 cm reduce rectal complication rates. Despite uncertainties due to rectal motion, studies of dose-volume histograms (DVHs) show that rectal toxicity is strongly influenced by the percent volumes of rectal wall exposed to doses - 70 Gy and higher. Recent data suggests that percent volumes of rectal wall exposed doses between 40 to 50 Gy, and the existence of a reserve of unexposed tissue may also play a role in determining rectal bleeding rates. Copyright 9 2001 by W.B. Saunders Company
n the past 15 years, careful attention to the role of volume effects in rectal toxicity 1~ has greatly reduced the incidence of severe gastrointestinal complications of external beam radiotherapy of prostate cancer. With proper conformal techniques, obstruction and fistula requiring colostomy, once clear obstacles to attempts to prescribe doses over 70 Gy,4 have become extremely rare events that may be associated with prior history of bowel disease or surgery. 4,5 Results from dose escalation protocols conducted in the past 10 years 1&6-1~have shown that, with proper attention to margins used at the prostate/rectal interface, the incidence of proctitis, ulceration, and rectal bleeding can also be controlled and to a large extent eliminated. 11 This has enabled a major increase in prescription doses. At some institutions it is now common practice to deliver over 80 Gy to the prostate, with initial rates of local control showing significant improvements at higher doses. 12,13
diation of the rectal wall, which is dircctly adjacent to these structures posteriorly. Severe late effects include radiation proctitis (including excessive mucosal discharge and rectal bleeding), ulceration, stricture, and fistula. By far the most common of these is rectal bleeding. Time to onset of bleeding varies widely and can occur at any time up to - 3 1/2 years and has a mcdian time to onset of - 1 2 months. 8 After onset, low-grade bleeding is responsive to t r e a t m e n t with steroids and usually resolves within a few months, but higher grade bleeding may require transfusions and/or coagulation procedures and may continue for up to 2 to 3 years. 14 The 2 major grading schemes, Radiation Therapy Oncology Group (RTOG)15 and Late Effects Normal Tissue Task Force (SOMA/LENT), 16 differ in their classifications of grades 2 and 3 rectal bleeding, and various institutions have made their own modifications to these grading schemes. 7,a,17 The major differences between these schemes concern the number of transfusions and or coagulation procedures necessary to define grade 3 rectal bleeding. Table 1 shows the differences in grading schemes of various institutions with respect to transfusion and coagulation procedures. With these variations in mind, careful attention should be paid to the specific symptoms and procedures reported when comparing results ti-om different institutions.
I
Late Rectal Toxicity Radiation treatments of cancers of the prostate and cervix have traditionally been limited by complications arising from the concomitant irra-
t'~rom the Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Andrew Jackson, PhD, Memorial SloanKettering Cancer Center, 1275 York Ave, New York, N Y 10021. Copyright 9 2001 by W..B. Saunders Company 1053-4296/01/1103-0005535.00/0 doi:10.1053/srao.2001.23 481
Findings From Pathology and Endoscopy Coia et al la have reviewed the chronic pathologic changes occurring in the intestine after radio-
Seminars in Radiation Oncology, Vol 11, No 3 (.]-uly), 2001: pp 215-223
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Table 1. Grading Systems
Institution
Grade 2
1. Memorial SloanKettering Cancer Center (Modified RTOG)
Moderate diarrhea and colic; bowel movement -> 5 times daily; excessive rectal mucus or intermittent rectal bleeding
Obstruction or bleeding requiring surgery, coagulation procedure or tramfi~sion
Necrosis, perforation, fistula
2. Fox Chase Cancer Center (Modified RTOG
Moderate diarrhea and colic; bowel movement -> 5 times daily; rectal bleeding with <--2 coagulation procedures; pain requiring nonnarcotic medication
Dysfunction requiring nonsurgical hospitalization; rectal bleeding requiring ->3 coagulation procedures; pain requiring narcotics
Dysfunction requiring surgical intervention; necrosis, perforation, fistula; life threatening bleeding
3. University of Michigan Medical Center (RTOG)
Bleeding simple therapy
Minor outpatient surgery
Major surgery or prolonged hospitalization
4. Massachusetts General Hospital (RTOG)
Symptoms responding to simple outpatient managcment, life style (performance status) not affected
Distressing symptoms altering a patient's lifestyle (performance status) and/or hospital for diagnosis or minor surgical intervention
Major surgical intcrvention or prolonged hospitalization
5. Netherlands Cancer Institute ("Severe") 6. M.D. Anderson Cancer Center (modified RTOG, SOMA/LENT)
Grade 3
Grade 4
Any laser treatment or transfusion ->2 Antidiarrheals per week. Rectal bleeding with <-2 coagulation procedures. OccasionaI steroids for ulceration. Occasional dilatation. Intermittent use of incontinence pads. Regular non-narcotic or occasional narcotic for pain.
->2 Antidiarrheals per day. Rectal bleeding requiring >-3 coagulation procedures or a ~ transfusion; Prolonged steroids per enema. Hyperbaric oxygen for bleeding/ ulceration. Regular dilatation. Persistent use of incontinence pads. Regular narcotic for pain.
Dysfunction requiring surgery intervention. Perforation. L/~threatening bleeding
Grading systems (grade 2 and higher) adopted by the institutions reporting late rectal complications. Where explicitly stated by the reporting authors, the numbers of coagulation procedures or transfusions are shown in italics. Netherlands Cancer Institute reported results using 3 different grading schemes. Correlations of rectal bleeding with dose volume cutoffs were seen with the "Severe" scheme given here. therapy. These include fibrosis and vascular insufficiency, with possible focal areas of stenosis and ulceration. The mucosa appears pale and teangiectatic. Microscopically, the most m a r k e d changes are found in the submucosa, where atypical fibroblasts, collagen proliferation, thickening of walls of small arteries and telangiectatic vessels m a y be found. Endoscopic examinations of the rectal walls of patients treated after prostate t h e r a p y show that grade 2 (or 3) rectal bleeding is usually accompanied by telangiectasia (and ul-
ceration) of the nmcosa of the anterior rectal wall. 19 W a c h t e r et al 2~ performed endoscopy on 44 patients who had received 3-dimensional conformal radiotherapy (3D-CRT) for prostate cancer with isocenter doses of 66 Gy in 2 Gy fi'actions, of whom 9 patients had grade 2 rectal bleeding. All patients were treated with opposed anterior/posterior and lateral beams. Findings included single, multiple, and confluent multiple talengiectatic lesions; congested mucosa, consisting of edema (combined with either focal diffuse
Partial Irradiation of the Rectum
or confluent diffuse reddening); and microulceration. Observations were classified into 3 circumferential regions (anterior, left and right lateral and posterior) in each of 4 superior-inferior regions (0-4, 4-8, 8-12, >12 cm above the anus) in each patient. Attempts were made to correlate endoscopic findings with dose distributions as calculated from each patient's t r e a t m e n t plan. Multiple confluent telangiectatic lesions were found only in the anterior region between 4 to 8 cm above the anus, which was calculated to receive doses greater than 60 Gy in all patients. No telangiectatic lesions were found greater than 12 cm above the anus, which was outside the radiation field. Below this level, single and multiple (but not confluent) telangiectatic lesions could be seen around the circumference of the rectum. Regions calculated to receive less than 30 Gy were either free of telangiectasia or had only single telangiectatic lesions. It should be noted, however, that endoscopic findings did not correlate perfectly with clinical rectal bleeding. While 7 of the 9 patients with grade 2 rectal bleeding showed multiple telangiectatic lesions and/or congested mucosa (edema with confluent diffuse reddening) and microulceration, 7 of the 35 patients without grade 2 bleeding showed similar changes.
Geometry and Motion of the Rectal Wall Doses delivered t o normal organs are conventionally assessed using dose distributions calculated from a single computed tomography (CT) scan taken prior to t r e a t m e n t (the planning scan). Morbidity arising from t r e a t m e n t is usually reported in terms of dose-volume histograms and/or a number of summary statistics of the dose distribution calculated from the planning scan, such as prescription dose, dose to 95% of the organ volume, mean dose, and normal tissue complication probabilities (NTCPs). The geometry of the rectum raises several questions concerning the accuracy and relevancy of these techniques, none of which can be fully addressed at present. The rectum is a flexible tube about 15 to 20 cm long, running from the sigmoid colon through the floor of the pelvis to the anal canal, and constitutes the end of the digestive tract. 2t The upper third of the rectum (the rectal ampulla) is highly
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extensible and may expand greatly as the rectum fills prior to defecation. The rectal wall consists of 2 muscle layers (1 longitudinal muscle layer surrounding a circumferential one) and a mucosal inner lining that reaches into the upper part of the anal canal. Since the mucosa and subnmcosa is the site of rectal bleeding, the dose on the inner surface of the rectal wall would appear to be the quantity of interest. This geometry has led several groups to develop novel ways of describing the dose distributions in the rectal wall. The dose-surface histogram (DSH) 22 quantifies the area of the surface of the rectal wall exposed to a given dose level. The normalized dose-surface histogram (NDSH) 23,24 attempts to account for the stretching of the rectal wall. The dose-circumference histogram (DCH) 25 quantifies the percent circumference of the rectal wall exposed to a given dose as a function of the length along the wall. The spatial dose-volume histogram (zDVH) 26 quantifies the volume of rectal wall on a given C T slice exposed to a particular dose. At present, these novel tools have not been used to analyze bleeding rates in any substantial series of patients. A simple problem (which potentially undermines all the sophisticated methods above) arises from the common practice of partially contouring the length of the rectum. 8,27 In m a n y institutions, for prostate cancer patients, rectal contours are only drawn in slices near to the target volume and DVHs reported in terms of percent volume. Thus, the normalization of each patient's histogram is determined by the length of the target volume, rather than by the total volume of the rectal wall. Additionally, because it is a thin tube, it is difficult to contour the rectal wall in a way that consistently reflects its thickness at any point. 2~ Perhaps the most important limitation of all current methods of analyzing doses to the rectum lies in the fact that the rectal wall moves during the course of treatment, both by distorting (eg, by expanding or contracting), and by moving bodily (eg, in the anterior-posterior direction). Studies of patients with multiple CT scans taken during t r e a t m e n t for prostate cancer 28-34 show that (chiefly as a result of rectal filling) the anterior rectal wall can move - 1 cm in the anteriorposterior direction with respect to the bony anatonly. While the dosimetric consequences of this movement depend on t r e a t m e n t technique, s3-35 it
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should be noted that use of posterior margins of 1 cm or more to define the PTV in prostate treatment will mean that portions of the anterior rectal wall will regularly receive the full prescription dose. These studies show that it may bc impossible to use the planning scan to assess the total dose distribution delivered to the mucosa over the course of treatment. Assuming that variables of the delivered dose distribution do correlate with rectal bleeding, any dosimetric variables from the planning scan that correlate with rectal bleeding must be regarded as surrogates for them. The relationship between such variables from the delivered dose distributions and their surrogates from the planning scans cannot be known until the effects of the motion of the rectal wall are thoroughly understood. It should be noted that differences in treatment technique (such as treating patients prone or supine) are likely to have a large influence on this question, making it presently very difficult to compare predictors of rectal bleeding from institutions using different treatment techniques. With these important caveats, we now turn to the available data on the dose/volume dependence of rectal bleeding.
Dose Distributions and Complication Probabilities Prior to 3D-CRT, quantitative evidence for volume effects in rectal toxicity was essentially nonexistent. Emami et al, 3~ in their widely quoted article on organ tolerance doses, assumed that there was no volume effect for severe late effects in the rectum, but stated that published articles contained little or no information on this subject. Nevertheless, studies of prostate cancer patients treated prior to the advent of 3D-CRT established that late rectal complications increased with prescription doses at or above 70 Gy. Pilepich et a137 reported treatment-related morbidity from RTOG study 77-06, a phase III randomized trial comparing prostate irradiation alone with pelvic irradiation followed by a prostatic boost. For 224 patients whose treatment included pelvic irradiation, the prescription dose to the prostate was found to be significantly correlated with rectal bleeding. A similar, but less dramatic, trend could be seen in rectal bleeding rates for 228 patients who received prostatic irradiation alone, but this was not significant. Smit et al 4
studied the high incidence of radiation proctitis in 154 patients treated between 1983 and 1985. CT scans were taken of all patients and the target (defined as prostate, seminal vesicles and the periprostatic tissue) and rectum were outlined on each slice. Patients were treated supine using a 3-field technique (left and right posterior oblique fields and 1 anterior field) to deliver 70 Gy in 2 Gy fractions to an isodose level encompassing the target. Anterior, posterior, and average rectal doses were estimated by forming the union of the rectal contours when projected vertically onto the isocenter slice. Doses at the points along an anterior-posterior line through the isocenter that fell at the anterior and posterior of this union were used to define the anterior and posterior doses for each patient. Average doses for each patient were calculated as the average within the union on the isocenter slice. Rectal complications were defined as mild, moderate, and severe. Proctitis was called moderate if it required medical treatment such as retention enemas and blood transfusions and severe if it required major surgical procedures such as colostomy. Thc number of mild, moderate, and severe cases of proctitis were 33, 24, and 6, respectively. All 6 severe cases required colostomy. Multivariate analysis revealed that prior bowel disease or pelvic surgery, anterior dose, and mean dose were significantly associated with the incidence of moderate and severe proctitis. Actuarial rates of all grades of proctitis at 30 months were --30%, - 5 0 % , and - 7 5 % for patients with anterior doses of--<70 Gy, 70 to 75 Gy, and greater than 75 Gy, respectively. Despite the lack of evidence for volume effects in rectal complications, with the advent of 3DCRT, several dose escalation trials were established for the treatment of prostate cancer, assuming that the tolerance doses of the rectum would increase as the irradiated volume of the rectum decreased. 5,7,19,13,38-4~ Initial results revealed that the ability of conformal techniques to reduce rectal complications depended on the techniques used. Sandler et al 3~ studied 721 patients treated at University of Michigan Medical Center and Providence Hospital between 1987 to 1992 with prescription doses increasing from 59.4 to 80.4 Gy. A total of 462 of these (generally patients with high T-stage or Gleason score) were treated with pelvic fields to 45 Gy; 60 of them were postprostatectomy patients. The target initially included prostate and seminal vesicles with
Partial Irradiation oJthe Rectum
a 0.5 cm margin in all directions to account for setup error and organ motion. After 1989, the seminal vesicles of patients with T1 to T2 stage disease were treated to 55 Gy. Blocks were custom designed to ensure target coverage by the 95% prescription isodose line. Initially patients were treated supine with a 4-field box technique, but this evolved into a 6-field axial, and then a 4 field nonaxial oblique technique. Rectal toxicity was graded using the R T O G scheme (grade 1, rectal bleeding not requiring therapy; grade 2, bleeding requiring simple therapy; grade 3, requiring minor outpatient surgery; grade 4, major surgery or prolonged hospitalization), and confirmed by endoscopy. Rectal complications were observed in 96 patients, including 12 with grade 3 and 2 with grade 4 complications. The overall actuarial rate of ->grade 3 rectal complication at 3 years was 3%. On univariate analysis, prescription dose was found to be significantly associated with risk of grade 3 or 4 complications. Both grade 4 patients were treated to doses -> 69 Gy. When analyzed by dose, the actuarial rate of ->grade 3 complications at 3 years rose to ~ 8 % for patients treated to greater than 69 Gy. For patients treated to doses of 69 to 71 Gy, a comparison between the 3 t r e a t m e n t techniques could be made. Patients treated with 4 field nonaxial oblique fields had an actuarial complication rate for any rectal toxicity at 2 years of less than 10%, whereas the 6-field and 4-field box axial techniques had rates o f - 2 0 % . Schultheiss et al 6,41 studied late gastrointestinal (GI) toxicity in 712 patients treated supine with 10 to 18 MV photons to prescription doses ranging from 65 to 75 Gy between 1986 and 1994 at Fox Chase Cancer Center. A total of 581 patients received more than 70 Gy. No postprostatectomy patients were included in the study. A total of 562 patients were treated with conformal techniques, and 377 patients (assessed to have high risk of nodal disease) were treated with pelvic fields. T r e a t m e n t plans for patients treated with hormones were generally done on the prostate volume before hormone therapy was begun. Patients treated with pelvic fields received 45 Gy in 1.8 Gy fractions with fields extending from the middle of $1 to 1 cm below the urethrogram cone with the posterior half of the rectum blocked. The clinical target volume (CTV) was the prostate and 1 or both seminal vesicles for patients with stage T2c disease and higher, the
219
PTV included a 1-cm margin for most patients. The target volume was treated with a 4-field technique (opposed AP-PA and lateral fields), with doses usually prescribed to the 95% isodose surface (which usually approximated the PTV) and delivered in 2 Gy fractions. A total of 88 patients were treated to 70 to 71 Gy with an additional 0.5 cm blocking of the rectum posteriorly for the last 10 Gy of treatment. 3 Rectal complications were analyzed using a modified R T O G scheme. 17 These modifications were: grade 2, rectal bleeding with 2 or fewer coagulation procedures or pain requiring nonnarcotic medication; grade 3, dysfunction requiring nonsurgical hospitalization or rectal bleeding requiring transfusion or 3 or more coagulation procedures or pain requiring narcotics; grade 4, dysfunction requiring surgical intervention or life-threatening bleeding. It should be noted that in this modified scheme, patients with grades 2 and 3 complications may suffer more severe effects than those classified according to Sandler (given above) or the modified R T O G scheme used at Memorial Sloan Kettering Cancer Center (MSKCC), a which treat a single cautery procedure as a grade 3 complication. A total of 115 patients suffered grade 2 or higher GI complications, 15 of these had grade 3 or higher complications. Multivariate analysis revealed that central axis dose was the strongest correlate with late rectal grade 2 morbidity. O t h e r significant factors were androgen deprivation therapy, lack of increased rectal shielding, acute GI toxicity, and history of diabetes (borderline). T r e a t m e n t with pelvic fields, or seminal vesicle doses greater than 57 Gy, were not significant. Among patients treated without the additional rectal shielding, central axis dose was found to be strongly correlated with grade 2 rectal morbidity, with actuarial rates rising from - 6 % to 7% at 60 months for central axis doses less than 68 Gy, to greater than 40% at 36 months fbr central axis doses of ->77 Gy. Grade 3 rectal morbidity also showed a significant dose response, with actuarial rates of rectal bleeding rising from 0% at 60 months for central axis doses of less than 68 Gy to ~12% at 36 months for central axis doses of ->77 Gy. While follow-up for patients with additional rectal shielding was less than 2 years, treatment with additional rectal shielding reduced the actuarial bleeding rate at 18 months. Kaplan Meyer analysis showed that patients treated without ad-
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Andrew ,Jackson
ditional rectal blocking to central axis doses both from 71 to 74 Gy and from 74 to 77 Gy had rates of >--grade 2 rectal morbidity at 18 months of - 2 0 % . This was reduced to - 1 2 % among patients treated with additional rectal blocking (all of which were treated to doses between 73 to 76 Gy central axis dose). T r e a t m e n t without additional rectal blocking was associated with a relative risk of 2.0 for late grade 2 rectal morbidity. Neither Sandier et al nor Schultheiss et al used DVHs in their analysis, so they could not give definite evidence of volume effects in their data. Schulthiess et al observed that the dependence of rectal toxicity on hormone therapy may have been due to the fact that, since planning was performed before hormone therapy, the prostate volume was likely to have shrunk, and more normal tissue would have been included in the highdose volume. They also noted that although one explanation for the decrease in toxicity from increased rectal shielding might be a volume effect, it could also be explained as a dose effect. Benk et aP reported data from cumulative DVHs of 41 patients treated at the Massachusetts General Hospital (MGH) after 1982. Patients were treated supine with 10 to 25 MV photon whole pelvis and 160 MeV perineal proton boost fields to prescription doses of 75.6 cobalt gray equivalent (CGE). Whole pelvis doses of 50.4 Gy were delivered in 1.8 Gy fractions with a 4-field box technique. Prostate boost doses of 25.2 CGE were delivered in 2.1 CGE fractions with the rectal wall localized by a lucite probe. The proton beam was designed with a 0.5 cm margin between the target volume and the 90% isodose line, as outlined on a CT scan taken in the treatment position with the lucite probe in place. A schematic representation of the dose distribution indicates that the m i n i m u m dose to the rectal wall on the isocenter slice from both courses of therapy was between 35 and 45 Gy and the m a x i m u m dose in excess of 75 Gy. Contour.s for the anterior rectal wall were defined on the CT scan from the superior limit of the anus to 2 cm superior to the target volume and extended laterally and posteriorly to a midcoronal plane dividing the anterior and posterior rectum. Rectal complications (consisting of rectal bleeding) were defined using the R T O G criteria, x5 A total of 14 cases of rectal bleeding (6 grade 1, and 8 grade 2) were observed, and the presence of telangiectasia was confirmed by endoscopy. Percent volume of ante-
rior rectal wall exposed to 75 CGE was calculated, and Kaplan-Meyer analysis showed that actuarial bleeding rates at 4 years were reduced from greater than 70% to - 2 0 % for patients with ->40% and less than 40% anterior rectal wall exposed to 75 CGE, respectively (P < .005). Hartford et a142 extended this analysis and found that a range of dose-volume cutoffs at lower doses Gy (down to ->70% of the anterior wall receiving 60 Gy) also produced significant correlation with bleeding, as did a model of NTCP. Boersma et al 7 studied DVHs from 130 patients treated for prostate cancer at Netherlands Cancer Institute (NKI). Patients were treated to isocenter doses between 70 to 78 Gy in 2 Gy fractions with 3-field 3D-CRT (opposed wedged laterals and 1 anterior field). Prescription doses were 70, 74 to 76, and 78 Gy for 78, 11, and 41 patients, respectively. Seminal vesicles were included in the C T V for patients with stage --> T3, and for stage T2 patients if the estimated risk of nodal involvement was greater than 15%. 43 The PTV was defined on CT scans using a 1-cm margin around the CTV. Doses above 70 Gy were delivered to a coned down PTV (CTV + 0.5 cm margin) to provide additional rectal shielding. Pelvic nodes were treated to 64% prescription dose ( - 4 5 Gy) at 1.28 Gy per fraction using a simultaneous boost technique delivered with partial transmission shielding. Rectal wall volumes were defined from the sigmoid colon (usually at the sacroilliac joint) to 15 m m below the apex of the prostate. Late rectal toxicity was assessed both by a modified R T O G scheme and by a modified SOMA/LENT scale (similar to the one used by Schultheiss et al) and also by a scheme that classified toxicity as severe if any transfusion or laser cauterization procedures were used to treat rectal bleeding. Grade 2 or higher rectal bleeding (RTOG) was observed in 18 patients; 4 of these cases were called severe because they required 1 or more laser treatments and blood transfusions. No significant correlation with dose-volume parameters was seen for -->grade 2 rectal bleeding. However, actuarial incidence of severe rectal bleeding was significantly correlated with percent volumes of rectal wall receiving doses greater than 65 Gy (volumes greater than 40%, 30%, and 5% for doses greater than 65, 70, and 75 Gy, respectively). All 4 severe cases occurred in patients treated to prescription doses greater than 74 Gy, but this was not statistically significant.
Partial Irradiation of the Rectum
Recently, Storey et al 9 analyzed morbidity in 189 patients with -->2 years follow-up who were treated supine at M.D. Anderson Cancer Center as part of a randomized study begun in 1993.4~ A total of 91 patients in this group were treated with conformal therapy and received total prescription doses of 78 Gy delivered with 28 MV photons. A total of 46 Gy was delivered in 2 Gy fractions by a 4-field technique (AP-PA and opposed lateral fields). The lateral field blocks split the rectum posteriorly, followed the curvature of the rectum and included the seminal vesicles in the field. Cone down boost fields delivered an additional 38 Gy in 2 Gy fractions to the isocenter using a 6-field technique (opposed laterals and 2 pairs of opposed oblique beams, offset 30 ~ from lateral, with 37% of the boost dose coming from the laterals). The CTV was defined as prostate and seminal vesicles, as defined on CT scan. The PTV volume included a 0.75-cm margin posteriorly around the CTV. Rectal contours were defined within the superior and inferior borders of the initial APPA fields (typically - 1 1 cm in length, with the inferior border at the ischial tuberosities) and used to generate DVHs for the rectum. Rectal morbidity was classified using modified R T O G and FCLENT schemes. 17 Storey et al found that the actuarial incidence of->grade 2 rectal toxicity was significantly correlated with percent volume of rectum receiving greater than 70 Gy. Actuarial incidence of ->grade 2 rectal toxicity at 4 years was less than 15% or greater than 35% for patients with --<25% or >25% of rectum exposed to greater than 70 Gy, respectively. The analyses of DVH data from MGH, NKI, and M.D. Anderson discussed above all found correlations between complication rates and rectal volumes exposed to doses at 2arger than 65 Gy. All of these institutions treated large volumes of the rectal wall with large fields delivering between 40 to 50 Gy, which may have saturated any effects of volumes exposed to relatively low doses such as 40 to 50 Gy (although we do not know if the authors looked for such effects). In contrast, Skwarchuk et al 8 and Jackson et al 1~ analyzed factors correlating with rectal bleeding in 171 prostate cancer patients, all of whom were treated prone with a standard 6-field conformal beam arrangement. These patients were selected from 743 patients treated between 1988 and 1995 at MSKCC. ~2,46The CTV was defined as prostate plus seminal vesicles as defined on CT scan, and
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the PTV defined as CTV plus a 1 cm margin, except at the prostate, rectum interface, where a 0.6 cm margin was used to decrease the risk of rectal toxicity. ~2,46 Prescription doses were delivered in 1.8 Gy fractions to the surrounding isodose line on 3 orthogonal planes through the isocenter using 15 to 25 MV photons. One pair of opposed laterals and 2 pairs of opposed oblique (at 45 ~ fi'om lateral) axial fields were used, with the lateral fields delivering - 5 0 % prescription dose. No more than 30% of the rectal wall volume (defined at the time of planning to extend 1 C T slice either side of the PTV) was allowed to receive doses greater than 75.6 Gy. 2 Rectal bleeding was graded according to a modified R T O G scale: grade 2, intermittent bleeding; grade 3, bleeding requiring surgery, coagulation procedure, or transfusion. Eligibility criteria for inclusion in the DVH and dosimetric study were: prescription doses of 70.2 or 75.6 Gy, without rectal bleeding at ->30 months (designated as without bleeding) or diagnosis of rectal bleeding before 30 months (designated as bleeding). T r e a t m e n t plans from all bleeding patients were restored from archive if possible (13 and 36 of 13 and 38 eligible patients treated at 70.2 and 75.6 Gy, respectively), together with a random subset from patients without bleeding (39 and 83 of 208 and 192 eligible patients treated at 70.2 and 75.6 Gy, respectively). The rectal walls of all restored patients were recontoured to correspond to a consistent anatomic definition of the rectum extending from just above the anal verge to just below the sigmoid flexure. Rectal wall DVHs and other dosimetric and geometric summaries of the dose distribution were calculated. Multivariate analysis indicated that models based on either total rectal wall volume, the m a x i m u m rectal wall dose, and enclosure of the rectal wall by the 50% isodose line on the central C T slice, or total rectal wall volume, percent rectal wall volume exposed to 77 Gy, and percent rectal wall volume exposed to 47 Gy were roughly equally good at predicting incidence of rectal bleeding in patients treated to 75.6 Gy. The values of the percent volumes of rectal wall volume exposed to 77 Gy and 47 Gy were determined by the location of the lateral and oblique beam boundaries, respectively. Preliminary analysis shows that the total volume of rectal wall may be replaced by the absolute volume of rectal wall unexposed to doses of 40 to 50 Gy in these models, indicating the
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possible importance of a reserve of unexposed tissue. 47 Similar results were found for patients treated to 70.2 Gy. Skwarchuk et al 8 also examined the actuarial rates of grades 2 and 3 late rectal toxicity in the full set of 743 patients and found a significant dose response for the 6-field t r e a t m e n t plan. Five-year actuarial rates of -->grade 2 toxicity increased from less than 5% at prescription doses less than 65 Gy to - 1 6 % at 75.6 Gy. Model fits of the dose response in the data for the standard 6-field plan indicated an expected grade 2 rectal toxicity rate of - 2 8 % at 81 Gy. However, in response to the increasing rates of rectal bleeding, the 6-field t r e a t m e n t plan was modified for the first patients treated to 81 Gy. The last 9 Gy was delivered with a separate boost plan consisting of wedged posterior oblique beams with the rectum fully blocked. This was successful in keeping rates of 5-year actuarial grade 2 rectal toxicity at 17% for these patients. Preliminary data on patients treated later with intensity modulated radiation therapy (IMRT) to 81 Gy ll indicates that rectal toxicity may be drastically reduced with this t r e a t m e n t modality. DVH data from 4 institutions clearly indicate that the percent volume of rectal wall exposed to doses above 70 Gy 1,7-1~ plays a crucial role in determining the rectal morbidity of prostate treatment. The decrease in rectal toxicity associated with treatment with increased rectal shielding seen at Fox Chase Cancer Center 3,6 supports this hypothesis. Data from Memorial Sloan-Kettering Cancer Center suggest that percent volumes of rectal wall exposed to doses between 40 to 50 Gy and the existence of a reserve of unexposed tissue may also play a role in determining rectal bleeding rates. The quantitative relationship between volumes exposed to given doses and rectal complication rates may be expected to differ between institutions because of differences in t r e a t m e n t technique and consequent differences in organ motion.
References 1. Benk VA, Adams JA, Shipley WU, et al: Late rectal bleeding following combined X-ray and proton high dose irradiation for patients with stages T3-T4 prostate carcinoma. I n t J Radiat Oncol Biol Phys 26:551-557, 1993 2. Kutcher GJ, Leibel SA, Ling CC, et al: New wine in an old bottle? Dose escalation under dose-volume constraints: A
model of conformal therapy of the prostate [editorial; comment]. I n t J Radiat Oncol Biol Phys 35:415-416, 1996 3. Lee WR, Itanks GE, Hanlon AL, et al: Lateral rectal shielding reduces late rectal morbidity tbllowing high dose three-dimensional conformal radiation therapy for clinically localized prostate cancer: Further evidence for a significant dose effect. Int J Radiat Oncol Biol Phys 35: 251-257, 1996 4. Smit WG, Helle PA, van Putten WL, et al: Late radiation damage in prostate cancer patients treated by high dose external radiotherapy in relation to rectal dose. Int J Radiat Oncol Biol Phys 18:23-29, 1990 5. Zelef~ky MJ, Cowen DM, Fuks Z, et al: Long term tolerance of high dose three-dimensional conformal radiotherapy in the treatment of localized prostate cancer. Cancer 85:2460-2468, 1999 6. Schultheiss TE, Lee WR, Hunt MA, et al: Late GI and GU complications in the treatment of prostate cancer. Int J Radiat Oncol Biol Phys 37:3-11, 1997 7. Boersma LJ, van den Brink M, Bruce AM, et ah Estimation of the incidence of late bladder and rectum complications aller high-dose (70-78 GY) conformal radiotherapy for prostate cancer, using dose-volume histograms. I n t J Radiat Oncol Biol Phys 41:83-92, 1998 8. Skwarchuk M, ,Jackson A, Zelefsky M, et al: Late rectal toxicity after 3D-conformal radiation therapy of prostate cancer: Multivariate analysis and dose-response. Int J Radiat Oncol Biol Phys 47:103-113, 2000 9. Storey MR, Pollack A, Zagars G, et al: Complications from radiotherapy dose escalation in prostate cancer: Preliminary results of a randomized trial. Int J Radiat Oncol Biol Phys 48:635-642, 2000 10..Jackson A, Skwarchuk M, Zelefsky M, et al: Late rectal bleeding after 3D-conformal radiation therapy of prostate cancer (II): Volume effects and dose volume histograms. Int J Radiat Oncol Biol Phys 49:685-698, 2001 1i. Zelefsky M, Fuks Z, Happersett L, et al: Clinical experience with intensity modulated radiation therapy (IMRT) in prostate cancer. Radiother Oncol 55:241-249, 2000 12. Zelefsky MJ, Leibel SA, Gaudin PB, et al: Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. IntJ Radiat Oncol Bioi Phys 41:491-500, 1998 13. Hanks GE, Hanlon AL, Schultheiss TE, et al: Dose escalation with 3D conformal treatment: Five year outcomes, treatment optimization, and future directions. Int J Radiat Oncol Biol Phys 41:50t-510, 1998 14. Teshima T, Hanks GE, Hanlon AL, et al: 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 39:77-83, 1997 15. Lawton CA, Won M, Pilepich MV, et al: Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: Analysis of RTOG studies 7506 and 7706. Int J Radiat Oncol Biol Phys 21:935939, 1991 16. Pavy JJ, Dcnekamp J, Letschert J, et al: EORTC Late Effects Working Group. Late Effects toxicity scoring: The SOMA scale. I n t J Radiat Oncol Biol Phys 31:1043-1047, 1995 17. Hanlon AL, Schultheiss TE, Hunt MA, et al: Chronic rectal bleeding after high-dose conformal treatment of
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during contormal radiotherapy of T3 prostate cancer. Int J Radiat Oncol Biol Phys 33:1109-1119, 1995 34. Zelefsky MJ, IIappersett L, Leibel SA, et al: The effect of treatment positioning on normal tissue dose in patients with prostate cancer treated with three-dimensional conformal radiotherapy. Int J Radiat Oncol BioI Phys 37:I319, 1997 35. Yah D, Jaffray DA, Wong JW: A model to accumulate fractionatcd dose in a deforming organ. Int J Radiat Oncol Biol Phys .44:665-675, 1999 36. Emami B, LymanJ, Brown A, et al: Tolerance of normal tissue to therapeutic irradiation. I n t J Radiat Oncol Biol Phys 21:109-122, 1991 37. Pilepich M'V, Asbcll SO, Krall JM, et ah Correlation of radiotherapeutic parameters and treatment related morbidity-analysis of RTOG Study 77-06. IntJ Radiat Oncol Biol Phys 13:1007-1012, 1987 38. Sandler HM, McLaughlin PW, Ten ttaken RK, et al: Three dimensional conformal radiotherapy for the treatment of prostate cancer: Low risk of chronic rectal morbidity observed in a large series of patients. Int J Radiat Oncol Biol Phys 33:797-801, 1995 39. Michalski JM, Purdy JA, Winter K, et ah Preliminary report of toxicity following 3D radiation therapy for prostate cancer on 3DOG/RTOG 9406. Int J Radiat Oncol Biol Phys 46:391-402, 2000 40. Perez CA, Michalski JM, Purdy JA, et al: Three dimensional conformal therapy or standard irradiation in localized carcinoma of prostate: Preliminary results of a nonrandomized comparison. Int J Radiat Oncol Biol Phys 47:629-637, 2000 41. Schultheiss TE, Hanks GE, Hunt MA, et ah Incidence of and factors related to late complications in conformal and conventional radiation treatment of cancer of the prostate. Int J Radiat Oncoi Biol Phys 32:643-649, I995 42. Hartford AC, Niemierko A, Adams JA, et ai: Conformal irradiation of the prostate: Estimating long-term rectal bleeding risk using dose-volume histograms. Int J Radiat Oncol Biol Phys 36:721-730, 1996 43. Roach MI: Re: The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J UroI 150:19231924, 1993 44. Pollack A, Zagars GK, Starkschall G, et ah Conventional vs. conformal radiotherapy for prostate cancer: Preliminary results of dosimetry and acute toxicity. Int J Radiat OncoI Biol Phys 34:555-564, 1996 45. Jackson A, Zelefsky M, Cowen D, et al: Rectal bleeding after conformal radiotherapy of prostate cancer and dose volume histograms. Int J Radiat Oncol Biol Phys 42:217, 1998 (abstr) 46. Leibel SA, Zelet~ky MJ, Kutcher GJ, et ah The biological basis and clinical application of three-dimensional conformal external beam radiation therapy in carcinoma of the prostate. Semin Oncol 21:580-597, t994 47. Jackson A, Skwarchuk M, Levegrun S: Volume effects in external beam treatments of prostate cancer. 5th International Symposium on 3D Contbrmal Radiation Therapy and Brachytherapy, New York, NY, 197-199, June 1-3, 2000