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Purpose: Women with locally advanced cervical cancer (LACC) undergoing primary platinum-based chemoradiotherapy and brachytherapy often experience toxicities. Normal-tissue complication probability (NTCP) models quantify toxicity risk and aid in optimizing radiation therapy to minimize side effects. However, it is unclear which predictors to include in an NTCP model. The aim of this systematic review was to provide an overview of the identified predictors contributing to gastrointestinal (GI), genitourinary (GU), and vaginal toxicities and insufficiency fractures for LACC., Methods and Materials: A systematic search was performed and articles evaluating the relationship between predictors and toxicities in women with LACC treated with primary chemoradiation were included. The Quality In Prognosis Studies tool was used to assess risk of bias, with high-risk studies being excluded from further analysis. Relationships between dose-volume parameters, patient and treatment characteristics, and toxicity endpoints were analyzed., Results: Seventy-three studies were identified. Twenty-six had a low or moderate risk of bias and were therefore included. Brachytherapy-related dose-volume parameters of the GI tract, including rectum and bowel equivalent dose in 2 Gy fractions (EQD2) D2 cm 3 , were frequently related to toxicities, unlike GU dose-volume parameters. Furthermore, (recto)vaginal point doses predicted toxicities. Few studies evaluated external beam radiation therapy dose-volume parameters and identified rectum EQD2 V30 Gy, V40 Gy, and V55 Gy, bowel and bladder EQD2 V40 Gy as toxicity predictors. Also, total reference air kerma and vaginal reference length were associated with toxicities. Relationships between patient characteristics and GI toxicity were inconsistent. The extent of vaginal involvement at diagnosis, baseline symptoms, and obesity predicted GU or vaginal toxicities. Only 1 study evaluated insufficiency fractures and demonstrated lower pretreatment bone densities to be associated., Conclusions: This review detected multiple candidate predictors of toxicity. Larger studies should consider insufficiency fractures, assess dose levels from external beam radiation therapy, and quantify the relationship between the predictors and treatment-related toxicities in women with LACC to further facilitate NTCP model development for clinical use., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Many patients experience bowel and bladder toxicity during the acute phase of radiation therapy for prostate cancer. Recent literature indicates that hypofractionation (HF) might increase this acute response but little is known on patient-reported outcome during this phase with HF. We evaluated the course of patient-reported acute symptoms during HF versus standard fractionated (SF) radiation therapy within the hypofractionated irradiation for prostate cancer (HYPRO) trial., Methods and Materials: In the HYPRO trial patients were treated with either 64.4 Gy (HF) in 19 fractions (3 times per week) or 78 Gy (SF) in 39 fractions (5 times per week). Normalized total dose for 2 Gy/fractions (NTD 2Gy )for acute toxicity (α/β ratio of 10) for HF was 72.1 Gy with a similar dose rate of 10.2 Gy per week. Among the 794 patients who were previously eligible for acute grade ≥2 toxicity assessment, 717 had filled out ≥1 symptom questionnaires. For each maximum symptom, we scored "any complaint" and "moderate-severe complaint." Differences were tested by χ 2 test, and associations with clinical factors were tested using logistic regression. Significance was set at P ≤ .008 to adjust for multiple testing., Results: We observed significantly higher rates of moderate-severe painful defecation (HF 10.8%, SF 5.3%), any mucus discharge (HF 47.1%, SF 37.4%), any rectal blood loss (HF 16.1%, SF 9.3%), increased daily stool frequency ≥4 and ≥6 (HF 34.6%/13.8%, SF 25.6%/7.0%), and any urinary straining (HF 69.9%, SF 58.0%). At 3 months postradiation therapy, rates dropped considerably with similar levels for HF and SF. Hormonal treatment was associated with less acute gastrointestinal symptoms., Conclusion: The increased patient-reported acute rectal symptoms with HF confirmed the previously reported results on acute grade ≥2 rectal toxicity. The increase in bladder symptoms with HF was not identified previously. These observations contradict the NTD 2Gy calculations. We observed no patterns of persisting complaints with HF after the acute period; therefore, HF is well tolerated and only associated with a temporary increase of symptoms., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: In the multicenter, phase 3, HYpofractionated irradiation for PROstate cancer trial, hypofractionated (HF) radiation therapy was compared with conventionally fractionated (CF) radiation therapy. In previous reports, we could not demonstrate the postulated superiority of hypofractionation in terms of relapse-free survival at 5 years. The frequent use of long-term androgen deprivation therapy might have had substantial effects on relapse-free survival. In the current analysis, we provide updated 7-year relapse-free survival outcomes., Methods and Materials: We enrolled patients with intermediate- to high-risk T1b-T4NX-N0MX-M0 localized prostate cancer. Patients were randomly assigned (1:1) to either HF (64.6 Gy in 19 fractions) or CF (78.0 Gy in 39 fractions) radiation therapy. Based on an estimated α/β ratio for prostate cancer of 1.5 Gy, the EQD2 was 90.4 Gy for HF versus 78.0 Gy for CF radiation therapy. The primary endpoint of the present analysis is relapse-free survival at 7 years., Results: A total of 820 patients were enrolled, of whom 804 were assessable for the current evaluation (407 HF versus 397 CF). Median follow-up was 89 months (interquartile range, 83-99). Concomitant androgen deprivation therapy was prescribed for 537 (67%) of 804 patients for a median duration of 32 months (interquartile range, 10-44). Treatment failure at 7 years was reported in 220 (27.4%) of 804 patients, 107 (26.3%) in HF versus 113 (28.5%) in CF radiation therapy. Seven-year relapse-free survival was 71.7% (95% confidence interval [CI], 66.4-76.4) for HF versus 67.6% (95% CI, 62.0-72.5) for CF (P = .52). Overall survival was 80.8% (95% CI, 76.5-84.4) in HF versus 77.6% (95% CI, 73.0-81.5) in CF radiation therapy (P = .17)., Conclusions: The current results of 7-year relapse-free survival confirmed our previous findings that the hypothesized dose escalation in the HF arm did not translate to superior tumor control compared with the CF arm., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The phase 3 Hypofractionated Irradiation for Prostate Cancer trial compared hypofractionated radiation therapy with conventionally fractionated radiation therapy in patients with localized prostate cancer. Similar 5-year relapse-free survival rates were achieved in both groups, but noninferiority of hypofractionation was not confirmed for genitourinary and gastrointestinal toxicity. Here, we present the secondary trial endpoint on patient-reported quality of life., Methods and Materials: A total of 820 patients with intermediate-risk or high-risk prostate cancer were randomized to hypofractionation (19 fractions of 3.4 Gy) or conventional fractionation (39 fractions of 2.0 Gy). Quality of life was measured using a validated questionnaire, the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Cancer 25 module. Subscales (score range, 0-100) on urinary symptoms, gastrointestinal symptoms, symptoms related to androgen deprivation therapy, sexual function, and sexual activity were analyzed. Changes from baseline of at least 5 points were considered clinically relevant. Inferiority of hypofractionation for separate subscales was rejected if the mean difference in the 3-year incidence of clinically relevant deterioration between treatments was <8.0%., Results: A total of 697 men were eligible for this quality-of-life analysis. Baseline characteristics were comparable between both groups. At 3-year follow-up, the incidence of clinically relevant deterioration of urinary symptoms was 33% for both treatments (difference 0.49% in favor of conventional fractionation; 90% confidence interval, -7.20% to 8.18%). Such deterioration of gastrointestinal symptoms was reported in 38% of patients receiving hypofractionation versus 36% of patients receiving conventional fractionation (2.03% in favor of conventional fractionation; 90% confidence interval, -6.18% to 10.23%). Therefore, we could not demonstrate noninferiority of hypofractionation for genitourinary and gastrointestinal quality of life. For all other subscales, noninferiority of hypofractionation was demonstrated., Conclusions: Noninferiority of the hypofractionated treatment was not demonstrated for genitourinary and gastrointestinal quality of life, and therefore we cannot rule out that relevant differences may exist between both treatments. Noninferiority of hypofractionation was demonstrated for symptoms related to androgen deprivation therapy, sexual activity, and sexual function., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: The phase 3 HYpofractionated irradiation for PROstate cancer (HYPRO) trial randomized patients with intermediate- to high-risk localized prostate cancer to conventionally fractionated (78 Gy in 39 fractions) or hypofractionated (64.6 Gy in 19 fractions) radiation therapy. Differences in techniques and treatment protocols were present between participating centers. This study aimed to compare dose parameters and patient-reported gastrointestinal symptoms between these centers., Methods and Materials: From the trial population, we selected patients (N=572) from 4 treatment centers who received image guided (IG) intensity modulated radiation therapy (IMRT). Center A (n=242) applied planning target volume (PTV) margins of 5 to 6 mm and was considered the reference center. In center B (n=170, 7-mm margins), magnetic resonance imaging (MRI) was integrated in treatment planning. An endorectal balloon (ERB) was applied in center C (n=85, 7-mm margins). Center D (n=75) applied the largest PTV margins of 8 mm. The study protocol provided identical anorectal dose constraints, and local protocols were applied for further treatment optimization. Anorectal dose-surface histograms were compared by applying t tests. Rectal complaints during follow-up (6 months to 4 years) were compared in a generalized linear model, adjusting for age, follow-up, treatment arm, and hormone therapy., Results: Favorable anorectal dose distributions were found for center B (MRI delineation) and center C (ERB application) as compared with centers A and D. These were associated with significantly lower incidences of patient-reported complaints of rectal incontinence, use of incontinence pads, and rectal discomfort in these centers. Furthermore, lower incidences of increased stool frequency (≥4 per day) and mucous loss were observed for center C., Conclusions: Despite comparable IG-IMRT techniques and predefined dose constraints, pronounced differences in dose distributions and toxicity rates were observed. MRI delineation and ERB application were associated with favorable rectal dose parameters and toxicity profiles, whereas a 2- to 3-mm difference in PTV margins did not translate into observed differences. We conclude that choices for treatment optimization of IG-IMRT are important and clinically relevant for patients since these affect symptoms experienced in daily life., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Technical developments in the field of external beam radiation therapy (RT) enabled the clinical introduction of image guided intensity modulated radiation therapy (IG-IMRT), which improved target conformity and allowed reduction of safety margins. Whether this had an impact on late toxicity levels compared to previously applied three-dimensional conformal radiation therapy (3D-CRT) is currently unknown. We analyzed late side effects after treatment with IG-IMRT or 3D-CRT, evaluating 2 prospective cohorts of men treated for localized prostate cancer to investigate the hypothesized reductions in toxicity., Methods and Materials: Patients treated with 3D-CRT (n=189) or IG-IMRT (n=242) to 78 Gy in 39 fractions were recruited from 2 Dutch randomized trials with identical toxicity scoring protocols. Late toxicity (>90 days after treatment) was derived from self-assessment questionnaires and case report forms, according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG-EORTC) scoring criteria. Grade ≥2 endpoints included gastrointestinal (GI) rectal bleeding, increased stool frequency, discomfort, rectal incontinence, proctitis, and genitourinary (GU) obstruction, increased urinary frequency, nocturia, urinary incontinence, and dysuria. The Cox proportional hazards regression model was used to compare grade ≥2 toxicities between both techniques, adjusting for other modifying factors., Results: The 5-year cumulative incidence of grade ≥2 GI toxicity was 24.9% for IG-IMRT and 37.6% following 3D-CRT (adjusted hazard ratio [HR]: 0.59, P=.005), with significant reductions in proctitis (HR: 0.37, P=.047) and increased stool frequency (HR: 0.23, P<.001). GU grade ≥2 toxicity levels at 5 years were comparable with 46.2% and 36.4% following IG-IMRT and 3D-CRT, respectively (adjusted HR: 1.19, P=.33). Other strong predictors (P<.01) of grade ≥2 late toxicity were baseline complaints, acute toxicity, and age., Conclusions: Treatment with IG-IMRT reduced the risk of late grade ≥2 complications, whereas GU toxicities remained comparable. This clinically relevant observation demonstrates that IMRT and image-guidance should therefore be the preferred treatment option, provided that margin reduction is implemented with caution., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Image-guided intensity modulated radiation therapy (IG-IMRT) allows significant dose reductions to organs at risk in prostate cancer patients. However, clinical data identifying the benefits of IG-IMRT in daily practice are scarce. The purpose of this study was to compare dose distributions to organs at risk and acute gastrointestinal (GI) and genitourinary (GU) toxicity levels of patients treated to 78 Gy with either IG-IMRT or 3D-CRT., Methods and Materials: Patients treated with 3D-CRT (n=215) and IG-IMRT (n=260) receiving 78 Gy in 39 fractions within 2 randomized trials were selected. Dose surface histograms of anorectum, anal canal, and bladder were calculated. Identical toxicity questionnaires were distributed at baseline, prior to fraction 20 and 30 and at 90 days after treatment. Radiation Therapy Oncology Group (RTOG) grade ≥1, ≥2, and ≥3 endpoints were derived directly from questionnaires. Univariate and multivariate binary logistic regression analyses were applied., Results: The median volumes receiving 5 to 75 Gy were significantly lower (all P<.001) with IG-IMRT for anorectum, anal canal, and bladder. The mean dose to the anorectum was 34.4 Gy versus 47.3 Gy (P<.001), 23.6 Gy versus 44.6 Gy for the anal canal (P<.001), and 33.1 Gy versus 43.2 Gy for the bladder (P<.001). Significantly lower grade ≥2 toxicity was observed for proctitis, stool frequency ≥6/day, and urinary frequency ≥12/day. IG-IMRT resulted in significantly lower overall RTOG grade ≥2 GI toxicity (29% vs 49%, respectively, P=.002) and overall GU grade ≥2 toxicity (38% vs 48%, respectively, P=.009)., Conclusions: A clinically meaningful reduction in dose to organs at risk and acute toxicity levels was observed in IG-IMRT patients, as a result of improved technique and tighter margins. Therefore reduced late toxicity levels can be expected as well; additional research is needed to quantify such reductions., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To investigate the relationship between late urinary obstruction and the details of the dose distribution of irradiated prostate cancer patients, taking into account their baseline symptoms and acute complaints., Patients and Methods: We selected patients from the Dutch multicenter trial randomized between 68 Gy and 78 Gy, for whom toxicity data and dose data were available (n = 557). The absolute dose surface parameters of the delineated bladder were calculated. Next, we constructed three-dimensional dose maps of the area around the prostate, providing an approximate identification of the corresponding anatomic locations. The dose difference maps were constructed by subtracting the mean dose maps of the patients with and without late urinary obstruction. Selected local dose points were analyzed using Cox regression analysis., Results: Urinary obstruction was scored for 40 patients, including 19 of 296 patients who received 68-72 Gy and 21 of 261 patients who received 76-78 Gy. A total of 19 events occurred within 2 years after irradiation and 21 events after 2 years. The bladder surface receiving >or=80 Gy predicted (p <.01) the occurrence of obstruction within 2 years. The dose difference map indicated highly significant differences in the bladder neck situated in the trigonal region (p < .001) that were especially predictive of obstruction after 2 years and of the diagnosis of bladder neck obstruction. Baseline complaints and transurethral resection of the prostate and acute complaints were mainly predictive for obstruction within 2 years., Conclusion: Relatively early events of urinary obstruction were associated with urinary problems existing before RT, acute toxicity, previous transurethral resection of the prostate, and hotspots in the bladder. Events after 2 years were associated with the local dose in the trigonal area., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Purpose: For prostate cancer patients at risk for subclinical spread of the disease, we investigated whether incidental dose outside the target was associated with tumor control., Methods and Materials: We selected 352 intermediate-risk (mainly T2b-T3a) and high-risk (mainly T3b) patients treated in a randomized trial. Target volume was prostate (68-78 Gy) and seminal vesicles (50-78 Gy). Failure (clinical or biochemical) was evaluated at 4 years. To compare three-dimensional dose distributions, an automated mapping procedure was introduced. Between patients, these maps provide an approximate identification of corresponding anatomical locations. Maps of the dose difference between patients with and without failure were constructed. Univariate and multivariate analyses were performed including the dose in selected points., Results: Dose differences were mainly found in the obturatorial region for the high-risk patients, and in the presacral region for the intermediate risk group (>7 Gy, p < 0.01). Univariate hazard ratios per 10 Gy for selected dose points were 0.83 (p = 0.01, obturatorial) and 0.72 (p = 0.002, presacral). These hazard ratios were stable under multivariate analysis correcting for established prognostic factors, hospital, and dose to the prostate., Conclusions: Patients without failure have received on average a higher dose to regions where regional cancer spread could be expected.

Purpose: To compare the acute and late gastrointestinal (GI) and genitourinary (GU) toxicity in prostate cancer patients treated to a total dose of 78 Gy with either a three-conformal radiotherapy technique with a sequential boost (SEQ) or a simultaneous integrated boost using intensity-modulated radiotherapy (SIB-IMRT)., Patients and Methods: A total of 78 prostate cancer patients participating in the randomized Dutch trial comparing 68 Gy and 78 Gy were the subject of this analysis. They were all treated at the same institution to a total dose of 78 Gy. The median follow-up was 76 and 56 months for the SEQ and SIB-IMRT groups, respectively. The primary endpoints were acute and late GI and GU toxicity., Results: A significantly lower incidence of acute Grade 2 or greater GI toxicity occurred in patients treated with SIB-IMRT compared with SEQ (20% vs. 61%, p = 0.001). For acute GU toxicity and late GI and GU toxicity, the incidence was lower after SIB-IMRT, but these differences were not statistically significant. No statistically significant difference were found in the 5-year freedom from biochemical failure rate (Phoenix definition) between the two groups (70% for the SIB-IMRT group vs. 61% for the SEQ group, p = 0.3). The same was true for the 5-year freedom from clinical failure rate (90% vs. 72%, p = 0.07)., Conclusion: The results of our study have shown that SIB-IMRT reduced the toxicity without compromising the outcome in patients with localized prostate cancer treated to 78 Gy radiation.

Purpose: To update the analysis of the Dutch dose-escalation trial of radiotherapy for prostate cancer., Patients and Methods: A total of 669 patients with localized prostate cancer were randomly assigned to receive 68 or 78 Gy. The patients were stratified by age, institution, use of neoadjuvant or adjuvant hormonal therapy, and treatment group. The primary endpoint was freedom from failure (FFF), with failure defined as clinical or biochemical failure. Two definitions of biochemical failure were used: the American Society for Therapeutic Radiology and Oncology definition (three consecutive increases in prostate-specific antigen level) and the Phoenix definition (nadir plus 2 microe secondary endpoints were freedom from clinical failure, overall survival, and genitourinary and gastrointestinal toxicity., Results: After a median follow-up of 70 months, the FFF using the American Society for Therapeutic Radiology and Oncology definition was significantly better in the 78-Gy arm than in the 68-Gy arm (7-year FFF rate, 54% vs. 47%, respectively; p = 0.04). The FFF using the Phoenix definition was also significantly better in the 78-Gy arm than in the 68-Gy arm (7-year FFF rate, 56% vs. 45%, respectively; p = 0.03). However, no differences in freedom from clinical failure or overall survival were observed. The incidence of late Grade 2 or greater genitourinary toxicity was similar in both arms (40% and 41% at 7 years; p = 0.6). However, the cumulative incidence of late Grade 2 or greater gastrointestinal toxicity was increased in the 78-Gy arm compared with the 68-Gy arm (35% vs. 25% at 7 years; p = 0.04)., Conclusion: The results of our study have shown a statistically significant improvement in FFF in prostate cancer patients treated with 78 Gy but with a greater rate of late gastrointestinal toxicity.

Purpose: To evaluate the influence of a dietary protocol on cone beam computed tomography (CBCT) image quality, which is an indirect indicator for short-term (intrafraction) prostate motion, and on interfraction motion. Image quality is affected by motion (e.g., moving gas) during imaging and influences the performance of automatic prostate localization on CBCT scans., Methods and Materials: Twenty-six patients (336 CBCT scans) followed the dietary protocol and 23 patients (240 CBCT scans) did not. Prostates were automatically localized by using three dimensional (3D) gray-value registration (GR). Feces and (moving) gas occurrence in the CBCT scans, the success rate of 3D-GR, and the statistics of prostate motion data were assessed., Results: Feces, gas, and moving gas significantly decreased from 55%, 61%, and 43% of scans in the nondiet group to 31%, 47%, and 28% in the diet group (all p < 0.001). Since there is a known relation between gas and short-term prostate motion, intrafraction prostate motion probably also decreased. The success rate of 3D-GR improved from 83% to 94% (p < 0.001). A decrease in random interfraction prostate motion also was found, which was not significant after Bonferroni's correction. Significant deviations from planning CT position for rotations around the left-right axis were found in both groups., Conclusions: The dietary protocol significantly decreased the incidence of feces and (moving) gas. As a result, CBCT image quality and the success rate of 3D-GR significantly increased. A trend exists that random interfraction prostate motion decreases. Using a dietary protocol therefore is advisable, also without CBCT-based image guidance.

Purpose: To investigate whether a large rectum filling visible on the planning CT scan was associated with a decrease in freedom from any failure (FFF) and freedom from clinical failure (FFCF) for prostate cancer patients., Methods and Materials: Patients from the Dutch trial (78 Gy vs. 68 Gy) with available acute toxicity data were analyzed (n = 549). A 10-mm margin was applied for the first 68 Gy and 0-5 mm for the 10-Gy boost. The dose in the seminal vesicles (SVs) was prescribed within four treatment groups according to the estimated risk of SV involvement. Two potential risk factors (RFs) for a geometric miss were defined: (1) an anorectal volume > or = 90 cm(3) and > or = 25% of treatment-time diarrhea (RF1); and (2) the mean cross-sectional area of the anorectum (RF2). We tested whether these were significant predictors for FFF and FFCF within each treatment group., Results: Significant results were observed only for patients with a risk of SV involvement > 25% (dose of 68-78 Gy to the SVs, n = 349). We found a decrease in FFF (p = 0.001) and FFCF (p = 0.01) for the 87 patients with RF1 (for RF2, p = 0.02 and p = 0.01, respectively). The estimated decrease in the FFCF rate at 5 years was 15%., Conclusion: Tumor control was significantly decreased in patients with a risk of SV involvement > 25% and at risk of geometric miss. Current image guidance techniques offer several solutions to geometrically optimize the treatment. Additional research is needed to evaluate whether geometric misses can be prevented using these techniques.

Purpose: The aim of this study was to determine the maximum tolerated dose (MTD) delivered within 6 weeks in patients with non-small-cell lung cancer (NSCLC). The impact of tumor volume and delivered dose on failure-free interval (FFI) and overall survival (OS) were also studied., Methods and Materials: A Phase I/II trial was performed including inoperable NSCLC patients. According to the relative mean lung dose (rMLD), five risk groups with different starting doses were defined: Group 1, rMLD 0.0 to 0.12; Group 2, rMLD 0.12 to 0.18; Group 3, rMLD 0.18 to 0.24; Group 4, rMLD 0.24 to 0.31; and Group 5, rMLD 0.31 to 0.40. Patients underwent irradiation with 2.25 Gy per fraction and a fixed overall treatment time of 6 weeks. The dose was escalated with 6.75 Gy after 6 months follow-up without dose-limiting toxicity. If more than 30 fractions were prescribed, twice-daily irradiation was performed with at least a 6-h interval., Results: A total of 88 patients were included. Tumor Stage I or II was found in 53%, IIIA in 31%, and IIIB in 17%. The MTD was not achieved in risk Group 1 (reached dose, 94.5 Gy). For risk Groups 2 and 3 the MTD was 81 Gy. The 74.3-Gy dose was determined to be safe for Group 4 and the 60.8-Gy dose for Group 5. In 2 patients (5%) an isolated nodal relapse occurred. Based on multivariable analysis, higher doses significantly increased the FFI (p = 0.02) for the total group. The OS was increased in the lower risk groups (p = 0.05) but not in the higher risk groups (p = 0.4)., Conclusion: Dose escalation is safe up to 94.5 Gy in 42 fractions in 6 weeks in patients with an MLD 13.6 Gy or less. Higher doses are associated with a better FFI and OS for smaller tumor volumes. Involved-field irradiation results in a low percentage of isolated nodal relapses.

Purpose: To analyze whether inclusion of predisposing clinical features in the Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model improves the estimation of late gastrointestinal toxicity., Methods and Materials: This study includes 468 prostate cancer patients participating in a randomized trial comparing 68 with 78 Gy. We fitted the probability of developing late toxicity within 3 years (rectal bleeding, high stool frequency, and fecal incontinence) with the original, and a modified LKB model, in which a clinical feature (e.g., history of abdominal surgery) was taken into account by fitting subset specific TD50s. The ratio of these TD50s is the dose-modifying factor for that clinical feature. Dose distributions of anorectal (bleeding and frequency) and anal wall (fecal incontinence) were used., Results: The modified LKB model gave significantly better fits than the original LKB model. Patients with a history of abdominal surgery had a lower tolerance to radiation than did patients without previous surgery, with a dose-modifying factor of 1.1 for bleeding and of 2.5 for fecal incontinence. The dose-response curve for bleeding was approximately two times steeper than that for frequency and three times steeper than that for fecal incontinence., Conclusions: Inclusion of predisposing clinical features significantly improved the estimation of the NTCP. For patients with a history of abdominal surgery, more severe dose constraints should therefore be used during treatment plan optimization.

Purpose: Late gastrointestinal (GI) toxicity after radiotherapy can be partly explained by late effects of acute toxicity (consequential late damage). We studied whether there is a direct relationship between acute and late GI toxicity., Patients and Methods: A total of 553 evaluable patients from the Dutch dose escalation trial (68 Gy vs. 78 Gy) were included. We defined three outcomes for acute reactions: 1) maximum Radiation Therapy Oncology Group acute toxicity, 2) maximum acute mucous discharge (AMD), and 3) maximum acute proctitis. Within a multivariable model, late endpoints (overall toxicity and five toxicity indicators) were studied as a function of acute toxicity, pretreatment symptoms, and relevant dose parameters., Results: At multivariable analysis, AMD and acute proctitis were strong predictors for overall toxicity, "intermittent bleeding," and "incontinence pads" (p < or = 0.01). For "stools > or =6/day" all three were strong predictors. No significant associations were found for "severe bleeding" and "use of steroids." The predictive power of the dose parameters remained at the same level or became weaker for most late endpoints., Conclusions: Acute GI toxicity is an independent significant predictor of late GI toxicity. This suggests a significant consequential component in the development of late GI toxicity.

Purpose: To identify dosimetric parameters derived from anorectal, rectal, and anal wall dose distributions that correlate with different late gastrointestinal (GI) complications after three-dimensional conformal radiotherapy for prostate cancer., Methods and Materials: In this analysis, 641 patients from a randomized trial (68 Gy vs. 78 Gy) were included. Toxicity was scored with adapted Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer (RTOG/EORTC) criteria and five specific complications. The variables derived from dose-volume histogram of anorectal, rectal, and anal wall were as follows: % receiving > or =5-70 Gy (V5-V70), maximum dose (Dmax), and mean dose (D(mean)). The anus was defined as the most caudal 3 cm of the anorectum. Statistics were done with multivariate Cox regression models. Median follow-up was 44 months., Results: Anal dosimetric variables were associated with RTOG/EORTC Grade > or =2 (V5-V40, D(mean)) and incontinence (V5-V70, D(mean)). Bleeding correlated most strongly with anorectal V55-V65, and stool frequency with anorectal V40 and D(mean). Use of steroids was weakly related to anal variables. No volume effect was seen for RTOG/EORTC Grade > or =3 and pain/cramps/tenesmus., Conclusion: Different volume effects were found for various late GI complications. Therefore, to evaluate the risk of late GI toxicity, not only intermediate and high doses to the anorectal wall volume should be taken into account, but also the dose to the anal wall.

Purpose: To identify dosimetric variables predictive of acute gastrointestinal (GI) and genitourinary (GU) toxicity and to determine whether hormonal therapy (HT) is independently associated with acute GI and GU toxicity in prostate cancer patients treated with conformal radiotherapy (RT)., Methods and Materials: This analysis was performed on 336 patients participating in a multicenter (four hospitals) randomized trial comparing 68 Gy and 78 Gy. The clinical target volume consisted of the prostate with or without the seminal vesicles, depending on the risk of seminal vesicle involvement. The margin from the clinical target volume to the planning target volume was 1 cm. For these patients, the treatment plan for a total dose of 68 Gy was used, because nearly all toxicity appeared before the onset of the 10-Gy boost. Acute toxicity (<120 days) was scored according to the Radiation Therapy Oncology Group criteria. The dosimetric parameters were obtained from the relative and absolute dose-volume/surface histograms derived from the rectal wall (rectal wall volume receiving > or =5-65 Gy) and the bladder surface (bladder surface receiving > or =5-65 Gy). Additionally, relative and absolute dose-length histograms of the rectum were created, and the lengths of rectum receiving more than a certain dose over the whole circumference (rectal length receiving > or =5-65 Gy) were computed. The clinical variables taken into account for GI toxicity were neoadjuvant HT, hospital, and dose-volume group; for GU toxicity, the variables pretreatment GU symptoms, neoadjuvant HT, and transurethral resection of the prostate were analyzed. The variable neoadjuvant HT was divided into three categories: no HT, short-term neoadjuvant HT (started < or =3 months before RT), and long-term neoadjuvant HT (started >3 months before RT)., Results: Acute GI toxicity Grade 2 or worse was seen in 46% of the patients. Patients with long-term neoadjuvant HT experienced less Grade 2 or worse toxicity (27%) compared with those receiving short-term neoadjuvant HT (50%) and no HT (50%). The volumes of the prostate and seminal vesicles were significantly smaller in both groups receiving neoadjuvant HT compared with those receiving no HT. In multivariate logistic regression analysis, including the two statistically significant clinical variables neoadjuvant HT and hospital, a volume effect was found for the relative, as well as absolute, rectal wall volumes exposed to intermediate and high doses. Of all the length parameters, the relative rectal length irradiated to doses of > or =5 Gy and > or =30 Gy and absolute lengths receiving > or =5-15 and 30 Gy were significant. Acute GU toxicity Grade 2 or worse was reported in 56% of cases. For patients with pretreatment GU symptoms, the rate was 93%. The use of short-term and long-term neoadjuvant HT resulted in more GU toxicity (73% and 71%) compared with no HT (50%). In multivariate analysis, containing the variables pretreatment symptoms and neoadjuvant HT, only the absolute dose-surface histogram parameters (absolute surface irradiated to > or =40, 45, and 65 Gy) were significantly associated with acute GU toxicity., Conclusion: A volume effect was found for acute GI toxicity for relative, as well as absolute, volumes. With regard to acute GU toxicity, an area effect was found, but only for absolute dose-surface histogram parameters. Neoadjuvant HT appeared to be an independent prognostic factor for acute toxicity, resulting in less acute GI toxicity, but more acute GU toxicity. The presence of pretreatment GU symptoms was the most important prognostic factor for GU symptoms during RT.

Purpose: To compare acute and late gastrointestinal (GI) and genitourinary (GU) side effects in prostate cancer patients randomized to receive 68 Gy or 78 Gy., Methods and Materials: Between June 1997 and February 2003, 669 prostate cancer patients were randomized between radiotherapy with a dose of 68 Gy and 78 Gy, in 2 Gy per fraction and using three-dimensional conformal radiotherapy. All T stages with prostate-specific antigen (PSA) <60 ng/mL were included, except any T1a and well-differentiated T1b-c tumors with PSA < or =4 ng/mL. Stratification was done for four dose-volume groups (according to the risk of seminal vesicles [SV] involvement), age, hormonal treatment (HT), and hospital. The clinical target volume (CTV) consisted of the prostate with or without the SV, depending on the estimated risk of SV invasion. The CTV-planning target volume (PTV) margin was 1 cm for the first 68 Gy and was reduced to 0.5 cm (0 cm toward the rectum) for the last 10 Gy in the 78 Gy arm. Four Dutch hospitals participated in this Phase III trial. Evaluation of acute and late toxicity was based on 658 and 643 patients, respectively. For acute toxicity (<120 days), the Radiation Therapy Oncology Group (RTOG) scoring system was used and the maximum score was reported. Late toxicity (>120 days) was scored according to the slightly adapted RTOG/European Organization for Research and Treatment of Cancer (EORTC) criteria., Results: The median follow-up time was 31 months. For acute toxicity no significant differences were seen between the two randomization arms. GI toxicity Grade 2 and 3 was reported as the maximum acute toxicity in 44% and 5% of the patients, respectively. For acute GU toxicity, these figures were 41% and 13%. No significant differences between both randomization arms were seen for late GI and GU toxicity, except for rectal bleeding requiring laser treatment or transfusion (p = 0.007) and nocturia (p = 0.05). The 3-year cumulative risk of late RTOG/EORTC GI toxicity grade > or =2 was 23.2% for 68 Gy, and 26.5% for 78 Gy (p = 0.3). The 3-year risks of late RTOG/EORTC GU toxicity grade > or =2 were 28.5% and 30.2% for 68 Gy and 78 Gy, respectively (p = 0.3). Factors related to acute GI toxicity were HT (p < 0.001), a higher dose-volume group (p = 0.01), and pretreatment GI symptoms (p = 0.04). For acute GU toxicity, prognostic factors were: pretreatment GU symptoms (p < 0.001), HT (p = 0.003), and prior transurethral resection of the prostate (TURP) (p = 0.02). A history of abdominal surgery (p < 0.001) and pretreatment GI symptoms (p = 0.001) were associated with a higher incidence of late GI grade > or =2 toxicity, whereas HT (p < 0.001), pretreatment GU symptoms (p < 0.001), and prior TURP (p = 0.006) were prognostic factors for late GU grade > or =2., Conclusions: Raising the dose to the prostate from 68 Gy to 78 Gy resulted in higher incidences of acute and late GI and GU toxicity, but these differences were not significant, except for late rectal bleeding requiring treatment and late nocturia. Other factors than the studied dose levels appeared to be important in predicting toxicity after radiotherapy, especially previous surgical interventions (abdominal surgery or TURP), hormonal therapy, and the presence of pretreatment symptoms.

Purpose: To study the correlations between the dose distributions in the anorectal region and late GI symptoms in patients treated for localized prostate carcinoma., Methods and Materials: Data from a randomized study were analyzed. In this trial, patients were treated with either rectangular or conformal fields with a dose of 66 Gy. Data concerning GI symptoms were collected from questionnaires of 197 patients. The distributions of the anorectal region were projected on maps, and the dose parameters were calculated. The incidences of complaints were studied as a function of the dose-area parameters and clinical parameters, using a proportional hazard regression model. Finally, we tested a series of dose parameters originating from different parts of the anorectal region., Results: Analyzing the total region, only a statistically significant dose-area effect relation for bleeding was found (p < 0.01). Defining subareas, we found effect relations for bleeding, soiling, fecal incontinence, and mucus loss. For bleeding and mucus loss, the strongest correlation was found for the dose received by the upper 70-80% of the anorectal region (p < 0.01). For soiling and fecal incontinence, we found the strongest association with the dose to the lower 40-50% (p < 0.05)., Conclusion: We found evidence that complaints originate from specific regions of the irradiated lower GI tract. Bleeding and mucus loss are probably related to irradiation of the upper part of the rectum. Soiling and fecal incontinence are more likely related to the dose to the anal canal and the lower part of the rectum.

Purpose: To identify dose-volume parameters related to late rectal bleeding after radiotherapy for prostate cancer., Materials and Methods: Clinical complication data from a randomized trial were collected and linked to the individual dose-volume data. In this trial, patients with prostate cancer were treated with either conventional (with rectangular fields) or three-dimensional conformal radiotherapy to a dose of 66 Gy. Patient complaints, including rectal blood loss, were collected for 199 patients, using questionnaires. Absolute and relative dose-volume histograms (DVHs) of the rectal wall (with and without the anal region) were calculated with and without rectal filling. A proportional hazard regression (PHR) model was applied to estimate the probability of any rectal blood loss within 3 years, as a function of several DVH parameters. In a multivariable analysis, dose-volume parameters were tested together with patient- and treatment-related parameters (age, smoking, diabetes, cardiovascular disease, tumor stage, neo-adjuvant androgen deprivation, conformal vs. conventional and rectal bleeding during treatment)., Results: The estimated incidence of any and moderate/severe rectal bleeding at 3 years was 33% and 8%, respectively. Differences between the conventional and conformal technique were small and not significant. The analysis of relative DVHs of the rectal wall (with and without the anal region), showed significant (p < 0.01) relations between the irradiated volume and the probability of rectal blood loss within 3 years for dose levels between 25 Gy and 60 Gy. This relationship was shown in subgroups defined by dose-volume cutoff points as well as in the PHR model, in which a continuously rising risk was seen with increasing volumes. For absolute DVHs and DVHs of the rectum including filling, less or no significant results were observed. The most significant volume-effect relation (p = 0.002) was found at 60 Gy for the rectum wall excluding the anal region. The probability of rectal bleeding increased from 10% to 63% when the irradiated rectum volume at 60 Gy increased from 25% to 100%. Other factors. including age, smoking, diabetes, cardiovascular disease, tumor stage, neo-adjuvant androgen deprivation, conformal vs. conventional, rectal bleeding during treatment, rectum length. and whole rectum volume. did not have a significant effect in the multivariable analysis. When controlling for the volumes at 60 Gy, the volumes at lower dose levels (25-55 Gy) were no longer significant (p = 0.5)., Conclusions: For any rectal bleeding within 3 years, an overall incidence of 33% was observed for patients treated to 66 Gy. For this endpoint, a volume-effect relation was found for DVH parameters of the relative rectal wall volume. This relationship appeared to be most significant for the rectum without the anal region and for the higher dose levels (50-60 Gy).