Anorectal Dose Research Articles

Feasibility, pitfalls and results of a structured concept-development phase for a randomized controlled phase III trial on radiotherapy in primary prostate cancer patients

ObjectiveFailure rate in randomized controlled trials (RCTs) is > 50%, includes safety-problems, underpowered statistics, lack of efficacy, lack of funding or insufficient patient recruitment and is even more pronounced in oncology trials. We present results of a structured concept-development phase (CDP) for a phase III RCT on personalized radiotherapy (RT) in primary prostate cancer (PCa) patients implementing prostate specific membrane antigen targeting positron emission tomography (PSMA-PET).Materials and methodsThe 1 yr process of the CDP contained five main working packages: (i) literature search and scoping review, (ii) involvement of individual patients, patients’ representatives and patients’ self-help groups addressing the patients’ willingness to participate in the preparation process and the conduct of RCTs as well as the patient informed consent (PIC), (iii) involvement of national and international experts and expert panels (iv) a phase II pilot study investigating the safety of implementation of PSMA-PET for focal dose escalation RT and (v) in-silico RT planning studies assessing feasibility of envisaged dose regimens and effects of urethral sparing in focal dose escalation.Results(i) Systematic literature searches confirmed the high clinical relevance for more evidence on advanced RT approaches, in particular stereotactic body RT, in high-risk PCa patients. (ii) Involvement of patients, patient representatives and randomly selected males relevantly changed the PIC and initiated a patient empowerment project for training of bladder preparation. (iii) Discussion with national and international experts led to adaptions of inclusion and exclusion criteria. (iv) Fifty patients were treated in the pilot trial and in- and exclusion criteria as well as enrollment calculations were adapted accordingly. Parallel conduction of the pilot trial revealed pitfalls on practicability and broadened the horizon for translational projects. (v) In-silico planning studies confirmed feasibility of envisaged dose prescription. Despite large prostate- and boost-volumes of up to 66% of the prostate, adherence to stringent anorectal dose constraints was feasible. Urethral sparing increased the therapeutic ratio.ConclusionThe dynamic framework of interdisciplinary working programs in CDPs enhances robustness of RCT protocols and may be associated with decreased failure rates. Structured recommendations are warranted to further define the process of such CDPs in radiation oncology trials.

Anorectal dose–effect relations for late gastrointestinal toxicity following external beam radiotherapy for prostate cancer in the FLAME trial

Background and purposeThe phase III FLAME trial (NCT01168479) showed an increase in five-year biochemical disease-free survival, with no significant increase in toxicity when adding a focal boost to external beam radiotherapy (EBRT) for localized prostate cancer [Kerkmeijer et al. JCO 2021]. The aim of this study was to investigate the association between delivered radiation dose to the anorectum and gastrointestinal (GI) toxicity (grade ≥2). Material and methodsAll patients in the FLAME trial were analyzed, irrespective of treatment arm. The dose–effect relation of the anorectal dose parameters (D2cm3 and D50%) and GI toxicity grade ≥2 in four years of follow-up was assessed using a mixed model analysis for repeated measurements, adjusted for age, cardiovascular disease, diabetes mellitus, T-stage, baseline toxicity grade ≥1, hormonal therapy and institute. ResultsA dose–effect relation for D2cm3 and D50% was observed with adjusted odds ratios of 1.17 (95% CI 1.13–1.21, p < 0.0001) and 1.20 (95% CI 1.14–1.25, p < 0.0001) for GI toxicity, respectively. ConclusionAlthough there was no difference in toxicity between study arms, a higher radiation dose to the anorectum was associated with a statistically significant increase in GI toxicity following EBRT for prostate cancer. This dose–effect relation was present for both large and small anorectal volumes. Therefore, further increase in dose to the anorectum should be weighed against the benefit of focal dose escalation for prostate cancer.

Derivation of Dose/Volume Constraints for the Anorectum from Clinician- and Patient-Reported Outcomes in the CHHiP Trial of Radiation Therapy Fractionation

The CHHiP trial randomized 3216 men with localized prostate cancer (1:1:1) to 3 radiation therapy fractionation schedules: 74 Gy in 37 fractions over 7.4 weeks; 60 Gy in 20 fractions over 4 weeks; and 57 Gy in 19 fractions over 3.8 weeks. Literature-based dose constraints were applied with arithmetic adjustment for the hypofractionated arms. This study aimed to derive anorectal dose constraints using prospectively collected clinician-reported outcomes (CROs) and patient-reported outcomes (PROs) and to assess the added predictive value of spatial dose metrics. A case-control study design was used; 7 CRO and 5 PRO bowel symptoms were evaluated. Cases experienced a moderate or worse symptom 1 to 5 years after-radiation therapy and did not have the symptom before radiation therapy. Controls did not experience the symptom at baseline or between 1 to 5 years after radiation therapy. The anorectum was recontoured from the anal verge to the rectosigmoid junction; dose/volume parameters were extracted. Univariate logistic regression, atlases of complication indices, and bootstrapped receiver-operating-characteristic analysis (1000 replicates, balanced outcomes) were used to derive dose constraints for the whole cohort (hypofractionated schedules were converted to 2-Gy equivalent schedules using α/β = 3 Gy) and separate hypofractionated/conventional fractionation cohorts. Only areas under the curve with 95% confidence interval lower limits >0.5 were considered statistically significant. Any constraint derived in <95% to 99% of bootstraps was excluded. Statistically significant dose constraints were derived for CROs but not PROs. Intermediate to high doses were important for rectal bleeding, whereas intermediate doses were important for increased bowel frequency, fecal incontinence, and rectal pain. Spatial dose metrics did not improve prediction of CROs or PROs. A new panel of dose constraints for hypofractionated schedules to 60 Gy or 57 Gy are V20Gy <85%, V30Gy <57%, V40Gy <38%, V50Gy <22%, and V60Gy <0.01%. Dose constraints differed among symptoms, indicating potentially different pathogenesis of radiation-induced side effects. Derived dose constraints were stricter than those used in CHHiP and may reduce bowel symptoms after radiation therapy.

Patterns in ano-rectal dose maps and the risk of late toxicity after prostate IMRT

Purpose: The aim of this work was to determine how the spatial pattern of dose in the ano-rectal wall is related to late gastro-intestinal toxicity for prostate cancer patients treated with mainly IMRT.Patients and methods: Patients from the DUE-01 multicentre study with patient-reported (prospective) follow-up and available dosimetric data were included. Conventionally fractionated patients received 74–80 Gy and hypofractionated patients received 65–75.2 Gy. A large majority of the patients were treated with intensity-modulated radiotherapy (IMRT). Dose-surface maps (DSMs) for the anal canal and rectum as a single structure, and for the anal canal and the rectum separately, were co-registered rigidly in two dimensions and, for the patients with and without toxicity, respectively, the mean value of the dose in each pixel was calculated. A pixel-wise t-test was used to highlight the anatomical areas where there was a significant difference between the ‘mean dose maps’ of each group. Univariate models were also fitted to a range of spatial parameters. The endpoints considered were a mean grade ≥1 late fecal incontinence and a maximum grade ≥2 late rectal bleeding.Results: Twenty-six out of 213 patients had fecal incontinence, while 21/225 patients had rectal bleeding. Incontinence was associated with a higher dose in the caudal region of the anal canal; the most relevant spatial parameter was the lateral extent of the low and medium isodoses (5–49 Gy in EQD2). Bleeding was associated with high isodoses reaching the posterior rectal wall. The spatial dose parameters with the highest AUC value (.69) were the lateral extent of the 60–70 Gy isodoses.Conclusions: To avoid fecal incontinence it is important to limit the portion of the anal canal irradiated. Our analysis confirms that rectal bleeding is a function of similar spatial dose parameters for patients treated with IMRT, compared to previous studies on patients treated with three-dimensional conformal radiotherapy.

Derivation of dose/volume constraints for the anorectum from clinician-reported outcomes (CRO) in the CHHiP trial of radiotherapy (RT) fractionation.

87 Background: CHHiP (ISRCTN97182923, CRUK/06/016) randomised 3216 men with localised prostate cancer (1:1:1) to 3 RT fractionation schedules: 74Gy/37 fractions (f) over 7.4 weeks, 60Gy/20f/4 weeks and 57Gy/19f/3.8 weeks. Literature-based dose constraints were applied with adjustment for the hypofractionated arms. For standard fractionation the constraints (absolute dose) included V30Gy≤80%, V40Gy≤70%, V50Gy≤60%, V60Gy≤50%, V70Gy≤15%. This study aimed to derive anorectal dose constraints based on prospectively collected CRO. Methods: A case-control study design was used, 4 bowel symptoms were independently evaluated. Cases were patients experiencing a moderate or worse grade symptom 1 to 5 years post RT, who had not had the symptom pre-RT. Controls did not experience the symptom between 1 and 5 years post RT. The anorectum was re-contoured from the anal verge to the recto-sigmoid junction using VODCA software. Dose/volume parameters were extracted and hypofractionated dose schedules were converted to 2Gy equivalent schedules using an α/β ratio of 3Gy. Bootstrapped ROC analysis (1000 replicates, balanced outcomes) was used to derive dose constraints using both the Youden index and “Closest top Left” (CtL). Only AUC with a lower limit of the 95% confidence interval &gt;0.5 were considered statistically significant. Any constraint derived in &lt;99% of bootstraps was excluded. Results: Statistically significant dose constraints were derived for rectal bleeding, increased bowel frequency, faecal incontinence and rectal pain (table). Conclusions: Dose constraints differed between symptoms, indicating potentially different pathogenesis of each radiation-induced side effect. Derived dose constraints were tighter than those used in CHHiP; use of these may reduce anorectal symptoms post RT. Comparable data derived from the hypofractionated cohorts will be presented. [Table: see text]

Dynamics of rectal balloon implant shrinkage in prostate VMAT

PurposeTo assess the effect of a shrinking rectal balloon implant (RBI) on the anorectal dose and complication risk during the course of moderately hypofractionated prostate radiotherapy.MethodsIn 15 patients with localized prostate cancer, an RBI was implanted. A weekly kilovolt cone-beam computed tomography (CBCT) scan was acquired to measure the dynamics of RBI volume and prostate–rectum separation. The absolute anorectal volume encompassed by the 2 Gy equieffective 75 Gy isodose (V75Gy) was recalculated as well as the mean anorectal dose. The increase in estimated risk of grade 2–3 late rectal bleeding (LRB) between the start and end of treatment was predicted using nomograms. The observed acute and late toxicities were evaluated.ResultsA significant shrinkage of RBI volumes was observed, with an average volume of 70.4% of baseline at the end of the treatment. Although the prostate–rectum separation significantly decreased over time, it remained at least 1 cm. No significant increase in V75Gy of the anorectum was observed, except in one patient whose RBI had completely deflated in the third week of treatment. No correlation between mean anorectal dose and balloon deflation was found. The increase in predicted LRB risk was not significant, except in the one patient whose RBI completely deflated. The observed toxicities confirmed these findings.ConclusionsDespite significant decrease in RBI volume the high-dose rectal volume and the predicted LRB risk were unaffected due to a persistent spacing between the prostate and the anterior rectal wall.

Local Protocol Variations for Image Guided Radiation Therapy in the Multicenter Dutch Hypofractionation (HYPRO) Trial: Impact of Rectal Balloon and MRI Delineation on Anorectal Dose and Gastrointestinal Toxicity Levels

The phase 3 HYpofractionated irradiation for PROstate cancer (HYPRO) trial randomized patients with intermediate- to high-risk localized prostate cancer to conventionally fractionated (78Gy in 39 fractions) or hypofractionated (64.6Gy 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. 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 6mm 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 8mm. 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 (6months to 4years) were compared in a generalized linear model, adjusting for age, follow-up, treatment arm, and hormone therapy. 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. 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.

OC-0038: Patterns in ano-rectal dose maps and the risk of late toxicity after prostate radiotherapy

OC-0038: Patterns in ano-rectal dose maps and the risk of late toxicity after prostate radiotherapy

The effect of endorectal balloon on anorectal dose during postoperative volumetric arc radiotherapy of prostate cancer

PurposeTo evaluate the impact of endorectal balloon (ERB) on anorectal dose during postoperative VMAT of prostate cancer. MethodsIn ten patients referred for salvage radiotherapy CTs were obtained without ERB and with air-filled ERB of 50ml and 100ml. CTs were repeated weekly (4–6 control CTs) and registered to the respective planning CT. For each planning CT, a VMAT plan was made with defined anorectal dose constraints and propagated on the respective control CTs. The dose volumes V40Gy, V60Gy and V65Gy of the rectal and anal wall (Rwall and Awall, respectively) and the ERB position were obtained from each plan. ResultsIn plans with ERB, the mean Rwall dose volumes V40Gy, V60Gy and V65Gy were higher by 8%, 5% and 2% (ERB 50ml) and 2%, 3% and 3% (ERB 100ml) in comparison to plans without ERB. The respective Awall dose volume differences were 2%, 0%, −1% (ERB 50ml), and −3%, −2%, −2% (ERB 100ml). The dose volume variability of the Rwall was comparable with and without ERB, but was slightly reduced by ERB for the Awall. The mean ERB position variability was >2mm in anterior–posterior and inferior–superior directions. ConclusionThe use of ERB during post-operative VMAT has no advantages for anorectal dose.

Proof of Systemic Safety of a Lidocaine Ointment in the Treatment of Patients with Anorectal Pain

The aim of the study was to demonstrate that repeated anorectal administration of a 5% lidocaine ointment (CAS 137-58-6; LidoPosterine Salbe, Posterisan akut Rektalsalbe) in the treatment of patients with acute anorectal pain does not result in systemically efficacious plasma concentrations of lidocaine. In an open single-center study 24 male or female patients with anorectal pain due to hemorrhoids, anal fissures, fistulas or proctitis administered lidocaine ointment as a single anorectal dose (2.5 g ointment corresponding to 125 mg lidocaine) followed by repeated administration (2.5 g ointment t.i.d.) for 4 days. Safety evaluation was performed with respect to plasma concentrations of lidocaine, vital signs, electrocardiogram (ECG), physical findings and adverse events. Blood samples were drawn prior to the first single administration and at 13 time points over the first 24 h in order to create a pharmacokinetic profile. Blood samples were also drawn prior to administration of the last dose on day 5 and thereafter using the identical time points for blood sampling as on day 1. Vital signs and ECG were recorded immediately before and 1 and 4 h after the first and last administration, respectively. Adverse events and skin tolerability were also recorded at predefined times during the study period. After a single dose of 125 mg lidocaine the average extent of exposure in terms of the AUC(tau,sd) during a 6 h dosage interval amounted to 397.7 ng/ml x h (geometric mean). C(max,sd) reached a mean value of 131.8 ng/ml (geometric mean). Only a minor accumulation of the lidocaine plasma concentrations was observed after multiple dose application. The geometric mean of the AUC(tau,md) (503.8 ng/ml x h, tau = 6 h) and the geometric mean of C(max,md) (145.9 ng/ml) were slightly higher than the corresponding single dose values. The AUC accumulation ratio was calculated as 127% (90% CI: 108-148%) and the C(max) accumulation ratio reached 120% (90% CI: 101-139%). Plasma peak concentrations of lidocaine in all subjects remained with a sufficient safety margin below the minimal effective therapeutic plasma concentration (1.5 microg/ml) as well as by an order of magnitude below toxic concentrations (5 microg/ml). There were neither unexpected, serious nor severe adverse events. There were no clinically relevant findings with respect to vital signs and ECG. Repeated anorectal administration of a 5% lidocaine ointment proved to be safe with respect to systemic plasma concentrations of lidocaine and vital signs.

Association of anorectal dose–volume histograms and impaired fecal continence after 3D conformal radiotherapy for carcinoma of the prostate

Purpose: The late toxicity of fecal incontinence after pelvic radiotherapy is now frequently recognized but the etiology poorly understood. We therefore investigated associations between dose–volume histogram (DVH) parameters of the rectum and the anal canal with fecal continence as measured by an established 10-item questionnaire. Methods and materials: Forty-four patients treated for carcinoma of the prostate with 58–72 Gy of 3D conformal radiotherapy between 1995 and 1999 who completed the questionnaire formed the study population. Total continence scores of treated patients obtained 1.5 years (median) after radiotherapy were compared to a control group of 30 patients before radiotherapy. Median, mean, minimum and maximum doses as well as the volume (% and ml) treated to 40, 50, 60 and 70 Gy were determined separately for anal canal and rectum. DVH parameters were correlated with total continence score (Spearman rank test) and patients grouped according to observed continence were compared regarding DVH values (Mann–Whitney U-test). Results: Median fecal continence scores were significantly worse in the irradiated than in the control group (31 vs. 35 of a maximum 36 points). In treated patients, 59%/27%/14% were classified as fully continent, slightly incontinent and severely incontinent. Continence was similar in the 58-to-62-Gy, 66-Gy and 68-to-72-Gy dose groups. No DVH parameter was significantly correlated with total continence score, but severely incontinent patients had a significantly higher minimum dose to the anal canal than fully continent/slightly incontinent, accompanied by portals extending significantly further inferiorly with respect to the ischial tuberosities. Conclusions: Excluding the inferior part of the anal canal from the treated volume in 3D conformal therapy for carcinoma of the prostate appears to be a promising strategy to prevent radiation-induced fecal incontinence.