Risk Of Rectal Toxicity Research Articles

S2689 A Rare Case of SpaceOARTM Hydrogel-Induced Rectal Ulcer Leading to Hematochezia

Introduction: SpaceOAR hydrogel is a soft gel-like synthetic material that was FDA approved in 2015 for prostate cancer patients who are planning to undergo radiotherapy (RT). It is intended to position the anterior rectal wall away from the prostate during RT thereby reducing the dose of radiation delivered to the rectum and minimizing complications. We present a case of rectal ulcer after implantation of SpaceOAR prior to the patient receiving RT. Case Description/Methods: A 76-year-old male was diagnosed with prostate cancer- Gleason 3+4 and was planned for RT. He underwent implantation of spaceOAR hydrogel and gold fiducial markers before RT to minimize his risk of rectal toxicity. Approximately 10 days after placement, he started experiencing severe rectal pain and hematochezia. On physical exam his abdomen was benign, but a digital rectal exam showed bright red blood. Labs revealed normal hemoglobin of 16 g/dL. A computerized tomography (CT) scan without contrast was obtained showing the presence of hydrogel between the posterior margin of the prostate and the anterior wall of the low rectum with focal proctitis in that area of the rectum. Due to ongoing hematochezia, he was scheduled for a colonoscopy which confirmed CT findings of focal proctitis but also showed a large ulcer with overlying fibrotic tissue congruent with the site of his recent urological procedure. The tissue was friable and not amenable to biopsy. He was managed with a course of levofloxacin and given polyethylene glycol to avoid constipation. At a follow-up visit, he reported resolution of hematochezia and improvement in his rectal pain. He will proceed with the initiation of RT for prostate cancer. (Figure) Discussion: The SpaceOAR Hydrogel is designed to reduce rectal toxicity during RT for prostate cancer so a higher dose of radiation can be delivered to the prostate. There have been only a few cases of rectal ulcers after placement of the Hydrogel before the patient received RT. In most reported cases, the management was conservative. The mechanisms of injury are thought to be from infection, inflammation, or ischemia due to mechanical injury. We managed our patient with a course of antibiotics and laxatives resulting in improvement of his symptoms and he will proceed with RT as planned. This case is unique in that the patient developed symptoms only 10 days after implantation of SpaceOAR when all other documented cases took at least a few weeks to a few months.Figure 1.: A- Focal proctitis and large rectal ulcer in the anterior wall B- Friable tissue not amenable to biopsy C- CT scan showing hydrogel and focal proctitis.

A Single Institutional Experience of the Utilization of Hydrogel Spacer for Prostate SBRT

Purpose: External beam radiation for prostate cancer is associated with a risk of rectal toxicity. Recent research has supported the use of biodegradable rectal spacers for radiation therapy in patients with localized prostate cancer. This hydrogel is inserted between the prostate and the rectum, increasing the space between these two organs. This results in decreased radiation dose to the rectum, as the radiation dose falls off in the hydrogel, instead of the rectum. This is specifically important in the use of the hypofractionated stereotactic body radiation therapy (SBRT) to the prostate.

SpaceOAR© hydrogel rectal dose reduction prediction model: a decision support tool.

Prostate cancer external beam radiation therapy can result in toxicity due to organ at risk (OAR) dose, potentially impairing quality of life. A polyethylene glycol‐based spacer, SpaceOAR© hydrogel (SOH), implanted between prostate gland and rectum may significantly reduce dose received by the rectum and hence risk of rectal toxicity. SOH implant is not equally effective in all patients. Determining patients in which the implant will offer most benefit, in terms of rectal dose reduction, allows for effective management of SOH resources. Several factors have been shown to be correlated with reduction in rectal dose including distance between rectum and planning treatment volume (PTV), volume of rectum in the PTV, and change in rectum volume pre‐ to post‐SOH. Several of these factors along with other pre‐SOH CT metrics were able to predict reduction in rectal dose associated with SOH implant. Rectal V55Gy metric, was selected as the dose level of interest in the context of 60 Gy in 20 fraction treatment plans. Models were produced to predict change in RV55Gy and pre‐SOH hydrogel RV55Gy. These models offered R‐squared between 0.81 and 0.88 with statistical significance in each model. Applying an ω1 = 3% lower limit of pre‐SOH RV55 Gy and an ω2 = 3.5% lower limit on change in RV55 Gy, retained 60% of patients experiencing the largest rectal dose reduction from the hydrogel. This may offer a clinically useful tool in deciding which patients should receive SOH implant given limited resources. Predictive models, nomograms, and a workflow diagram were produced for clinical management of SOH implant.

Maximizing rectal dose sparing with hydrogel: A retrospective planning study.

External beam radiation therapy for prostate cancer can result in urinary, sexual, and rectal side effects, often impairing quality of life. A polyethylene glycol‐based product, SpaceOAR© hydrogel (SOH), implanted into the connective tissue between the prostate gland and rectum can significantly reduce the dose received by the rectum and hence risk of rectal toxicity. The optimal way to manage the hydrogel and rectal structures for plan optimization is therefore of interest. In 13 patients, computerized tomography (CT) scans were taken pre‐ and post‐SpaceOAR© implant. A prescription of 60 Gy in 20 fractions was planned on both scans. Six treatment plans were produced per anonymized dataset using either a structure of rectum plus the hydrogel, termed composite rectum wall (CRW), or rectal wall (RW) as an inverse optimization structure and intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) as a treatment technique. Dose‐volume histogram metrics were compared between plans to determine which optimization structure and treatment technique offered the maximum rectal dose sparing. RW structures offered a statistically significant decrease in rectal dose over CRW structures, whereas the treatment technique (IMRT vs VMAT) did not significantly affect the rectal dose. There was improvement seen in bladder and penile bulb dose when VMAT was used as a treatment technique. Overall, treatment plans using the RW optimization structure offered the lowest rectal dose while VMAT treatment technique offered the lowest bladder and penile bulb dose.

Predictive factors of long-term rectal toxicity following permanent iodine-125 prostate brachytherapy with or without supplemental external beam radiation therapy in 2216 patients

PurposeWe analyzed factors associated with rectal toxicity after iodine-125 prostate brachytherapy (BT) with or without external beam radiation therapy (EBRT). Methods and MaterialsIn total, 2216 prostate cancer patients underwent iodine-125 BT with or without EBRT between 2003 and 2013. The median followup was 6.9 years. Cox proportional hazards modeling was used for univariate and multivariate analyses to assess clinical and dosimetric factors associated with rectal toxicity. Dosimetric parameters from 1 day after implantation (Day 1) and 1 month after implantation (Day 30) were included in the analyses. ResultsThe 7-year cumulative incidence of Grade 2 or higher rectal toxicity was 5.7% in all patients. The multivariate analysis revealed that antiplatelet or anticoagulant therapy, neoadjuvant androgen deprivation therapy, treatment modality, Day 1 rectal volume receiving 100% of the prescribed dose (RV100), and the Day 30 minimal percent of the prescribed dose delivered to 30% of the rectum (RD30) were associated with rectal toxicity. Day 1 RV100 was a common predictor in both BT-alone and the BT + EBRT groups. The 5-year cumulative incidence of Grade 2 or higher rectal toxicity was 12.6%, 5.9%, and 1.7% for BT + 3-dimensional conformal radiation therapy, BT + intensity-modulated radiation therapy, and the BT-alone groups, respectively (p < 0.001). ConclusionsRectal dosimetric parameters in BT were associated with late rectal toxicity. Although the risk of rectal toxicity was higher when EBRT was combined with BT, with proper and achievable rectal dose constraints intensity-modulated radiation therapy yielded less toxicity than 3-dimensional conformal radiation therapy.

Hydrogel spacers in prostate radiotherapy: a promising approach to decrease rectal toxicity.

High-dose radiation is a well-established method of treatment for prostate cancer. The main limiting structure for dose escalation is the rectum. The risk of rectal toxicity is related to dose received by the rectum. Several strategies for reducing dose to rectum have been explored; these include endorectal balloons as well as injection of rectal spacers like hydrogels. They create greater distance between rectal wall and prostate to confer a dosimetric advantage to the rectum. Early clinical studies with hydrogels have shown favorable outcomes. A low incidence of major procedural adverse effects with hydrogel use has been reported and it is well tolerated by patients. Hydrogel holds promise in establishing itself as an adjunct to standard of care in prostate radiation.

Late rectal toxicity after image-based high-dose-rate interstitial brachytherapy for postoperative recurrent and/or residual cervical cancers: EQD2 predictors for Grade ≥II toxicity.

To investigate the correlation of rectal dose volume metrics with late rectal toxicity after high-dose-rate pelvic interstitial brachytherapy. From October 2009 to November 2012, 50 patients with residual or recurrent cervical cancer were included. Patients received external radiation 50 Gy in 25 fractions over 5 weeks with weekly cisplatin. Rectum and rectal mucosal (RM) contours were delineated retrospectively. RM was defined as the outer surface of the flatus tube inserted at brachytherapy. The dose received by 0.1, 1, 2, 5 cc of rectum, RM, and sigmoid was recorded. Cumulative equivalent dose in 2 Gy (EQD2) for organs at risk was calculated assuming α/β of 3. Univariate analysis was performed to identify predictors of rectal toxicity. At a median follow-up of 34 months (12-51 months), Grade II and III late rectal toxicity was observed in 9 (18%) and 2 (4%) patients, respectively. On univariate analysis, rectal doses were not significant predictors; however, D 0.1-cc RM dose >72 Gy (p = 0.04), D 1-cc RM dose >65 Gy (p = 0.004), D 2-cc RM dose >62.3 Gy (p = 0.004), and D 5-cc RM dose >60 Gy (p = 0.007) correlated with Grade ≥II toxicity. On probit analysis, the estimated dose in EQD2 for a 10% and 20% risk of rectal toxicity was D 2-cc rectum of 55 and 66 Gy, and RM <55 and 63 Gy, respectively. Limiting 2-cc RM and rectal doses within the proposed thresholds can minimize Grade ≥II toxicity for gynecologic high-dose-rate interstitial brachytherapy.

Prostate Hypofractionated Radiation Therapy With Injection of Hyaluronic Acid: Acute Toxicities in a Phase 2 Study

Hypofractionated radiation therapy (RT) in prostate cancer can be developed only if the risk of rectal toxicity is controlled. In a multicenter phase 2 trial, hypofractionated irradiation was combined with an injection of hyaluronic acid (HA) to preserve the rectal wall. Tolerance of the injection and acute toxicity rates are reported. The study was designed to assess late grade 2 toxicity rates. The results described here correspond to the secondary objectives. Acute toxicity was defined as occurring during RT or within 3 months after RT and graded according to the Common Terminology Criteria for Adverse Events version 4.0. HA tolerance was evaluated with a visual analog scale during the injection and 30 minutes after injection and then by use of the Common Terminology Criteria at each visit. From 2010 to 2012, 36 patients with low-risk to intermediate-risk prostate cancer were included. The HA injection induced a mean pain score of 4.6/10 ± 2.3. Thirty minutes after the injection, 2 patients still reported pain (2/10 and 3/10), which persisted after the intervention. Thirty-three patients experienced at least 1 acute genitourinary toxicity and 20 patients at least 1 acute gastrointestinal toxicity. Grade 2 toxicities were reported for 19 patients with urinary obstruction, frequency, or both and for 1 patient with proctitis. No grade 3 or 4 toxicities were reported. At the 3-month visit, 4 patients described grade 2 obstruction or frequency, and no patients had any grade 2 gastrointestinal toxicities. The injection of HA makes it possible to deliver hypofractionated irradiation over 4 weeks with a dose per fraction of > 3 Gy, with limited acute rectal toxicity.

Current role of spacers for prostate cancer radiotherapy.

Radiotherapy is an established curative treatment method for prostate cancer. Optimal tumor control rates can only be achieved with high local doses, associated with a considerable risk of rectal toxicity. Apart from already widely adapted technical advances, as intensity-modulated radiation therapy, the application of spacers placed between the prostate and rectum has been increasingly used in the last years. Biodegradable spacers, including hydrogel, hyaluronic acid, collagen or an implantable balloon, can be injected or inserted in a short procedure under transrectal ultrasound guidance via a transperineal approach. A distance of about 1.0-1.5 cm is usually achieved between the rectum and prostate, excluding the rectal wall from the high isodoses. Several studies have shown well tolerated injection procedures and treatments. Apart from considerable reduction of rectal irradiation, a prospective randomized trial demonstrated a reduction of rectal toxicity after hydrogel injection in men undergoing prostate image-guided intensity-modulated radiation therapy. The results are encouraging for continuing evaluation in dose escalation, hypofractionation, stereotactic radiotherapy or re-irradiation trials in the future.

The difference in implantation quality between loose seed and variable spacing strand seeds in the field of prostate brachytherapy.

252 Background: Concordance between intraoperative and postoperative dosimetry is a well-known marker of implant quality in prostate brachytherapy. The aim of the study was to evaluate if the use of variable distance strand seeds allows an improvement in the quality of the post implantation dosimetry. Methods: Before December 2010, an iodine 125 loose-seed technique was used for prostate brachytherapy. Since this date, patients have been treated with new variable distance strand seeds (ProLink; Bard). Post implant dosimetry was compared to intraoperative dosimetry in 30 patients treated with loose seeds and 29 patients treated with strand seeds. The prescribed dose was 145Gy. Variations of dosimetric parameters were used to set the two techniques against one another: prostate V100 and D90 and rectum V145 and V160. Results: There was a significant difference between intraoperative and postoperative V100 and D90 for all 59 patients: V100 preop-postop: mean 6,65% +/- SD 4,5; D90 preop-postop: 18,73Gy +/- SD 15 (p&lt;0,0001). This dosimetric difference between pre and post-operative dosimetry is more important using loose seeds brachytherapy: V100 preop-postop: 9,5% +/- SD 4,1 vs 3,7% +/- SD 2,7 for loose seeds and strand seeds respectively (p&lt;0,0001), and D90 preop-postop: 27,9Gy +/-SD 13,6 vs 9,2Gy +/- SD 9,7 for loose seeds and strand seeds respectively (p&lt;0,0001). For V145 rectum and V160 rectum, dosimetric difference wasn't significant: V145 rectum preop-postop: -0,9% +/- SD 1,4 with stranded seeds vs. -1,6% +/- SD 2,1 with loose seeds (p=0,14) and V160 rectum pre-postop: -0,5% +/- SD 0,8 with strand seeds vs. -0,5% +/- SD 0,8 with loose seeds (p=0,16). Conclusions: Stranded seeds implantation increases the quality of implantation by reducing the dosimetric difference (V100 and D90) between intra and post-operative dosimetry to a maximum of 6% and 7% vs. more than 20% with loose seed implantation. Moreover, this technique doesn’t seem to modify the risk of rectal toxicity. This achievement in implantation and dosimetric quality might lead to a gain in clinical results.

Effect of endorectal balloon positioning errors on target deformation and dosimetric quality during prostate SBRT

An inflatable endorectal balloon (ERB) is often used during stereotactic body radiation therapy (SBRT) for treatment of prostate cancer in order to reduce both intrafraction motion of the target and risk of rectal toxicity. However, the ERB can exert significant force on the prostate, and this work assessed the impact of ERB position errors on deformation of the prostate and treatment dose metrics. Seventy-one cone-beam computed tomography (CBCT) image datasets of nine patients with clinical stage T1cN0M0 prostate cancer were studied. An ERB (Flexi-Cuff, EZ-EM, Westbury, NY) inflated with 60 cm3 of air was used during simulation and treatment, and daily kilovoltage (kV) CBCT imaging was performed to localize the prostate. The shape of the ERB in each CBCT was analyzed to determine errors in position, size, and shape. A deformable registration algorithm was used to track the dose received by (and deformation of) the prostate, and dosimetric values such as D95, PTV coverage, and Dice coefficient for the prostate were calculated. The average balloon position error was 0.5 cm in the inferior direction, with errors ranging from 2 cm inferiorly to 1 cm superiorly. The prostate was deformed primarily in the AP direction, and tilted primarily in the anterior–posterior/superior–inferior plane. A significant correlation was seen between errors in depth of ERB insertion (DOI) and mean voxel-wise deformation, prostate tilt, Dice coefficient, and planning-to-treatment prostate inter-surface distance (p < 0.001). Dosimetrically, DOI is negatively correlated with prostate D95 and PTV coverage (p < 0.001). For the model of ERB studied, error in ERB position can cause deformations in the prostate that negatively affect treatment, and this additional aspect of setup error should be considered when ERBs are used for prostate SBRT. Before treatment, the ERB position should be verified, and the ERB should be adjusted if the error is observed to exceed tolerable values.

Injection of hyaluronic acid (HA) to better preserve the rectal wall in prostate hypofractionated radiotherapy (HFR).

202 Background: Several studies are in favor of an α/β ratio of less than 3Gy for prostate (P) cancer, encouraging HFR. However, the development of such radiation patterns can only be done if the risk of rectal toxicity is well controlled. The objective of the present study was to evaluate the contribution of an injection of HA between the rectum and the P to reduce the risk of rectal toxicity in a HFR approach. Methods: A phase II study of HFR at 62Gy in 20 fractions (BED = 84Gy; α / β = 1.5Gy) is currently conducted. A transperineal injection of 10cc of HA (NASHA Spacer gel, Q-Med AB, Uppsala, Sweden) is systematically performed, between the rectum and the P, under local anesthesia and under ultrasound guidance. A dosimetric CT scan is performed before (CT1) and after injection (CT2). Patients are treated with a 7 beams IMRT plan, optimized on the CT2. For the first 10 patients included in the study, the same treatment plan was optimized on CT1. The rectum was empty on the 2 CTs and defined from 2cm above the seminal vesicles to 2 cm below the P. The rectal wall was defined by an internal expansion of 5 mm. The volumes of rectum irradiated, with and without HA, were compared on the following dosimetric parameters: maximum dose (D max), dose to 2.5cc (D2.5), 5cc (D5) and 10cc (D10) of rectal wall and volume of rectum receiving 90% (V90), 80% (V80) and 70% (V70) of the prescribed dose of 62Gy. To limit a potential impact of variation of rectal volume between the two CT, all results are given in cc and not in % of volume. Results: The mean P volume was 52.4cc (30cc - 93.8cc) on the CT1 and 52cc (32.5 - 92.7) on the CT2. The injection of HA reduced the mean D max value to the rectal wall of 4.5Gy (57.5Gy vs 62 Gy). The mean values of V90, V80, and V70 are reduced by 69% (1.9cc vs 6.1cc), 46% (4.5cc vs 8.4cc) and 32% (7.4cc vs 10.9cc). Same way, the average values of D2.5, D5 and D10 are reduced by 6.2 Gy (54.6Gy vs 60.8Gy) 9.3Gy (49.0Gy vs 58.3Gy) and 7.8Gy (39.7Gy vs 47.5Gy). Conclusions: In this study, the injection of HA limited the doses to the rectal wall. These results suggest that late toxicities could be significantly reduced. A phase II study is underway to assess the rate of late rectal toxicities when a HFR at 62Gy in 20 fractions is combined with an injection of HA.

Influence of Organ at Risk Definition on Rectal Dose-Volume Histograms in Patients with Prostate Cancer Undergoing External-Beam Radiotherapy

To evaluate rectal dose-volume relations during three-dimensional conformal radiotherapy of patients with prostate cancer by means of different rectal volume contours. 55 patients with prostate cancer underwent three-dimensional conformal external-beam radiotherapy. Rectal dose-volume histograms were calculated for four separately contoured rectal volumes in all patients resulting in four groups. In group 1 the outer rectal wall was contoured two CT slices above and below the planning target volume. The rectal contour of group 2 was drawn from the anal verge up to the sigmoid. Furthermore, the posterior half of the rectum was contoured for both volumes mentioned above (groups 1a and 2a). Statistical analysis was then performed using nonparametric Wilcoxon tests. The mean target dose was 72.9 Gy (standard deviation [SD] +/- 2.1 Gy). The minimum target dose was 70.2 Gy. Mean rectum dose (+/- SD) over all patients was 50.7 Gy (+/- 4.6 Gy), 45.2 Gy (+/- 5.4 Gy), 43.2 Gy (+/- 4.2 Gy), and 38.7 Gy (+/- 5.5 Gy) for group 1, 2, 1a, and 2a, respectively. The corresponding volumes receiving > or = 70 Gy for groups 1 and 2 were 14.0% (+/- 5.3%) and 11.9% (+/- 4.5%). These differences were statistically significant. Comparison of minimum and mean rectal dose also revealed a statistically significant difference toward higher doses in groups 1 and 1a (p < 0.001). Maximum rectal doses for groups 1 and 2 as well as for groups 1a and 2a revealed no statistically significant difference (p = 1.0). Data from the literature on normal-tissue complication probability (rectal bleeding) refer to different rectal contours. When applying dose restrictions to the rectum, contouring becomes a significant factor that determines the risk of rectal toxicity. The results of this study show that different ways of rectal contouring significantly influence doses to the rectum. The influence of organ at risk contouring should be considered thoroughly in conformal radiotherapy of prostate cancer patients, especially in dose escalation studies. It is recommended to calculate the doses for absolute rectal volumes and correlate these data with toxicity in order to be able to achieve comparable results among different institutions.

The use of dose volume constraints to achieve rectal isotoxicity: A phase II prostate cancer radiation therapy dose escalation study

4628 Background: The primary limiting factor for prostate cancer irradiation is the risk of rectal toxicity. Rectal toxicity is associated with the dose and volume of the rectum irradiated. This dose escalation study has the unique feature of using dose volume histogram (DVH) constraints to determine the prescribed dose. Methods: From 1999–2002, 331 patients with clinical stage T1-T3N0M0 prostate cancer were prospectively treated with 3D conformal adaptive RT. A patient-specific confidence-limited planning target volume was constructed based on multiple CT scans. For each case, the rectum (rectal solid) was contoured in its entirety. The rectal wall was defined using a 3-mm wall thickness (median volume: 29.8 cc). The prescribed dose level was chosen using the following rectal wall dose constraints: 1) <30% of the rectal wall volume can receive >75.6 Gy. 2) <5% of the rectal wall can receive >82 Gy. The risk of chronic toxicity (NCI Common Toxicity Criteria 2.0) was assessed for the different dose levels prescribed. Median follow-up was 1.6 years. Results: 34 patients (10%) experienced grade 2 chronic rectal toxicity (9% rectal bleeding, 6% proctitis, 3% diarrhea, 1% rectal pain) at a median interval of 1.1 years. Nine patients (3%) experienced grade ≥3 chronic rectal toxicity (1 grade 4) at a median interval of 1.2 years (table). The 3-year rates of grade ≥2 and grade ≥3 chronic rectal toxicity were 20% and 4%, respectively. There was no significant difference by dose level in the 2-year rate of grade ≥2 chronic rectal toxicity. These rates were 27%, 15%, 14%, 17% and 24% for the ≤72, 73.8, 75.6, 77.4, and 79.2 Gy dose level groups respectively (p = 0.27). Conclusions: High dose levels (79.2 Gy) can be safely delivered if selected DVH constraints are met. The prescribed dose should be based on DVH information (toxicity risk) and the benefit of a specific dose level. No significant financial relationships to disclose.

The use of dose volume constraints to achieve rectal isotoxicity: A phase II prostate cancer radiation therapy dose escalation study

4628 Background: The primary limiting factor for prostate cancer irradiation is the risk of rectal toxicity. Rectal toxicity is associated with the dose and volume of the rectum irradiated. This dose escalation study has the unique feature of using dose volume histogram (DVH) constraints to determine the prescribed dose. Methods: From 1999–2002, 331 patients with clinical stage T1-T3N0M0 prostate cancer were prospectively treated with 3D conformal adaptive RT. A patient-specific confidence-limited planning target volume was constructed based on multiple CT scans. For each case, the rectum (rectal solid) was contoured in its entirety. The rectal wall was defined using a 3-mm wall thickness (median volume: 29.8 cc). The prescribed dose level was chosen using the following rectal wall dose constraints: 1) 75.6 Gy. 2) 82 Gy. The risk of chronic toxicity (NCI Common Toxicity Criteria 2.0) was assessed for the different dose levels ...