Acute Rectal Toxicity Research Articles

Five-Year Outcomes of a Phase 1 Dose-Escalation Study Using Stereotactic Body Radiosurgery for Patients With Low-Risk and Intermediate-Risk Prostate Cancer

To report toxicity outcomes, prostate-specific antigen (PSA) relapse, and cumulative incidence posttreatment biopsy results among patients treated on a prospective dose escalation study using ultra-hypofractionated stereotactic body radiation therapy (SBRT) for patients with low- and intermediate-risk prostate cancer. A total of 136 patients were enrolled in a phase 1 dose-escalation study to determine the tolerance of escalating radiation dose levels of SBRT for the treatment of localized prostate cancer. The initial dose level was 32.5Gy in 5 fractions, and doses were then sequentially escalated to 35Gy, 37.5Gy, and 40Gy. Eligibility criteria included only patients with low and intermediate risk, and the maximum prostate volume was 60cm3. Patients treated with neoadjuvant androgen deprivation were excluded. The median follow-up in survivors for the 4 dose levels was 5.9, 5.4, 4.1, and 3.5years, respectively. The incidence of acute grade 2 rectal toxicities for dose levels 1 to 4 were 0%, 2.9%, 2.8%, and 11.4% respectively. No grade 3 or 4 acute rectal toxicities were observed. The incidence of acute grade 2 urinary toxicities for dose levels 1 to 4 were16.7%, 22.9%, 8.3%, and 17.1%, respectively. No grade 3 or 4 acute urinary toxicities were observed. No grade 2 or higher rectal toxicities were observed. The incidence of late grade 2 urinary toxicities for dose levels 1 to 4 was 23.3%, 25.7%, 27.8%, and 31.4%, respectively. Only 1 late grade 3 urinary toxicity (urethral stricture) developed in the 40-Gy dose arm; the stricture was corrected with transurethral resection. No grade 4 late urinary toxicity was observed. The 5-year cumulative incidence of prostate-specific antigen failure for dose levels 1 to 4 was 15%, 6%, 0%, and 0%. The incidence of a 2-year positive posttreatment biopsy was 47.6%, 19.2%, 16.7%, and 7.7%, respectively for the 4 dose arms (P=.013). SBRT doses ranging from 32.5 to 40Gy in 5 fractions were well tolerated without severe urinary or rectal toxicities. Biopsy outcomes suggest improved rates of tumor clearance observed with higher doses.

Radiomics modelling of IMRT induced acute rectal toxicity using clinical and magnetic resonance imaging features

Introduction: Rectal toxicity is a dose limiting issue in prostate cancer radiotherapy. Prediction of these effects may be used to tailor the therapy. The purpose of this work was to develop predictive radiomic models based on clinical, dosimetric and radiomic features extracted from rectal wall magnetic resonance image (MRI). Materials and Methods: This study was conducted on 30 prostate cancer patients underwent intensity modulated radiation therapy (IMRT). Patient’s clinical and dosimetric parameters were collected and proctitis was assessed. All patients underwent MRI before and after IMRT with same protocol. Several radiomic features were extracted from rectal wall MR images including T2 weighted (T2W) and apparent diffusion coefficient (ADC) scans and robust features were found. Lasso regularization was used to create multivariable Elastic Net logistic regression model, based on clinical, dosimetric and robust features for prediction and feature selection, simultaneously. All models were cross-validated using repeated five-fold cross-validation and their performance were evaluated by area under the curve of the ROC curve (AUC), sensitivity and specificity. Results: Eleven predictive models including one clinical and ten radiomic models were built. All models were found as high predictive performance (AUC≥0.83). T2 based radiomic models were more predictive rather than ADC models. Post-IMRT T2W radiomic model also showed a good predictive performance. Image features enhanced the all model’s predictive performance. Conclusion: Rectal wall MR radiomic features integrating with clinical and dose-volume parameters could improve the prediction performance of radiotherapy induced proctitis. The authors have demonstrated the performance of radiomic features extracted from pre IMRT T2W and ADC MR Images for prediction of IMRT induced rectal toxicity. These results may be used to tailor the therapy in terms of patient and.

Can Modeling of Acute Rectal Toxicity in IMRT Treatments for Prostate Cancer be Used for Quality Assurance?

Can Modeling of Acute Rectal Toxicity in IMRT Treatments for Prostate Cancer be Used for Quality Assurance?

A novel model to correlate hydrogel spacer placement, perirectal space creation, and rectum dosimetry in prostate stereotactic body radiotherapy

BackgroundThe SpaceOAR hydrogel is employed to limit rectal radiation dose during prostate radiotherapy. We identified a novel parameter – the product of angle θ and hydrogel volume – to quantify hydrogel placement. This parameter predicted rectum dosimetry and acute rectal toxicity in prostate cancer patients treated with stereotactic body radiotherapy to 36.25 Gy in 5 fractions.MethodsTwenty men with low- and intermediate-risk prostate cancer underwent hydrogel placement from 2015 to 2017. Hydrogel symmetry was assessed on the CT simulation scan in 3 axial slices (midgland, 1 cm above midgland, 1 cm below midgland). Two novel parameters quantifying hydrogel placement – hydrogel volume and angle θ formed by the prostate, hydrogel, and rectum – were measured, and the normalized product of θ and hydrogel volume calculated. These were then correlated with perirectal distance, rectum maximum 1–3 cc point doses (rDmax 1–3 cc), and rectum volumes receiving 80–95% of the prescription dose (rV80–95%). Acute rectal toxicity was recorded per RTOG criteria.ResultsIn 50% of patients, hydrogel placement was symmetric bilaterally to within 1 cm of midline in all three CT simulation scan axial slices. Lateral hydrogel asymmetry < 2 cm in any one axial slice did not affect rectum dosimetry, but absence of hydrogel in the inferior axial slice resulted in a mean increase of 171 cGy in the rDmax 1 cc (p < 0.005). The perirectal distance measured at prostate midgland, midline (mean 9.1 ± 4.3 mm) correlated strongly with rV95 (R2 0.6, p < 0.001). The mean hydrogel volume and θ were 10.3 ± 4.5 cc and 70 ± 49°, respectively. Perirectal distance, rV95 and rDmax 1 cc correlated with hydrogel angle θ (p < 0.01), and yet more strongly with the novel metric θ*hydrogel volume (p < 0.001). With a median follow up of 14 months, no rectal toxicity >grade 2 was observed. Low grade rectal toxicity was observed in a third of men and resolved within 1 month of SBRT. Men who had these symptoms had higher rDmax 1 cc and smaller θ*hydrogel volume measurements.ConclusionsOptimal hydrogel placement occurs at prostate midgland, midline. The novel parameter θ*hydrogel volume describes a large proportion of rectum dosimetric benefit derived from hydrogel placement, and can be used to assess the learning curve phenomenon for hydrogel placement.

3D-conformal hypofractionated radiotherapy for prostate cancer with daily transabdominal ultrasonography prostate localization: toxicity and outcome of a pilot study.

To evaluate the feasibility, toxicity and patient outcome of hypofractionated 3-dimensional conformal radiotherapy for low- and intermediate-risk prostate cancer, using daily an ultrasound targeting system (BAT). Between May 2005 and October 2006, 25 patients (cT1-T2, GS < or = 7, mean initial PSA = 7.06 ng/ml) received a dose of 72 Gy in 30 fractions. Only the prostate was included in the clinical target volume. Immediately before each radiotherapy session, BATTM ultrasound alignment was performed. Acute and late toxicity was evaluated according to the Radiation Therapy Oncology Group criteria; the Phoenix definition (PSA = nadir + 2 ng/ml) was applied to define biochemical failure. BAT localization data were provided for 300 out of 750 procedures. No interruptions in 3-dimensional conformal radiotherapy due to toxicity were registered. There was no acute rectal toxicity in 52% of patients; 28% had G1, 16% had G2, and 1 patient had a G3 event. No acute urinary toxicity was observed in 28% of the patients. G1 toxicity occurred in 40%, G2 in 28%, and G3 in 1 patient; no G4 event was observed. With an average follow-up of 45 months, one biochemical relapse was observed; late toxicity showed an excellent profile: 78% of the patients had no rectal toxicity, 16% had G1, and 1 patient had G2 toxicity. Most of the patients (68%) had no late urinary complications, whereas 32% had G1 toxicity. Localization data showed systematic and random errors in relation to some procedure biases. Promising tumor control and toxicity profile were observed with this mildly hypofractionated BAT-based 3-dimensional conformal radiotherapy.

Radiotherapy for prostate cancer – Does daily image guidance with tighter margins improve patient reported outcomes compared to weekly orthogonal verified irradiation? Results from a randomized controlled trial

BackgroundNovel cancer drugs are subject to strict scientific evaluation of safety and efficacy and usually undergo a cost effectiveness analysis before approval for use in clinical practice. For new techniques in radiotherapy (RT) such as image-guided radiotherapy (IGRT), this is often not the case. We performed a randomized controlled trial to compare daily cone beam computer tomography (CBCT) IGRT with reduced planning target volume (PTV) margins vs weekly orthogonal portal imaging with conventional PTV margins. The primary aim of the study was to investigate the effect of two different image guidance techniques on patient reported outcome (PRO) using early side effects as proxy outcome of late rectal side effects in patients receiving curative RT for prostate cancer. MethodsThis open label, phase 3 trial conducted at two RT centers in Norway enrolled men aged 18 years or older with previously untreated histologically proven intermediate or high-risk adenocarcinoma of the prostate. Patients eligible for radical RT received it after 3 months of total androgen blockage and were randomly assigned to 78 Gy in 39 fractions guided either by weekly offline orthogonal portal imaging (15 mm margins to PTV) or by daily online CBCT IGRT (7 mm margins to PTV). Based on previous results indicating that acute rectal side effects are a valid proxy outcome for late rectal side effects, the primary outcome was acute rectal toxicity at end of RT as evaluated by rectal bother scale (five of the items from PRO’s QUFW94). The RIC-trial is registered with ClinicalTrials.gov, number NCT01550237. FindingsBetween October 2012 and June 2015, 257 patients were randomly assigned to weekly offline portal imaging (n = 129) or daily online CBCT IGRT (n = 128). Out of 250 evaluable patients, 96% completed PROs at baseline and 97% at end of RT. Baseline analyses demonstrated balance between groups for baseline characteristics as well as for PROs. In general, patients reported a small degree of side effects at end of RT, and there was no difference between groups for primary outcome (rectal bother scale of QUFW94 1.871 vs 1.884, p = 0.804). In addition, there were no significant differences between groups for any other gastrointestinal or urinary symptom as reported by QUFW94. Health related quality of life analyses (EORTC QLQ 30) demonstrated no differences between groups. InterpretationIn radical RT for prostate cancer, daily CBCT IGRT with reduced PTV margins demonstrated no advantage with respect to patient reported side effects at end of RT as compared to weekly orthogonal offline portal imaging with standard PTV margins.

Modeling of Acute Rectal Toxicity to Compare Two Patient Positioning Methods for Prostate Cancer Radiotherapy: Can Toxicity Modeling be Used for Quality Assurance?

Purpose:Intensity Modulated Radiation Therapy (IMRT) allows for significant dose reductions to organs at risk in prostate cancer patients. However, the accurate delivery of IMRT plans can be compromised by patient positioning errors. The purpose of this study was to determine if the modeling of grade ≥ 2 acute rectal toxicity could be used to monitor the quality of IMRT protocols.Materials and Methods:79 patients treated with Image and Fiducial Markers Guided IMRT (FMIGRT) and 302 patients treated with trans-abdominal ultrasound guided IMRT (USGRT) was selected for this study. Treatment plans were available for the FMIGRT group, and hand recorded dosimetric indices were available for both groups. We modeled toxicity in the FMIGRT group using the Lyman Kutcher Burman (LKB) and Univariate Logistic Regression (ULR) models, and we modeled toxicity in USGRT group using the ULR model. We performed Receiver Operating Characteristics (ROC) analysis on all of the models and compared the Area under the ROC curve (AUC) for the FMIGRT and the USGRT groups.Results:The observed Incidence of grade ≥ 2 rectal toxicity was 20% in FMIGRT patients and 54% in USGRT patients. LKB model parameters in the FMIGRT group were TD50=56.8 Gy, slope m=0.093, and exponent n=0.131. The most predictive indices in the ULR model for the FMIGRT group were D25% and V50 Gy. AUC for both models in the FMIGRT group was similar (AUC=0.67). The FMIGRT URL model predicted less than a 37% incidence of grade ≥ 2 acute rectal toxicity in the USGRT group. A fit of the ULR model to USGRT data did not yield a predictive model (AUC=0.5).Conclusion:Modeling of acute rectal toxicity provided a quantitative measure of the correlation between planning dosimetry and this clinical endpoint. Our study suggests that an unusually weak correlation may indicate a persistent patient positioning error.

Evaluation of Mediators Associated with the Inflammatory Response in Prostate Cancer Patients Undergoing Radiotherapy

A recent “hot topic” in prostate cancer radiotherapy is the observed association between acute/late rectal toxicity and the presence of abdominal surgery before radiotherapy. The exact mechanism is unclear. Our working hypothesis was that a previous surgery may influence plasma level of inflammatory molecules and this might result in enhanced radiosensitivity. We here present results on the feasibility of monitoring the expression of inflammatory molecules during radiotherapy. Plasma levels of a panel of soluble mediators associated with the inflammatory response were measured in prostate cancer patients undergoing radical radiotherapy. We measured 3 cytokines (IL-1b, IL-6, and TNF alpha), 2 chemokines (CCL2 and CXCL8), and the long pentraxin PTX3. 20 patients were enrolled in this feasibility evaluation. All patients were treated with IMRT at 78 Gy. 3/20 patients reported grade 2 acute rectal toxicity, while 4/20 were scored as grade 2 late toxicity. CCL2 was the most interesting marker showing significant increase during and after radiotherapy. CCL2 levels at radiotherapy end could be modelled using linear regression including basal CCL2, age, surgery, hypertension, and use of anticoagulants. The 4 patients with late toxicity had CCL2 values at radiotherapy end above the median value. This trial is registered with ISRCTN64979094.

Placement of an absorbable rectal hydrogel spacer in patients undergoing low-dose-rate brachytherapy with palladium-103

PurposeRates of rectal toxicity after low-dose-rate (LDR) brachytherapy for prostate cancer are dependent on rectal dose, which is associated with rectal distance from prostate and implanted seeds. Placement of a hydrogel spacer between the prostate and rectum has proven to reduce the volume of the rectum exposed to higher radiation dose levels in the setting of external beam radiotherapy. We present our findings with placing a rectal hydrogel spacer in patients following LDR brachytherapy, and we further assess the impact of this placement on dosimetry and acute rectal toxicity. Methods and MaterialsBetween January 2016 and April 2017, 74 patients had placement of a hydrogel spacer, immediately following a Pd-103 seed-implant procedure. Brachytherapy was delivered as follows: as a monotherapy to 26 (35%) patients; as part of planned combination therapy with external beam radiotherapy to 40 (54%) patients; or as a salvage monotherapy to eight (11%) patients. Postoperative MRI was used to assess separation achieved with rectal spacer. Acute toxicity was assessed retrospectively using Radiation Oncology Therapy Group radiation toxicity grading system. Rectal dosimetry was compared with a consecutive cohort of 136 patients treated with seed implantation at our institution without a spacer, using a 2-tailed paired Student's t test (p < 0.05 for statistical significance). ResultsOn average, 11.2-mm (SD 3.3) separation was achieved between the prostate and the rectum. The resultant mean rectal volume receiving 100% of prescribed dose (V100%), dose to 1 cc of rectum (D1cc), and dose to 2 cc of rectum (D2cc) were 0 (SD 0.05 cc), 25.3% (SD 12.7), and 20.5% (SD 9.9), respectively. All rectal dosimetric parameters improved significantly for the cohort with spacer placement as compared with the nonspacer cohort. Mean prostate volume, prostate V100 and dose to 90% of gland (D90) were 29.3 cc (SD 12.4), 94.0% (SD 3.81), and 112.4% (SD 12.0), respectively. Urethral D20, D5cc, and D1cc were 122.0% (SD 17.27), 133.8% (SD 22.8), and 144.0% (SD 25.4), respectively. After completing all treatments, at the time of first the followup, 7 patients reported acute rectal toxicity—6 experiencing Grade 1 rectal discomfort and 1 (with preexisting hemorrhoids) experiencing Grade 1 bleeding. ConclusionsInjection of rectal spacer is feasible in the post-LDR brachytherapy setting and reduces dose to the rectum with minimal toxicity. Prostate and urethral dosimetries do not appear to be affected by the placement of a spacer. Further studies with long-term followup are warranted to assess the impact on reduction of late rectal toxicity.

Predictors of urinary and rectal toxicity after external conformed radiation therapy in prostate cancer: Correlation between clinical, tumor and dosimetric parameters and radical and postoperative radiation therapy

ObjectiveTo determine rectal and urinary toxicity after external beam radiation therapy (EBRT), assessing the results of patients who undergo radical or postoperative therapy for prostate cancer (pancreatic cancer) and their correlation with potential risk factors. MethodA total of 333 patients were treated with EBRT. Of these, 285 underwent radical therapy and 48 underwent postoperative therapy (39 cases of rescue and 9 of adjuvant therapy). We collected clinical, tumor and dosimetric variable to correlate with toxicity parameters. We developed decision trees based on the degree of statistical significance. ResultsThe rate of severe acute toxicity, both urinary and rectal, was 5.4% and 1.5%, respectively. The rate of chronic toxicity was 4.5% and 2.7%, respectively. Twenty-seven patients presented haematuria, and 9 presented hemorrhagic rectitis. Twenty-five patients (7.5%) presented permanent limiting sequela. The patients with lower urinary tract symptoms prior to the radiation therapy presented poorer tolerance, with greater acute bladder toxicity (p=0.041). In terms of acute rectal toxicity, 63% of the patients with mean rectal doses >45Gy and anticoagulant/antiplatelet therapy developed mild toxicity compared with 37% of the patients with mean rectal doses <45Gy and without anticoagulant therapy. We were unable to establish predictors of chronic toxicity in the multivariate analysis. The long-term sequelae were greater in the patients who underwent urological operations prior to the radiation therapy and who were undergoing anticoagulant therapy. ConclusionsThe tolerance to EBRT was good, and severe toxicity was uncommon. Baseline urinary symptoms constitute the predictor that most influenced the acute urinary toxicity. Rectal toxicity is related to the mean rectal dose and with anticoagulant/antiplatelet therapy. There were no significant differences in severe toxicity between radical versus postoperative radiation therapy.

To prep or not to prep - that is the question: A randomized trial on the use of antiflatulent medication as part of bowel preparation for patients having image guided external beam radiation therapy to the prostate

IntroductionRadiation therapy is a standard treatment option for prostate cancer. With growing use of escalated doses and tighter margins, procedures to limit rectal size variation are needed to reduce prostate motion, increase treatment accuracy, and minimize rectal toxicity. This prospective study was done to determine whether the introduction of an antiflatulent medication would decrease rectal distention at computed tomography (CT) simulation and throughout a course of radiation therapy. Methods and materialsPatients undergoing a radical course of radiation therapy to the prostate/prostate bed were eligible to participate. Participants were randomly assigned to the intervention arm (antiflatulent medication) or the control arm (no medication). For each participant, the number of CT simulation rescans was recorded. Rectal diameters were measured on CT simulation and treatment cone beam CT scans. Acute rectal toxicities were assessed at baseline and weekly using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0. A χ2 analysis was used to compare the number of participants requiring a rescan in each study arm. Change in rectal diameter over time was assessed using repeated measures analysis of variance. ResultsA total of 78 patients participated, with equal numbers assigned to each study arm. There was no significant difference between arms in the number of participants requiring a CT simulation rescan (P = .5551). There was no significant variation in rectal diameter between arms (P = .8999); however, there was a significant effect of time (P = .0017) and a significant interaction effect between study arm and time on rectal diameter (P = .0141). No acute rectal toxicities above grade 2 were reported. ConclusionsThe addition of antiflatulent medication did not affect the frequency of CT simulation rescans. Both time and the interaction between study arm and time had a statistically significant effect on rectal diameter, although neither finding was clinically significant. Instead, standardized bowel preparation education developed for this study may have been sufficient to limit rectal size variation.

Factores predictivos de toxicidad urinaria y rectal tras radioterapia externa conformada en el cáncer de próstata: correlación de parámetros clínicos, tumorales y dosimétricos con radioterapia radical y postoperatoria

ObjectiveTo determine rectal and urinary toxicity after external beam radiation therapy (EBRT), assessing the results of patients who undergo radical or postoperative therapy for prostate cancer (pancreatic cancer) and their correlation with potential risk factors. MethodA total of 333 patients were treated with EBRT. Of these, 285 underwent radical therapy and 48 underwent postoperative therapy (39 cases of rescue and 9 of adjuvant therapy). We collected clinical, tumour and dosimetric variable to correlate with toxicity parameters. We developed decision trees based on the degree of statistical significance. ResultsThe rate of severe acute toxicity, both urinary and rectal, was 5.4% and 1.5%, respectively. The rate of chronic toxicity was 4.5% and 2.7%, respectively. Twenty-seven patients presented haematuria, and 9 presented haemorrhagic rectitis. Twenty-five patients (7.5%) presented permanent limiting sequela. The patients with lower urinary tract symptoms prior to the radiation therapy presented poorer tolerance, with greater acute bladder toxicity (P=0.041). In terms of acute rectal toxicity, 63% of the patients with mean rectal doses >45Gy and anticoagulant/antiplatelet therapy developed mild toxicity compared with 37% of the patients with mean rectal doses <45 Gy and without anticoagulant therapy. We were unable to establish predictors of chronic toxicity in the multivariate analysis. The long-term sequelae were greater in the patients who underwent urological operations prior to the radiation therapy and who were undergoing anticoagulant therapy. ConclusionsThe tolerance to EBRT was good, and severe toxicity was uncommon. Baseline urinary symptoms constitute the predictor that most influenced the acute urinary toxicity. Rectal toxicity is related to the mean rectal dose and with anticoagulant/antiplatelet therapy. There were no significant differences in severe toxicity between radical versus postoperative radiation therapy.

Statins Protect Against Acute RT-related Rectal Toxicity in Patients with Prostate Cancer: An Observational Prospective Study.

To analyze risk factors for acute rectal toxicity during hypofractionated intensity-modulated radiotherapy (IMRT) for prostate cancer. A total of 195 patients received 74.25 Gy in 33 fractions to the prostate and, if involved, to the seminal vescicles (SV). When the risk of SV involvement was >15% according to the Roach's formula, they received 62 Gy in 33 fractions. Overall, 107/195 patients (54.87%) received hormonal therapy (luteinizing hormone-releasing hormone analogue, anti-androgen, or both). Common Terminology Criteria for Adverse Events version 3.0 was used to classify rectal toxicity. Acute rectal toxicity occurred in 79 (40.51%) patients (grade 1 in 44). In univariate analysis, use of calcium channel blockers significantly reduced the acute rectal toxicity rate and 3-hydroxy-methylglutaryl CoA reductase inhibitors (statins) significantly reduced the rectal toxicity rate and grade. In multivariate analysis, only statin use was an independent protective factor. In patients with prostate cancer treated with a moderate hypofractionated IMRT schedule, use of statins lowered the incidence and grade of acute rectal toxicity.

Phase I/II study on stereotactic hypofractionated once-weekly radiation therapy (SHORT) for localized prostate cancer.

130 Background: The low α/β ratio of prostate cancer (PrCa) is well established. However, stereotactic hypofractionated radiotherapy (SRT) has been investigated primarily in highly selected patient populations with low-intermediate risk disease. We performed a clinical trial of SRT delivered in once-weekly fractions on an unselected cohort of patients with non-metastatic PrCa. Methods: In this Phase I/II study 30 patients with non-metastatic PrCa (multiparametric MRI cT1-4N0, M0, Gleason 6-10, PSA &lt; = 60 ng/ml) were treated with SRT to a prescription dose of 35Gy in 5 fractions delivered once a week (overall treatment time 29 days). Elective nodal RT at 25Gy/5Fr was delivered in patients high-risk by NCCN criteria, and androgen deprivation therapy given to intermediate and high-risk patients. SRT was planned using volumetric intensity modulated arc therapy (VMAT) or Helical Tomotherapy (HT) with pre-defined dose-criteria. The primary endpoint was acute toxicity NCI CTC v4, and secondary endpoints were biochemical control and late toxicity. Results: Thirty patients completed treatment per-protocol. Stage T3, Gleason 8-10, and PSA &gt; 10 was seen in 18 (60%), 7 (23%) and 24 (80%) respectively. Overall 20 (66.7%) were high-risk. Median of Mean PTV dose was 36Gy, and normal tissue constraints could be met in all patients (Table). Acute urinary toxicities (Gr 0: 1; Gr 1: 27; Gr 2: 1; Gr 3-4: 0) and acute rectal toxicities (Gr 0: 20; Gr 1: 10; Gr 2: 0; Gr 3-4: 0) were very modest. The mean IPSS scores at baseline, end of treatment and 3 months after treatment were 8.8, 14.7, and 9.9. With a median follow up of 23.7 months, the 2 year biochemical control was 96%. Late grade 2 rectal bleeding developed in 1 patient. Conclusions: Carefully planned stereotactic VMAT/HT based once-weekly SRT to a predominantly high-risk non-metastatic PrCa cohort was very well tolerated and found to be safe for clinical use. Preliminary biochemical control and late toxicity profiles are encouraging. Clinical trial information: CTRI/2016/02/006671. [Table: see text]

Californium-252 neutron intracavity brachytherapy alone for T1N0 low-lying rectal adenocarcinoma: A definitive anal sphincter-preserving radiotherapy

This study evaluated the 4-year results of 32 patients with T1N0 low-lying rectal adenocarcinoma treated solely with californium-252 (Cf-252) neutron intracavity brachytherapy (ICBT). Patients were solicited into the study from January 2008 to June 2011. All the patients had refused surgery or surgery was contraindicated. The patients were treated with Cf-252 neutron ICBT using a novel 3.5-cm diameter off-axis 4-channel intrarectal applicator designed by the authors. The dose reference point was defined on the mucosa surface, with a total dose of 55–62 Gy-eq/4 f (13–16 Gy-eq/f/wk). All the patients completed the radiotherapy in accordance with our protocol. The rectal lesions regressed completely, and the acute rectal toxicity was mild (≤G2). The 4-year local control, overall survival, disease-free survival, and late complication (≥G2) rates were 96.9%, 90.6%, 87.5% and 15.6%, respectively. No severe late complication (≥G3) occurred. The mean follow-up was 56.1 ± 16.0 months. At the end of last follow-up, 29 patients remained alive. The mean survival time was 82.1 ± 2.7 months. Cf-252 neutron ICBT administered as the sole treatment (without surgery) for patients with T1N0 low-lying rectal adenocarcinoma is effective with acceptable late complications. Our study and method offers a definitive anal sphincter-preserving radiotherapy for T1N0 low-lying rectal adenocarcinoma patients.

Image-Guided Radiotherapy Dose Escalation in Intermediate and High Risk Cancer Prostate Patients and Its Effect on Treatment Toxicity

Purpose: To study the effect of escalating radiation dose; in intermediate and high risk prostate cancer patients; via online image-guidance on acute toxicities. Patients and Methods: thirty-eight prostate cancer patients were treated by using simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT) with online image guided correction via kilo voltage cone beam computed tomography (KV-CBCT)/electronic portal imaging device (EPID) of trans-rectal ultrasound (TRUS)-inserted intraprostatic gold fiduciary markers. High-risk patients received a median dose of 80.5 Gy to prostate and 56 Gy to pelvic nodes in 35 fractions over 7 weeks. Intermediate-risk patients received a similar prostate dose over the same overall treatment time. Acute toxicity (bladder, rectal and bowel symptoms) was reported once weekly during the radiation course and up to 3 months from the end of the radiation course. Results: The image guided (IG)-IMRT allows escalating the radiation dose delivered to the prostate through minimizing the margin of setup error to less than 0.5 cm with subsequent sparing of nearby organs at risk. Out of thirty-eight patients, no patient developed >grade 1 acute rectal toxicity, 7.9% of patients experienced grade 3 urinary toxicity and there was no reported small intestinal toxicity. Conclusion: Escalating the radiation dose more than 80 Gy in intermediate and high risk prostate cancer patients was safe and not associated with grade 3 - 4 RTOG toxicity when guided by online verification of intra-prostatic fiducial markers.

Acute toxicity and its dosimetric correlates for high-risk prostate cancer treated with moderately hypofractionated radiotherapy

AimsTo report the acute toxicity and the dosimetric correlates after moderately hypofractionated radiotherapy for localized prostate cancer. MethodsA total of 101 patients with localized prostate cancer were treated with image-guided intensity-modulated radiation therapy. Patients were treated to 65Gy/25Fr/5 weeks (n = 18), or 60Gy/20Fr/4 weeks (n = 83). Most (82.2%) had high-risk or pelvic node-positive disease. Acute toxicity was assessed using Radiation Therapy Oncology Group (RTOG) acute morbidity scoring criteria. Dose thresholds for acute rectal and bladder toxicity were identified. ResultsThe incidence of acute grade 2 GI toxicity was 20.8%, and grade 2 genitourinary (GU) toxicity was 6.9%. No Grade 3 to 4 toxicity occurred. Small bowel toxicity was uncommon (Gr 2 = 4%). The 2Gy equivalent doses (EQD2) to the rectum and bladder (α/β = 3) calculated showed that the absolute doses were more consistent predictors of acute toxicities than the relative volumes. Those with grade 2 or more GI symptoms had significantly higher VEQD2-60Gy (13.2 vs 9.9cc, p = 0.007) and VEQD2-50Gy (20.6 vs 15.4cc, p = 0.005). Those with grade 2 or more GU symptoms had significantly higher VEQD2-70Gy (30.4 vs 18.4cc, p = 0.001) and VEQD2-65Gy (44.0 vs 28.8cc, p = 0.001). The optimal cutoff value for predicting grade 2 acute proctitis, for VEQD2-60Gy was 9.7cc and for VEQD2-50Gy was 15.9cc. For grade 2 GU symptoms, the threshold values were 23.6cc for VEQD2-70Gy and 38.1cc for VEQD2-65Gy. ConclusionsHypofractionated radiotherapy for prostate cancer is well tolerated and associated with manageable acute side effects. The absolute dose-volume parameters of rectum and bladder predict for acute toxicities.

Favorable Preliminary Outcomes for Men With Low- and Intermediate-risk Prostate Cancer Treated With 19-Gy Single-fraction High-dose-rate Brachytherapy

To report the toxicity and preliminary clinical outcomes of a prospective trial evaluating 19-Gy, single-fraction high-dose-rate (HDR) brachytherapy for men with low- and intermediate-risk prostate cancer. A total of 63 patients were treated according to an institutional review board-approved prospective study of single-fraction HDR brachytherapy. Eligible patients had tumor stage≤T2a, prostate-specific antigen level ≤15ng/mL, and Gleason score ≤7. Patients with a prostate gland volume >50cm3 and baseline American Urologic Association symptom score >12 were ineligible. Patients underwent transrectal ultrasound-guided transperineal implantation of the prostate, followed by single-fraction HDR brachytherapy. Treatment was delivered using 192Ir to a dose of 19Gy prescribed to the prostate, with no additional margin applied. Of the 63 patients, 58 had data available for analysis. Five patients had withdrawn consent during the follow-up period. The median follow-up period was 2.9years (range 0.3-5.2). The median age was 61.4years. The median gland volume at treatment was 34.8cm3. Of the 58 patients, 91% had T1 disease, 71% had Gleason score ≤6 (29% with Gleason score 7), and the median pretreatment prostate-specific antigen level was 5.1ng/mL. The acute and chronic grade 2 genitourinary toxicity incidence was 12.1% and 10.3%, respectively. No grade 3 urinary toxicity occurred. No patients experienced acute rectal toxicity grade ≥2, and 2 experienced grade ≥2 chronic gastrointestinal toxicity. Three patients experienced biochemical failure, yielding a 3-year cumulative incidence estimate of 6.8%. Single-fraction HDR brachytherapy is well-tolerated, with favorable preliminary biochemical and clinical disease control rates.

Absolute volume of the rectum and AUC from rectal DVH between 25Gy and 50Gy predict acute gastrointestinal toxicity with IG-IMRT in prostate cancer.

BackgroundTo determine whether dose/volume specific endpoints (DVSE) or Area under the rectal DVH curve (rAUC) better predict acute gastrointestinal (GI) toxicity in prostate cancer patients treated with IMRT in the era of daily image guidance (IG-IMRT).MethodsA set of DVSE was recorded from V25 to V75 (increments of 5Gy) (both in % and in cc) for 180 men. The rAUC was calculated for doses ranging between 25Gy and 50Gy (rAUC25–50). Univariate and multivariate logistic regressions were performed to determine the relationship between DVSE or rAUC25–50 and the appearance of any acute GI toxicity.ResultsThe rates of acute grade 1 (G1), G2 and G3 GI toxicities were 53.3 %, 10.6 % and 1.1 %, respectively. No G4+ toxicity was observed.Rectal V25 to V75 expressed in % were not predictive of G ≥ 1 GI toxicity (p ≥ 0.12) whereas rectal V25 to V50 expressed in cc did correlate with GI toxicity G ≥ 1 (p ≤ 0.04). rAUC25–50 expressed in cc. Gy correlated significantly with the occurrence of any acute GI toxicity G ≥ 1 (p = 0.027).ConclusionsThe absolute volume of the rectum between 25Gy and 50Gy and rAUC25–50 could significantly predict any acute rectal toxicity in prostate cancer patients treated with daily IG-IMRT.

MLH1 Ile219Val Polymorphism in Argentinean Families with Suspected Lynch Syndrome.

Heredity is a major risk factor for colorectal cancer (CRC). Identification of individuals and families at increased risk allows for targeted surveillance, which has been shown to reduce morbidity and mortality from CRC (1, 2). Lynch syndrome is a multi-tumor syndrome with particularly high risks for colorectal, endometrial, and ovarian cancer (3–6). The syndrome is caused by germline DNA-mismatch repair (MMR) gene mutations with major contributions from MLH1 (MIM#120436) (42%), MSH2 (MIM#609309) (33%), MSH6 (MIM#600678) (18%), and PMS2 (MIM#600259) (8%). Only about one-third of the Lynch syndrome families fulfill the Amsterdam criteria (AC) (7–9). The cumulative incidence of any cancer at 70 years of age is 72% for MLH1 and MSH2 mutation carriers but lower in MSH6 (52%) and PMS2 (18%) mutation carriers. MSH6 and PMS2 carriers developed no cancers before 40 years of age (10). Mutation screening in a relatively large proportion of South American families with suspected Lynch syndrome has recently identified 99 disease-predisposing mutations in MLH1 and MSH2, which mutation spectrum is predominated by MLH1 (60%) and MSH2 (40%). Among the reported mutations, genetic hot-spot regions, new and potential founder mutations have been described in the South American population (11, 12). Several genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in at least 15 independent loci associated with CRC risk (odds ratio ranging from 1.10 to 1.26 per risk allele) (13–15). Although there is no evidence that these SNPs associated with CRC in the general population are modifiers of the risk for MMR gene mutation carriers overall and therefore any evidence of proven clinical utility in Lynch syndrome (16). The MLH1 Ile219Val (rs1799977) is a common germline alteration, located in exon 8 at the nucleotide 655. This polymorphism has been described in a high frequency of the South American Lynch syndrome population, but no modifier effect of CRC risk and MMR disease-predisposing mutation carriers was observed (17). However, it has been reported to confer a twofold-increased risk of CRC development in sporadic Mexican patients (18). Other conditions that have been associated with this polymorphism include childhood acute lymphoblastic leukemia, breast cancer, radiation-induced rectal or bladder toxicity, and ulcerative colitis (19–23). It is unknown whether the MLH1 Ile219Val polymorphism has an effect on cancer risk and in the MMR capacity in Argentinean families with suspected Lynch syndrome. Thus, we aim to determine its frequency, its correlation with disease-predisposing MMR gene mutations, and to delineate the clinical characteristics from these families.