Late Rectal Toxicity Research Articles

OC-88 FIRST CLINICAL RESULTS OF THE GEC-ESTRO BREAST WG PHASE III MULTICENTRIC APBI TRIAL.

were transformed to match the day 1 anatomy using MORPHEUS, a specialized soft tissue deformation algorithm. Finally, the accumulated HR-CTV D90, rectal wall D2cm 3 (RW) and bladder wall D2cm 3 (BW) were estimated (in equivalent 2 Gy fractions) assuming stable anatomy and dosimetry between scans. These were compared to the planned values. Median follow-up was 2.1 years. Rectal and bladder toxicity were recorded using CTAC 4.0. Results: There were no significant differences between the mean accumulated doses (AD) and mean planned doses (PD) for HR-CTV, RW or BW. However, there were large potentially significant differences in individual patients, particularly for BW and RW. For BW, the AD was greater than the PD in 30% of patients with the largest increase being 11.5 Gy. There was only 1 patient with late radiation cystitis (PD 86 Gy, AD 90 Gy). For RW, the AD was greater than PD in 52% of patients, with absolute differences ranging from -7.4 Gy to 9.3 Gy. Rectal bleeding occurred in 4 patients and 1 other developed a fistula. The RW PD was >75 Gy in only 1 of these patients (79 Gy) but the AD was >75 Gy in 4 of 5 patients (76 88 Gy). Among all patients with RW AD dose >75 Gy, 50% developed late rectal toxicity compared to only 5% with a lower RW AD. Conclusions: Accumulated deformation dose compared to planned dose can vary greatly from patient to patient. Accumulated deformation dose for RW D2cm 3 appeared to be of greatest consequence, with rectal toxicity occurring more frequently in patients with D2cm 3 greater than 75 Gy, which may not have been predicted from planned day 1 dosimetry. Further follow-up is required for outcomes in bladder toxicity and local tumor control.

Commentary on “Multi-institutional phase II study of proton beam therapy for organ-confined prostate cancer focusing on the incidence of late rectal toxicities.” K. Nihei, T. Ogino, M. Onozawa, S. Murayama, H. Fuji, M. Murakami, Y. Hishikawa, Radiation Oncology Division, National Cancer Centre, Hospital East, Kashiwa, Japan: Int J Radiat Oncol Biol Phys 2011;81:390–6

Commentary on “Multi-institutional phase II study of proton beam therapy for organ-confined prostate cancer focusing on the incidence of late rectal toxicities.” K. Nihei, T. Ogino, M. Onozawa, S. Murayama, H. Fuji, M. Murakami, Y. Hishikawa, Radiation Oncology Division, National Cancer Centre, Hospital East, Kashiwa, Japan: Int J Radiat Oncol Biol Phys 2011;81:390–6

Increasing the risk of late rectal bleeding after high-dose radiotherapy for prostate cancer: The case of previous abdominal surgery. Results from a prospective trial

PurposeTo evaluate and discuss the role of specific types of abdominal surgery (SURG) before radical radiation therapy as a risk factor for late rectal toxicity in prostate cancer patients. MethodsResults concerning questionnaire-based scored late bleeding and faecal incontinence in 718 patients with a complete follow-up of 36months were analysed, focusing on the impact of specific pre-radiotherapy abdominal/pelvic surgery procedures. Patients were accrued in the prospective study AIROPROS 0102. Different types of surgery (rectum-sigma resection, kidney resection, cholecystectomy or appendectomy) were considered as covariates together with a number of different parameters previously found to be predictive of late toxicity and including clinical as well as dosimetric parameters. Univariate (UVA) and multivariate (MVA) logistic analyses were carried out. ResultsIn total 69/718 patients were previously submitted to one or more surgical procedures, mostly cholecystectomy (n=21) and appendectomy (n=27). Actuarial incidences of G2–G3 and G3 bleeding were 52 (7.2%) and 24 (3.3%) respectively; 19 (2.6%) chronic incontinence events were registered.Cholecystectomy was found to be highly correlated with late rectal bleeding at UVA: OR=4.3 and p=0.006 for G2–G3 and OR=5.4 and p=0.01 for G3. Considering MVA (including dosimetric and clinical factors), G2–G3 bleeding was significantly correlated to cholecystectomy (OR=6.5, p=0.002), V75Gy (OR=1.074, p=0.003) and secondarily with appendectomy (OR=2.7, p=0.10), presence of acute radioinduced rectal bleeding (OR=1.70, p=0.21) and androgen deprivation (OR=0.67, p=0.25).Appendectomy (OR=5.9, p=0.004) and cholecystectomy (OR=5.5, p=0.016) were very strong predictors of G3 bleeding with V75Gy playing a less significant role (OR=1.037, p=0.26). Conversely, no specific surgery was correlated with actuarial or chronic incontinence. ConclusionsThis analysis highlights previous SURG as the best predictor of late rectal bleeding. Among the different types of abdominal surgery, cholecystectomy and appendectomy play the major role, especially for severe late bleeding.

Early Proctoscopy is a Surrogate Endpoint of Late Rectal Toxicity in Prostate Cancer Treated With Radiotherapy

To predict the grade and incidence of late clinical rectal toxicity through short-term (1 year) mucosal alterations. Patients with prostate adenocarcinoma treated with curative or adjuvant radiotherapy underwent proctoscopy a year after the course of radiotherapy. Mucosal changes were classified by the Vienna Rectoscopy Score (VRS). Late toxicity data were analyzed according to the Kaplan-Meier method. Comparison between prognosis groups was performed by log-rank analysis. After a median follow-up time of 45 months (range, 18-99), the 3-year incidence of grade ≥ 2 rectal late toxicity according to the criteria of the European Organization for Research and Treatment of Cancer and the Radiation Therapy Oncology Group was 24%, with all patients (24/24; 100%) experiencing rectal bleeding. The occurrence of grade ≥ 2 clinical rectal late toxicity was higher in patients with grade ≥ 2 (32% vs. 15 %, p = 0.02) or grade ≥ 3 VRS telangiectasia (47% vs. 17%, p ≤ 0.01) and an overall VRS score of ≥ 2 (31% vs. 16 %, p = 0.04) or ≥ 3 (48% vs. 17%, p = 0.01) at the 1-year proctoscopy. Early proctoscopy (1 year) predicts late rectal bleeding and therefore can be used as a surrogate endpoint for late rectal toxicity in studies aimed at reducing this frequent complication.

Do Intermediate Radiation Doses Contribute to Late Rectal Toxicity? An Analysis of Data From Radiation Therapy Oncology Group Protocol 94-06

To investigate whether the volumes of rectum exposed to intermediate doses, from 30 to 50 Gy, contribute to the risk of Grade ≥ 2 late rectal toxicity among patients with prostate cancer receiving radiotherapy. Data from 1009 patients treated on Radiation Therapy Oncology Group protocol 94-06 were analyzed using three approaches. First, the contribution of intermediate doses to a previously published fit of the Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model was determined. Next, the extent to which intermediate doses provide additional risk information, after taking the LKB model into account, was investigated. Third, the proportion of rectum receiving doses higher than a threshold, VDose, was computed for doses ranging from 5 to 85 Gy, and a multivariate Cox proportional hazards model was used to determine which of these parameters were significantly associated with time to Grade ≥ 2 late rectal toxicity. Doses <60 Gy had no detectable impact on the fit of the LKB model, as expected on the basis of the small estimate of the volume parameter (n = 0.077). Furthermore, there was no detectable difference in late rectal toxicity among cohorts with similar risk estimates from the LKB model but with different volumes of rectum exposed to intermediate doses. The multivariate Cox proportional hazards model selected V75 as the only value of VDose significantly associated with late rectal toxicity. There is no evidence from these data that intermediate doses influence the risk of Grade ≥ 2 late rectal toxicity. Instead, the critical doses for this endpoint seem to be ≥ 75 Gy. It is hypothesized that cases of Grade ≥ 2 late rectal toxicity occurring among patients with V75 less than approximately 12% may be due to a "background" level of risk, likely due mainly to biological factors.

Use of the slope of the DVH curve for predicting late rectal toxicity in IMRT for patients with localized prostate cancer.

230 Background: Dose volume specific endpoints (DVSE) have been demonstrated to be reliable and reproducible for predicting late toxicity with conformal 3D-RT. New highly sophisticated delivery techniques such as IGRT or IMRT or combined IG-IMRT can spare rectum more efficiently while substantially increasing the delivered dose to the prostate. The purpose of this study is to investigate whether the slope of the DVH curve could predict late rectal toxicity more accurately than DVSE in prostate cancer (PCa) patients. Methods: Charts from164 men with complete DVH data who had a localized PCa were treated with exclusive IG-IMRT. The rectum was defined as a cylindrical structure around the outer rectal wall and contoured from the ischial tuberosities to the rectosigmoid junction. A set of DVSE were registered (V75, V70, V60). Four distinct DVH groupings were defined for each DVSE: [0–5%], ]5–10%], ]10–15%] and ]15–20%]. In parallel, we decided to calculate the slope of the DVH curves encompassing the 3 DVSE: 60Gy, 70Gy and 75Gy. The median dose prescribed to the prostate was 78Gy (min. 74Gy – max. 78Gy). Late toxicity was retrospectively scored according to the CTC v.3.0 morbidity grading scales. Univariate analysis using a logistic regression was performed to determine the relationship between DVSE, the slope 60-75Gy and the appearance of any late rectal toxicity (grade ≥ 1). Results: With a median follow-up of 38.3 months [5.25 – 87.3], the rates of grade (G) 1, G2 gastrointestinal toxicity were 20.4%, 2.4%. No grade 3 or 4 occurred. For the rectum, the average Dmean, D98, V75, V70 and V60 were 39.9 Gy [25.7–61.1], 8.9Gy [1.0–38.8], 1.1Gy [0.0–33.3], 6.0 Gy [0.0–44.0] and 19.0 Gy [1.0–70.0]. DVH groupings for V75, V70 and V60 were not predictive of any G≥1 late rectal toxicity (p= 0.836, p= 0.580 and p= 0.152, respectively). The slope 60-75Gy was significantly correlated with late rectal toxicity ≥ G1 (OR= 0.55, [CI95%: 0.33–0.92], p= 0.024). Conclusions: DVSE could be irrelevant with IG-IMRT, thus jeopardizing the clinical benefit of dose escalation. The slope of the curve predicts more accurately late toxicity when attempting to optimize dose distribution.

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.

Clinical outcomes with high-dose image guided radiotherapy (IGRT) compared with non-IGRT for the treatment of clinically localized prostate cancer.

12 Background: To compare toxicity profiles and biochemical tumor control outcomes between patients treated with high-dose image-guided radiotherapy (IGRT) and high-dose intensity-modulated radiotherapy (IMRT) for clinically localized prostate cancer. Methods: 186 patients with prostate cancer were treated with IGRT to a dose of 86.4 Gy with daily correction of the target position based upon kilovoltage imaging of implanted prostatic fiducial markers. This group of patients was retrospectively compared with a similar cohort of 190 patients who were treated with IMRT to the same prescription dose without, implanted fiducial markers in place (non-IGRT). In both groups the margins used for the prostate were the same. The median follow-up time was 2.8 years (range, 2-4 years). Results: A significant reduction in late urinary toxicity was observed for IGRT patients compared with the non-IGRT patients. The 3-year likelihood of urinary toxicity for the IGRT and non-IGRT cohorts were 10.4% and 20.0%, respectively (p=0.02).Multivariate analysis identifying predictors for late urinary toxicity demonstrated that, in addition to the baseline IPSS, IGRT was associated with significantly less late urinary toxicity compared with non-IGRT. The incidence of late rectal toxicity was low for both treatment groups (1.0% and 1.6%, respectively; p = 0.81). No differences in prostate-specific antigen relapse–free survival outcomes were observed for low- and intermediate-risk patients when treated with IGRT and non-IGRT. For high-risk patients a significant improvement was observed at 3-years for patients treated with IGRT compared with non-IGRT. Conclusions: IGRT is associated with a reduction in late urinary toxicity and improvement in biochemical tumor control after definitive high-dose external beam radiotherapy compared with high-dose IMRT. These data suggest that, for definitive radiotherapy, the placement of fiducial markers and daily tracking of target positioning should be the preferred mode of external beam radiotherapy delivery for the treatment of prostate cancer.

Hypofractionated Prostate Radiotherapy with or without Conventionally Fractionated Nodal Irradiation: Clinical Toxicity Observations and Retrospective Daily Dosimetry

Purpose. To evaluate toxicity associated with the addition of elective nodal irradiation (ENI) to a hypofractionated regimen for the treatment of prostate cancer. Methods and Materials. Fifty-seven patients received pelvic image-guided IMRT to 50.4 Gy in 28 fractions with a hypofractionated simultaneous boost to the prostate to 70 Gy. Thirty-one patients received prostate-only treatment to 70 Gy in 28 fractions. Results. Median followup was 41.1 months. Early grade ≥2 urinary toxicity rates were 49% (28 of 57) for patients receiving ENI and 58% (18 of 31) for those not (P = 0.61). Early grade ≥2 rectal toxicity rates were 40% (23 of 57) and 23% (7 of 31), respectively (P = 0.09). The addition of ENI resulted in a 21% actuarial rate of late grade ≥2 rectal toxicity at 4 years, compared to 0% for patients treated to the prostate only (P = 0.02). Retrospective daily dosimetry of patients experiencing late rectal toxicity revealed an average increase of 2.67% of the rectal volume receiving 70 Gy compared to the original plan. Conclusions. The addition of ENI resulted in an increased risk of late rectal toxicity. Grade ≥2 late rectal toxicity was associated with worse daily rectal dosimetry compared to the treatment plan.

Parameters for the Lyman Kutcher Burman (LKB) model of Normal Tissue Complication Probability (NTCP) for specific rectal complications observed in clinical practise

Background and purposeThe Normal Tissue Complication Probability (NTCP) for rectum is usually defined for late rectal bleeding. This study calculates NTCP parameter values for additional rectal toxicity endpoints observed in clinical practise. Materials and methods388 patients from the multicentre MRC-RT01 prostate conformal radiotherapy trial (ISRCTN 47772397) were used to derive independent Lyman Kutcher Burman model (LKB) parameters for five late rectal toxicity endpoints: rectal bleeding, proctitis, stool frequency, loose stools and rectal urgency. The parameters were derived using maximum likelihood estimation. Bootstrap and leave-one-out methods were employed to test the generalisability of the results for use in a general population. ResultsA consistent pattern of increasing value of TD50(1) for Grade 2 toxicity only compared to Grades 1 and 2 toxicity was observed for all endpoints. Parameter values varied between endpoints (particularly for the volume parameter n). TD50(1), m and n were 68.5Gy (95% CI)(66.8–70.8), 0.15 (0.13–0.17) and 0.13 (0.10–0.17), respectively, for G2 rectal bleeding. Bootstrap and leave-one-out results showed that the rectal bleeding and proctitis parameter fits were extremely robust. ConclusionsThe variation between the values derived for different endpoints may indicate different patho-physiological responses of the rectum to radiation. Therefore different parameter sets would be required to predict specific rectal toxicity endpoints.

Impact of VEGF gene polymorphisms and haplotypes on radiation-induced late toxicity in prostate cancer patients

Vascular endothelial growth factor (VEGF) is an important determinant of microvascular permeability and angiogenesis and has been shown to be up-regulated during the late phase of radiation injury. The present prospective study was performed to evaluate the role of VEGF gene polymorphisms and haplotypes in the development of radiation-induced late side effects in prostate cancer patients. The association of VEGF gene polymorphisms and haplotypes with high-grade late rectal or urinary toxicity (defined as late toxicity EORTC/RTOG ≥ 2) was analyzed using 493 prostate cancer patients from the Austrian PROCAGENE study treated with definitive radiotherapy. Seven candidate polymorphisms in the VEGF gene were selected and determined by 5'-nuclease (TaqMan) assays. Within a median follow-up time of 48 months, 42 patients (8.6%) developed high-grade late rectal and 47 patients (9.6%) urinary toxicity, respectively. In a Kaplan-Meier analysis, carriers of the VEGF -7C > T polymorphism were at increased risk of high-grade late rectal toxicity (p = 0.003) and in a multivariate analysis including clinical and dosimetric parameters as potential confounders the VEGF -7C > T polymorphism remained a significant predictor (HR = 2.8, 95% CI 1.349-5.813; p = 0.006). Furthermore, the ATTGT haplotype formed by five polymorphisms upstream of the coding sequence demonstrated a significant association with late rectal toxicity grade ≥ 2 (p = 0.001). No significant associations were found for the remaining polymorphisms and haplotypes. We conclude that genetic variants in the VEGF gene may influence the risk of high-grade late rectal toxicity after definitive radiotherapy for prostate cancer.

High Dose Brachytherapy as Monotherapy for Intermediate Risk Prostate Cancer

We evaluated our retrospective, single institution experience with high dose rate brachytherapy as monotherapy for intermediate risk prostate cancer. Our cohort included 284 patients with intermediate risk prostate cancer, defined as clinical stage T2b/T2c, Gleason score 7 and/or prostate specific antigen 10 to 20 ng/ml, and 1-year minimum followup. Treatment was 2 high dose rate brachytherapy sessions at 3 fractions of 6.5 Gy each for a mean of 19 days. Prostate specific antigen failure was defined as nadir +2 ng/ml. Mean followup was 35.1 months (median 31.9). Actuarial 5-year cause specific survival and clinical local control were 100%, distant-metastasis-free survival 98.8% and biochemical disease-free survival 94.4%. Clinical stage predicted biochemical disease-free survival. For stage T2a or less 5-year biochemical disease-free survival was 95.1% vs 100% for stage T2b and 77.4% for T2c (p = 0.012). Percent positive biopsy cores and prostate specific antigen nadir were also predictive. International Prostate Symptom Score results remained stable and potency was maintained in 82.6% of patients at 2 years. Pads were used for the first time after brachytherapy in 22 patients (7.7%), mostly for grade 1 incontinence (occasionally or less per week). Excluding patients with prior transurethral prostatectomy, stroke or tremor 2.5% used pads for the first time after treatment. No patient had urethral stricture. Radiation Therapy Oncology Group grade 1 rectal toxicity developed in 12 patients (4.2%) but not beyond grade 1. High dose rate brachytherapy as monotherapy is safe and effective for patients with intermediate risk prostate cancer. We recommend caution for percent positive biopsy cores exceeding 75% or clinical stage T2c. Excluding such patients the 5-year biochemical disease-free survival rate was 97.5%.

Consolidating Risk Estimates for Radiation-Induced Complications in Individual Patient: Late Rectal Toxicity

To test the feasibility of a new approach to synthesize published normal tissue complication data using late rectal toxicity in prostate cancer as an example. A data survey was performed to identify the published reports on the dose-response relationships for late rectal toxicity. The risk estimates for Grade 1 or greater, Grade 2 or greater, and Grade 3 or greater toxicity were obtained for a test cohort of patients treated at our institution. The influence of the potential factors that might have affected the reported toxicity levels was investigated. The studies that did not conform to the general data trends were excluded, and single, combined risk estimates were derived for each patient and toxicity level. A total of 21 studies of nonoverlapping patient populations were identified. Three studies provided dose-response models for more than one level of toxicity. Of these 21 studies, 6, 14, and 5 were used to derive the initial risk estimates for Grade 1, 2, and 3 or greater toxicity, respectively. A comparison of risk estimates between the studies reporting rectal bleeding and rectal toxicity (bleeding plus other symptoms) or between studies with follow-up <36 months and ≥36 months did not reveal significant differences (p ≥ .29 for all comparisons). After excluding three reports that did not conform to the general data trends, the combined risk estimates were derived from 5 reports (647 patients), 11 reports (3,369 patients), and 5 reports (1,330 patients) for Grade 1, 2, and 3 or greater toxicity, respectively. The proposed approach is feasible and allows for more systematic use of published dose-response data to estimate the complication risks for the individual patient.

Inclusion of Clinical Risk Factors into NTCP Modeling of Late Rectal Toxicity after High Dose Radiotherapy for Prostate Cancer

Inclusion of Clinical Risk Factors into NTCP Modeling of Late Rectal Toxicity after High Dose Radiotherapy for Prostate Cancer

Interstitial High Dose Rate (HDR) Brachytherapy as Monotherapy for Early-stage Prostate Cancer: Median 8 Year Results in 321 Patients

Transrectal ultrasound (TRUS)-guided interstitial implant for prostate cancer using low dose rate (LDR) and high dose rate (HDR) technique has been reported with results comparing favorably to surgery and external beam radiation therapy (EBRT). Often, HDR and LDR interstitial implant is combined with EBRT. There is little published data on HDR alone. We report our results with HDR alone. Between 1997 and 2010, 321 patients with T1 and T2 localized prostate underwent TRUS guided interstitial implant, under spinal anesthetic or local anesthetic. There were no Gleason Score or PSA exclusions. No patient received EBRT or hormonal blockade. Median Gleason Score was 7 (range, 4 – 10). Median PSA was 9.3 (2.7 – 39.8). Treatment volumes ranged from 32 cm3 – 196 cm3. Treatment volume included the prostate and seminal vesicles in all cases. Radiation treatment planning was performed using CT scanning and the Nucletron Plato Treatment Planning System. Our IRB protocol for HDR alone, has called for two HDR Implants, spaced 4 weeks apart. The treatment volume received 2250 cGy in 3 fractions prescribed to the 100% Isodose line, given over 24 hours. A second implant was performed 4 weeks later, delivering a further 2250 cGy in 3 fractions, bringing the final dose to the prostate to 4500 cGy in 6 fractions. Urethral dose points (12 – 16) were followed, and limited to ≤105% of the prescription dose. With a median follow-up of 102 months (range, 6 months – 176 months), PSA disease-free survival was 88.8% (285/321). Actuarial 8 year PSA disease-free survival was 86%. The actuarial 8 year PSA disease-free survivals by risk group, were 94% for low-risk, 86% for intermediate-risk, and 65% for high-risk. The procedure was well tolerated, with all patients having completed the procedure. Acute and chronic complications were uncommon. Acute urinary retention occurred in 5.3% (17/321) of the patients, requiring temporary insertion of an indwelling Foley catheter. Urethral stricture requiring dilatation has developed in 5.9% (19/321) of patients. Urinary stress incontinence has occurred in 2.8% (9/321). RTOG late bladder toxicities were: 0% Grade 4, 0% Grade 3, and 2.8% (9/321) Grade 2. RTOG late rectal toxicities were: 0.6% (2/321) Grade 4, 0% Grade 3, 0.9% (3/321) Grade 2, and 1.2% (4/321) Grade 1. Eight-year results with HDR implant alone compare favorably to EBRT, LDR +/- EBRT, and HDR + EBRT, both with regard to PSA disease-free survival, and complications. HDR offers other advantages over LDR, such as no radiation exposure to hospital personnel, no seed migration, greater dose flexibility and precision of radiation dose delivery. Larger volumes can be treated with HDR. By omitting EBRT, bladder and rectal complications appear to be significantly reduced.

Is single fraction 15 Gy the preferred high dose-rate brachytherapy boost dose for prostate cancer?

Background and purposeHigh dose-rate (HDR) brachytherapy is most commonly administered as a boost in two or more fractions combined with external beam radiotherapy (EBRT). Our purpose is to compare outcomes with a single fraction HDR boost to that with a standard fractionated boost in intermediate risk prostate cancer. Materials and methodsResults of two sequential phase II clinical trials are compared. The Single Fraction protocol consists of 15Gy HDR in one fraction followed by 37.5Gy EBRT in 15 fractions over 3weeks; the Standard Fractionation protocol consisted of two HDR fractions each of 10Gy, 1week apart, followed by 45Gy EBRT in 25 fractions. Patients had intermediate risk disease, and were well balanced for prognostic factors. Patients were followed prospectively for efficacy, toxicity and health-related quality of life (Expanded Prostate Index Composite). Efficacy was assessed biochemically using the Phoenix definition, and by biopsy at 2years. ResultsThe Single Fraction protocol accrued 123 patients and the Standard Fractionation protocol, 60. With a median follow-up of 45 and 72months, respectively, the biochemical disease-free survival was 95.1% and 97.9% in the Single and Standard Fractionation trials (p=0.3528). Two-year prostate biopsy was positive in only 4% and 8%, respectively. There was no difference in late urinary or rectal toxicity rates, or in health-related quality of life between the two protocols. ConclusionsThe Single Fraction HDR protocol results in high disease control rate and low toxicity similar to our previous protocol using two HDR insertions, with significant savings in resources. While mature results with longer follow-up are awaited, a single 15Gy may be considered as a standard fractionation regimen in combination with EBRT for men with intermediate risk disease.

Rectal toxicity and rectal dosimetry in low-dose-rate 125I permanent prostate implants: A long-term study in 1006 patients

ObjectiveTo describe the acute and late rectal toxicity in 1006 prostate brachytherapy patients implanted 1998–2003. To determine whether rectal dose–volume histogram as well as patient and treatment factors were associated with rectal toxicity. Methods and materialsMedian followup was 60.7 months. Rectal dosimetry was calculated as dose–volume histogram of the rectum using Day 28 CT-based dosimetry and expressed as volume of the rectum in cc receiving 50%, 100%, and 150% of the prescription dose (VR50cc, VR100cc, and VR150cc, respectively). Univariate and multivariate analyses were performed to examine the influence of patient, implant, dosimetry, and learning curve factors on the development of acute and late toxicities using a modified Radiation Therapy Oncology Group (RTOG) scale. Acute toxicity was analyzed using logistic regression and late toxicity using Cox proportional hazards regression. Analysis of variance was used to examine the association between rectal toxicity and rectal dose. ResultsRectal dosimetry in 93.5% and rectal toxicity in 96.2% have been recorded. Median VR100=1.05cc. Late RTOG Grades 0, 1, 2, 3, and 4 were recorded in 68%, 23%, 7.3%, 0.9%, and 0.2% patients, respectively. On multivariate analysis, acute RTOG ≥2 rectal toxicity was associated with urinary retention (p=0.036) and learning curve (p=0.015); late RTOG ≥2 was associated with the presence of acute toxicity (p=0.0074), higher VR100 (p=0.030) and learning curve (p=0.027). ConclusionsLate rectal RTOG ≥2 rectal toxicity in this cohort was 8%. Increased VR100, presence of acute rectal toxicity, and learning curve were associated with higher rate of late RTOG ≥2 toxicity. Severe late rectal toxicity after prostate brachytherapy was rare.

Inclusion of clinical risk factors into NTCP modelling of late rectal toxicity after high dose radiotherapy for prostate cancer

Background and purposeTo fit an NTCP model including clinical risk factors to late rectal toxicities after radiotherapy for prostate cancer. Methods and materialsData of 669 patients were considered. The probability of late toxicity within 36months (bleeding and incontinence) was fitted with the original and a modified Logit-EUD model, including clinical factors by fitting a subset specific TD50s: the ratio of TD50s with and without including the clinical variable was the dose-modifying factor (Dmod). ResultsAbdominal surgery (surg) was a risk factor for G2–G3 bleeding, reflecting in a TD50=82.7Gy and 88.4Gy for patients with and without surg (Dmod=0.94; 0.90 for G3 bleeding); acute toxicity was also an important risk factor for G2–G3 bleeding (Dmod=0.93). Concerning incontinence, surg and previous diseases of the colon were the clinical co-factors. Dmod(surg) and Dmod(colon) were 0.50 and 0.42, respectively for chronic incontinence and 0.73 and 0.64, respectively for mean incontinence score ⩾1. Best-fit n values were 0.03–0.05 and 1 for bleeding and incontinence, respectively. The inclusion of clinical factors always improved the predictive value of the models. ConclusionsThe inclusion of predisposing clinical factors improves NTCP estimation; the assessment of other clinical and genetic factors will be useful to reduce parameter uncertainties.

Is It Time to Tailor the Prediction of Radio-Induced Toxicity in Prostate Cancer Patients? Building the First Set of Nomograms for Late Rectal Syndrome

Development of user-friendly tools for the prediction of single-patient probability of late rectal toxicity after conformal radiotherapy for prostate cancer. This multicenter protocol was characterized by the prospective evaluation of rectal toxicity through self-assessed questionnaires (minimum follow-up, 36 months) by 718 adult men in the AIROPROS 0102 trial. Doses were between 70 and 80 Gy. Nomograms were created based on multivariable logistic regression analysis. Three endpoints were considered: G2 to G3 late rectal bleeding (52/718 events), G3 late rectal bleeding (24/718 events), and G2 to G3 late fecal incontinence (LINC, 19/718 events). Inputs for the nomogram for G2 to G3 late rectal bleeding estimation were as follows: presence of abdominal surgery before RT, percentage volume of rectum receiving >75 Gy (V75Gy), and nomogram-based estimation of the probability of G2 to G3 acute gastrointestinal toxicity (continuous variable, which was estimated using a previously published nomogram). G3 late rectal bleeding estimation was based on abdominal surgery before RT, V75Gy, and NOMACU. Prediction of G2 to G3 late fecal incontinence was based on abdominal surgery before RT, presence of hemorrhoids, use of antihypertensive medications (protective factor), and percentage volume of rectum receiving >40 Gy. We developed and internally validated the first set of nomograms available in the literature for the prediction of radio-induced toxicity in prostate cancer patients. Calculations included dosimetric as well as clinical variables to help radiation oncologists predict late rectal morbidity, thus introducing the possibility of RT plan corrections to better tailor treatment to the patient's characteristics, to avoid unnecessary worsening of quality of life, and to provide support to the patient in selecting the best therapeutic approach.

More space, less toxicity: Toxicity report of the first patients with prostate cancer treated in Heidelberg within the SpaceOAR hydrogel study.

e15052 Background: Delivering high radiation dose to prostate while sparing adjacent OARs like the rectum and bladder is challenging. We evaluated acute and late genitourinary (GU) and gastrointestinal (GI) toxicities in prostate cancer patients within the SpaceOAR Hydrogel study. Methods: Overall, 20 patients with localized prostate cancer recieved definitive radiotherapy by tomotherapy from Oct. 2009 through Jan. 2011. Patients were treated within the SpaceOAR Hydrogelstudy, a prospective, multi-center, open-label trial. Before treatment planning the spacer gel, an absorbable polyethylene glycol (PEG) hydrogel spacer, which extends the space between anterior rectum wall and prostate, was perennially injected between rectum and prostate. Absorption time of the gel is about 6 months. The prescribed dose for the PTV (= [prostate+2/3 seminal vesicle] +margin of 5mm in all directions) was 78 Gy in 39 fractions. During the treatment and at 3, 6 and 12 months after treatment GI and GU toxicity was evaluated utilizing the grading developed by the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC). Late rectal toxicity was also detected by using proctoscopy 12 months after the completion of irradiation and scored by using the Vienna rectoscopy score (VRS-Score). Results: The space between rectum and prostate could be increased an average of 10.48mm at base, 9.61mm at mid gland and 9.35mm at the apex. So far, 13 patients have finished irradiation. The incidences of acute Grade 1 GI or GU toxicities at the end of treatment were 7% and 46% in these patients. One patient showed Grade 2 GU toxicity (n=13). After 3 months follow up 27% had Grade 1 GU toxicity but no patient showed GI toxicity (n=11). After 6 month fu Grade 1 GU toxicity decrease to 25% (n=8). After one year (n=4) no patient showed late GI toxicities and 2 patients had Grade I GU toxicity No patient showed any problems of the rectal mucosa in the rectoscopy after 12 months (100% VRS score 0). Conclusions: Use of SpaceOAR Hydrogelis an easy and safe way to reduce toxicity to the rectum. Further evaluations with dose escalation to the prostate or application in other regions are possible.