Late Urinary Toxicity Research Articles

Urinary toxicity in patients treated with radical EBRT for prostate cancer: Analysis of predictive factors in an historical series

The present study aims to identify predictive factors for urinary toxicity and self-reported symptoms after external beam radiotherapy (EBRT) for prostate cancer. Two-hundred and eighty patients treated with EBRT for prostate cancer were included in the present study. Toxicity was scored following the grading system based on Radiation Therapy Oncology Group (RTOG) scale. International Prostatic Symptom Score (IPSS) and Consultation on Incontinence Questionnaires-Short Form (ICIQ-SF) were used to analyse self-reported symptoms. Acute and late urinary toxicities were correlated to clinical and treatment parameters, radiation dosimetry data, IPSS and ICIQ-SF. Median patient age was 74 years (range, 64-83). Thirty-one percent experienced acute G1 urinary toxicity, 24% G2 and 3% G3. Fourteen percent experienced G1 late urinary toxicity and 3% G2. Bladder volume<200 cc was associated with acute urinary toxicity (P=0.014); use of MRI for treatment planning allowed a lower incidence of late toxicity (P=0.062) and use of IMRT allowed for reduced incidence in late toxicity (P=0.038). Maximum bladder dose correlated with late urinary toxicity (P=0.014). The analysis of self-reported symptoms showed a significant correlation between IPSS baseline values (P=0.009), presence of nocturia (P=0.002), bladder urgency (P=0.024) and incontinence (P=0.024) and development of acute urinary toxicity at univariate analysis. At multivariate logistic regression analysis, bladder filling, IPSS value, nocturia, and urinary incontinence retained significant correlation with acute toxicity (P=0.0003). Significant independent predictors for acute urinary toxicity grade≥2 were bladder filling, IPSS value, nocturia, and urinary incontinence at baseline assessment.

MO-0557 Estimates of α/β ratios for individual late urinary toxicity endpoints: analysis of a cohort trial

MO-0557 Estimates of α/β ratios for individual late urinary toxicity endpoints: analysis of a cohort trial

Biological Planning of Radiation Dose Based on In Vivo Dosimetry for Postoperative Vaginal-Cuff HDR Interventional Radiotherapy (Brachytherapy)

(1) Background: Postoperative vaginal-cuff HDR interventional radiotherapy (brachytherapy) is a standard treatment in early-stage endometrial cancer. This study reports the effect of in vivo dosimetry-based biological planning for two different fractionation schedules on the treatment-related toxicities. (2) Methods: 121 patients were treated. Group A (82) received 21 Gy in three fractions. Group B (39) received 20 Gy in four fractions. The dose was prescribed at a 5 mm depth or to the applicator surface according to the distance between the applicator and the rectum. In vivo dosimetry measured the dose of the rectum and/or urinary bladder. With a high measured dose, the dose prescription was changed from a 5 mm depth to the applicator surface. (3) Results: The median age was 66 years with 58.8 months mean follow-up. The dose prescription was changed in 20.7% of group A and in 41% of group B. Most toxicities were grade 1–2. Acute urinary toxicities were significantly higher in group A. The rates of acute and late urinary toxicities were significantly higher with a mean bladder dose/fraction of >2.5 Gy and a total bladder dose of >7.5 Gy. One patient had a vaginal recurrence. (4) Conclusions: Both schedules have excellent local control and acceptable rates of toxicities. Using in vivo dosimetry-based biological planning yielded an acceptable dose to the bladder and rectum.

Radiation Dose to the Intraprostatic Urethra Correlates Strongly With Urinary Toxicity After Prostate Stereotactic Body Radiation Therapy: A Combined Analysis of 23 Prospective Clinical Trials

Clinical trials assessing evaluation prostate stereotactic body radiation therapy (SBRT) have used a wide range of allowed doses to the intraprostatic urethra, but the relationship between urethral dose and urinary toxicity has not been thoroughly evaluated. The goal of this study was to characterize urinary toxicity outcomes according to urethral dose administered during prostate SBRT. The MEDLINE (PubMed) database was searched for published prospective studies of prostate SBRT through August 2020 that documented a maximum urethral dose metric (MUDM). Reported acute and late urinary toxicity rates were collected. Logistic regression and weighted Pearson correlation models were used to assess associations between urinary toxicity rates and MUDM. Twenty-three unique studies (n=2232 patients) met the inclusion criteria and included a wide range of MUDMs (equivalent dose in 2 Gy fractions [EQD2]: 69-141.75 Gy; α/β=3 Gy). The median follow-up ranged from 3 to 67 months (median, 32 months). On logistic regression analysis, the MUDM EQD2 was significantly associated with multiple urinary toxicity endpoints, including acute grade (G) 2+ (odds ratio [OR], 1.02; P < .001), late G2+ (OR, 1.03; P < .0001), and late G3+ (OR, 1.04; P=.003) urinary toxicity. On weighted Pearson correlation analysis, the MUDM was more closely associated with all evaluated urinary toxicity endpoints than prescription dose, including acute G2+ (r=0.51; P=.02), late G2+ (r=0.9; P < .0001), and late G3+ toxicity (r=0.7; P=.003). Multivariate analysis accounting for age, prostate size, bladder dosimetry, and baseline urinary function confirmed associations between urinary outcomes and MUDM. Within the studied dose range, each increase of 1 Gy to the MUDM corresponded to a 0.8% and 1.0% increase in acute G2+ and late G2+ toxicity, respectively. Radiation dose to the urethra correlates closely with urinary toxicity in patients with prostate cancer treated with SBRT. Attention should be paid to the urethral dose when delivering prostate SBRT to high doses, and approaches for urethral dose reduction warrant further investigation.

Radiation Dose to the Intraprostatic Urethra Correlates Strongly With Urinary Toxicity Following Prostate SBRT: A Combined Analysis of 23 Prospective Clinical Trials

Clinical trials of prostate SBRT have utilized a wide range of allowed doses to the intraprostatic urethra but the relationship between urethral dose and urinary toxicity has not been thoroughly evaluated. We aimed to characterize urinary toxicity outcomes according to urethral dose administered during prostate SBRT.We searched MEDLINE (PubMed) for published prospective studies of prostate SBRT through August 2020 that documented a maximum urethral dose metric (MUDM). Reported acute and late urinary toxicity rates were collected. Weighted correlation and weighted linear regression models were used to assess the associations between urinary toxicity rates and MUDM.Twenty-three unique studies (n = 2232 patients) met the inclusion criteria and included a wide range of MUDMs (EQD2 69 Gy to 141.75 Gy, a/b = 3). Median follow up ranged from 3-67 months (median 32 months). MUDM was strongly associated with urinary toxicity and was more closely associated with toxicity than prescription dose, including acute G2+ (r = 0.51, P = 0.02), late G2+ (r = 0.9, P < 0.0001) and late G3+ toxicity (r = 0.7, P = 0.003). Weighted linear regression accounting for age, prostate size and baseline urinary function confirmed association between urinary outcomes and MUDM. The weighted correlation model predicted late grade 2+ urinary toxicity rates of 2.5%, 5%, 10% and 15% corresponding to MUDMs of 34.2 Gy, 37.7 Gy, 43.9 Gy and 49.4 Gy, respectively, for 5 fraction regimens. Within the studied dose range, each increase of 1 Gy to the MUDM corresponded to a 0.8% and 0.9% increase in acute G2+ and late G2+ toxicity, respectively.Radiation dose to the urethra correlates closely with urinary toxicity in prostate cancer patients treated with SBRT. Attention should be paid to urethral dose when delivering prostate SBRT to high doses and approaches for urethral dose reduction warrant further investigation. These techniques may be facilitated by online adaptive planning with daily urethral delineation.

Influence of hydrogel spacer placement with prostate brachytherapy on rectal and urinary toxicity.

To determine the influence of rectal hydrogel spacer placement (HSP) on late rectal toxicity outcomes in prostate cancer patients treated with low-dose-rate (LDR) brachytherapy, with or without supplemental external beam radiotherapy (EBRT). A total of 224 patients underwent LDR brachytherapy with HSP, as monotherapy or combined with EBRT, between January 2016 and December 2019. Dosimetric variables reflecting the extent of rectal sparing and late rectal toxicity outcomes were evaluated. This spacer cohort was retrospectively compared to a similar patient group (n = 139) in whom HSP was not used. Hydrogel spacer placement was associated with significantly reduced rectal doses for all dosimetric variables; the median percentage rectal dose to 1 cc of rectum and rectal dose to 2 cc of rectum of the spacer cohort were all significantly lower compared to the non-spacer cohort. The incidence rates of overall (any grade) and grade ≥2 rectal toxicity were lower in patients with HSP compared to patients who did not undergo HSP: 12% and 1.8% vs 31% and 5.8%, respectively. The 3-year cumulative incidence of overall rectal toxicity was significantly lower with HSP than without (15% vs 33%; P < 0.001), corresponding to an overall rectal toxicity reduction on univariable analysis (hazard ratio 0.45, 95% confidence interval 0.28-0.73; P = 0.001). In this patient cohort treated with prostate brachytherapy, none of the urethral dosimetric variables or the presence or absence of HSP was associated with late urinary toxicity. Hydrogel rectal spacer placement is a safe procedure, associated with significantly reduced rectal dose. HSP translates to a decrease in overall late rectal toxicity in patients receiving dose-escalated brachytherapy-based procedures.

Clinical predictors of severe late urinary toxicity after curative intensity-modulated radiation therapy for localized prostate cancer.

Intractable late urinary toxicity is a serious complication after radiotherapy for patients with localized prostate cancer (LPC). We assessed clinical factors correlated with severe late urinary toxicity in LPC treated with curative image-guided intensity-modulated radiation therapy (IMRT). A total of 452 patients with LPC treated with IMRT between 2002 and 2016 were retrospectively analyzed. Among them, 432 patients received androgen deprivation therapy (ADT). The median total irradiated doses were 80 (range, 76-80) Gy. Each daily dose was 2 Gy per fraction. The median follow-up was 83 (range, 4-210) months. Late urinary toxicity was scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03. Grade 3 late urinary toxicity was observed in 27 patients. No cases with grade ≥ 4 late urinary toxicity were observed. The 5-, 10-, and 12.5-year grade 3 late urinary toxicity-free survival rates were 97%, 91.8% and 88.1%, respectively. Age, risk classification, total irradiated dose, ADT duration, antithrombotic therapy (AT), cardiovascular disease, hypertension (HT), diabetes mellitus (DM), dyslipidemia (DL), prior transurethral resection of the prostate (TURP) and prior high-intensity focused ultrasound (HIFU) were investigated for correlations with grade 3 late urinary toxicity. In univariate analysis, AT and prior HIFU and no other studied factors, were correlated with grade 3 late urinary toxicity. AT and prior HIFU appear to be predictive of grade 3 late urinary toxicity. Patients with LPC with these relevant clinical factors should be carefully followed up by sharing detailed information with the urology department.

Moderately Hypofractionated Radiotherapy and Androgen Deprivation Therapy for High-risk Localised Prostate Cancer: Predictors of Long-term Biochemical Control and Toxicity

AimsThere is a paucity of long-term data on outcomes of high-risk prostatic adenocarcinoma after moderately hypofractionated radiotherapy with elective nodal treatment and long-term androgen deprivation therapy (ADT). We report long-term control and toxicity outcomes and analyse the predictors of failure and toxicity. Materials and methodsThe records of 120 consecutive high-risk prostate cancer patients treated in a single institution between February 2012 and December 2016 were retrospectively analysed. A moderately hypofractionted radiotherapy (HypoRT) regimen of 60 Gy in 20 fractions over 4 weeks with simultaneous elective pelvic irradiation to 44 Gy in 20 fractions with intensity-modulated radiotherapy was used, together with long-term ADT with either orchiectomy or medical castration for a total duration of 2–3 years. We analysed biochemical control, metastasis-free survival and late toxicities and their predictive factors using survival analysis. ResultsPatients had locally advanced cancers (cT3 77.5%, median pretreatment prostate-specific antigen 30 ng/ml, Gleason score 8–10 in 45.8%). The median follow-up time was 70 months. The 3- and 5-year probability of freedom from biochemical progression was 93% and 80%, respectively. The 5-year probability of freedom from local relapse/intra-pelvic nodal relapse/distant metastases as the site of first failure was 96%/97%/86%, respectively. Gleason score 8–10 and medical ADT for 2–3 years (as opposed to orchidectomy) were independent risk factors for distant metastases. A total of 18 grade 2 and above late gastrointestinal toxicity events and a total of 23 grade 2 and above late genitourinary toxicity events were documented. Patients who underwent a transurethral resection of prostate prior to radiotherapy had worse urological toxicity. ConclusionsHypoRT with elective nodal treatment results in excellent pelvic control. Distant metastases are the primary mode of failure. Risk of metastases is associated with Gleason score and the duration of ADT. Late urinary toxicities are more common in those with prior transurethral resection of prostate.

Long-term outcomes after bladder-preserving tri-modality therapy for patients with muscle-invasive bladder cancer

Purpose To evaluate trimodal conservative treatment as an alternative to radical surgery for urothelial muscle-invasive bladder cancer (MIBC). Patients and methods This retrospective study reported the carcinologic and functional results of patients (pts) presenting a cT2/T3 N0M0 operable MIBC and fit for surgery, treated by a conservative strategy. Treatment consisted of a transurethral resection (TURB) followed by concomitant bi-fractionated split-course radiochemotherapy (RCT) with 5FU-Cisplatine. A control cystoscopy was performed six weeks after the induction RCT (eq45Gy) with systematic biopsies. Patients with complete histologic response achieved RCT protocol. Salvage surgery was proposed to pts with persistent tumor. Results 313 pts (83% cT2 and 17% cT3) treated between 1988 and 2013 were included, with a median follow-up of 59 months and 67-year mean age. After the induction RCT, the histologic response rate was 83%. After five years, overall, disease-free, and functional bladder-intact survival rates were respectively 69%, 61%, and 69%, significantly better for pts in complete response after induction RCT. Late urinary and digestive toxicities were limited, with respective rates of 4% and 1.5% of grade 3 toxicity. Conclusion Trimodal strategy with RCT after TURB showed interesting functional and oncologic results and should be considered as an alternative to surgery in well-selected pts.

Focal Brachytherapy for Localized Prostate Cancer: Midterm Outcomes

PurposeFocal brachytherapy (F-BT) is a suitable technique for focal therapy in localized prostate cancer. It has the ability to adapt the seed implantation to the volume and location of the tumor. The aim of this study was to assess F-BT oncologic, functional, and toxicity midterm outcomes in men who underwent prostate cancer treatment. Methods and MaterialsThe study included 39 men with low- to intermediate-risk prostate cancer treated with F-BT between 2010 and 2015. The dose prescription was 145 Gy. Failure was defined as the presence of any residual prostate cancer in the treated area. The primary and secondary endpoints were the F-BT oncologic and functional outcomes, respectively. A 2-sided P value < .05 indicated statistical significance. ResultsThe mean follow-up time was 65 months (range, 43-104 months). After 24 months, 34 patients underwent control biopsies and 5 patients refused. The biopsies were negative in 27 cases (79%) and positive in 7 cases (21%), all outside the volume treated. Biochemical relapse-free survival at 5 years, disease-free survival, and overall survival were 96.8% ± 0.032%, 79.5% ± 0.076%, and 100%, respectively. The mean International Prostate Symptom Score at 2 months was significantly higher than initially (P = .0003), with no significant difference later. No late urinary, sexual, or rectal toxicity was observed. Salvage treatment was possible with good tolerance at 3.4 years of follow-up. Limitations of this study include the retrospective nature and lack of randomization. ConclusionsF-BT is a safe and effective treatment for selected patients presenting with low- or intermediate-risk localized prostate cancer.

Prostate Stereotactic Body Radiation Therapy: An Overview of Toxicity and Dose Response

Ultrahypofractionationed radiation therapy for prostate cancer is increasingly studied and adopted. The American Association of Physicists in Medicine Working Group on Biological Effects of Hypofractionated Radiotherapy therefore aimed to review studies examining toxicity and quality of life after stereotactic body radiation therapy (SBRT) for prostate cancer and model its effect. We performed a systematic PubMed search of prostate SBRT studies published between 2001 and 2018. Those that analyzed factors associated with late urinary, bowel, or sexual toxicity and/or quality of life were included and reviewed. Normal tissue complication probability modelling was performed on studies that contained detailed dose/volume and outcome data. We found 13 studies that examined urinary effects, 6 that examined bowel effects, and 4 that examined sexual effects. Most studies included patients with low-intermediate risk prostate cancer treated to 35-40 Gy. Most patients were treated with 5 fractions, with several centers using 4 fractions. Endpoints were heterogeneous and included both physician-scored toxicity and patient-reported quality of life. Most toxicities were mild-moderate (eg, grade 1-2) with a very low overall incidence of severe toxicity (eg, grade 3 or higher, usually <3%). Side effects were associated with both dosimetric and non-dosimetric factors. Prostate SBRT appears to be overall well tolerated, with determinants of toxicity that include dosimetric factors and patient factors. Suggested dose constraints include bladder V(Rx Dose)Gy <5-10 cc, urethra Dmax <38-42 Gy, and rectum Dmax <35-38 Gy, though current data do not offer firm guidance on tolerance doses. Several areas for future research are suggested.

Efficacy and Toxicity of Stereotactic Body Radiation Therapy for Localized Prostate Cancer: A Twelve-Year Study

This is the first study using Stereotactic Body Radiotherapy (SBRT) for organ confined prostate cancer to have patients with twelve-year follow-up. In this study, we report outcomes for prostate robotic SBRT in 560 patients, with NCCN low-, intermediate- and high- risk disease. We report on biochemical disease-free survival (bDFS), toxicity and Quality of Life (QOL). We studied 560 patients with organ-confined prostate cancer, treated with SBRT to a dose covering the PTV (prostate +3-5 mm) of 35-36.25 Gy. The prostate was covered by a dose of 38.4-40 Gy. Treatment was delivered in 5 daily fractions between 2006-2009. We included 45 high risk patients who received a 18-21 Gy SBRT boost after 45 Gy to the pelvis with EBRT. Median follow up is 132 months. The median age was 69 years, and median PSA was 6.58. 324 patients were low-risk, 153 were intermediate-risk and 83 were high-risk. ADT up to 9 months was administered to 102 patients. Patients were further stratified into low-intermediate risk versus high-intermediate risk, with high-intermediate risk criteria of Gleason 4+3 = 7 or >1 intermediate risk factors (cT2b-c, PSA 10-20, Gleason 7). Biochemical failure was assessed using the Phoenix criterion. Cox regression analysis was used to determine which risk factors were significantly associated with increased risk of biochemical failure. Twelve-year bDFS was 92.0, 79.1 and 64.0% for low, intermediate and high-risk group patients, respectively. Local control was 97.0, 91.7 and 88.0% respectively. Favorable intermediate-risk patients had excellent outcomes, with no significant difference compared to low-risk patients with 12-year bDFS 89.8 vs 92.0%, respectively (p = 0.35). Unfavorable intermediate-risk patients had outcomes similar to high risk patients, with 12-year bDFS of 67.5 and 64.0% respectively (p = .24). Median PSA declined to 0.1. For low and intermediate risk patients, Gleason score was the only significant factor predicting for biochemical failure on multivariate analysis (p = 0.0003), with ADT, dose and PSA not significant. For high risk patients, PSA was the only significant predictor of bDFS (p = .01), with Gleason score, ADT or EBRT not significant. Toxicity was mild. 36.25 Gy was associated with more Grade 2-3 late urinary toxicity than 35 Gy. (13.8% vs 6%) p = .01 Patients receiving EBRT had a higher rate of late Grade 2 late rectal toxicity. Mean EPIC QOL urinary and bowel domains for all patients declined during the first 3 months and then returned to baseline, where they remain. Mean sexual QOL scores have slowly declined by 47% This study suggests that early excellent control rates for SBRT for prostate cancer remain durable over 12 years. Similarly, toxicity rates remain low and QOL scores remain high over that period. For patients receiving SBRT alone, 35 Gy is as effective as 36.25 Gy with less urinary toxicity, suggesting 35 Gy may be the optimal dose. For high risk patients, use of EBRT and ADT do not appear to increase long term control rates.

Clinical Predictors Of Severe Late Urinary Toxicity After Curative Intensity-Modulated Radiation Therapy For Localized Prostate Cancer

Clinical Predictors Of Severe Late Urinary Toxicity After Curative Intensity-Modulated Radiation Therapy For Localized Prostate Cancer

Is hypofractionated whole pelvis radiotherapy (WPRT) as well tolerated as conventionally fractionated WPRT in prostate cancer patients? The HOPE trial

BackgroundPatients with high-risk prostate cancer are at increased risk of lymph node metastasis and are thought to benefit from whole pelvis radiotherapy (WPRT). There has been recent interest in the use of hypofractionated radiotherapy in treating prostate cancer. However, toxicity and cancer outcomes associated with hypofractionated WPRT are unclear at this time. This phase II study aims to investigate the impact in quality of life associated with hypofractionated WPRT compared to conventionally fractionated WPRT.MethodsFifty-eight patients with unfavourable intermediate-, high- or very high-risk prostate cancer will be randomized in a 1:1 ratio between high-dose-rate brachytherapy (HDR-BT) + conventionally fractionated (45 Gy in 25 fractions) WPRT vs. HDR-BT + hypofractionated (25 Gy in 5 fractions) WPRT. Randomization will be performed with a permuted block design without stratification. The primary endpoint is late bowel toxicity and the secondary endpoints include acute and late urinary and sexual toxicity, acute bowel toxicity, biochemical failure-, androgen deprivation therapy-, metastasis- and prostate cancer-free survival of the hypofractionated arm compared to the conventionally fractionated arm.DiscussionTo our knowledge, this is the first study to compare hypofractionated WPRT to conventionally fractionated WPRT with HDR-BT boost. Hypofractionated WPRT is a more attractive and convenient treatment approach, and may become the new standard of care if demonstrated to be well-tolerated and effective.Trial registrationThis trial was prospectively registered in ClinicalTrials.gov as NCT04197141 on December 12, 2019.

Dose to the bladder neck is not correlated with urinary toxicity in patients with prostate cancer treated with HDR brachytherapy boost

PurposeThe purpose of this study was to evaluate whether the dose to bladder neck (BN) is a predictor of acute and late urinary toxicity after high-dose-rate brachytherapy (HDRB) boost for prostate cancer. Methods and MaterialsBetween 2014 and 2016, patients with prostate cancer treated at our institution with external beam radiation therapy and 15 Gy single-fraction HDRB boost for intermediate- and high-risk disease according to D'Amico definition were reviewed. Intraoperative CT scan–based inverse planning and ultrasound-based inverse planning were performed in 173 and 136 patients, respectively. The following structures were prospectively contoured: prostate, urethra, rectum, bladder, and the BN defined as 5 mm around the urethra between the catheter balloon and the prostatic urethra. Dose to the BN was reported only, no constraint was applied. Acute and late urinary toxicity were assessed using the International Prostate Symptom Score (IPSS) and the Common Terminology Criteria for Adverse Events v.4.0. Clinical and dosimetry factors associated with urinary toxicity were analyzed using generalized linear models. ResultsA total of 309 patients with median age of 71 years (range 50–89) were included. Median followup was 25 months (range 0–39 months). Using D'Amico definition, 71% of the patients had intermediate-risk disease, whereas 29% had high-risk disease. The mean pretreatment prostate-specific antigen value was 9.65 ng/mL. The mean pretreatment, after 6 weeks and over 6 months IPSSs were 8.34, 12.14, and 10.02, respectively. Urinary obstruction was reported in 14 cases (4.5%). Pretreatment IPSS (p = 0.003) and prostate volume (p = 0.024) were significantly associated with acute and late urinary toxicity. The dose for the most exposed 2 cc (D2cc) of BN was not correlated with acute (p = 0.798) or late urinary toxicity (p = 0.859). BN D2cc was not correlated with urinary obstruction (p = 0.272), but bladder V75 was (p = 0.021). ConclusionsHigh pretreatment IPSS, large prostate volume and bladder V75 were the only predictors of acute and late urinary toxicity after HDRB boost in our study. Although BN D2cc was associated with acute and late urinary toxicity after low-dose-rate brachytherapy, no correlation was found after HDRB. A prospective study comparing dose to the BN in HDRB monotherapy would validate the impact of BN dose on acute and late urinary toxicity.

Hyaluronic acid spacer in focal prostate reirradiation: A single centre experience

PurposeThe optimal management of locally recurrent prostate cancer after curative radiotherapy is still unknown. In this study, we evaluated the preliminary results of reirradiation using stereotactic body radiotherapy for locally recurrent prostate cancer after initial definitive local radiotherapy. Materials and methodsBetween April 2016 and February 2019, 11 patients with recurrent disease at the previously irradiated prostate were treated. Local recurrence was detected by radiological with or without functional imaging modalities including prostate multiparametric/pelvic MRI or positron-emission tomography–computerised tomography with (68Ga)-labelled prostate-specific membrane antigen performed after rising prostate specific antigen serum level during follow-up. All patients received stereotactic body radiotherapy to the recurrent nodule to a total dose of 30Gy in five fractions. Hyaluronic acid spacer was injected between prostate and rectum in seven patients to decrease the rectal dose. Acute toxicity was evaluated by using Common Terminology Criteria for Adverse Events version 4.0, and late toxicity was evaluated by using Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer late radiation morbidity scoring schema. ResultsAt the diagnosis, the median age was 64 years, and the mean prostate specific antigen serum concentration was 17.7ng/mL. The median interval time between local recurrence and initial definitive radiotherapy was 63 months. Mean prostate specific antigen concentration nadir value during follow-up was 0.43ng/mL. With a median follow up of 19 months, three patients developed either local or distant relapse. One patient had grade 3 acute rectal toxicity, and one patient had grade 2 late urinary toxicity. We did not observe any acute or late toxicity due to hyaluronic acid spacer injection. ConclusionReirradiation after local recurrence following initial definitive radiotherapy together with hyaluronic acid spacer use seems to be effective and safe.

Implementation of image-guided brachytherapy as part of non-surgical treatment in inoperable endometrial cancer patients

ObjectiveThis study assessed outcomes of inoperable endometrial cancer (IEC) patients treated with definitive external beam radiation therapy (EBRT) followed by a 3D image-guided brachytherapy boost. MethodsAll consecutive patients treated with EBRT followed by 3D image-guided brachytherapy for IEC were retrospectively included. EBRT delivered a dose of 45Gy. Then, patients had an uterovaginal brachytherapy guided by 3D imaging. Clinical target volume (CTVBT) included the whole uterus and the initial disease extent. Gross tumour volume (GTVres) included the residual disease at time of brachytherapy. ResultsTwenty-seven patients were identified. Causes of inoperability were comorbidities (37%) or tumour loco regional extent (63%). Including EBRT and brachytherapy, the median D90 (minimal dose delivered to 90% of the volume) was 60.7 GyEQD2 (IQR = 56.4–64.2) for the CTVBT, and was 73.6 GyEQD2 (IQR = 64.1–83.7) for the GTVres. The median overall treatment time was 50 days (IQR = 46–54). The mean follow-up was 36.5 months (SD = 30.2). The cumulative incidence of local, pelvic and distant failures was 19% (n = 5), 7% (n = 2) and 26% (n = 7), respectively. Five-year overall survival was 63% (95% CI = 43–91). Late urinary and gastro intestinal toxicities ≥ grade 2 were reported in four (15%) and two patients (7%) respectively. No vaginal toxicity ≥ grade 2 was reported. ConclusionsEBRT followed by intracavitary brachytherapy seems to be an effective option for IEC. The implementation of 3D concepts at time of brachytherapy may contribute to high local control probability and low toxicity profile. Large scale retrospective or prospective data are needed to confirm these early data.

Preliminary result of carbon-ion radiotherapy using the spot scanning method for prostate cancer

BackgroundCarbon-ion radiotherapy (CIRT) for prostate cancer was initiated at Kanagawa Cancer Center in 2015. The present study analyzed the preliminary clinical outcomes of CIRT for prostate cancer.MethodsThe clinical outcomes of 253 patients with prostate cancer who were treated with CIRT delivered using the spot scanning method between December 2015 and December 2017 were retrospectively analyzed. The irradiation dose was set at 51.6 Gy (relative biological effectiveness) delivered in 12 fractions over 3 weeks. Biochemical relapse was defined using the Phoenix definition. Toxicities were assessed according to CTCAE version 4.0. Results: The median patient age was 70 (47–86) years. The median follow-up duration was 35.3 (4.1–52.9) months. According to the D’Amico classification system, 8, 88, and 157 patients were classified as having low, intermediate, and high risks, respectively. Androgen deprivation therapy was administered in 244 patients. The biochemical relapse-free rate in the low-, intermediate-, and high-risk groups at 3 years was 87.5, 88.0, and 97.5%, respectively (P = 0.036). Grade 2 acute urinary toxicity was observed in 12 (4.7%) patients. Grade 2 acute rectal toxicity was not observed. Grade 2 late urinary toxicity and grade 2 late rectal toxicity were observed in 17 (6.7%) and 3 patients (1.2%), respectively. Previous transurethral resection of the prostate was significantly associated with late grade 2 toxicity in univariate analysis. The predictive factor for late rectal toxicity was not detected.ConclusionThe present study demonstrated that CIRT using the spot scanning method for prostate cancer produces favorable outcomes.

Local dose analysis to predict acute and late urinary toxicities after prostate cancer radiotherapy: Assessment of cohort and method effects

PurposeTo perform bladder dose-surface map (DSM) analysis for (1) identifying symptom-related sub-surfaces (Ssurf) and evaluating their prediction capability of urinary toxicity, (2) comparing DSM with dose-volume map (DVM) (method effect), and (3) assessing the reproducibility of DSM (cohort effect). Methods and materialsUrinary toxicities were prospectively analyzed for 254 prostate cancer patients treated with IMRT/IGRT at 78/80 Gy. DSMs were generated by unfolding bladder surfaces in a 2D plane. Pixel-by-pixel analysis was performed to identify symptom-related Ssurf. Likewise, voxel-by-voxel DVM analysis was performed to identify sub-volumes (Svol). The prediction capability of Ssurf and Svol DVHs was assessed by logistic/Cox regression using the area under the ROC curve (AUC). The Ssurf localization and prediction capability were compared to (1) the Svol obtained by DVM analysis in the same cohort and (2) the Ssurf obtained from other DSM studies. ResultsThree Ssurf were identified in the bladder: posterior for acute retention (AUC = 0.64), posterior–superior for late retention (AUC = 0.68), and inferior–anterior–lateral for late dysuria (AUC = 0.73). Five Svol were identified: one in the urethra for acute incontinence and four in the posterior bladder part for acute and late retention, late dysuria, and hematuria. The overlap between Ssurf and Svol was moderate for acute retention, good for late retention, and bad for late dysuria, and AUCs ranged from 0.62 to 0.81. The prediction capabilities of Ssurf and Svol models were not significantly different. Among five symptoms comparable between cohorts, common Ssurf was found only for late dysuria, with a good spatial agreement. ConclusionSpatial agreement between methods is relatively good although DVM identified more sub-regions. Reproducibility of identified Ssurf between cohorts is low.

DNA repair gene polymorphisms, tumor control, and treatment toxicity in prostate cancer patients treated with permanent implant prostate brachytherapy.

Radiotherapy and brachytherapy are common treatments for localized prostate cancer (PCa). However, very few studies evaluated the association of variations in DNA damage response genes and treatment outcomes and toxicity in brachytherapy-treated patients. To evaluate the association of inherited germline variations in DNA repair-associated genes with tumor control and treatment toxicity in patients treated with low-dose-rate prostate brachytherapy (LDRB). The cohort consists of 475 I-125 LDRB patients with a median follow-up of 51 months after seed implantation. Patients were genotyped for 215 haplotype tagging single nucleotide variations (htSNPs) in 29 candidate genes of DNA damage response and repair pathways. Their association with biochemical recurrence (BCR) was assessed using Cox regression models and Kaplan-Meier survival curves. Linear regressions and analysis of covariance (ANCOVA) between early and late International Prostate Symptom Score (IPSS) with htSNPs were used to evaluate the association with urinary toxicity. After adjustment for the established risk factors, six htSNPs in five genes were found to be significantly associated with an altered risk of BCR, with adjusted hazard ratios (HRadj. ) ranging between 3.6 and 11.1 (P < .05). Compared to carriers of the ERCC3 rs4150499C allele, patients homozygous for the T allele (n = 22) had a significant higher risk of BCR with a HR of 11.13 (IC95 = 3.9-32.0; P < .0001; q < 0.001). The Kaplan-Meier survival curve revealed a mean BCR-free survival time reduced from 213 ± 7 to 99 ± 12 months (log-rank P < .0001) for homozygous T carriers compare to noncarriers. For late IPSS (>6 months after treatment), htSNP rs6544990 from MSH2 showed a statistically significant b-coefficient of 1.85 ± 0.52 (P < .001; q < 0.1). Homozygous carriers of the MSH2 rs6544990C allele (n = 62) had a mean late IPSS 3.6 points higher than patients homozygous for the A allele (n = 132). This difference was significant when tested by ANCOVA using pretreatment IPSS as a covariate (P < .01). This study suggests an association of the intronic variants of the DNA nucleotide excision repair ERCC3 and DNA mismatch repair MSH2 genes with elevated risk of BCR and late urinary toxicity respectively after LDRB. Further validation is required before translational clinical advances.