Urinary Toxicity Research Articles

Timing of Early Salvage Therapy for Patients With Biochemical Relapse of Prostate Carcinoma.

Between 25% and 33% of patients after radical prostatectomy experience a relapse of the disease. The risk of relapse increases in patients with risk factors up to 50%-80%. For a long time, adjuvant radiotherapy has been considered the standard of care. Four large prospective trials, that compared adjuvant and salvage radiotherapy in patients with biochemical relapse, showed the superiority of the adjuvant approach in biochemical and local relapse-free survival, but no consistent benefit in long-term endpoints (i.e., metastasis-free survival, overall survival, or carcinoma-specific survival) at the expense of increased urinary and bowel toxicity. Three large international studies comparing adjuvant and salvage radiotherapy paved the way toward early salvage radiotherapy. However, the optimal threshold of the PSA level (range of 0.2-0.5ng/mL) for initiating early salvage radiotherapy remains unresolved and still poses a challenge in everyday clinical practice when balancing the need for early radiotherapy and the associated toxicity. Imprecise stratification of biochemical relaps patients according to the risk of clinical relapse drives efforts to find additional molecular biomarkers that would improve the timing of the salvage therapy.

Reirradiation salvage radiotherapy for recurrent prostate cancer after primary low-dose brachytherapy.

Local recurrence of prostate cancer after low-dose rate brachytherapy is a clinical problem with limited salvage treatment options. This prospective study evaluated the tolerability and outcome of salvage external beam radiation therapy (S-EBRT) for locally recurrent prostate cancer after primary low-dose rate prostate brachytherapy (LDR-BT). Between October 2012 and 2022, 18 patients with biopsy-proven locally recurrent prostate cancer after primary LDR-BT and received S-EBRT. We evaluated biochemical failure (BF), overall survival (OS) and acute/late gastrointestinal and urinary toxicities (CTCAE v5.0 or CTCAE v4, only before 2017). Median follow-up was 32months (range, 5-124). The median age was at S-EBRT 68years (range 59-79). 34% (6/18) were low risk, 44% (8/18) intermediate risk, 5% (1/18) high risk, and 17% (3/18) not specified. All patients were treated with IMRT/VMAT and received 60Gy (2.5Gy/fraction) to the prostate and 40% (7/18) 55.2Gy (2,3Gy/fx) to the seminal vesicles. 56% received ADT The 3-year OS and biochemical relapse-free survival after S-EBRT were 100% and 89%, respectively, with a median PSA nadir 0,035ng/mL (0,01-0,34). Acute cystitis was present in 72% (13/18) of patients (27% of Grade > 2). Urethritis was present in 78% (14/18) patients (16% of cases Grade > 3), and acute rectitis occurred in 22% (4/18) of patients (no cases Grade > 3). Our data suggest that the treatment of locally recurrent prostate cancer with S-EBRT could provide adequate disease control safely and be used as an additional treatment in the natural history of prostate cancer patients. However, the results are still early and the sample is small; larger studies with longer follow-up would be mandatory.

State of the art and future challenges of urethra-sparing stereotactic body radiotherapy for prostate cancer: a systematic review of literature

PurposeDoses delivered to the urethra have been associated with an increased risk to develop long-term urinary toxicity in patients undergoing stereotactic body radiotherapy (SBRT) for prostate cancer (PCa). Aim of the present systematic review is to report on the role of urethra-sparing SBRT (US-SBRT) techniques for prostate cancer, with a focus on outcome and urinary toxicity.MethodA systematic review of the literature was performed on the PubMed database on May 2023. Based on the urethra-sparing technique, 13 studies were selected for the analysis and classified in the two following categories: “urethra-steering” SBRT (restriction of hotspots to the urethra) and “urethra dose-reduction” SBRT (dose reduction to urethra below the prescribed dose).ResultsBy limiting the urethra Dmax to 90GyEQD2 (α/β = 3 Gy) with urethra-steering SBRT techniques, late genitourinary (GU) grade 2 toxicity remains mild, ranging between 12.1% and 14%. With dose-reduction strategies decreasing the urethral dose below 70 GyEQD2, the risk of late GU toxicity was further reduced (< 8% at 5 years), while maintaining biochemical relapse-free survival rates up to 93% at 5 years.ConclusionUS-SBRT techniques limiting maximum doses to urethra below a 90GyEQD2 (α/β = 3 Gy) threshold result in a low rate of acute and late grade ≥ 2 GU toxicity. A better understanding of clinical factors and anatomical substructures involved in the development of GU toxicity, as well as the development and use of adapted dose constraints, is expected to further reduce the long-term GU toxicity of prostate cancer patients treated with SBRT.

Locally advanced cervical cancer: how the improvement in techniques in external beam radiotherapy and brachytherapy impacts on survival outcomes and long-term toxicities.

Platinum-based chemoradiotherapy and brachytherapy are the standard treatment for locally advanced cervical cancer. Reported long-term outcomes for treated with both IMRT and 3D-Image-guided-adaptive brachytherapy are lacking. This retrospective study included 165 patients with FIGO Stage IB-IVB cervical cancer, treated with chemoradiotherapy in combination with brachytherapy. External beam radiotherapy was delivered as IMRT/VMAT/TOMO helical or 3DCRT. The intracavitary brachytherapy treatment (ICBT) was performed using two different planning system (with or without optimization). Among the patient subgroups, comprising those who received IMRT/VMAT/Tomo helical and 3DCRT, as well as those who underwent ICBT planning optimization and those who did not, homogeneity was observed in terms of age, performance status, T stage, N status, TNM stage, and histology. With a median follow-up time of 60.5months, the 5-year overall survival (OS) in the 3DCRT and IMRT groups was 74.9% and 92.8%, respectively (p = 0.033). The 5-year OS in the ICBT planning optimization group was 93.7%, compared to 75% in the non-optimization group (p = 0.014). Regarding late radiation toxicities, patients in the IMRT group had a lower incidence of chronic rectal toxicity compared to those in the 3DCRT group (6.5% vs. 34.1%, p = 0.001). The group with ICBT planning optimization had a lower incidence of late urinary toxicities (10.4%) compared to the non-optimized ICBT planning group (18.2%, p = 0.012). Similarly, the ICBT planning optimization group had a lower incidence of late rectal toxicity (6.5% with 80% grade 1 and 20% grade 2) compared to the non-optimized ICBT planning group (34.1%, p = 0.001). In this series, the group of patients receiving optimized ICBT had an advantage in terms of OS and CSS suggesting that the use of new Treatment Planning Systems associated with 3D imaging, improves the long-term survival. Additionally, a significant reduction in late rectal and urinary toxicity has been observed.

Locoregional Treatment in Patients With Metastatic Cervical Cancer: Benefit of Dose Escalation Strategies

The objective of this work was to examine the benefit of an intensive locoregional treatment including an image guided adaptive brachytherapy (IGABT) among patients with cervical cancer and extrapelvic extension. Medical records of consecutive patients with a metastatic cervical cancer and receiving external beam radiation therapy and IGABT boost in Gustave Roussy Institute as part of their first line of treatment were examined. Depending on tumor sites, patients received pelvic ± para-aortic external beam radiation therapy. For those with visceral or supradiaphragmatic lymph node metastases, chemoradiation was delivered after usually 3 cycles of chemotherapy. All patients received a brachytherapy boost, guided by magnetic resonance imaging and aimed at increasing the dose to the high-risk clinical target volume (CTVHR). Local control (LC), patient overall survival (OS), progression-free survival, and radiation therapy-related side effects were examined, and prognostic factors were searched. One hundred sixty-four patients were included; 76.2% had para-aortic lymph node extension without distant metastasis (N2) and 23.8% had distant metastatic sites (M1). There was not a statistically significant difference in survival between both groups. With a median follow-up of 36 months, OS, progression-free survival, and LC at 3 years were 55.5% (95% CI, 48%-64%), 40.6% (95% CI, 38%-54%), and 90% (95% CI, 85%-96%), respectively. In multivariate analysis, a D90CTVHR dose ≥80 Gy was significant for better OS (hazard ratio, 0.96; 95% CI, 0.94-0.98; P < .001). Most toxicities were mild to moderate, with 2% grade 3 late urinary toxicity, 7% late grade 2 vaginal sequelae, and 1 grade 3 proctitis. During follow-up, rectovaginal fistula occurred in 2 patients without local relapse. IGABT permits dose escalation and high LC rates for patients with cervical cancer and extrapelvic extension. Dose/effect relationships for survival were shown. Because of high frequency of distant events, systemic intensification should be tested more specifically among these patients.

Urethral identification using three-dimensional magnetic resonance imaging and interfraction urethral motion evaluation for prostate stereotactic body radiotherapy.

Prostatic urethra identification is crucial in prostate stereotactic body radiotherapy (SBRT) to reduce the risk of urinary toxicity. Although computed tomography (CT) with a catheter is commonly employed, it is invasive, and catheter placement may displace the urethral position, resulting in possible planning inaccuracies. However, magnetic resonance imaging (MRI) can overcome these weaknesses. Accurate urethral identification and minimal daily variation could ensure a highly accurate SBRT. In this study, we investigated the usefulness of a three-dimensional (3D) T2-weighted (T2W) sequence for urethral identification, and the interfractional motion of the prostatic urethra on CT with a catheter and MRI without a catheter for implementing noninvasive SBRT. Thirty-two patients were divided into three groups. The first group underwent MRI without a catheter to evaluate urethral identification by two-dimensional (2D)- and 3D-T2W sequences using mean slice-wise Hausdorff distance (MSHD) and Dice similarity coefficient (DSC) of the contouring by two operators and using visual assessment. The second group provided 3-day MRI data without a catheter using 3D-T2W, and the third provided 3-day CT data with a catheter to evaluate the interfractional motion using MSHD, DSC, and displacement distance (Dd). The MSHD and DSC for the interoperator variability in urethral identification and visual assessment were superior in 3D-T2W than in 2D-T2W. Regarding interfractional motion, the Dd value for prostatic urethra was smaller in MRI than in CT. These findings indicate that the 3D-T2W yielded adequate prostatic urethral identification, and catheter-free MRI resulted in less interfractional motion, suggesting that 3D-T2W MRI without a catheter is a feasible noninvasive approach to performing prostate SBRT.

Associations of Clinical and Dosimetric Parameters with Urinary Toxicities after Prostate Brachytherapy: A Long-Term Single-Institution Experience.

To examine the association of clinical, treatment, and dose parameters with late urinary toxicity after low-dose-rate brachytherapy (LDR-BT) for prostate cancer, we retrospectively studied patients with prostate cancer who underwent LDR-BT from January 2007 through December 2016. Urinary toxicity was assessed using the International Prostate Symptom Score (IPSS) and Overactive Bladder (OAB) Symptom Score (OABSS). Severe and moderate lower urinary tract symptoms (LUTS) were defined as IPSS ≥ 20 and ≥ 8, respectively; OAB was defined as a nocturnal frequency of ≥ 2 and a total OABSS of ≥ 3. In total, 203 patients (median age: 66 years) were included, with a mean follow-up of 8.4 years after treatment. The IPSS and OABSS worsened after 3 months of treatment; these scores improved to pretreatment levels after 18-36 months in most patients. Patients with a higher baseline IPSS and OABSS had a higher frequency of moderate and severe LUTS and OAB at 24 and 60 months, respectively. LUTS and OAB at 24 and 60 months were not correlated with the dosimetric factors of LDR-BT. Although the rate of long-term urinary toxicities assessed using IPSS and OABSS was low, the baseline scores were related to long-term function. Refining patient selection may further reduce long-term urinary toxicity.

Abstract 34: Evaluation of Potential Risk for Developing Treatment-Associated Late Effects Among Childhood Cancer Survivors in Northern Tanzania

Abstract Purpose: Global advancement in pediatric cancer treatment has significantly increased survival rates for children with cancer. Childhood cancer survivors (CCS) now represent a growing population at risk of potentially debilitating late effects of their treatment. This study evaluates the potential risk for long-term complications related to cancer therapy among childhood cancer survivors who completed treatment in Tanzania at Bugando Medical Centre (BMC), and compares the relative risk assessment of childhood cancer survivors at BMC as compared to the published British Childhood Cancer Survivor Study (BCCSS) cohort. Methods: Files of all patients age &amp;lt;18 yo with an oncologic diagnosis who received and completed their treatment at BMC from 2016 to 2020 were retrospectively reviewed. Extracted data included patient demographics, primary disease diagnosis and site, treatment received, and cumulative treatment doses. BCCSS risk assessment was assigned and predicted long-term follow-up surveillance needs were extrapolated from published Children’s Oncology Group Long-Term Follow-Up Guidelines. Results: 190 patients were initially identified, with 17 excluded due to missing treatment information. Among the remaining 173 patients, the mean age was 7yo, 47% were female (n=82), and the most common diagnoses were Wilms tumour (30%, n=52) and Burkitt’s Lymphoma (26%, n=45). 98% received chemotherapy (n=170), 42% (n=73) underwent tumour resection, and 8% (n=18) received radiation. Distribution of BCCSS late effect risk assessment included 6% low risk (n=10), 80% moderate risk (n=139) and 14% (n=24) high risk. This was a higher rate of moderate/severe risk (94%) compared to the published UK BCCSS cohort (84%). Based on treatment received, the late effects with highest potential risk were cardiomyopathy (57% of patients, n=98), bladder and urinary tract toxicity (50%, n=87), and ototoxicity (22%, n=38). Conclusion: Childhood cancer survivors at BMC have a higher risk of late effects as compared to published survivor cohorts in high-income countries. There is a need to develop and improve long-term follow-up care for survivors by enhancing patient and provider education to promote early detection of late effects. Based on risk assessment, survivorship programs in Tanzania should at a minimum include the capacity to perform echocardiograms, urinalysis, renal ultrasound, audiological evaluation, fundoscopic and neurological exams, and renal function test. Citation Format: Goodluck Nchasi, Gaudence Ajuaye, David Noyd, Hannah Spiegl, Erica Sanga, Heronima Joas, Kristin Schroeder. Evaluation of Potential Risk for Developing Treatment-Associated Late Effects Among Childhood Cancer Survivors in Northern Tanzania [abstract]. In: Proceedings of the 11th Annual Symposium on Global Cancer Research; Closing the Research-to-Implementation Gap; 2023 Apr 4-6. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(6_Suppl):Abstract nr 34.

PO-1537 What factors may influence late urinary toxicities after radiation therapy of prostate cancers?

PO-1537 What factors may influence late urinary toxicities after radiation therapy of prostate cancers?

PO-1508 Urinary toxicity after prostate cancer stereotactic reirradiation : frequency and predictors

PO-1508 Urinary toxicity after prostate cancer stereotactic reirradiation : frequency and predictors

PD-0572 Late urinary toxicity with extreme and moderate hypofractionated prostate RT with prior TURP

PD-0572 Late urinary toxicity with extreme and moderate hypofractionated prostate RT with prior TURP

Toxicity and Outcomes of Moderately Hypofractionated Radiation for Prostate Cancer With Seminal Vesicle Involvement

The aim of this study was to assess the toxicity and outcomes following treatment of prostate cancer with seminal vesicle involvement (SVI) evident on magnetic resonance imaging or clinical examination with moderately hypofractionated radiation therapy (MHRT). Forty-one patients treated with MHRT to the prostate and 1 or both seminal vesicles from 2013 to 2021 at a single institution were identified and propensity score matched to 82 patients treated during the same period with prescription dose given to the prostate alone. Dosimetry of the planning target volume, bladder, and rectum were compared. Urinary and bowel toxicity were scored by National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Clinical outcomes including freedom from biochemical recurrence, prostate cancer-specific survival, and overall survival were assessed. Of the 41 patients identified with SVI, 26.8% had SVI by clinical examination and 95.1% had high-risk prostate cancer. Compared with the cohort without SVI, treatment plans to include SVI had a larger planning target volume (152.2 vs 109.9 cc; P < .001), maximum point dose (107.9% vs 105.8%; P < .001), and volume receiving 100% of the prescription dose (143.1 vs 95.9 cc; P < .001). No difference in bladder dosimetric variables between cohorts was observed, but there was an increase in the rectal maximum point dose (103.9% vs 102.8%; P=.030) and rectal volume receiving 100% of the prescription dose (1.8 vs 1.2 cc; P=.016). Despite these differences, there was no difference in the cumulative incidence of grade 2+ urinary (hazard ratio [HR], 0.73; 95% CI, 0.39-1.35; P=.31) or bowel (HR, 0.35; 95% CI, 0.04-3.03; P=.34) toxicity. Freedom from biochemical recurrence (HR, 0.47; 95% CI, 0.16-1.38; P=.17), prostate cancer-specific survival (HR, 0.31; 95% CI, 0.04-2.49; P=.31), and overall survival (HR, 0.35; 95% CI, 0.10-1.16; P=.09) also did not differ with or without SVI, respectively. Treatment of SVI to prescription dose with MHRT for localized prostate cancer does not increase bowel or urinary toxicity. Similar clinical outcomes were also observed with or without SVI.

Electronic brachytherapy for gynecological cancers - a systematic review.

The purpose of this manuscript is to provide an in-depth literature review of the management of endometrial and cervical cancers with electronic brachytherapy. An extensive literature search was performed and 9 articles were selected based on preset criteria. The reviewed studies provided dosimetric and clinical results. Patient populations were diverse and prescribed doses varied. When treatment plans were compared to those using cobalt 60 (60Co) and iridium 192 (192Ir) sources researchers found lower or equivalent doses in organs at risk while the doses at the applicator surface were significantly higher for electronic brachytherapy. In the eligible studies, a total of 72 patients received treatment with AxxentXoft vaginal applicator, 29 were treated with the Intrabeam vaginal applicator, and 8 with AxxentXoft cervical applicator. All authors found that electronic brachytherapy was safe and well tolerated as higher mucosal doses did not present as adverse clinical effects. Electronic brachytherapy for gynecological cancers has the potential to achieve equivalent tumor control while minimizing bowel and urinary toxicity thus improving the quality of life. More clinical data is needed to stratify patients who would benefit the most.

Abstract 4387: Total toxicity burden of FDA approved immune checkpoint inhibitors in USA

Abstract Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for multiple cancers, demonstrating effective and durable responses and becoming the standard of care for a variety of malignancies. However, ICI-based treatment has resulted in the rise of unique immune-related adverse events (irAEs). To date, very little information is available on the frequency, significance, and management of single-organ or multiorgan irAEs in clinic. In this study, the irAEs associated with the treatment of seven FDA-approved ICIs, including three PD-1 inhibitors (cemiplimab, nivolumab and pembrolizumab), three PD-L1 inhibitors (atezolizumab, avelumab and durvalumab), and one CTLA4 inhibitor (ipilimumab), were analyzed based on the data of 149,303 report cases (January 1, 2015 - June 30, 2022) collected from FDA Adverse Events Reporting System (FAERS) public dashboard. Our data reveal that irAEs associated with the treatment of anti-PD-1 ICIs (e.g., pembrolizumab) require less hospital care resources compared with anti-PD-L1 and anti-CTLA4 ICIs. Tissue and organ toxicity of ICIs are age and gender specific. ‘Cardiac disorders’ is the main disorder caused by these ICIs in cancer patients aged 65-85, while ‘reproductive system and breast disease’ is the main disorder in cancer patients aged 18-64. There are risks of respiratory and urinary system toxicity in male patients and reproductive system toxicity in female patients when they receive the treatment of ICIs. Studies such as this one provide the statistical data for understanding patients at risk of developing irAEs, which will underscore the importance of further exploring research strategies to predict, detect, and mitigate toxicities from ICIs. Citation Format: Fan Yang, Chloe Shay, Zhaohui Qin, Nabil Saba, Yong Teng. Total toxicity burden of FDA approved immune checkpoint inhibitors in USA. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4387.

Early Safety and Efficacy Profile of Homogeneously Dosed Salvage Stereotactic Body Radiotherapy (SBRT) for Intraprostatic Recurrences After Low Dose Rate (LDR) Brachytherapy.

We set out to evaluate the safety and efficacy of homogeneously dosed salvage stereotactic body radiation therapy (SBRT) for intraprostatic recurrences following low dose rate (LDR) brachytherapy. An institutional prostate SBRT database was interrogated for patients treated between January 2018 and December 2021 with salvage SBRT for intraprostatic recurrences who were previously treated with LDR brachytherapy. Patients received 30 to 34 Gy in 5 fractions to the prostate with a simultaneous integrated boost of 34 to 37.5 Gy to gross disease. The maximum urethral dose allowed was 34 Gy. Toxicities were graded using Common Terminology Criteria for Adverse Events, version 5.0. Eleven patients met our study's inclusion criteria with a median follow-up time of 37.9 months (range, 24.3-51.8 months). Median time between LDR brachytherapy and salvage SBRT was 7 years (range, 2-11 years) with a median PSA of 3.15 ng/mL (range, 0.90-9.83) at the time of salvage radiation. All 11 patients were alive at the time of last follow-up. Our 3-year Kaplan-Meier progression-free survival rate was 70.1%. Median time to recurrence was 24.1 months (range, 18.7-29.7 months). Late (≥3 months) grade 1, 2, and 3 urinary toxicity rates were 27.3%, 36.4%, and 9.1%, respectively. Late (≥3 months) grade 1, 2, and 3 gastrointestinal toxicity rates were 18.2%, 0%, and 9.1%, respectively. Homogeneous salvage SBRT to the prostate with urethral dose minimization has a favorable safety and efficacy profile for treating intra-prostatic recurrences following LDR brachytherapy. This may represent an ideal form of salvage SBRT for re-irradiation.

The efficacy of radiotherapy based combined therapy for unresectable locally invasive bladder cancer and its associated factors analysis

Objective: Retrospective analysis of the efficacy and influencing factors of bladder preservation integrated therapy for unresectable invasive bladder cancer confined to the pelvis was done, also including the bladder function preservation and adverse effects analysis. Methods: Sixty-nine patients with unresectable locally invasive bladder cancer who received radiotherapy-based combination therapy from March 1999 to December 2021 at our hospital were selected. Among them, 42 patients received concurrent chemoradiotherapy, 32 underwent neoadjuvant chemotherapyand 43 with transurethral resection of bladder tumors (TURBT) prior to radiotherapy. The late adverse effect of radiotherapy, preservation of bladder function, replase and metastasis and survival were followed-up. Cox proportional hazards models were applied for the multifactorial analysis. Results: The median age was 69 years. There were 63 cases (91.3%) of uroepithelial carcinoma, 64 of stage Ⅲ and 4 of stage Ⅳ. The median duration of follow-up was 76 months. There were 7 grade 2 late genito urinary toxicities, 2 grade 2 gastrointestinal toxicities, no grade 3 or higher adverse events occurred. All patients maintained normal bladder function, except for 8 cases who lost bladder function due to uncontrolled tumor in the bladder. Seventeen cases recurred locally. There were 11 cases in the concurrent chemoradiotherapy group with a local recurrence rate of 26.2% (11/42) and 6 cases in the non-concurrent chemoradiotherapy group with a local recurrence rate of 22.2% (6/27), and the difference in local recurrence rate between the two groups was not statistically significant (P=0.709). There were 23 cases of distant metastasis (including 2 cases of local recurrence with distant metastasis), including 10 cases in the concurrent chemoradiotherapy group with a distant metastasis rate of 23.8% (10/42) and 13 cases in the non-concurrent chemoradiotherapy group with a distant metastasis rate of 48.1% (13/27), and the distant metastasis rate in the non-concurrent chemoradiotherapy group was higher than that in the concurrent chemoradiotherapy group (P=0.036). The median 5-year overall survival (OS) time was 59 months and the OS rate was 47.8%. The 5-year progression-free survival (PFS) time was 20 months and the PFS rate was 34.4%. The 5-year OS rates of concurrent and non-concurrent chemoradiotherapy group were 62.9% and 27.6% (P<0.001), and 5-year PFS rates were 45.4% and 20.0%, respectively (P=0.022). The 5-year OS rates of with or without neoadjuvant chemotherapy were 78.4% and 30.1% (P=0.002), and the 5-year PFS rates were 49.1% and 25.1% (P=0.087), respectively. The 5-year OS rates with or without TURBT before radiotherapy were 45.5% and 51.9% (P=0.233) and the 5-year PFS rates were 30.8% and 39.9% (P=0.198), respectively. Multivariate Cox regression analysis results showed that the clinical stage (HR=0.422, 95% CI: 0.205-0.869) was independent prognostic factor for PFS of invasive bladder cancer. The multivariate analysis showed that clinical stages (HR=0.278, 95% CI: 0.114-0.678), concurrent chemoradiotherapy (HR=0.391, 95% CI: 0.165-0.930), neoadjuvant chemotherapy (HR=0.188, 95% CI: 0.058-0.611), and recurrences (HR=10.855, 95% CI: 3.655-32.638) were independent prognostic factors for OS of invasive bladder cancer. Conclusion: Unresectable localized invasive bladder cancer can achieve satisfactory long-term outcomes with bladder-preserving combination therapy based on radiotherapy, most patients can retain normal bladder function with acceptable late adverse effects and improved survival particularly evident in patients with early, concurrent chemoradiotherapy and neoadjuvant chemotherapy.

Dose Distribution of High Dose-Rate and Low Dose-Rate Prostate Brachytherapy at Different Intervals—Impact of a Hydrogel Spacer and Prostate Volume

The study aimed to compare the dose distribution in permanent low-dose-rate brachytherapy (LDR-BT) and high-dose-rate brachytherapy (HDR-BT), specifically focusing on the impact of a spacer and prostate volume. The relative dose distribution of 102 LDR-BT patients (prescription dose 145 Gy) at different intervals was compared with the dose distribution of 105 HDR-BT patients (232 HDR-BT fractions with prescription doses of 9 Gy, n = 151, or 11.5 Gy, n = 81). A hydrogel spacer (10 mL) was only injected before HDR-BT. For the analysis of dose coverage outside the prostate, a 5 mm margin was added to the prostate volume (PV+). Prostate V100 and D90 of HDR-BT and LDR-BT at different intervals were comparable. HDR-BT was characterized by a considerably more homogenous dose distribution and lower doses to the urethra. The minimum dose in 90% of PV+ was higher for larger prostates. As a consequence of the hydrogel spacer in HDR-BT patients, the intraoperative dose at the rectum was considerably lower, especially in smaller prostates. However, prostate volume dose coverage was not improved. The dosimetric results well explain clinical differences between these techniques reported in the literature review, specifically comparable tumor control, higher acute urinary toxicity rates in LDR-BT in comparison to HDR-BT, decreased rectal toxicity after spacer placement, and improved tumor control after HDR-BT in larger prostate volumes.

HDR brachytherapy and radiotherapy as salvage treatment for macroscopic recurrence in the prostate bed after radical prostatectomy.

370 Background: To present early and late toxicity, biochemical, local, regional and distant control and survival in a prospective series of 75 patients with macroscopic local recurrence in the prostate bed after radical prostatectomy treated by salvage HDR brachytherapy. Methods: Between 12/1999 and 12/2020, 75 patients (pts) with exclusive macroscopic recurrence in the prostate bed after radical prostatectomy without nodal or distant metastases, were included in the study. Pts were prospectively treated by 46 Gy IMRT radiotherapy to the surgical bed followed by 16 Gy HDR brachytherapy in 2 implants of 8Gy each, one week apart and hormone therapy for 36 months. Rectal limitant dose was 85% and for urethra 115% of the prescribed dose. Toxicity was recorded according to the EORTC/RTOG criteria. Special attention to PSA levels, biochemical, local, nodal and distant metastases control and survival, as well as to quality of life was taken. Results: All pts completed treatment. No pts experienced grade 3 or higher rectal or urinary toxicity. odos los pacientes completaron el tratamiento. 2 pts presented G1 rectal toxicity (ocasional rectorragia) and 1 pts G2 rectitis (persistent rectorragia), that ceased with topic treatment (cortisone ointment) 1 Pts had G1 urethral toxicity (dysuria), that spontaneously disappeared qat few months no requiring any medical intervention. No patient developed stenosis, necrosis or urethral fistula during follow-up. With a median follow-up of 102 months, 13 pts had failure of the disease: 6 biochemical-only, 2 local recurrence, 2 pelvic recurrence, 1 paraaortic recurrence and 2 distant metastases. 2 patients died by the disease and 1 patient died by other cause (age related). Conclusions: IMRT plus HDR brachytherapy was a safe treatment without any early or late significant side-effect. Combined treatment by IMRT and HDR plus androgen deprivation was extraordinary effective in the control or macroscopic local recurrences in the prostatectomy bed after radical prostatectomy. Further studies are warranted.

A phase II trial of intravesical chemoimmunotherapy with gemcitabine and bacillus Calmette-Guérin (BCG) for patients with BCG-exposed, high-grade, non-muscle–invasive bladder cancer.

TPS579 Background: The standard of care for high-risk non-muscle invasive bladder cancer (NMIBC) after exposure to induction only BCG or relapse &gt;12 months after “adequate” BCG is retreatment with BCG. However, ~50% of patients will relapse within 6 months. Thus, there is a critical need to develop novel combination therapies to improve BCG immunotherapy efficacy. Combination BCG with immune checkpoint inhibition is associated with a ~12-18% risk of serious treatment-related adverse events and BCG combined with Mitomycin C (MMC) has unacceptable urinary toxicity. Intravesical Gemcitabine (GEM) is a common treatment for NMIBC, is well tolerated, has better efficacy after BCG than MMC, and, based on preclinical data, may synergistically enhance the efficacy of BCG by augmenting the immune tumor microenvironment. We completed a prospective Phase I trial of chemoimmunotherapy with gemcitabine and BCG in BCG-relapsed/BCG-exposed NMIBC that was well-tolerated (no treatment related grade ≥3 adverse events) with promising early efficacy (95% [19/20] 6-month complete response rate). No dose limiting toxicities were seen. The maximum tolerated dose (MTD) was 2000 mg gemcitabine and 50 mg TICE BCG. Methods: To address the need for more effective and less toxic bladder preserving treatment options by enhancing the effectiveness of BCG, we launched an investigator-initiated phase I/II trial of combination intravesical gemcitabine with BCG in patients with BCG-exposed NMIBC (NCT04179162). The Phase II portion is currently enrolling patients with BCG-exposed carcinoma in-situ (CIS ±Ta/T1) that recurred within 24 months of last BCG (BCG-exposed/BCG-relapsing NMIBC). Patients with BCG-unresponsive disease, contraindication to BCG, or prostatic/ureteral urothelial disease are excluded. Induction intravesical GEM (2000mg, twice weekly) is given weeks 1, 4, 7, and 10 and intravesical BCG (40mg, Tice strain, weekly) is given weeks 2, 3, 5, 6, 8, and 9. Responders receive SWOG maintenance BCG. The primary endpoint is clinical complete response (CR) at 6 months (absence of high-grade disease on cystoscopy/TURBT and negative cytology) using a Simon’s optimal 2-stage design testing the null hypothesis of a true CR of 55% at 6 months (based on historical outcomes of BCG alone) against a 1-sided alternative. In the first stage, the study would stop if ≤ 9/15 patients had a CR. In the second stage, the null hypothesis will be rejected if ≥ 29 CRs are observed in 43 total patients (type I error rate 5% and power of 80% if the true CR rate is 75%). Phase I patients treated at the MTD (14/25) are included in Phase II. Secondary outcomes include recurrence-free, progression-free, and cystectomy-free survival. Correlative studies explore immune and molecular predictors of response and resistance to chemoimmunotherapy in tumor tissue, urine, and blood. Clinical trial information: NCT04179162 .

The Association between Acute and Late Genitourinary and Gastrointestinal Toxicities: An Analysis of the PACE B Study

Several studies have demonstrated the association between acute and late radiotherapy toxicity in prostate cancer using older radiotherapy techniques. However, whether this association is present with newer techniques such as stereotactic body radiotherapy (SBRT), remains unclear. We use univariable and multivariable logistic regression to analyse the association between grade 2 or worse acute gastrointestinal (GI) and genitourinary (GU) toxicities with equivalent late toxicities in patients treated with SBRT and conventional or moderately fractionated radiotherapy (CRT) within the PACE-B study. 842 patients were included in this analysis. Common Terminology Criteria for Adverse Events (CTCAE) was the primary clinician reported outcome measure used in this analysis. In univariable analysis, experiencing a grade 2+ acute GU toxicity was significantly associated with developing a grade 2+ late GU toxicity after SBRT (OR 4.63, 95% CI (2.96-7.25), p < 0.0001) and CRT (OR 2.83, 95% CI (1.69-4.71), p < 0.0001). This association remained significant in multivariable analysis. In univariable analysis, experiencing a grade 2+ acute GI toxicity was also associated with developing a grade 2+ late GI toxicity after SBRT (OR 3.67, 95% CI (1.91-7.03), p < 0.0001) and CRT (OR 4.4, 95% CI (2.04-9.47), p < 0.0001). This association also remained significant in multivariable analysis. Grade 2+ baseline GU symptoms were also associated with grade 2+ late urinary toxicity in both univariable and multivariable analysis. Overall, acute toxicity is an important predictor variable for late GU/GI toxicity after localised prostate radiotherapy using SBRT and CRT. Future work should test whether optimising symptoms pre-treatment and early intervention in those with significant acute toxicities could mitigate the development late of toxicity.