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The prognostic utility of preoperative β2 microglobulin in patients with renal cell carcinoma.
565 Background: β2 microglobulin is a nonglycosylated protein synthesized by all nucleated cells. It has been utilized as a tumor marker in several different malignancies, however, studies examining its role in renal cell carcinoma (RCC) are limited. Methods: Using the Emory kidney cancer database, patients with any stage or histology RCC who underwent partial or radical nephrectomy from 2000 to 2022 and had an available β2 microglobulin within 90 days before surgery were included. β2 microglobulin ≥ 2.34 mg/L was considered elevated. Patient and surgical characteristics were recorded. Kaplan-Meier curves and multivariable Cox hazards models were used to assess the association between an elevated β2 microglobulin and overall (OS) and cancer-specific survival (CSS). Subgroup analysis was performed based on renal function (estimated glomerular filtration rate (eGFR) ≤ or > 60 mL/min/1.73m 2 ) and metastatic disease status. Results: Of 429 patients who met inclusion criteria, 178 (41.5%) had an elevated preoperative β2 microglobulin. After adjusting for confounders, an elevated β2 microglobulin was independently associated with worse CSS (HR 2.08 [95% CI 1.20–3.60]; p = 0.009) and OS (HR 1.58 [95% CI 1.03–2.41]; p = 0.035) compared to a normal β2 microglobulin. On subgroup analysis, however, elevated β2 microglobulin remained significantly associated with worse OS/CSS only in patients with normal renal function and non-metastatic disease (Table). Conclusions: A preoperatively elevated β2 microglobulin level is independently associated with worse OS and CSS in patients with RCC undergoing nephrectomy. The utility of β2 microglobulin as a prognostic indicator is most relevant for patients with normal renal function and non-metastatic disease. Multivariable Cox hazards model for the effect of preoperative β2 microglobulin on cancer-specific and overall survival in patients with renal cell carcinoma according to renal function and metastatic disease status. Covariants n(%) Cancer-specific SurvivalHazard Ratio (95% CI) p-value Overall SurvivalHazard Ratio (95% CI) p-value β2 microglobulin ≥ 2.34 mg/L metastatic disease 102 (63) 0.95 (0.51-1.76) 0.872 0.93 (0.56-1.55) 0.779 non-metastatic disease 76 (28.5) 4.55 (1.24-16.77) 0.023 2.99 (1.37-6.54) 0.006 eGFR ≤ 60* 99 (23.1) 1.31 (0.69-2.49) 0.410 1.51 (0.95-2.41) 0.083 eGFR > 60* 79 (18.4) 2.90 (1.54-5.44) < 0.001 2.00 (1.19-3.36) 0.009 β2 microglobulin < 2.34 mg/L eGFR ≤ 60* 50 (11.7) 1.24 (0.55-2.78) 0.600 1.39 (0.74-2.60) 0.309 eGFR > 60* 201 (46.9) Ref Ref *Calculated using Chronic Kidney Disease Epidemiology Collaboration 2021 equation. Variables in model include age, sex, race, Body Mass Index (BMI), Charlson Comorbidity Index (CCI) pT stage, Fuhrman grade, presence of IVC thrombus, receipt of systemic therapy, and IMDC risk score (metastatic patients only).
Sociodemographic predictors of the late-stage diagnosis in patients with prostate cancer: A retrospective cohort study.
132 Background: Distant metastasis at the time of prostate cancer (PCa) diagnosis is associated with increased morbidity and mortality. This study aimed to assess the impact of sociodemographic characteristics on distant metastasis at the time of PCa diagnosis. Methods: The Surveillance Epidemiology and End Results (SEER) database (2000-2021), including PCa patients from 17 registries, was queried. Patients with late-stage diagnosis (LSD) were defined as those who were initially diagnosed with stage IV disease, indicating distant metastasis. Sociodemographic predictors included race, ethnicity, age, marital status, residential status, and median household income. Multicollinearity was assessed using variance inflation factors (VIF). Univariable logistic regression was performed to identify significant predictors of LSD, which were further analyzed in multivariable logistic regression using a maximum likelihood estimation approach. Odds ratios with 95% confidence intervals (CI) were computed with a p-value of <0.05 indicating a statistically significant association. Results: Of the 1,089,736 PCa patients diagnosed, 64,983 (6%) had an LSD. The majority were white (80%), non-Hispanic/Latino (HL) (91%), aged ≥65 years (60%), married (75%), residents in metropolitan areas (88%), and had an annual house income of ≥$70,000 (70%). Multivariable logistic regression identified Black (OR: 1.24; 95%CI: 1.22-1.27), Asian or Pacific Islander (1.35; 1.30-1.40), and American Indian/Alaska Native (1.70; 1.53-1.89) to have higher odds of LSD compared to White patients (Table). In addition, HL ethnicity compared to non-HL (OR: 1.45; 95% CI: 1.42-1.49), age ≥65 compared to <65 (1.68; 1.65-1.71), unmarried status compared to married (1.88; 1.85-1.91), residency in non-metropolitan areas compared to metropolitan (1.10; 1.07-1.12), and household income <$70,000 compared to ≥$70,000 (1.03; 1.01-1.05) had a significant association with LSD. Conclusions: Older, non-White (Black, Asian/Pacific Islander, American Indian/Alaska Native), Hispanic/Latino, unmarried men, residents of non-metropolitan areas, or those with lower annual household incomes have higher odds of late-stage diagnosis. Interventions targeting early detection in these at-risk groups may improve prostate cancer outcomes in the US. Variable Odds Ratio (95% CI) p-value Race (Black vs White) 1.24 (1.22-1.27) <0.01 Race (Asian or Pacific Islander vs White) 1.35 (1.31-1.40) <0.01 Race (American Indian/Alaska Native vs White) 1.70 (1.53-1.89) <0.01 Ethnicity (Hispanic/Latino vs non-/Hispanic/Latino) 1.45 (1.42-1.49) <0.01 Age (≥65 vs <65) 1.68 (1.65-1.71) <0.01 Marital status (unmarried vs married) 1.88 (1.85-1.91) <0.01 Residence status (non-metropolitan vs metropolitan) 1.10 (1.07-1.12) <0.01 Household income (<$70,000 vs ≥$70,000) 1.03 (1.01-1.05) <0.01
Approach to treatment of metastatic hormone-sensitive prostate (mHSPC) cancer among cooperative oncology groups (CCTG, SWOG, and Alliance) in North America.
263 Background: Randomized clinical trials have demonstrated the efficacy of both doublet (androgen deprivation therapy (ADT) + androgen receptor pathway inhibitor (ARPi)) and triplet (ADT + ARPi + docetaxel) regimens in the treatment of mHSPC. However, the optimal clinical setting for each approach remains unclear. We surveyed genitourinary oncologists to identify their practice patterns with respect to systemic therapy for mHSPC. Methods: A 13-question survey was distributed to clinicians associated with the Canadian Clinical Trials Group (CCTG), SWOG, and Alliance for Clinical Trials in Oncology between March 2024 and June 2024. We collected data on clinician specialty, practice setting, location, years of clinical experience, and approach to management for patients with mHSPC. Results: 542 responses were solicited, and 104 (19%) surveys were completed. 24 respondents were from Canada (CCTG) and 80 were from the United States (47 SWOG, 33 Alliance). 88% (92/104) respondents indicated that less than 50% of their mHSPC patients are started on triplet therapy (Table). The most important factors when considering the use of doublet vs. triple therapy were volume of disease (88/104, 85%) and patient comorbidities (82/104, 79%). Physicians favored triplet therapy in high volume, de novo (95/104, 91%) or recurrent (70/104, 67%) disease, but not in low volume, de novo (2/104, 2%) or recurrent (2/104, 2%) disease. The greatest barriers to triplet therapy were toxicity concerns (75/104, 72%) and patient factors (66/104, 63%). In the scenario where prostate specific antigen (PSA) remained at 4 ng/ml after 6 months of doublet therapy, 77% (80/104) would not make any changes, while 23% (24/104) could consider additional intensification strategies, including clinical trial enrollment. In the scenario where PSA was undetectable after two years on doublet therapy, 63% (65/104) would continue therapy without de-escalation, while 37% (38/104) would consider deintensification, and 1 declined to answer. Responses were concordant between American and Canadian participants. Conclusions: North American genitourinary oncologists consider disease volume, patient comorbidities, and toxicity when opting for doublet vs. triplet therapy, and feel there is a role to explore PSA-based de/intensification strategies in future clinical trials. Alliance (n = 33) SWOG (n = 47) CCTG (n = 24) Total (n = 104, %) Specialty Medical Oncology 32 39 24 95 (91%) Radiation Oncology 0 4 0 4 (4%) Surgical Oncology 0 3 0 3 (3%) Other 1 1 0 2 (2%) Practice setting Academic 31 41 24 96 (92%) Private 0 1 0 1 (1%) Other 2 5 0 7 (7%) Years from fellowship <5 years 11 8 6 25 (24%) 5-10 years 6 10 5 21 (20%) 10-20 years 8 15 9 32 (31%) >20 years 8 13 4 25 (24%) Other / Skipped 0 1 0 1 (1%) Percent of patients offered triplet therapy <10% 9 14 8 31 (30%) 11-30% 12 20 13 45 (43%) 31-50% 7 9 0 16 (15%) 51-75% 3 3 2 8 (8%) >76% 2 1 1 4 (4%)
A novel predictive model using changes in clinical and serum biomarkers and automated quantitative imaging for mCRPC patients treated with AR-directed therapy.
264 Background: In mCRPC, standard risk models use baseline clinical and blood-based biomarkers, excluding imaging. This study developed a new predictive model incorporating baseline and early on-treatment clinical, blood, and imaging biomarkers to inform overall survival (OS). The training set was derived from COU-AA-302 and validated using Alliance 031201 (A031201). Eligibility required patients to have at least two CT and bone scans within 6 months of randomization (COU-AA-302: n = 785; A031201: n = 582). Methods: Conventional biomarker data included PSA, albumin, alkaline phosphatase, hemoglobin, and ECOG status. Imaging data included > 1000 radiomic features and the automated Bone Scan Index (aBSI). Six-month biomarker trajectories were summarized using the intercept and slope from a random effects model, yielding over 2000 risk biomarkers. Due to the high dimensionality, an elastic net proportional hazards model was applied. Predictive concordance probability, which evaluates the ability to distinguish between long-term and short-term survivors, and R-square, a calibration measure that indicates how accurately the model predicts actual survival time were determined. Results: 46 biomarkers were selected from over 2000, including 9 blood-based, 4 from aBSI, 1 tumor volume measure, and the remaining from radiomic features. In contrast, the non-imaging risk model contained 10 risk factors. Risk scores from these models were categorized into low, moderate, and high-risk groups. The median survival per group revealed significant separation, with a difference of over 30 months between low and high-risk groups. This separation was observed regardless of whether imaging was included in the model. Conclusions: This is the first model for mCRPC to integrate pre-treatment and early on-treatment serum, imaging, and clinical data from two large phase 3 trials, with external validation. While both imaging and non-imaging models showed good predictive accuracy, imaging did not significantly improve the discrimination of long-term from short-term survivors or enhance the precision of the model-based survival predictions. Clinical + Serum biomarkers with imaging Clinical + Serum biomarkers without imaging Total # of risk factors 46 10 # of clinical/serum factors 9 10 # of radiomics factors 32 0 # of aBSI factors 4 0 # of tumor volume factors 1 0 Median Survival (mos) Low risk group 55 54 Moderate risk group 38 39 High risk group 20 21 Predictive Concordance Probability 0.74 0.73 R-square Measure of Calibration 0.37 0.39
Cancer-control outcomes of metastatic castration resistant prostate cancer patients with <i>BRCA</i> -gene or tumor suppressor mutations undergoing 177-lutetium PSMA radioligand therapy.
71 Background: Several tumor gene mutations are known for metastatic castration-resistant prostate cancer (mCRPC) are known. The individual response to 177-Lutetium Prostate-specific membrane antigen (Lu-PSMA) therapy is under current investigation regarding the genomic profile of mCRPC patients. Methods: We relied on the FRAMCAP database and compared progression-free (PFS) and overall survival (OS) rates of mCRPC patients with Breast Cancer related antigen ( BRCA ) or tumor suppressor gene mutations ( TP53, PTEN, RB1 [TSG]). Especially, subgroup analyses were performed for Lu-PSMA-treated mCRPC patients. Results: Of 194 mCRPC patients, 22% were BRCA1/2 vs. 14% TSG vs. 63% without one of these mutations. Patients with no mutation harbored significantly lower Gleason score 8-10, relative to BRCA and TSG patients. In PFS analyses of first line mCRPC, no difference between all three groups was observed, while median OS differed significantly with 46.3 vs. 48.7 vs. 95.4 months for BRCA vs. TSG vs. no mutated patients (p<0.05). In univariable Cox regression models, BRCA mutated patients were at higher risk for death (hazard ratio [HR]: 2.57, p<0.01), while TSG patients were not (p=0.4). Of 87 Lu-PSMA treated mCRPC patients, significant differences in PFS and OS were made (both p≤0.02). In univariable and multivariable Cox regression models, BRCA mutated Lu-PSMA patients were at higher risk for death, while TSG patients had similar outcomes as no mutated patients. Conclusions: In real-world setting, substantially lower OS in mCRPC is observed for BRCA and TSG mutated patients, while no difference in first line PFS could be computed. In Lu-PSMA-treated patients, worst outcomes were observed for BRCA patients. Age at mCRPC, years 149 68 (61, 75) 66 (61, 71) 69 (65, 80) 69 (63, 76) 0.3 PSA at CRPC, ng/ml 105 12 (3, 50) 12 (1, 72) 5 (3, 36) 13 (4, 46) 0.8 Treatment lines mCRPC 194 3.00 (1.00, 4.00) 3.00 (1.00, 4.50) 3.00 (1.00, 4.00) 3.00 (1.00, 4.00) 0.6 ECOG status at mCRPC 79 0.017 0 47 (59%) 7 (44%) 12 (92%) 28 (56%) 1 32 (41%) 9 (56%) 1 (7.7%) 22 (44%) ≥2 0 (0%) 0 (0%) 0 (0%) 0 (0%) Cardiovascular disease 168 52 (31%) 9 (23%) 6 (21%) 37 (37%) 0.15 Gleason Score 179 0.032 8-10 130 (73%) 34 (83%) 22 (81%) 74 (67%) De Novo mHSPC 186 123 (66%) 32 (76%) 18 (64%) 73 (63%) 0.3 High volume mHSPC 126 73 (58%) 24 (71%) 12 (63%) 37 (51%) 0.13 Metastatic sites at mCRPC 92 0.2 M1a 6 (6.5%) 1 (4.5%) 2 (10%) 3 (6.0%) M1b 75 (82%) 15 (68%) 17 (85%) 43 (86%) M1c 11 (12%) 6 (27%) 1 (5.0%) 4 (8.0%) PARPi Treatment 194 25 (13%) 15 (35%) 1 (3.6%) 9 (7.3%) <0.01 1 Median (IQR); n (%). 2 Kruskal-Wallis rank sum test; Fisher’s exact test; Pearson’s Chi-square test.
Feasibility and efficacy of cisplatin-based neoadjuvant chemotherapy for muscle invasive bladder cancer in older patients: A retrospective French GETUG study.
735 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) and radical cystectomy is the gold standard in localized muscle-invasive bladder cancer (MIBC), for fit patients. However, NAC is less prescribed in older patients, mainly due to safety concerns. This study aimed to evaluate the feasibility and efficacy of NAC for patients aged ≥ 75. Methods: We retrospectively included older patients, from 14 French GETUG centers. All patients had received at least one cycle of cisplatin-based NAC for localized MIBC, between 2010 and 2022. Primary outcome was NAC feasibility evaluated as the rate of patients that underwent optimal treatment, defined as at least 4 cycles of chemotherapy followed with local treatment (surgery or chemoradiotherapy). Secondary outcomes were NAC safety and efficacy. Results: 156 pts were included. Median age was 77 (from 75 to 96), with 20% aged ≥ 80. Patients were in good general condition: 54% were PS 0, with a median serum albumin level of 39 g/L, and 86% had a creatinine clearance ≥ 60 ml/min. 108 (69%) had a cT2N0 MIBC. 75 (48%) received dose dense MVAC (ddMVAC), 80 (51%) received gemcitabine-cisplatin (GC) and one patient received MVAC. 96 (62%) received an optimal treatment. 50 patients (32%) prematurely stopped NAC, due to death (3 pts, 2 from unknown causes), progressive disease (4), infection (3), toxicity (34 patients) mainly renal and hematological ones. Among them, 38 (76%) underwent local treatment. Among the 112 patients that underwent cystectomy, pathological complete response (pCR) was significantly more frequent when they received ≥ 4 cycles (36/78 = 46% versus 5/34 = 15%, p = 0.002). Median follow up from diagnosis was 28 months, with 97 patients (62%) that were still alive at the end of follow-up. Median disease-free survival was 3 years and 3 months. 2-years overall survival (OS) was 72%; 5-years OS was 56%. Conclusions: These data suggest that NAC for MIBC is feasible in selected older patients, even if toxicity was the main reason for cisplatin-based regimen discontinuation. Older patients who received optimal treatment were more often in pCR. OS in the this cohort of older patients was very similar to the results published in younger patients.
Leveraging tumor organoids to model drug response in clear cell renal cell carcinoma.
579 Background: Clear cell renal cell carcinoma (ccRCC) is characterized by a highly immunosuppressive tumor microenvironment that plays a crucial role in promoting tumor progression and conferring resistance to conventional treatments, such as chemotherapy and radiotherapy. Systemic therapies, including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), have become central to the management of ccRCC. However, patient responses to these treatments vary significantly. Given the pivotal role of ICIs in ccRCC therapy, recreating the tumor-immune microenvironment in vitro is essential to address the current lack of reliable biomarkers. Patient-derived tumor organoids (PDTOs) offer a highly accurate platform for evaluating drug efficacy tailored to individual patients, significantly enhancing therapeutic decision-making. These models closely replicate the three-dimensional architecture, genetic profile, and behavior of the original tumor tissue. Moreover, PDTOs can be co-cultured with various cell types, such as cancer-associated fibroblasts (CAFs) and immune cells, to simulate the tumor-immune microenvironment. The aim of our study is to set an in vitro drug screening by providing more physiologically relevant PDTOs which could enable researchers to study how therapies, especially TKIs and ICIs, interact with both tumor and immune cells. Methods: This is a translational on-going study including patients with diagnosis ccRCC. We successfully established five patient-derived ccRCC PDTO lines from individuals who underwent partial or radical laparoscopic robotic assisted nephrectomy. All the models faithfully recapitulated the original tumors at both the histological and genetic levels, harboring somatic mutations in key genes such as VHL (50%), PBRM1 (30%), SETD2, and BAP1. The PDTOs were treated with standard-of-care compounds, including Cabozantinib, Lenvatinib, and Axitinib, and the resulting dose-response curves observed. Results: When co-cultured with autologous cancer-associated fibroblasts (CAFs) and immune cells, and treated with the same compounds, the PDTOs exhibited different response patterns compared to PDTOs alone, indicating that the tumor microenvironment significantly modulates drug response. We tested Ipilimumab, Nivolumab, and Pembrolizumab in our co-culture system, both as monotherapies and in combination. The resulting dose-response curves revealed heterogeneous levels of drug sensitivity and resistance. Conclusions: In conclusion, by faithfully replicating the tumor microenvironment and facilitating comprehensive drug screening, this approach aims to identify optimal treatment regimens and uncover mechanisms of resistance. Ultimately, it seeks to create a personalized, predictive model that can enhance clinical decision-making in the management of ccRCC.
Early findings from a national quality improvement (QI) program to address disparities in bladder cancer (BLCA) care.
697 Background: Rates of guideline-concordant treatment for BLCA remain <50%, driven by access and care delivery barriers. The Association of Cancer Care Centers (ACCC) designed a 6-month QI program to identify and implement site-specific strategies to support equitable care delivery at cancer programs. We aim to characterize findings from participating sites’ pre-implementation assessments as well as initial directions for QI. Methods: The ACCC QI program was conducted with cancer programs between November 2023 – November 2024, guided by an advisory committee, patient advocacy partners, and multidisciplinary faculty. Each program completed a pre-assessment to characterize organizational resources, catchment population demographics, patient volume, sentiment regarding organizational culture, practice patterns and identified barriers. Open-ended questions and those regarding sentiment used a 5-point Likert scale. During each in-person workshop, participants discussed barriers and prioritized interventions using an impact-feasibility matrix. Descriptive summary data are presented. Results: Three programs (one in California, North Carolina and Kentucky) were selected; one in an urban setting and two suburban; two NCI-designated and one Comprehensive Community Cancer program. Annual case volumes ranged from 103-1439, with 167-220 new diagnoses; >50% of cases were non-muscle invasive at each site and male-predominant (up to 30% female), with variable patient diversity (up to 50% Asian and 15% Black). Insurance coverage varied across programs: 52-80% Medicare, 17-29% Private, 0-3% uninsured. All programs agreed/strongly agreed leadership, staff and multidisciplinary team members were committed to improving equitable care, but only 1 program had processes to regularly assess disparities and 1 felt they had adequate training or culturally appropriate educational materials. Program-specific barriers to care included limitations around transportation support, limited care coordination, few community practitioners providing specialized care, and limited awareness of available resources. Based on impact and feasibility ratings, intervention targets included assessing and aligning care coordination preferences, mapping supportive care resources and addressing gaps, and tailoring educational materials to patient populations. Conclusions: Our study demonstrates a strong recognition by health systems of disparities affecting BLCA care, shows the feasibility of developing a QI program focused on addressing disparities in diverse practice settings and highlights the importance of systems-level support. Implementing mitigation strategies require program-specific understanding of barriers to provide equitable care. Health systems level strategies require a community-based approach to address barriers and deliver equitable care tailored to the needs of communities served.
A novel CD28 x Nectin-4 costimulatory bispecific antibody for advanced bladder cancer.
810 Background: Effective T-cell activation is driven by multiple signals. CD3 bispecific antibodies (bsAbs) stimulate T-cell activation through the TCR. CD3 bsAbs demonstrate durable responses in hematological malignancies, but multiple clinical trials suggest that signaling through CD3 alone is insufficient to treat solid tumors. Recent results suggest that a robust T-cell response in solid tumors can be achieved by tumor-targeted costimulatory bsAbs that promote sustained T-cell activity. Bladder cancer is the tenth most prevalent cancer worldwide with suboptimal progression free survival in the locally advanced and metastatic setting. Efficacy of checkpoint inhibitors (CPI) in metastatic urothelial cancer (mUC) patients indicates the presence of tumor antigen-specific T-cell activity, and thus, treatment with a costimulatory bsAb as a single agent may elicit a durable and robust anti-tumor response. Here we describe RNDO-564, a novel CD28 x Nectin-4 bispecific molecule. RNDO-564 was developed preclinically with optimal potency to provide robust anti-tumor activity and safety by localizing co-stimulatory activity to the site of the tumor and avoiding super-agonist activity. Methods: High throughput antibody discovery was completed on CD28 and Nectin-4. A panel of agonistic bispecific CD28 antibodies was generated by combining high affinity Nectin-4 binders with CD28 binders of varying potencies using knobs-in-hole technology. Bispecific antibodies were tested for their ability to enhance T-cell mediated cytotoxicity and cytokine release on tumor cell lines expressing varying levels of Nectin-4 in the presence of suboptimal signal 1. Lead candidates were then tested for efficacy using in vivo syngeneic mouse models. Results: Affinity tuning of CD28 agonistic activity was performed by testing a diverse panel of CD28 effector arms to identify optimal costimulatory activity that lacked super agonist activity. One of these CD28 binders was paired with a high affinity Nectin-4 binder to generate RNDO-564. With an affinity tuned CD28 arm and a high affinity Nectin-4 arm driving localization to tumor cells, RNDO-564 exhibited potent and specific cytotoxicity and cytokine release to Nectin-4 expressing tumor cells in vitro. In vivo , RNDO-564 alone and in combination with an anti-PD-1 mAb resulted in dose-dependent tumor growth inhibition in signal 1-proficient syngeneic models, indicating clinical potential for both monotherapy and combination activity. In addition, RNDO-564 was well-tolerated in non-human primates and had normal pharmacokinetics after a single dose infusion. Conclusions: RNDO-564 has a high affinity Nectin-4 binding arm and an affinity-tuned CD28 arm optimized for activity in metastatic bladder cancer. A phase 1 study is planned to evaluate the safety, tolerability, PK/PD, and clinical activity of RNDO-564 alone and in combination with CPI in mUC.
Management strategies and patient outcomes among LPC patients with persistently positive PSA after RP.
353 Background: Patients (pts) with localized high-risk/very high-risk prostate cancer (PCa) have an elevated risk of metastases and Prostate Cancer (PC)-specific death following local therapy. This risk is significantly higher for patients with a persistently elevated PSA (pPSA) after Radical Prostatectomy (RP) We aim to better understand the current management strategies for this population using real world data. Methods: We performed a retrospective population-based cohort study using province-wide linked administrative data from 2010-2022, in Ontario, Canada. Patterns of patient management in the intermediate (IR)/High-/very high risk (h/vHR) LPC patients who underwent RP with persistently elevated PSA≥0.1 ng/ml were analyzed. Results: In this retrospective cohort between 2010-2021, 31,571 patients diagnosed with LPC were identified. Cohorts were stratified by IR (58.2%, n=18,365) and H/vHR (41.8%, n=13,206). Overall, 13493 pts with IH/HvHR received RP as their treatment for LPC, from which 314 pts (Intermediate Risk=127; High-Very high risk=187) had a persistently positive PSA after RP. 46.8% (n=147) of pts with pPSA received RT, 40.4% (n=127) ADT and 21.7% (n=68) RT+ADT as their next line of treatment (p=<.0001; SD=0.880). PSA value after RP and immediately preceding start of next line of therapy was 0.6 ng/ml (Median IQR: 0.2-1.5 ng/ml) in the RT subgroup and 5.8 ng/ml (Median IQR 2.9-10.5 ng/ml) and 0.9 ng/ml in ADT and ADT+RT groups respectively (Median IQR 0.2-4.3 ng/ml; p=<.0001). Median (IQR) time to CRPC was 9 years (7-11.3) in pts without a pPSA and 7.4 years (5.2-10) in patients with a persistent PSA (P=<.0001). Conclusions: Patients who do not achieve a PSA<0.1 ng/ml after radical prostatectomy have a worse prognosis. LPC patients should be monitored closely after RP to identify the sub-population with persistent PSA that could benefit from additional therapies intensified systemic therapies including Androgen Receptor Pathway Inhibitors (ARPIs). Time to progression to CRPC, PC event, and mortality by persistent PSA status among patients with RP. Persistent PSA Label Total No Yes P Value Variable (Sample size) N=14,084 N=13,770 N=314 Time to CRPC n (%) 186 (1.3%) 148 (1.1%) 38 (12.1%) <.0001 Median (IQR), Years 9.1 (7-11.3) 9 (7-11.3) 7.4 (5.2-10) <.0001 Time to PC event n (%) 6,001 (42.6%) 5,744 (41.7%) 257 (81.8%) <.0001 Median (IQR), Years 6.7 (1.9-3.6) 6.8 (1.5-10) 0.8 (0.4-4) <.0001 PSA value before RP (PSA test closest to RP) Median (IQR), (1) ng/ml 6.7 (5.1-9.6) 6.7 (5.0-9.6) 9.0 (5.9-12.8) <.0001
PSA dynamics: Enhancing predictive models in prostate cancer follow-up.
424 Background: Advances in prostate cancer (PC) care have led to a 98% 10-year survival rate. Prostate Specific Antigen (PSA) is the primary method of follow-up after definitive radiotherapy (RT), with benign PSA ‘bounce’ occurring in up to 30% of patients, causing uncertainty and anxiety. Distinguishing between PSA bounce and biochemical recurrence (BCR) remains challenging. The Phoenix Criteria is the standard definition of BCR since 2006, defined as PSA nadir + 2 ng/dl, but does not consider patient specific information. Our study aims to explore factors associated with bounce and BCR and develop a predictive tool to differentiate between these two events. Methods: PC patients who received RT at our institution between 2006 and 2022 were identified, including only patients with a PSA increase during follow-up. Exclusion criteria included palliative RT, prostatectomy, or insufficient follow-up information. Patients’ clinical data was collected, and PSA increase was classified as bounce or BCR. Variables were compared using Kruskal Wallis or Chi-square. Multivariate logistic regression was performed in the subset of patients with absolute PSA value >2 (n= 581). Results: Of 1783 patients reviewed due to PSA rise after treatment, 694 met the inclusion criteria. There were 213 (30.7%) with PSA bounce and 481 (69.3%) with recurrence. Prior to meeting the Phoenix Criteria, 20 (4.2%) had biopsy-proven recurrence and 18 (3.7%) imaging-proven recurrence. The median delta PSA was 0.8 ng/mL for bounce vs 5 ng/mL for recurrence (p<0.001). The median time from treatment to event was 14.4 months for bounce vs 45.3 months for BCR (p<0.001). Recurrence was significantly associated (p<0.001) with older age at diagnosis, N1 stage, higher risk category, Gleason score, and higher baseline PSA. In the subgroup of patients without ADT, recurrence was associated with a lower median first PSA post-RT (1.9 vs. 2.4, p=0.046) and a lower median nadir before event (0.6 vs. 1.8, p<0.001). Multivariate logistic regression achieved an accuracy of 0.94, with a sensitivity of 0.83, specificity of 0.98, and an area under the curve (AUC) of 0.97. Conclusions: Our results highlight significant differences in clinical factors between bounce and recurrence in post-RT patients. The multivariate logistic regression differentiated the events with 94% accuracy for patients with a rising PSA value >2 subgroup. We highlight the possible improvement that could be accomplished by personalizing a PSA threshold for recurrence versus the Phoenix definition. This tool offers patients and providers a highly specific tool to differentiate between PSA recurrence and bounce, and may reduce stress and unnecessary testing, or help diagnosis recurrence faster. Next steps include prospective validation of the model to assess the impact on clinical practice costs, patient experience, and cancer outcomes.
Further Optimizing Care of Patients With Operable Hormone Receptor–Sensitive Breast Cancer
Harmonized global collaborations are crucial to improving outcomes in hormone sensitive operable breast cancer.
Use of geospatial analysis with multiplex immunofluorescence to analyze tumor immune microenvironment patterns and prognosis in penile cancer.
12 Background: Previous studies utilizing multiplex Immunofluorescence (mIF) have described cell density patterns of immune exhaustion implicating both innate and adaptive immune system components across varying stages of penile squamous cell carcinoma (PSCC). Here we studied geospatial clustering patterns of various immune effector cells within the tumor immune microenvironment (TIME). Methods: Tissue microarray (TMA) was constructed for 57 cases of invasive PSCC and immunostained for CD20, CD3, CD4, CD8, CD45RO, CD68, CD206, CD163, NKp46, FOXP3 using OPAL TM 7 kit (AKOYA Biosciences). Areas of tumor and stroma were identified using an image analysis system (InForm 2.2.4). Spatial analysis and co-clustering of cell phenotypes was performed using Ripley’s K. Survival curves were determined using Kaplan Meier method and tested using logrank and cox regression. Univariate and bivariate analysis describes co-clustering and proximity to tumor cells, respectively. Results: 57 PSCC patients (median age 60, [IQR (interquartile range) 31-92]); 60% HPV negative, and 31/57 with pN+ had mIF analysis. A high clustering pattern of CD68+, a general marker for macrophages, was associated with a significant OS benefit on univariate analysis (162 vs 36 mos, p=0.006) and an OS, RFS, and CSS benefit on bivariate analysis (84 vs 27 mos; NA vs 14 mos; NA vs 27 mos p=0.007, 0.014, 0.001). High clustering of CD3+CD4+, a marker for T-helper-lymphocytes, within the tumor and the tumor-stroma interface was associated with an OS benefit on bivariate analysis (84 v 20 mos, p=0.009). Low intra-tumoral clustering of CD68+CD163+, marker for M2 protumor macrophages, was associated with improved RFS on bivariate analysis (NA v 15 mos, p=<0.01). Low clustering of CD68+CD163+ in HPV+ patients was associated with a CSS benefit compared to high clustering in HPV- patients (p=0.024). High versus low clustering of CD68+CD163+ was inconsequential in HPV- patients (p=0.66).Overall, low intratumoral clustering pattern of FOXP3+, a marker for regulatory immune-suppression, was associated with an improved CSS on bivariate analysis (p=0.017). Low clustering of FOXP3+ in HPV+ patients was associated with an improved CSS versus low clustering of FOXP3+ in HPV- patients (p=0.041). Conclusions: Spatial analysis shows that proximity of CD68+ and CD3+CD4+, a general marker for macrophages and T-helper cells, to tumor cells has a positive impact survival in PSCC. Interestingly, proximity of protumor M2 macrophages to cancer cells confers a survival benefit specifically in HPV+ tumors and has no impact on survival in HPV- tumors. Decreased intratumoral FOXP3+ activity, a marker for regulatory immune-suppressive T cells, shows a preferential survival benefit in in HPV+ tumors. These findings point to diverging tumorigenic pathways related to HPV status that may be attributable to their poorer prognosis.
Chromosomal instability in tumor suppressor genes–altered prostate cancer.
226 Background: Metastatic prostate cancer (PC) accumulates significant genomic alterations as the disease progresses, exhibiting the highest levels of chromosomal instability (CIN) among all metastatic tumors (Bakhoum, Nature 2018). Furthermore, tumor suppressor genes (TSG; RB1 , PTEN and TP53 ) are frequently altered in metastatic PC and are associated with adverse outcomes. Here, we aim to investigate CIN in metastatic hormone-sensitive PC (mHSPC) harbouring alterations in TSG. Methods: TSG and whole transcriptome gene expression was assessed by nCounter platform (N=354) and RNA-seq (N=60) in mHPSC samples, respectively. TSG low was considered when ≥2 out of 3 TSG presented low expression of a previously stablished cut-off, and TSG wt in the remaining cases. Differential gene expression analysis between TSG low vs TSG wt tumors of our RNA-seq cohort (N=60) and TCGA cohort (N=333) was performed. Differential expressed genes (DEGs) were considered if FDR <0.05 and log2FoldChange (LFC)>0.5. DEGs were correlated with castration-resistance PC-free survival (CRPC-FS) and overall survival (OS) by Cox analysis. CIN gene signatures were obtained from literature and the rest of Hallmark signatures from MSigDB. Results: In our cohort of mHSPC patients treated with androgen deprivation therapy + docetaxel, TSG low tumors (16.7%) displayed higher levels of CIN compared with TSG wt (CIN25 normalized enrichment score [NES] 2.13, p<0.001 and CIN70 NES 2.54, p<0001). Cell cycle and DNA-repair signatures were also overexpressed in TSG low tumors, contrasting with a low expression of androgen receptor pathway. Results were validated in the TCGA cohort, where TSG low presented also overexpression of CIN signatures. In our RNA-seq cohort, we found 22 DEGs associated with CIN (29.3% of the total DEGs) in TSG low tumors compared with TSG wt . 51 genes were significantly correlated with CRPC-FS in a multivariate analysis and 16 of them (31,3%) were CIN-associated genes. Among these genes, 5 encode proteins that are targetable for metastatic PC, with specific inhibitors already developed: BUB1 (LFC 1.06, FDR 0.034), CDC7 (LFC 12.4 FDR 0.003), KIFC1 , (LFC 11,7, FDR 0.01), PLK1 (LFC 1.08, FDR <0.001) and WEE1 (LFC 0.79, FDR 0.011). Conclusions: TSG-altered mHSPC tumors harbor high levels of CIN, and differentially expressed CIN-associated genes could potentially be targets in mHSPC.
Modeling survival outcomes of KEYNOTE-564 with standard of care control arm treatment: A simulation study.
517 Background: The KEYNOTE-564 study, reporting improved overall survival (OS) with use of adjuvant checkpoint inhibitor (CPI), pembrolizumab, following surgery for renal cell carcinoma (RCC) suffers from a common challenge: a large portion of the control arm received non-standard of care (nSOC) subsequent therapy upon progression (in this case dual CPI or CPI + tyrosine kinase inhibitor [TKI]), thus underestimating survival in this group. We sought to model the survival of KEYNOTE-564 control group patients had they received CPI/TKI per current standard of care (SOC) to more accurately assess this intervention. Methods: Data were extracted from the Kaplan-Meier plots as published in KEYNOTE-426 and KEYNOTE-564. Patient-level survival data were simulated using an iterative process to adjust the censored and event rates to ensure consistency with published reference survival curves derived from KEYNOTE-426. Thus, these measures estimate a counterfactual survival parameter for the KEYNOTE-564 control group based on results from the KEYNOTE-426 study to approximate the expected increase in survival probability if the percent of control patients which received nSOC therapy had received SOC. The analytical process was conducted using R version 4.3.1, with MASS, splines, survival, dplyr, and survminer packages. Results: A total of 52% (N = 109) of patients in the control arm of KEYNOTE-564 that progressed did not receive CPI in the first-line setting. Based on KEYNOTE-426, we estimated a one-year mortality risk of 9.5% for those receiving axitinib-pembrolizumab versus 19.8% in those receiving TKI alone, equating to a 10.3% attributable risk between these arms. When KMA was performed on extracted data where that proportion of patients in the control arm were simulated to have avoided death on an annual basis distributed randomly across five years (n = 51 patients), the re-estimated, unadjusted hazard ratio in this was 1.41 (0.93 to 2.14). As a sensitivity analysis, we conducted this model with a survival parameter of 5% instead of 10% annual mortality risk, resulting in an unadjusted hazard ratio of 0.88 (0.61 to 1.28), and with 2.5% (unadjusted HR 0.72 (0.50 - 1.02). Conclusions: We report and validate method for modeling appropriate subsequent therapy for clinical trials where nSOC treatment in the control group limits the interpretation of their conclusions. In a simulation correcting for the under-estimated survival in the control arm of KEYNOTE-564, the reported survival benefit of adjuvant CPI may not be statistically durable.
Spatial analysis of the immune microenvironment and identification of phenotypes of prognostic significance in penile squamous cell carcinoma (PSCC).
13 Background: Advanced penile cancer is a rare but aggressive malignancy. Over 70% of patients with bulky metastases relapse or have primary refractory disease with current treatments. Immunotherapy represents a promising modality, but response rates remain low. While prior studies explored single immune factors within the tumor microenvironment (TME), understanding complex interactions between T cells and macrophages and in relation to the tumor cells is crucial to best characterize the TME. Methods: We performed multiplex immunofluorescence (mIF) on 59 PSCC tissues obtained from MD Anderson to analyze expression of 12 key immune cell markers (CD3, CD8, CD68, CD86, CD206, CD163, ARG, CSF1R, MHC-II, PD-1, PD-L1). Spatial analysis and co-clustering of cell phenotypes was performed using Ripley’s K. Overall (OS), recurrence free (RFS), and cancer specific survival (CSS) curves were determined using Kaplan Meier method and tested using logrank and cox regression models. Results: The median age was 60 (IQR 24-86) and majority were HPV negative (64%). High densities and clustering of cytotoxic CD8+ T cells and CD68+ tumor associated macrophages (TAMs) were each associated with improved OS (126 vs 61 months, p= 0.03; 140 vs 61 months, p= 0.04, respectively]. Conversely, high densities of antigen-experienced CD8+PD-1+ cytotoxic T cells and antigen-experienced CD68+PD-1+ macrophages were associated with worse OS [HR 1.44 (1-2.05), p= 0.04 and HR 1.48 (1.04-2.12), p=0.03 respectively], PFS [HR 1.45 (1.03-2.05), p= 0.03 and HR 1.53 (1.06-2.19), p= 0.02 respectively ] and CSS [HR 1.52 (1.03-2.24), p= 0.03 and HR 1.63 (1.12-2.36), p= 0.01 respectively]. Clustering of CD86+ M1 macrophages was associated with improved OS (104.5 vs 29.1 months, p=0.02), while clustering of CD163+ and CD206+ M2 macrophages correlated with decreased OS (67.8 vs 199.7 months, p=0.03; 100.6 vs NA months, p=0.01 respectively). Bivariate analysis revealed improved OS associated with co-clustering of CD8+ T cells with TAMs (104 vs 42 months, p=0.03). Similarly, co-clustering of CD8+T cells with CK+ tumor cells was associated with improved OS (140 vs 61 months; p=0.02). While co-clustering of CD86+ M1 macrophages to cytokeratin (CK+) tumor cells correlated with improved OS (126 vs 42 months, p=0.03), co-clustering of CD 206+ M2 macrophages to CK+ tumor cells associated with poor RFS (48 vs NA months, p=0.03). Co-clustering of antigen experienced T cells with TAMs was also associated with decreased RFS (29 vs NA months, p =0.03). Conclusions: Using spatial analysis, we showed that interaction between T cells and macrophages impact clinical outcomes in PSCC. High densities and proximity of CD8+ T cells and M1 macrophages, and low levels of antigen experienced T cells and macrophages were associated with improved survival in PSCC.
Impact of adjuvant intraarterial chemotherapy on survival for patients with stage IIIA-IIIB bladder urothelial carcinoma after radical cystectomy: An open-label, prospective, randomized clinical trial.
772 Background: The aim of this trial was to evaluate the survival benefit of adjuvant intraarterial chemotherapy (IAC) in patients who received radical cystectomy (RC) and pathologically confirmed stage IIIA-IIIB bladder urothelial carcinoma. Methods: This was a multicenter, randomized study. Patients with stage IIIA-IIIB (pT3-4 or positive node) disease after RC were randomly assigned (1:1) to the IAC group or the observation group. Adjuvant IAC with cisplatin and gemcitabine (GC) was performed through a percutaneous catheter system. The GC regimen consisted of gemcitabine 800 mg/m² and cisplatin 25 mg/m² on days 1, 8, and 15 every 28 days for three cycles. The primary endpoint was recurrence-free survival (RFS). The secondary endpoint was overall survival (OS). The trial was designed to detect a 20% improvement in 5-year RFS, from 35% to 55% in IAC group (HR: 0.57), with a two-sided significance level of 0.05 and 80% power. Considering a 10% loss to follow-up, the calculated sample size was 212 patients (106 for each arm), to be accrued over 7 years. Survival curves were estimated using the Kaplan–Meier method and compared using the log-rank test. Results: The interim analysis was cancelled in the 8th year after enrolling 186 patients due to poor accruals. Based on the actual accrual interval, the sample size was recalculated, reducing the target to 184 patients with approximately 100 events. One hundred eighty-six patients were randomly assigned to two arms (93 in the IAC group and 93 in the observation group). The median age was 63 years (quartiles 57-70), with 169 (91%) of the 186 patients being male. Among the patients, 110 (59%) had pT3 disease, and 51 (27%) had pT4 disease. Lymph node involvement (LNI) was 54.3% in total, and was comparable between the two groups (54% vs. 55%). With a median follow-up of 77.9 months, 106 (57%) patients experienced recurrence (48 in the IAC group and 58 in the observation group). In the intention-to-treat (ITT) population, IAC significantly prolonged RFS (HR: 0.66, 95% CI: 0.45-0.96; p = 0.031), with a 5-year RFS of 47.7% (95% CI: 38.0%-60.0%) in the IAC group and 35.2% (95% CI: 26.5%-46.8%) in the observation group. OS was better in the IAC group as compared with the observation group, although the improvement reaches statistical significance only in per-protocol population (PP) (HR: 0.60, 95% CI: 0.39-0.94; p = 0.025). Grade 3/4 treatment-related adverse events occurred in 34.6% of the patients, and a significantly lower incidence of grade 3/4 leukopenia (9.0%) and thrombocytopenia (3.9%) was observed when compared to intravenous chemotherapy. Conclusions: Adjuvant IAC significantly improved RFS in patients with stage IIIA-IIIB bladder urothelial carcinoma, with a good safety and tolerability profile. OS was also significantly improved in the IAC group among the PP population. Clinical trial information: NCT01627197 .
Cognitive effects of androgen receptor (AR) directed therapies for advanced cancer of the prostate (COGCaP): A comparison of enzalutamide vs abiraterone acetate.
131 Background: Whether treatment with androgen receptor pathway inhibitors (ARPIs) with distinct mechanisms of action and central nervous system (CNS) penetration has distinct effects on cognitive function or quality of life (QOL) has been incompletely described. We compared cognitive function and QOL between patients with advanced prostate cancer treated with abiraterone acetate (AA) or enzalutamide (ENZ) in US patients enrolled from one of six sites. Methods: Patients with metastatic hormone sensitive prostate cancer (mHSPC), metastatic castration-resistant prostate cancer (mCRPC) or non-metastatic castration-resistant prostate cancer (nmCRPC) who were initiating treatment with enzalutamide or abiraterone acetate (AA) were prospectively enrolled. Patients underwent cognitive testing (written and computer-based) and completed patient reported outcome measures (PROMs) at baseline, 3, 6, and 12 months. The primary endpoint compared median changes in CANTAB computer-assessed cognitive function between groups at 3 months, and secondary endpoints included comparison of longitudinal cognitive function and PROMs. Results: In total 74 of planned 100 participants enrolled: 51 treated with AA and 23 treated with ENZ. Participants were approximately 90% White race, with slightly younger age (70 vs 74 years, p = 0.5) and greater education status (16 vs 13 years, p = 0.2) among AA vs ENZ patients, respectively. Baseline CANTAB and PROs were similar between groups and there were not clinically meaningful changes over time (Table). Median change in all CANTAB module scores was similar between groups at 3, 6 and 12 months, without clinically meaningful change over time (Table). Conclusions: No measurable changes were identified on cognitive testing between baseline and 3 months within or between treatment groups, and QOL decreased minimally over time and was similar between treatment groups despite different effects of treatment in the CNS. Reasons may include lack of difference in effect between agents or an inability to detect differences with existing measures in an all-comers population not enriched for patients most vulnerable to cognitive change. Further analyses of genetic factors and functional MRI studies associated with cognitive change are ongoing. Clinical trial information: NCT03016741 . Example cognitive test and PROM. Baseline 3 Month 6 Month 12 Month AA, N = 48 1 Enz, N = 20 1 p-value 2 AA, N = 35 1 Enz, N = 17 1 p-value 2 AA, N = 34 1 Enz, N = 15 1 p-value 2 AA N = 25 1 Enz, N = 13 1 p-value 2 PAL -0.53 (-1.08, 0.07) -0.44(-0.88, 0.16) 0.7 0.00 (-0.58, 0.63) -0.46(-0.65, 0.29) 0.2 0.00(-0.58, 0.65) 0.27(-0.47, 0.78) 0.7 0.00(-0.23, 0.23) 0.00(-0.29, 0.50) 0.9 FACT Cog 128.0(111.0, 136.8) 132.0 (120.5, 138.5) 0.5 -9.0(-17.5, 2.0) -2.0(-16.2, 3.5) 0.6 -2.0(-13.0, 3.5) -3.0(-16.0, 4.0) >0.9 -7.5(-17.5, 2.2) -1.2 (-6.9, 4.8) 0.4 1 Median (IQR); 2 Wilcoxon rank sum test.
A phase 1b/2 study evaluating the activity of tinengotinib in combination with androgen receptor pathway inhibitors (ARPIs) in patients with metastatic castration resistant prostate cancer (mCRPC).
TPS290 Background: Androgen receptor pathway inhibitors (ARPIs) are standard life-prolonging therapies for patients with metastatic castration-resistant prostate cancer (mCRPC), but patients ultimately progress on these agents. Resistance has been shown to occur in part via lineage plasticity mediated by increased activity of kinases including JAK1 and FGFR. Preclinical studies have shown that ARPI sensitivity can be restored by inhibiting these kinases. Tinengotinib is an orally bioavailable, potent multi-kinase inhibitor that targets JAK1 and receptor tyrosine kinases (FGFRs, VEGFRs). We hypothesize that in patients with mCRPC who are progressing on ARPIs, the addition of tinengotinib will restore sensitivity to ARPIs and result in objective responses. Methods: This is a multi-center, phase 1b/2 study of tinengotinib plus either abiraterone/prednisone or enzalutamide in patients with mCRPC. Eligible patients must be on ongoing therapy with abiraterone/prednisone or enzalutamide started at least 90 days prior to study participation consent and progressing by Prostate Cancer Working Group 3 (PCWG3) criteria. Tinengotinib will be added to abiraterone/prednisone or enzalutamide at the time of progression. Phase 1b (N = up to 24) uses a 3+3 de-escalation schema to assess the safety and tolerability of tinengotinib with either abiraterone/prednisone or enzalutamide. The starting dose of tinengotinib will be 10 mg PO QD, with the possibility of de-escalation to 8 mg PO QD if a combination is not tolerated. Phase 2 employs a two-stage Simon minimax design; patients will be enrolled to evaluate the safety and efficacy of the recommended phase 2 dose (RP2D) of tinengotinib with abiraterone acetate/prednisone or enzalutamide (N = 32). Since abiraterone acetate and enzalutamide target the same pathway, response will be evaluated in combination in the signal-seeking phase 2 portion of the study. As of October 2024, 2 patients have been enrolled in phase 1b across 1 site. Enrollment for phase 2 is expected to begin in January 2025. Clinical trial information: NCT06457919 .
Reduction of systemic chemotherapy by primary retroperitoneal lymph node dissection in low volume metastatic seminoma.
626 Background: Still, standard treatment of low-volume metastatic semimoma is either systemic chemotherapy or radiotherapy. Both options are associated with significant acute and long-term toxicities including mortality due to secondary malignancies in long-term follow-up. We calculated the number of potentially unnecessary chemotherapy cycles per hundred patients undergoing primary RPLND or Chemotherapy. Methods: In long-term follow-up of the COTRIMS-trial, 34 (12%) patients developed outfield relapses after a median follow-up of 41 months. All relapsing patients were cured by salvage PEB-chemotherapy. The base of our calculation are 12 recurrences on 100 Pts compared to 100 patients receiving chemotherapy upfront. Short term side effects of chemotherapy are from a historic patient cohort. Results: 12 relapsing patients received 36 cycles of PEB instead of 300 cycles of chemotherapy if given as first-line treatment. Significant PEB-associated acute toxicities mostly affect haematoxicity with neutropenia in 4 and 37 patients, resp., and febrile neutropenia in 1.7 and 14 patients, resp.. Based on our previous studies (Paffenholz P et al., World J Urol 2019; 37:1907), thrombembolic venous or arterial events are expected in 1.2 and 0.8 , resp. versus 10 and 7 patients, resp.. Therapy associated mortality would be expected in 0.2 and 2 patients, resp.. No data on long-term toxicities are available. Conclusions: All patients with relapses after primary RPLND can be cured by salvage chemotherapy. The number of chemotherapy cycles can be reduced by 88% without impairing oncological efficacy if surgery is performed in an experienced reference center. Thus overall acute toxicity rate affecting patients quality of life and even treatment associated deaths can be reduced dramatically. Although the reduction of long-term toxicities associated with cytotoxic therapy cannot be anticipated today, we strongly recommend to include primary nsRPLND in the therapeutic armentarium of clinical stage IIA/B seminomas.