Higher Rate Of Grade Research Articles

Exposure-response relationships of venetoclax in combination with carfilzomib and dexamethasone in relapsed/refractory t(11;14) multiple myeloma patients

Venetoclax is a first in class BCL-2 inhibitor, currently under investigation for the treatment of t(11;14) multiple myeloma (MM). The objective of this analysis was to characterize the exposure-efficacy and exposure-safety relationships of venetoclax when combined with carfilzomib and dexamethasone (VenKd) in t(11;14)-positive relapsed or refractory (R/R) MM patients from a phase 2 study. Fifty-seven patients receiving VenKd or Kd were included in the analysis. Efficacy endpoints included progression-free survival and clinical response rates of overall response, very good partial response or better and complete response or better. Grade ≥ 3 neutropenia, Grade ≥ 3 infections, Grade ≥ 3 treatment-emergent adverse events and any grade serious treatment-emergent adverse events were evaluated. The analysis demonstrated that adding venetoclax to Kd resulted in increased ORR, ≥VGPR and ≥ CR rates compared to the control arm. Within the venetoclax treatment arms (VenKd), no significant exposure-efficacy relationships were observed for ORR and ≥ VGPR rates. Higher ≥ CR rates trended with higher venetoclax exposures. While both 400 mg and 800 mg venetoclax in VenKd arms were generally tolerated, higher rates of Grade ≥ 3 neutropenia were observed with higher venetoclax exposures. Higher venetoclax exposures however were not associated with increased rates of Grade ≥ 3 treatment-emergent adverse events, Grade ≥ 3 infections, or serious treatment-emergent adverse events (any grade). These results confirm the benefit of adding venetoclax to carfilzomib and dexamethasone and support continued evaluation of venetoclax 400–800 mg once daily in this combination in t(11;14)-positive R/R MM patients. NCT02899052 registered April 18, 2017.

Dose dense versus 3 weekly AC during neoadjuvant chemoimmunotherapy for triple negative breast cancer

Neoadjuvant pembrolizumab plus chemotherapy (P + CT) has emerged as a standard of care for stage II-III triple-negative breast cancer (TNBC). However, the best anthracycline-cyclophosphamide (AC) schedule remains to be determined. While the KEYNOTE-522 regimen employs AC every 3 weeks (q3w AC), previous studies have shown overall survival benefits of dose-dense regimens for early-stage breast cancer. The Neo-Real study (GBECAM-0123) is a real-world data effort evaluating patients with TNBC treated with neoadjuvant P + CT in ten cancer centers since July 2020. The objective of this analysis was to evaluate the effectiveness and safety of dose-dense AC (ddAC) versus q3w AC. Among 333 patients included until November 2023, 311 completed neoadjuvant therapy and 279 underwent surgery with pathology reports available; ddAC was used in 58.2% and q3w AC in 41.8% of the cases. Most patients (69.1%) had stage II TNBC. A pCR was observed in 65.4% with ddAC and 58.7% with q3w AC (P = 0.260), while RCB 0-1 occurred in 82.4% and 73.5%, respectively (P = 0.115). Patients with stage III disease had a numerically higher pCR with ddAC (59% vs 40%, P = 0.155), while pCR rates were similar regardless of AC regimen in stage II disease (66.6% vs 64.5%; P = 0.760). While no significant disparities in drug discontinuation was noted, ddAC showed a trend towards higher rates of grade ≥3 AE (40.5% vs. 30.7%, P = 0.092). The Neo-Real study could not rule out a difference between ddAC and q3w AC during neoadjuvant P + CT. The observation of a potentially higher pCR with ddAC in stage III disease warrants further investigation.

Comparative Efficacy and Safety of Lorlatinib Versus Alectinib and Lorlatinib Versus Brigatinib for ALK-Positive Advanced/Metastatic NSCLC: Matching-Adjusted Indirect Comparisons

IntroductionThe comparative efficacy and safety of lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), versus second-generation ALK TKIs as a first-line treatment for ALK+ advanced/metastatic nonsmall cell lung cancer (NSCLC) remains uncertain as there are no head-to-head clinical trials. MethodsMatching-adjusted indirect comparisons (MAICs) were conducted using phase III trial data demonstrating superior efficacy over crizotinib, a first-generation ALK TKI. MAICs were conducted to compare lorlatinib (CROWN) versus alectinib (ALEX and ALESIA) and brigatinib (ALTA-1L) with matching based on prespecified effect modifiers. Efficacy outcomes included progression-free survival (PFS), objective response (OR), and time to progression in the central nervous system (TTP-CNS). Safety outcomes included Grade ≥3 adverse events (AEs) and AEs leading to treatment discontinuation, dose reduction, or dose interruption. ResultsLorlatinib was estimated to improve PFS compared to alectinib (ALEX) (HR: 0.54 [95% CI: 0.33, 0.88]) and brigatinib (ALTA-1L) (HR: 0.51 [95% CI: 0.31, 0.82]). Lorlatinib was estimated to improve TTP-CNS compared with brigatinib (HR: 0.19 [95% CI: 0.05, 0.71]). The estimated Grade ≥3 AE rate was higher with lorlatinib than with alectinib (RR: 1.48 [95% CI: 1.13, 1.94]); however, no differences were observed in other safety endpoints (ie, AEs leading to discontinuation, dose reduction, or interruption) or compared to brigatinib. ConclusionLorlatinib was estimated to have superior efficacy over first- and second-generation ALK-TKIs, but a higher rate of Grade ≥3 AEs compared to alectinib. These data support the use of lorlatinib as a first-line treatment for ALK+ advanced/metastatic NSCLC.

Incidence, Risk Factors, Short-term Outcomes, and Microbiome of Ventilator-associated Pneumonia in Very-low-birth-weight Infants: Experience at a Single Level III Neonatal Intensive Care Unit.

Ventilator-associated pneumonia (VAP) is a common hospital-acquired infection in neonates on invasive mechanical ventilation, resulting in high morbidity and mortality. The objective of this study is to determine the incidence, risk factors, short-term outcomes and microbiome associated with VAP in very-low-birth-weight (VLBW) infants born at <32 weeks of gestational age (GA). Retrospective study of intubated VLBW infants born at <32 weeks of GA admitted to the Los Angeles General Medical Center neonatal intensive care unit from July 2015 to July 2021 who had routine tracheal aspirate cultures obtained. Neonates were retrospectively classified into 3 groups, confirmed VAP, suspected VAP and no VAP, for comparison of risk factors, outcomes and airway microbial colonization. Eighty-seven infants met inclusion criteria with a mean GA of 26.1 ± 1 weeks and mean birth weight of 812 ± 281 g. The incidence of VAP was 7.8 per 1000 ventilator days, and the most common causative organisms were Gram-positive organisms (39%), predominantly coagulase-negative Staphylococcus. Duration of postnatal dexamethasone exposure predicted VAP compared to no VAP (coefficient, 0.31; 95% CI 0.03-0.59; P = 0.03) after adjusting for duration of intubation, surfactant use and antenatal steroid exposure. Infants with VAP had higher rate of grade 2/3 bronchopulmonary dysplasia (P = 0.03) and longer hospital stay (P = 0.04). VAP occurs at a high rate in VLBW infants who are exposed to prolonged dexamethasone use. It is predominantly caused by Gram-positive organisms.

Canadian cancer trials group LY.17: A randomized phase II study evaluating novel salvage therapy pre-autologous stem cell transplant in relapsed/refractory diffuse large B-cell lymphoma-outcome of rituximab-dose-intensive cyclophosphamide, etoposide, cisplatin (R-DICEP) versus R-GDP.

The Canadian Cancer Trials Group (CCTG) LY.17 is an ongoing multi-arm randomized phase II trial evaluating novel salvage therapies compared with R-GDP (rituximab, gemcitabine, dexamethasone and cisplatin) in autologous stem cell transplantation (ASCT)-eligible patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL). This component of the LY.17 trial evaluated a dose-intensive chemotherapy approach using a single cycle of inpatient R-DICEP (rituximab, dose-intensive cyclophosphamide, etoposide and cisplatin) to achieve both lymphoma response and stem cell mobilization, shortening time to ASCT. This report is the result of the protocol-specified second interim analysis of the 67 patients who were randomized to either 1 cycle of R-DICEP or to 3 cycles of R-GDP. The overall response rate (ORR) was 65.6% for R-DICEP and 48.6% for R-GDP. The ASCT rate was 71.9% versus 54.3%, and 1-year progression-free survival rate was 42% versus 32%, respectively, for R-DICEP versus R-GDP. Although the improvement in ORR for R-DICEP versus R-GDP exceeded the pre-specified 10% threshold to proceed to full accrual of 64 patients/arm, higher rates of grade 3-5 toxicities, and the need for hospitalization led to the decision to stop this arm of the study. CCTG LY.17 will continue to evaluate different salvage regimens that incorporate novel agents.

High-dose alemtuzumab and cyclosporine vs tacrolimus, methotrexate, and sirolimus for chronic graft-versus-host disease prevention

AbstractChronic graft-versus-host disease (cGVHD) remains a significant problem for patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although in vivo lymphodepletion for cGVHD prophylaxis has been explored in the myeloablative setting, its effects after reduced-intensity conditioning (RIC) are not well described. Patients (N = 83) with hematologic malignancies underwent targeted lymphodepletion chemotherapy followed by a RIC allo-HSCT using peripheral blood stem cells from unrelated donors. Patients were randomized to 2 GVHD prophylaxis arms: alemtuzumab and cyclosporine (AC; n = 44) or tacrolimus, methotrexate, and sirolimus (TMS; n = 39), with the primary end point of cumulative incidence of severe cGVHD. The incidence of severe cGVHD was lower with AC vs TMS prophylaxis at 1- and 5-years (0% vs 10.3% and 4.5% vs 28.5%; overall, P = .0002), as well as any grade (P = .003) and moderate-severe (P < .0001) cGVHD. AC was associated with higher rates of grade 3 to 4 infections (P = .02) and relapse (52% vs 21%; P = .003) with no difference in 5-year GVHD-free-, relapse-free-, or overall survival. AC severely depleted naïve T-cell reconstitution, resulting in reduced T-cell receptor repertoire diversity, smaller populations of CD4Treg and CD8Tscm, but a higher ratio of Treg to naïve T-cells at 6 months. In summary, an alemtuzumab-based regimen successfully reduced the rate and severity of cGVHD after RIC allo-HSCT and resulted in a distinct immunomodulatory profile, which may have reduced cGVHD incidence and severity. However, increased infections and relapse resulted in a lack of survival benefit after long-term follow-up. This trial was registered at www.ClinicalTrials.gov as #NCT00520130.

Androgen deprivation alone versus combined with pelvic radiation for adverse events and quality of life in clinically node-positive prostate cancer

The COHORT trial was conducted to compare the efficacy of androgen deprivation therapy (ADT) alone versus combined with radiation therapy (ADT + RT) for clinically node-positive prostate cancer. We reported adverse events and quality of life between the two treatment groups. Fifty-nine patients were randomized to receive ADT alone or ADT + RT and analyzed as per-protocol. Patients allocated to the ADT alone arm received ADT for at least 2 years. Patients in the ADT + RT arm received additional pelvic RT. Higher rates of grade ≥ 2 acute genitourinary (0% vs. 7.1%) and late gastrointestinal adverse events (0% vs. 14.3%) were reported in the ADT + RT arm compared with the ADT alone. However, grade ≥ 2 late genitourinary toxicity was more common in the ADT alone than the ADT + RT arm (9.7% vs. 3.6%). No grade ≥ 3 adverse events were reported. There was no statistically significant difference in EPIC scores between two treatment arms. However, the urinary and bowel domains tended to decrease and recover in the ADT + RT arm. In conclusion, ADT + RT demonstrated higher rates of adverse events compared to ADT alone. However, the addition of RT did not significantly impact the quality of life.

Impact of Treatment Modality and Route of Administration on Cytokine Release Syndrome in Relapsed or Refractory Multiple Myeloma: A Meta-Analysis.

B-cell maturation antigen (BCMA)-targeting immunotherapies (e.g., chimeric antigen receptor T cells (CAR-T) and bispecific antibodies (BsAbs)) have achieved remarkable clinical responses in patients with relapsed and/or refractory multiple myeloma (RRMM). Their use is accompanied by exaggerated immune responses related to T-cell activation and cytokine elevations leading to cytokine release syndrome (CRS) in some patients, which can be potentially life-threatening. However, systematic evaluation of the risk of CRS with BCMA-targeting BsAb and CAR-T therapies, and comparisons across different routes of BsAb administration (intravenous (i.v.) vs. subcutaneous (s.c.)) have not previously been conducted. This study utilized a meta-analysis approach to compare the CRS profile in BCMA-targeting CAR-T vs. BsAb immunotherapies administered either i.v. or s.c. in patients with RRMM. A total of 36 studies including 1,560 patients with RRMM treated with BCMA-targeting CAR-T and BsAb therapies were included in the analysis. The current analysis suggests that compared with BsAbs, CAR-T therapies were associated with higher CRS incidences (88% vs. 59%), higher rates of grade ≥ 3 CRS (7% vs. 2%), longer CRS duration (5 vs. 2 days), and more prevalent tocilizumab use (44% vs. 25%). The proportion of CRS grade ≥ 3 may also be lower (0% vs. 4%) for BsAb therapies administered via the s.c. (3 studies, n = 311) vs. i.v. (5 studies, n = 338) route. This meta-analysis suggests that different types of BCMA-targeting immunotherapies and administration routes could result in a range of CRS incidence and severity that should be considered while evaluating the benefit-risk profiles of these therapies.

Guadecitabine vs TC in relapsed/refractory AML after intensive chemotherapy: a randomized phase 3 ASTRAL-2 trial

AbstractGuadecitabine is a novel hypomethylating agent (HMA) resistant to deamination by cytidine deaminase. Patients with relapsed/refractory acute myeloid leukemia (AML) were randomly assigned to guadecitabine or a preselected treatment choice (TC) of high-intensity chemotherapy, low-intensity treatment with HMAs or low-dose cytarabine, or best supportive care (BSC). The primary end point was overall survival (OS). A total of 302 patients were randomly assigned to guadecitabine (n = 148) or TC (n = 154). Preselected TCs were low-intensity treatment (n = 233 [77%; mainly HMAs]), high-intensity chemotherapy (n = 63 [21%]), and BSC (n = 6 [2%]). The median OS were 6.4 and 5.4 months for guadecitabine and TC, respectively (hazard ratio 0.88 [95% confidence interval, 0.67-1.14]; log-rank P = .33). Survival benefit for guadecitabine was suggested in several prospective subgroups, including age <65 years, Eastern Cooperative Oncology Group performance status 0 to 1, refractory AML, and lower peripheral blood blasts ≤30%. Complete response (CR) + CR with partial hematologic recovery rates were 17% for guadecitabine vs 8% for TC (P < .01); CR+CR with incomplete count recovery rates were 27% for guadecitabine vs 14% for TC (P < .01). Safety was comparable for the 2 arms, but guadecitabine had a higher rate of grade ≥3 neutropenia (32% vs 17%; P < .01). This study did not demonstrate an OS benefit for guadecitabine. Clinical response rates were higher for guadecitabine, with comparable safety to TC. There was an OS benefit for guadecitabine in several prespecified subgroups. This study was registered at www.clinicaltrials.gov as #NCT02920008.

Impact of baseline liver function on survival outcomes in patients with unresectable hepatocellular carcinoma (uHCC) treated with camrelizumab + rivoceranib vs sorafenib: A post hoc analysis of study CARES-310.

509 Background: CARES-310 study (NCT03764293) evaluated the combination of camrelizumab, an anti-PD-1 inhibitor, and rivoceranib, a highly selective VEGFR-2 tyrosine kinase inhibitor, (cam + rivo) vs sorafenib (sora) for the treatment of uHCC. Cam + rivo significantly improved median overall survival ([mOS] 22.1 months [mo] vs 15.1 mo) and median progression-free survival ([mPFS] 5.6 mo vs 3.7 mo) compared to sora. This post-hoc analysis evaluated the impact of baseline albumin-bilirubin (ALBI) grade and Child-Pugh (CP) class on survival outcomes. Methods: In this randomized, open-label, international, multicenter, phase 3 study, patients were randomized 1:1 to receive cam 200 mg IV Q2W + rivo 250 mg PO QD (n=272) or sora 400 mg PO BID (n=271). Median overall survival (mOS), median progression free survival (mPFS), objective response rate (ORR), disease control rate (DCR), and safety were assessed by baseline ALBI grade and CP class. Results: mOS, mPFS, DCR, and ORR improved with cam + rivo vs sora regardless of baseline liver function (Table). Although treatment-related grade 3/4 AEs occurred at a greater rate in the cam + rivo arm vs the sora arm, the rate of these events was similar for patients with baseline ALBI grade 1 and grade 2 (cam + rivo, 82.1% and 81.7% vs sora, 53.9% and 54.0%, respectively). Median time-to-deterioration (mTTD) to CP class B was similar between treatment arms for ALBI grade 1 (not evaluable [NE], NE) and grade 2 (cam + rivo, 10.1 mo; sora, 10.6 mo; HR, 0.99). Conclusions: In this post-hoc analysis of Study CARES-310, the efficacy of cam + rivo was superior to sora regardless of baseline liver function as measured by both ALBI grade and CP class. Despite a higher rate of grade 3/4 AEs, there was no detrimental effect of cam +rivo on liver function in patients with both well- and moderately- preserved liver function compared to sora. These results support cam + rivo as a potential new first-line treatment option for patients with uHCC regardless of baseline liver function. Clinical trial information: NCT03764293 . [Table: see text]

The Role of Plasma Trough Concentration of Voriconazole and Voriconazole N-Oxide in Its Hepatotoxicity in Adult Patients.

Hepatotoxicity is an important cause of early withdrawal of voriconazole (VCZ). The role of the plasma trough concentration of VCZ (C0) in hepatotoxicity is confusion. VCZ N-oxide is the primary metabolite of VCZ in plasma. We investigated the role of VCZ C0 and plasma trough concentration of VCZ N-oxide (CN) in hepatotoxicity in adult patients. This was a prospective study. VCZ C0 and CN were measured using liquid chromatography-tandem mass spectrometry. In total, 601 VCZ C0 and CN from 376 adult patients were included. The percentage of grade 1 or higher adverse events for ALP, ALT, AST, γ-GT, and TBIL were 35.4%, 21.0%, 30.1%, 56.2%, and 22.2%, respectively. Compared with younger adult patients, elderly patients (≥65 years) had a higher rate of grade 1 or higher adverse events of ALP. In the multivariate analysis, VCZ C0 was a risk factor for grade 1 or higher adverse events of AST in elderly patients and TBIL in younger adult patients, and VCZ CN was a risk factor for grade 1 or higher adverse events of ALT, AST, and TBIL. Results of the receiver operating characteristic curve analysis indicated that when the VCZ C0 was higher than 4.0 μg/mL, or the VCZ CN was lower than 1.7 μg/mL, the incidence of grade 1 or higher adverse events of AST and TBIL increased. VCZ C0 and CN were associated with liver function-related adverse events. Measurement of VCZ CN should be considered for VCZ therapeutic drug monitoring.

A Comparative Study of Hyper-CVAD and Modified CALGB-10403 Regimens in Adults with Philadelphia-Negative Acute Lymphoblastic Leukemia

Introduction: Induction with pediatric-inspired regimens (PIR) in young adults with acute lymphoblastic leukemia (ALL) is being increasingly used due to its demonstrated improvement in overall survival (OS) compared to historical adult regimens. However, in certain comparisons, PIR, specifically augmented BFM, did not exhibit an OS benefit when compared to the adult Hyper-CVAD regimen. Additionally, Hispanic patients with ALL often present with disease-related high-risk features and a high prevalence of comorbidities like obesity and metabolic syndrome, which may contribute to unfavorable outcomes and a particular adverse event profile. This study aimed to compare the OS and relapse-free survival (RFS) of patients treated with a PIR, a modified CALGB 10403 (mCALGB), and the Hyper-CVAD regimen. Methods: This observational retrospective cohort study was conducted at a single reference center in Mexico City. The study included adult patients aged 18-49 years with newly diagnosed Philadelphia (Ph)-negative ALL who received induction chemotherapy with either mCALGB or Hyper-CVAD between January 2015 and May 2023. High-risk karyotype was defined by hypodiploid, complex, or t(v;11q23), and hyperleukocytosis was characterized by &amp;gt; 30 x 10 3/µL white blood cells. Measurable residual disease (MRD) was assessed via flow cytometry. A comparative analysis of sociodemographic, clinical, and laboratory characteristics was performed between the two treatment groups using Student's t-test (parametric) or U Mann-Whitney (non-parametric) for continuous variables, and the Chi-square / exact Fisher tests for categorical variables. OS and RFS were estimated using Kaplan-Meier survival analysis, and the log-rank test was used to compare both survivals. A Cox regression analysis was performed to identify prognostic factors for OS and RFS. Results: The study included 100 patients: 36 treated with Hyper-CVAD and 64 with mCALGB. The median age at diagnosis was 26 years (IQR 20.5-38), with 56% being male, and 52% being overweight or obese. No statistically significant differences were observed in the clinical and laboratory features between the treatment groups (see Table 1). Regarding induction-related mortality, febrile neutropenia, or admission to an intensive care unit during induction, no differences were found between Hyper-CVAD and mCALGB (see Table 1). A non-significant trend towards a higher rate of grade 3 or 4 hepatotoxicity during induction was observed in patients receiving the modified CALGB 10403: 56.3% vs. 36.1% with an odds ratio (OR) of 2.275 (95% CI 0.982-5.272), p=0.063. The complete response (CR) rate was 87.6%. MRD was assessed in 83% of patients, with &amp;lt;0.1% detected in 62.7% of them. There were no differences between Hyper-CVAD and mCALGB regarding CR or MRD&amp;lt;0.1% (88.9% vs. 86.9%, p=1, and 53.8% vs. 66.7%, p=0.330, respectively). The relapse rate for the entire population was 41.8%, with Hyper-CVAD demonstrating a higher relapse rate compared to mCALGB: 64.7% vs. 28.1%, p=0.001. The median RFS was 54.1 months (95% CI NR-NR) for mCALGB and 12.7 months (95% CI 2.9-22.5) for Hyper-CVAD, with a 3-year RFS of 61.2% vs. 31.5%, p=0.008. In a multivariate analysis for RFS, significant prognostic factors included WBC &amp;gt;30 x 10 3/µL (HR 4.47, 95% CI 2.09-9.57, p&amp;lt;0.001), post-induction MRD &amp;gt;0.1% (HR 4.07, 95% CI 1.86-8.90, p&amp;lt;0.001), and mCALGB vs. Hyper-CVAD (HR 0.37, 95% CI 0.18-0.78, p=0.01). The median OS for the entire cohort was 32.3 months (95% CI 28.3-80.1), with mCALGB demonstrating a non-reached (NR) median OS (95% CI NR-NR), and Hyper-CVAD exhibiting a median OS of 22.4 months (95% CI 13.8-31) with a 3-year OS of 64.8% vs. 35.0%, p=0.037 (see Figure 1). In a multivariate analysis for OS, significant prognostic factors included WBC &amp;gt;30 x 10 3/µL (HR 3.57, 95% CI 1.58-8.09, p=0.002), post-induction MRD &amp;gt;0.1% (HR 2.58, 95% CI 1.17-5.69, p=0.002), and mCALGB vs. Hyper-CVAD (HR 0.29, 95% CI 0.13-0.66, p=0.003). Conclusion: Among a cohort of Mexican patients, treatment with mCALGB was independently associated with better RFS and OS compared to Hyper-CVAD.

Single-Dose Post-Office Fulguration Mitomycin C Instillation Appears to Improve Recurrence-Free Survival in Patients With Low-Grade Noninvasive Bladder Cancer.

Perioperative instillation of mitomycin-C (MMC) has shown effectiveness in reducing the recurrence of low-grade non-muscle invasive bladder cancer (NMIBC). Data is lacking about the impact of single-dose MMC following office fulguration of low-grade urothelial carcinoma. We compared the outcomes of small-volume low-grade recurrent NMIBC in patients treated with office-fulguration - with and without an immediate single-dose instillation of MMC. A retrospective analysis of medical records of patients with recurrent small-volume (≤1 cm) low-grade papillary urothelial cancer who underwent fulguration in a single institution between January 2017 and April 2021 either with or without instillation of post-fulguration MMC (40mg/50 mL). The primary outcome was recurrence-free survival (RFS). Of 108 patients (27% women) who underwent fulguration, 41% received intravesical MMC. The treatment and control groups had similar sex ratio, mean age, mass size, tumor multifocality and or tumor grade. Median RFS was 20 months (95% CI 4-36) in the MMC group and 9 months (95% CI 5-13) in the control group (P=.038). Multivariate Cox regression analysis showed that MMC instillation was associated with longer RFS (OR=0.552, 95% CI 0.320-0.955, P=.034) and multifocality was associated with shorter RFS (OR=1.866, 1.078-3.229, P=.026). A higher rate of grade 1-2 adverse events was observed in the MMC group (18.2%) vs. the control (6.8%, P=.048). No complications grade 3 or higher were observed. A single dose of MMC instilled after office fulguration is associated with longer RFS compared to patients who did not receive MMC after the procedure, with no associated high-grade complications.

Pneumonitis after Palliative Thoracic Radiotherapy +/- Immunotherapy: A Retrospective Propensity-Matched Cohort Study

Patients (pts) with advanced lung cancer often receive combined palliative thoracic radiotherapy (RT) and immune checkpoint inhibitors (ICI). There are limited data assessing the toxicities of combined ICI-RT in this setting. We sought to compare the rates of clinically significant pneumonitis among pts with lung cancer receiving palliative thoracic RT with or without recent or concomitant ICI. We hypothesized there would be a higher rate of grade 2+ pneumonitis among RT pts who received recent or concomitant ICI compared to those who did not. We retrospectively identified consecutive pts with advanced/recurrent lung cancer from a tertiary academic center who received palliative thoracic RT with recent (defined as within 95 days of RT start) or concomitant ICI (ICI-RT group) between January 2014 and February 2020. Pts were propensity matched in a 1:1 manner (by age, sex, ECOG, RT modality, and RT dose) to lung cancer pts who received palliative thoracic RT without any history of ICI receipt (RT-only group). The presence and grade (CTCAE v5.0) of pneumonitis were independently assessed by two investigators. The primary endpoint was grade 2+ pneumonitis, estimated using the cumulative incidence function and compared between the ICI-RT and RT-only groups using Gray's test. The secondary endpoint was overall survival, estimated using the Kaplan-Meier method and compared between groups using the log-rank test. A total of 146 pts were included in the study (73 in each group). There were no statistically significant differences between the ICI-RT and RT-only groups with respect to age (median 67.7 vs. 67.6, p = 0.97), sex (52% vs. 52% female, p = 1.00), pre-treatment ECOG 0-1 (74% vs 75%, p = 0.85), or biologically effective dose greater than 45 (48% vs. 48%, p = 1.00). The most common RT regimens were 30 Gy in 10 fractions (33 pts, 23%) and 20 Gy in 5 fractions (18 patients, 12%). A plurality of cases utilized 3DCRT (67 pts, 46%). In the ICI-RT group, the median time from last dose of ICI to the start of palliative RT was 16 days; three pts in this group-initiated ICI while receiving RT treatment. The most common ICI was pembrolizumab (36 pts, 49%). A total of eleven grade 2+ pneumonitis events (nine grade 2 and two grade 3 events) were observed. The ICI-RT group had a higher cumulative incidence of grade 2+ pneumonitis compared with the RT-only group (1-year rate, 12.3% vs. 2.7%, p = 0.029); grade 3 pneumonitis occurred in 1/73 (1.4%) in each group. There was no difference in overall survival between groups (median 239 vs. 218 days, p = 0.76). In pts with advanced lung cancer treated with palliative thoracic RT, recent or concomitant ICI use was associated with a higher cumulative incidence of grade 2+ pneumonitis. However, the incidence of grade 3+ pneumonitis was low (1.4%) regardless of ICI receipt.

Risk-Adapted SABR for Ultra-Central Lung Tumors Attaining High BED10 to Targets in a Steep Dose-Response Window of 72-105 Gy under Tumor Tracking: A Planning Study

Higher rate of durable local control in stereotactic ablative radiotherapy (SABR) for ultra-central lung tumors (UCLTs) strongly correlates to a BED10 ≥ 100 Gy to the tumors. However, higher rates of grade 5 toxicities are reported to be directly associated with higher dose to the organs at risk (OARs) abutting or in close distance to the UCLTs, including trachea, proximal bronchial tree (PBT) and esophagus. This study evaluated two risk-adapted SABR schemes in a steep dose-response window of BED10 at 72 -105 Gy with isotoxic optimization and dynamic tumor tracking to safely attain high BED10 to the tumors while keeping dose to the OARs within evidence-based tolerances. A total of 12-16 patients are included for planning under two risk-adapted-SABR schemes of 60 Gy in 8 (scheme A) and15 (scheme B) fractions to attain high BED10 of ≥100 Gy to the distal sections of the PTV and yet potent BED10 at 72-84 Gy to the proximal sections of the PTV. Such inhomogeneous dose plans use a 3-5 mm GTV to PTV margins under a scenario that patients have at least one fiducial marker placed in or near the GTV for real-time tumor tracking on a robotic SRS-SABR system. All plans used fixed cone collimators and a planning tool's dose calculation to reach highest BED10 dose coverage achievable to the target volumes while respecting the OAR dose tolerances, including V105 Gy, V100 Gy, V84 Gy and V72 Gy in BED10 for target volumes and the maximum EQD2 dose tolerances (α/β = 3 Gy) in D0.03cc for the trachea/PBT ≤80.5-82.5 Gy and esophagus ≤64.0-77.6 Gy in scheme-A; and trachea/PBT≤97.7 Gy and esophagus ≤64.3 Gy in scheme-B. Median and range of plan dosimetry metrics are compared between the two schemes. For scheme-A, mean BED10 to PTV are 118.0 Gy (median) in105.5-133.5 Gy (range), and mean BED10 dose to GTV are 132.2 (118.3-149.4 Gy). EQD2 dose to trachea are 80.5 Gy (68.0-81.7 Gy), PBT 80.5 Gy (49.1-82.2 Gy), esophagus 67.2 Gy (51.6-77.3 Gy). PTV coverage by BED10 of 72 Gy, 84 Gy, 100 Gy and 105 Gy are 98.9% (87.5-100%), 97.1% (81.8-99.8%), 91.9% (72.5-98.6%) and 85.3% (68.5-97.9%). For scheme-B, mean BED10 to PTV are 102.2 Gy (93.4-106.0 Gy), and mean BED10 dose to GTV are 115.4 (103.4-117.3 Gy). EQD2 dose to trachea are 73.3 Gy (67.5-96.3 Gy), PBT 90.9 Gy (74.4-97.2 Gy), esophagus 61.4 Gy (41.9-64.1 Gy). PTV coverage by BED10 of 72 Gy, 84 Gy, 100 Gy and 105 Gy are 100% (94.9-100%), 95.5% (83.9-99.0%), 54.8% (31.2-65.4%) and 42.8% (17.9-53.2%). Two risk-adapted SABR of 7.5 Gyx8 and 4 Gyx15 are implemented for treating ultra-central lung tumors with BED10 ≥100 Gy to the distal sections of PTV and yet attain potent BED10 ≥72-84 Gy to the proximal sections of PTV that abut or overlap with trachea, proximal bronchial tree or esophagus. Accurate dose calculation by a planning tool and real-time tumor tracking are essential for safe and accurate delivery of such high-risk SABR treatments.

A territory-wide real-world efficacy and toxicity analysis of abiraterone acetate versus docetaxel in 574 Asian patients with metastatic hormone-sensitive prostate cancer

IntroductionAbiraterone acetate (ABI) or docetaxel (DOC), in addition to androgen-deprivation therapy (ADT), are current treatment options for metastatic hormone-sensitive prostate cancer (mHSPC). No randomized head-to-head trial has compared these 2 mHSPC treatments, and real-world data regarding their outcomes in Asian patients are lacking. Patients and MethodsThe medical records of mHSPC patients who began upfront ABI or DOC treatment in addition to ADT at seven public oncology centers in Hong Kong between 2015 and 2021 were reviewed. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), prostate-specific antigen (PSA) response, and toxicities. Kaplan-Meier and multivariate Cox regression analyses were performed. ResultsA total of 574 patients were included, of whom 419 received DOC and 155 received ABI. The median follow-up duration was 22.4 (DOC group: 23.8; ABI group: 17.3) months. The ABI group demonstrated significantly better PFS than the DOC group (not reached vs. 15.1 months: hazard ratio = 0.37; 95% confidence interval = 0.28-0.50; P < .001). No significant OS difference was observed (P = .58). Failure to achieve a ≥ 90% decline in PSA level at 3 months and failure to achieve an undetectable PSA nadir were each associated with unfavorable PFS and OS. Patients who received DOC had a higher rate of febrile neutropenia, whereas those who received ABI had higher rates of grade ≥ 3 hypokalemia and elevated alanine transaminase. Treatment discontinuation due to toxicities was more common in the DOC (3.6%) than the ABI (0.6%) group. ConclusionIn Asian mHSPC patients, upfront ABI + ADT was associated with better PFS than DOC + ADT, with no significant OS difference. PSA kinetics may help stratify the prognosis for treatment intensification. Toxicity profiles were different, with a higher rate of toxicity-related treatment discontinuation in the DOC group.

Paper 11: Hip Cartilage Defects in Elite Athletes: Their Association with Specific Sports and ‘At-risk’ Motions

Objectives: Chondral injuries, especially in high-level athletes, can have drastic functional detriments. Much of the prior work on osteochondral injury has studied the knee, however emphasis on the hip has emerged with advances in hip preservation techniques. While hip chondral defects have been shown to be associated with femoroacetabular impingement (FAI), a more in-depth understanding of the determining factors is needed due to the limited spontaneous repair capacity of cartilage. It is currently unclear if the type of sport or specific motions are related to the prevalence or severity of chondral defects seen in athletes. The purpose of this study is to evaluate the prevalence of chondral defects across specific sports and characterize the corresponding articular cartilage injury patterns in the hip, as found in elite and professional athletes. Methods: Elite athletes at least 18 years old, defined as those competing in college or professionally, who underwent arthroscopy for symptomatic FAI by a single surgeon between January 2005 and November 2018 were considered for inclusion. A review of records was performed of all the patients’ operative information was reviewed from the patient records database, including operative reports, operative photos, and extensive operative details. Exclusion criteria consisted of prior ipsilateral hip surgery, presence of osteoarthritis (joint space &lt; 2 mm), history of confounding injury or prior hip conditions. Patients were then classified by their sport using a classification system based on ‘at-risk’ hip motions (rotational, repetitive, extreme, contact, and high-speed). Prevalence, size, severity (Outerbridge grade), and location of chondral defects were compared. Results: The cohort consisted of a total of 431 hips (107 female, 324 male, mean age 26.8 ± 5.1) of elite athletes, representing 24 sports at various elite levels of play. Chondral defects (grade I-IV) were found in 408 (95%) of cases. Severe chondral defects (grade III/IV) were seen in 218 (51%) of cases and most commonly found in football, soccer, and baseball players. Microfracture was performed in 72 (17%) of total cases. There was significantly higher prevalence of acetabular (p=.046), femoral head (p=.038), and combined (p=.035) grade III/IV lesions in the rotational versus non-rotational group, as well as acetabular (p=&lt;.001) and combined (p=.018) grade III/IV lesions in the contact sport group versus non-contact group. Non-high speed sports (p=0.029) had significantly higher percentages of femoral head grade III/IV lesions compared to non-high speed, and non-extreme ranges of motion sports (p=0.002) had higher rates of grade III/IV lesions compared to extreme range of motion sports. Conclusions: In elite athletes, the prevalence of chondral defects was high when undergoing hip arthroscopy. The severity, size, and location varied based on type of motion and stress on the hip that was determined by the sport. The more severe (grade III/IV) defects were more common in the rotational and contact athletes according to the motion classification system. The nature of high speed and extreme range of motion sports may be somewhat protective or select-out for athletes with hip chondral defects. This classification system can be used to identify athletes at risk of chondral damage for close monitoring and injury prevention. This information can also be used to pre-operatively counsel these athletes on the likely findings and to set expectations. This can also inform the discussion as to timing of surgery for rehabilitative purposes and athletic career management. [Table: see text][Table: see text]

Association of the Duffy-null allele and endometrial cancer characteristics: An effort to explore racial disparity in Black women with endometrial cancer.

5603 Background: Efforts are needed to identify factors that account for the disparately high mortality in Black women with endometrial cancer. The Duffy antigen receptor for chemokines (DARC) is expressed on erythrocytes and endothelial cells and modulates levels of inflammatory chemokines in circulation and in tissues. The African ancestry-specific Duffy-null allele, in which erythrocyte expression and function of DARC is lost, is associated with worse breast cancer phenotypes and survival. Here, we characterize Duffy-null status and associated prognostic and clinical outcomes in patients with endometrial cancer. Methods: Patients with endometrial cancer were prospectively consented, and germline DNA was extracted from saliva or blood samples. Duffy-null genotype was determined using an allelic discrimination assay. Associations between Duffy-null genotype status and clinicopathologic characteristics were performed using Fisher’s Exact analysis. Results: 33 patients were enrolled (Table); 17 (51.5%) were Duffy-null, 5 (15.2%) were Duffy-null allele carriers, and 11 (33.3%) were non-carriers. Compared with non-carriers, Duffy-null patients were more likely to be Black (100% v 9.1%, p&lt;0.0001) and have non-endometrioid histology (64.7% v 10%, p=0.0173). There was a trend towards higher rates of grade 3 histology (70.6% v 36.6%), intact tumor mismatch repair (MMR) (86.7% v 54.6%), estrogen receptor (ER) negative tumor status (25% v 10%), advanced stage (37.5% v 18.2%), and positive lymph nodes (25% v 0%) (Table). Over a minimum of 12 months of follow up, only Duffy-null individuals died from disease (4 v 0, p=0.0006). Conclusions: Duffy-null status was associated Black race, aggressive histologic subtypes, intact MMR mechanisms, and worse survival. Further investigation is needed to explore the underlying mechanism of the Duffy-null phenotype on endometrial cancer outcomes to better elucidate risk factors and underlying causes that may contribute to endometrial cancer disparities.[Table: see text]

Dosing patterns and treatment patterns in real-world patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who received FOLFIRINOX in the first line.

e16255 Background: While FOLFIRINOX (FFX) demonstrated a significant overall and progression-free survival benefit vs. gemcitabine in the PRODIGE 4/ACCORD 11 trial among previously untreated patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC), treatment with FFX was associated with a higher rate of grade 3/4 adverse events (AEs). In an effort to reduce toxicity, modified FFX (mFFX) regimens that employ lower doses of components of the regimen have been developed. To better understand the frequency and degree of dose modifications in practice, we examined real-world (RW) dosing patterns among mPDAC pts receiving FFX in first line (1L). Methods: This retrospective observational study utilized the Ontada Clinical Data View: Pancreatic Cancer database. Adult pts diagnosed with mPDAC between January 2015 and November 2022 who initiated treatment with FFX or mFFX within 90 days of their diagnosis for metastatic disease (1L) were included in the study. Pts were required to have an available body surface area measurement within 7 days of the index date. Doses of each FFX component were measured during cycles in which pts received all four components of the FFX regimen on the same date. mFFX was defined as administration of &lt; 150mg/m2 of irinotecan or &lt; 2,720mg/m2 5-FU total during cycle 1. Results: Of the 1,326 pts eligible meeting inclusion criteria and receiving 1L treatment with FFX or mFFX, 1,325 received mFFX and 1 received FFX. The median age at 1L initiation was 65yr (IQR: 58–70), 57% (754 pts) were male, 69% (916 pts) were white, 15% (197 pts) had an ECOG score of 0, 42% (550 pts) had an ECOG score of 1, and 78% (1028 pts) were stage IV at diagnosis. The bolus of 5-FU was frequently omitted—only 20% (262 pts) received it in the first cycle. If pts received the bolus, they did not receive the 5-FU infusion, with the exception of 1 pt. For pts receiving at least two cycles, the percentage of pts with dose reductions of ≥10% (≥20%) between the first and last cycle were 20% (11%) for the 5-FU infusion, 18% (13%) for the 5-FU bolus, 34% (21%) for irinotecan, 12% (9%) for leucovorin, and 40% (28%) for oxaliplatin. Median starting doses were 2400, 401, 152, 399, and 85 mg/m2 for the 5-FU infusion, bolus 5-FU, irinotecan, leucovorin, and oxaliplatin components, respectively. The median number of cycles was 5 (IQR: 3–10) and the median dose intensity per week was 940 mg/m2 for 5-FU, 179 mg/m2 for leucovorin, 38 mg/m2 for oxaliplatin, and 73 mg/m2 for irinotecan. Conclusions: In a RW cohort of pts with mPDAC treated with 1L FFX, almost all received a modified version of the regimen. The 5-FU bolus was omitted for most pts. Doses of other components fell over time for a notable percentage of patients, which may reflect clinician efforts to manage FFX toxicity.

Increase in subcutaneous adipose tissue in the frontal scalp may be associated with androgenetic alopecia and metabolic syndrome.

Recent studies have suggested that androgenetic alopecia (AGA) may be associated with other disorders, especially metabolic syndrome (MetS). This study aimed to determine whether a connection exists between MetS and AGA based on the thickness of the subcutaneous adipose tissue in the scalp. This cross-sectional study included 34 participants with AGA who had MetS and 33 participants with AGA who did not have MetS. The Hamilton-Norwood scale was employed for classifying AGA and MetS was identified using the US National Cholesterol Education Programme Adult Treatment Panel III (NCEP-ATP III criteria). The body mass index (BMI), blood pressure, and lipid profiles of the participants were assessed. Hepatosteatosis and the thickness of the subcutaneous adipose tissue in the scalp were examined using ultrasonography. Compared with the control group, the MetS+AGA group had higher BMI (p = 0.011), systolic blood pressure (p < 0.001), diastolic blood pressure (p < 0.001) and waist circumference (p = 0.003). Furthermore, the MetS+AGA group had a higher prevalence of dyslipidemia, hypertension (HT) and diabetes mellitus (DM) and higher rates of grade 6 alopecia than the control group (p = 0.019). Compared with the control group, those with MetS had thicker subcutaneous adipose tissue in the frontal scalp (p = 0.018). The subcutaneous adipose tissue in the frontal scalp was thicker in individuals with AGA who had high Hamilton scores. The concomitance of AGA and MetS may be associated with a high increase in subcutaneous adipose tissue and less favorable metabolic parameters.